39Th Annual Advances in Infectious Diseases: New Directions for the Clinic and the Hospital

Department of Medicine, Division of Infectious Diseases University of California, San Francisco School of Medicine presents

39th Annual Advances in Infectious Diseases: New Directions for the Clinic and the Hospital

March 14-16, 2018 Holiday Inn Golden Gateway San Francisco, CA

Course Chairs Brian S. Schwartz, MD Lisa G. Winston, MD University of California, San Francisco

University of California, San Francisco School of Medicine

Table of Contents

Educational Objectives ...... 3 Accreditation ...... 4 General Information ...... 5 Linguistic Competency Information ...... 6 Course Faculty ...... 8 Disclosures ...... 10 Course Program ...... 11

Wednesday, March 14, 2018 Antimicrobials for Respiratory Tract Infections ...... 15 B. Joseph Guglielmo, PharmD Challenges Before and After Travel ...... 33 David Sears, MD C. difficile Difficulties ...... 53 Sarah Doernberg, MD, MAS HPV Infection...... 69 Cristina Brickman, MD, MAS Skin Deep – SSTIs (Notes Page) ...... 81 Vivek Jain, MD, MAS Kids and Bugs ...... 83 Andrea Marmor, MD UTI Update ...... 97 Brian Schwartz, MD HIV in 2018 ...... 115 Monica Gandhi, MD, MPH

Thursday, March 15, 2018 Hepatitis B and C –The World has Changed ...... 129 Annie Luetkemeyer, MD Can I Ask a Quick Question? – ID Curbsides ...... 143 Jennifer Babik, MD, PhD Herpes Viruses in Clinical Practice ...... 159 Jennifer Babik, MD, PhD Update in Respiratory Virus Infections ...... 175 Bryn Boslett, MD Lyme Disease – Fact and Fiction ...... 191 Richard Jacobs, MD, PhD Cutaneous Infections ...... 215 Kanade Shinkai, MD, PhD Fighting Infection in Diabetes ...... 239 Emily Abdoler, MD CAP/HAP/VAP (Notes Page) ...... 251 Bradley Sharpe, MD

Friday, March 16, 2018 Vaccine Update ...... 253 Lisa Winston, MD CNS Infections - Pearls and Perils ...... 271 Felicia Chow, MD, MAS Tuberculosis for the Clinician ...... 289 Pennan Barry, MD, MPH STDs – Now More than Ever ...... 303 Susan Philip, MD, MPH

University of California, San Francisco School of Medicine Presents

39th Annual Advances in Infectious Diseases: New Directions for the Clinic and the Hospital

The Division of Infectious Diseases, Department of Medicine, University of California, San Francisco presents its annual symposium on Advances in Infectious Diseases. Now marking its 39th year, this conference emphasizes state-of-the-art therapy for patients with infectious diseases and also provides reviews of new developments.

This educational activity is intended for internists, family physicians, general practitioners, nurse practitioners, physician assistants, nurses, pharmacists, and allied health professionals who are involved in the care of patients with infectious diseases.

Educational Objectives

Upon completion of this program, attendees will be able to:

 Select appropriate treatment regimens for specific infections such as community acquired pneumonia and urinary tract infections in both outpatient and inpatient settings;  Effectively manage common infections in the clinic and hospital, including upper respiratory infections, dermatologic infections, and diarrhea;  Relate infectious considerations in certain groups at special risk, including those with HIV and diabetes;  Discuss how the emergence of drug-resistant organisms is shaping therapy of common problems such as sexually transmitted diseases;  Interpret and apply up-to-date information on less common infections in the U.S., including tuberculosis, infections in travelers, and emerging infections;  Counsel patients regarding new vaccines and expanded indications for established vaccines.

Accreditation

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this live activity for a maximum of 18.00 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity meets the requirements under California Assembly Bill 1195, continuing education and cultural and linguistic competency.

Nurses: For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 CreditsTM issued by organizations accredited by the ACCME.

Physician Assistants: AAPA accepts category 1 credit from AOACCME, Prescribed credit from AAFP, and AMA PRA Category 1 CreditsTM from organizations accredited by the ACCME.

Pharmacy: The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 CreditsTM.

Family Physicians: This Live activity, Advances in Infectious Diseases: New Directions for the Clinic and the Hospital, with a beginning date of 03/14/2018, has been reviewed and is acceptable for up to 18.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Internal Medicine (ABIM) MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 18.00 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

General Information

Attendance Verification/Sign-In Sheet / CME Certificates Please remember to sign-in on the sign-in sheet when you check in at the UCSF Registration Desk on your first day. You only need to sign-in once for the course, when you first check in.

On the final day of the meeting you will receive an email from [email protected] with a link to complete your online Course Evaluation/ Electronic CME Certificate. Please make sure that you add this email to your safe senders list. The Qualtrics system will send you reminders to complete your CME Certificate Claiming until you complete it.

Upon completing the Electronic CME Certificate, your CME certificate will be automatically generated to print and/or email yourself a copy. For smartphone users, you may want to take a photo of your certificate as some settings prevent you from emailing the certificate.

The link will be available for 30 days after the last day of the course. However, after that date the link will expire and you will no longer be able to claim your credits online. You must then contact the Office of CME at [email protected] to receive your certificate and a $15 administrative fee may be applied.

Speaker Survey Your opinion is important to us – we do listen! The speaker survey is the yellow hand- out you received when you checked in. Please complete this during the meeting and turn it in to the registration desk at the end of the course.

Security We urge caution with regard to your personal belongings and syllabus books. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during lunch or breaks or overnight.

Final Presentations A link to PDF versions of the final presentations will be sent via e-mail approximately 3 – 4 weeks post course. Only presentations that have been authorized for inclusion by the presenter will be included

5 Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.

HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .

As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.

Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.

A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non- emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

6 In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.

The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.

It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

7 Faculty List

Course Chairs

Brian S. Schwartz, MD Associate Professor of Medicine Division of Infectious Diseases

Lisa G. Winston, MD Professor of Medicine Division of HIV, ID, and Global Medicine University of California, San Francisco Zuckerberg San Francisco General

Course Faculty (University of California, San Francisco unless indicated)

Emily Abdoler, MD Clinical Fellow Department of Medicine Division of Infectious Diseases

Jennifer Babik, MD, PhD Assistant Professor of Medicine Division of Infectious Diseases

Pennan Barry, MD Assistant Professor of Medicine

Bryn Boslett, MD Assistant Professor of Medicine Division of Infectious Diseases

Cristina Brickman, MD, MAS Assistant Professor of Medicine Division of Infectious Diseases

Felicia Chow, MD Assistant Professor of Neurology UCSF Neuro-Infectious Diseases Clinic Zuckerberg San Francisco General

Sarah Doernberg, MD, MAS Assistant Professor of Medicine Division of Infectious Diseases

8 Course Faculty (continued) (University of California, San Francisco unless indicated)

Monica Gandhi, MD, MPH Professor of Medicine Division of HIV, ID, and Global Medicine

B. Joseph Guglielmo, PharmD Dean, School of Pharmacy Troy C. Daniels Distinguished Professorship in Pharmaceutical Sciences

Richard A. Jacobs, MD, PhD Professor of Medicine (Emeritus) Division of Infectious Diseases and of Clinical Pharmacy

Vivek Jain, MD, MAS Associate Professor of Medicine Division of HIV, ID, and Global Medicine

Annie Luetkemeyer, MD Associate Professor of Medicine Division of HIV, ID, and Global Medicine

Andrea Marmor, MD Professor of Pediatrics

Susan Philip MD, MPH Assistant Professor of Medicine Director, Disease Prevention and Control Branch Population Health Division San Francisco Department of Public Health

David Sears, MD Assistant Professor of Medicine Division of Infectious Diseases

Bradley Sharpe, MD Professor of Medicine

Kanade Shinkai, MD, PhD Associate Professor of Dermatology

Disclosures

The following faculty speakers, moderators, and planning committee members have disclosed they have no financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Emily Abdoler Vivek Jain Jennifer Babik Andrea Marmor Pennan Barry Brian Schwartz Cristina Brickman David Sears Felicia Chow Bradley Sharpe Monica Gandhi Kanade Shinkai B. Joseph Guglielmo Lisa Winston Richard Jacobs

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

Bryn Boslett (Spouse) Consultant Roche

Sarah Doernberg Antibacterial Research Leadership Grant/Research Support Group (NIH), Infectious Diseases Society of America Actelion Consultant Genentech Consultant

Annie Luetkemeyer AbbVie Grant/Research Support Gilead Grant/Research Support Merck Grant/Research Support Proteus Grant/Research Support ACTG (NIH) Grant/Research Support

Susan Philip GlaxoSmithKline Grant/Research Support Roche Diagnostics Grant/Research Support

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced.

This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

10 39TH ANNUAL ADVANCES IN INFECTIOUS DISEASES: New Directions for the Clinic and the Hospital Golden Gateway Hotel - Holiday Inn, San Francisco, California WEDNESDAY, March 14 – FRIDAY, March 16, 2018 AGENDA

Wednesday, March 14, 2018

7:00 am Registration and Continental Breakfast

8:00 Welcome and Introduction Brian Schwartz, MD & Lisa Winston, MD

8:10 Antimicrobials for Respiratory Tract Infections B. Joseph Guglielmo, PharmD

9:10 Challenges Before and After Travel David Sears, MD

10:05 Break

10:20 C. difficile Difficulties Sarah Doernberg, MD, MAS

11:15 HPV Infection Cristina Brickman, MD, MAS

12:00 pm Lunch On Own

1:30 Skin Deep - SSTIs Vivek Jain, MD, MAS

2:20 Kids and Bugs Andrea Marmor, MD

3:10 Break

3:25 UTI Update Brian Schwartz, MD

4:20 HIV in 2018 Monica Gandhi, MD, MPH

5:15 pm Adjourn

Thursday, March 15, 2018

7:00 am Continental Breakfast

8:00 Hepatitis B and C - The World has Changed Annie Luetkemeyer, MD

9:00 Can I Ask a Quick Question? – ID Curbsides Jennifer Babik, MD, PhD

11 39TH ANNUAL ADVANCES IN INFECTIOUS DISEASES: New Directions for the Clinic and the Hospital Golden Gateway Hotel - Holiday Inn, San Francisco, California WEDNESDAY, March 14 – FRIDAY, March 16, 2018 AGENDA

Thursday, March 15, 2018 (continued)

9:50 Break

10:05 Herpes Viruses in Clinical Practice Jennifer Babik, MD, PhD

10:55 Update in Respiratory Virus Infections Bryn Boslett, MD

11:45 am Lunch on Own

1:15 Lyme Disease - Fact and Fiction Richard Jacobs, MD, PhD

2:15 Cutaneous Infections Kanade Shinkai, MD, PhD

3:10 Break

3:25 Fighting Infection in Diabetes Emily Abdoler, MD

4:15 CAP/HAP/VAP Bradley Sharpe, MD

5:15 pm Adjourn

Friday, March 16, 2018

7:00 am Continental Breakfast

8:00 Vaccine Update Lisa Winston, MD

8:55 – 9:50 CNS Infections - Pearls and Perils Felicia Chow, MD, MAS

9:50 Break

10:05 Tuberculosis for the Clinician Pennan Barry, MD, MPH

11:00 – 12:00 STDs – Now More than Ever Susan Philip, MD, MPH

12:00 pm Adjourn/Evaluations

14 Antimicrobials for Respiratory Disclosures Tract Infections No disclosures regarding conflict of interest B. Joseph Guglielmo, Pharm.D. Professor and Dean School of Pharmacy University of California San Francisco

What is the treatment of choice for ABRS?

1. Amoxicillin 25% 25% 25% 25% 2. Amoxicillin- Acute Bacterial Rhinosinusitis clavulanate 3. Azithromycin 4. No antibacterial therapy

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15 Antibiotics for adults with clinically Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta- diagnosed acute rhinosinusitis: a meta- analysis of individual patient data analysis of individual patient data

• Searched the Cochrane Central Register of • 15 patients with rhinosinusitis-like complaints Controlled Trials, Medline, and Embase, and would have to be given antibiotics before an reference lists of reports additional patient was cured • Individual patients' data from 2547 adults in nine • Patients who were older, reported symptoms for a trials were checked and re-analyzed longer period, or reported more severe symptoms took longer to cure but were no more likely to benefit from antibiotics than other patients (Lancet 2008; 371: 908) (Lancet 2008; 371: 908)

American College of Physicians 2012 IDSA Clinical Practice Guideline for (Jan 2016) Acute Bacterial Rhinosinusitis Antibacterial choice “Clinicians should reserve antibiotic treatment – Children: amoxicillin-clavulanate>amoxicillin (strong, for acute rhinosinusitis for patients with moderate recommendation) persistent symptoms for more than 10 days, – Adults: amoxicillin-clavulanate>amoxicillin (weak, onset of severe symptoms or signs of high fever low recommendation) – Other agents (>39 °C) and purulent nasal discharge or facial • High dose amoxicillin-clavulanate: with severe infection, pain lasting for at least 3 consecutive days, or daycare, age<2 or >65, previous antibacterial use, immunocompromised onset of worsening symptoms following a • No fluoroquinolones, macrolides, TMP-SMX, or 2nd and 3rd typical viral illness that lasted 5 days that was generation cephalosporins initially improving (double sickening)” • Doxycycline alternative to amoxicillin-clavulanate

16 What is the drug of choice for S. pneumoniae % Resistance acute bacterial otitis media?

1. Azithromycin 20% 20% 20% 20% 20% INT RES 2. Amoxicillin- Penicillin 12.7 21.5 clavulanate Amoxicillin 4.2 2.2 3. Amoxicillin Cefuroxime 2.0 25.3 4. Cefdinir Cefpodoxime 2.0 25.7 5. Cefuroxime Cefdinir 1.4 25.8 10

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2013 AAP Treatment Guidelines 2013 AAP Treatment Guidelines • Antibiotics indicated: • Drug of choice: high dose amoxicillin – Children (≥ 6 mos) with severe AOM (mod to • If receipt of amoxicillin in the past 30 days or severe otalgia or otalgia for ≥ 48 hrs or T 39Cº) purulent conjunctivitis or history of recurrent – Children (6-23 mos) with nonsevere bilateral AOM unresponsive to amoxicillin: an antibiotic AOM with additional β-lactamase coverage should be • Antibiotics or observation with close follow-up prescribed (i.e. amoxicillin-clavulanate), – Children (6-23 mos) with nonsevere unilateral AOM cefdinir, cefuroxime, cefpodoxime) – Older children with nonsevere AOM (Pediatrics 2013; 131: e964 -e999 ) (Pediatrics 2013; 131: e964 -e999 )

17 True or False? Penicillin is the drug of choice in the treatment of bacterial pharyngitis? Streptococcus pyogenes (% Resistance) 50% 50% 1. True Penicillin 0% 2. False Cefdinir 0% Macrolides 6.6-6.9% Clindamycin 0.5% Levofloxacin 0.05%

American College of Physicians Acute Bronchitis (Jan 2016) “Clinicians should test patients with symptoms • For >40 years, studies have demonstrated suggestive of group A streptococcal pharyngitis (for that antibiotics are not effective for acute example, persistent fevers, anterior cervical adenitis, bronchitis (Smith et al. Antibiotics for acute and tonsillopharyngeal exudates or other appropriate bronchitis. Cochrane Database Syst Rev combination of symptoms) by rapid antigen detection test and/or culture for group A 2014; 3 (4) CD000245) Streptococcus. Clinicians should treat patients with • 1980-1999: rate of antibiotic prescribing in antibiotics only if they have confirmed streptococcal U.S. was 60-80% (Steinman et al. Ann pharyngitis.” Intern Med 2003; 138: 525)

18 From: Antibiotic Prescribing for Adults With Acute Bronchitis in the United States, 1996-2010

JAMA. 2014;311(19):2020-2022. doi:10.1001/jama.2013.286141

A case of prescription fatigue?

American College of Physicians (Jan 2016)

“Clinicians should not perform testing or initiate antibiotic therapy in patients with bronchitis unless pneumonia is suspected”

Linder et al. JAMA Intern Med 2014; 174(12):2029-2031.

19 Etiology Outpatient-Treated CAP 2007* IDSA/ATS (in order of association) Recommendations: Outpatient • S. pneumoniae (most common organism in Treatment of CAP older patients and those with significant • Healthy, no use of antimicrobials within the underlying disease) past 3 months: • M. pneumoniae (most common in patients – A macrolide (level I evidence) <50 yo and no co-morbidities) – Doxycycline (level III evidence) • C. pneumoniae •Viruses *Update due Summer 2018

2007 IDSA/ATS 2007 IDSA/ATS Recommendations: Outpatient Recommendations: Outpatient Treatment of CAP Treatment of CAP

• Presence of co-morbidities or receipt of • “In regions with a high rate (>25%) of antimicrobials within the past 3 months in infection with high level (≥ 16 mcg/ml) which case an alternative from another class macrolide-resistant S. pneumoniae, consider should be used: the use of alternative agents.” – A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, 750 mg levofloxacin): strong recommendation and level I evidence – Beta-lactam plus macrolide: level I evidence

20 Pneumococcal Susceptibility

Macrolides: Role in Community • From the 1999–2000 to the 2004–2005 respiratory illness season: Acquired Pneumonia – Prevalence of isolates with intermediate penicillin resistance (minimum inhibitory concentration, 0.1–1 µg/mL) increased from 12.7% to 17.9% – Prevalence of penicillin-resistant isolates (minimum inhibitory concentration, ≥2 µg/mL) decreased from 21.5% to 14.6% – Prevalence of isolates resistant to erythromycin increased from 25.7% to 29.1% – The prevalence of multidrug resistance among isolates did not change (22.4% in 1999–2000 and 20.0% in 2004–2005) (Clin Infect Dis 2010; 48: e23-e33)

Why ever use clarithromycin? Macrolides in CAP . Clarithromycin (but not azithromycin) with calcium channel blockers: ↑ risk of hospitalization with • Primary strength is atypical coverage and kidney injury, ↑ hypotension and ↑ all-cause azithromycin/clarithromycin moderate in their mortality (JAMA published on line Nov 7, 2013) coverage of H. influenzae and M. catarrhalis . Combination of clarithromycin (or erythromycin) • Macrolides are unpredictable in pneumococcal with certain statins: ↑ risk for hospitalization due to susceptibility in certain high risk patients and rhabdomyolysis, kidney injury, and ↑ mortality (Ann resistance has been associated with clinical failure Intern Med 2013; 158: 869) . Increased risk of cardiac death associated with clarithromycin (BMJ Aug 19, 2014) . Increased neuropsychiatric events (JAMA Intern Med. 2016;176(6):828-834)

21 Doxycycline Doxycycline: Adverse Events

• Spectrum of activity is generally superior to • Upper gastrointestinal: nausea, heartburn, macrolides vs S. pneumoniae, and active epigastric pain, vomiting versus H. influenzae, M. catarrhalis, • Esophageal ulceration (particularly if atypical pathogens administered just prior to bedtime • Twice-daily (once-daily in elderly?) dosing • Photosensitivity regimen results in favorable adherence • Teeth/bone deposition (tetracyclines, but maybe not doxycycline)

Summary: Doxycycline

• Role in outpatient-treated community acquired pneumonia similar to that of the macrolides – Same or better spectrum of activity Fluoroquinolones – Used to be inexpensive compared to macrolides** – BID dosing (same as clarithromycin), but advantage to azithromycin – Upper GI side effects with both macrolides and doxycycline, but greater incidence of more “severe” upper GI effects with doxycycline

22 Quinolones in CAP: Pros Quinolones in CAP: Cons • Quinolones are (were?) active versus • Gemifloxacin, levofloxacin, moxifloxacin multidrug-resistant nosocomial gram- cover virtually all suspected pathogens negative organisms. (PCN R S. pneumoniae, H. influenzae, • Risk factors for the hypervirulent C. difficile Moraxella catarrhalis, Legionella, and MRSA Mycoplasma, Chlamydia) • Does it make sense to use these agents in • Once-daily dosing uncomplicated outpatient infection?

Quinolone Adverse Events Fluoroquinolones • Upper GI: nausea, vomiting • Prolonged QT (like macrolides), esp moxifloxacin • Fluoroquinolones used to be among those agents • Dysglycemia: ↑ with quinolones compared with beta- (cefepime, carbapenems, aminoglycosides) that lactams (Clin Infect Dis 2013; 57: 971) could logically be used in the treatment of resistant gram negative infection • Tendonitis and tendon rupture (age and steroids) • The decline in activity vs Pseudomonas, • Neuropathy: can occur rapidly and in some patients, Enterobacter, and E.coli, including ESBL- the disorder may be permanent. 2013 FDA warning producers have greatly diminished the role of (Med Lett 2013; 55: 89) these agents in the treatment of resistant gram • Aortic dissection and aneurysm (JAMA Intern Med negative pathogens, including E. coli 2015 Nov 1;175(11):1839-47) • Carpal tunnel syndrome (Clin Infect Dis 2017; 65: 684)

23 Choice of Antibiotic in the Outpatient Treatment of CAP • Patients with no co-morbidities and not recently A 77 year old man with a history of exposed to antibacterials: – First choice: azithromycin congestive heart failure is admitted – Second choice: doxycycline (if you can afford it!) to the hospital with a diagnosis of • “High risk” : community-acquired pneumonia. – First choice: respiratory fluoroquinolone OR combination B-lactam + azithromycin

Which choice is most appropriate in the IDSA/ATS Recommendations* treatment of CAP in this patient? (*Projected Publication Summer 2018)

1. Moxifloxacin 25% 25% 25% 25% Non-ICU Ward Admission 2. Ceftriaxone + PO/IV respiratory fluoroquinolone (levofloxacin azithromycin (750mg), moxifloxacin, gemifloxacin) OR IV 3. Piperacillin- beta-lactam (ceftriaxone, cefotaxime, ampicillin) plus macrolide or doxycycline tazobactam + azithromycin ICU Admission 4. Vancomycin + doxycycline IV beta-lactam (ceftriaxone, cefotaxime, ampicillin-sulbactam) plus an IV fluoroquinolone (levofloxacin, moxifloxacin) or IV azithromycin 123410

24 The cross-reactivity between Cross-reactivity: Penicillin and penicillin and ceftriaxone is: Cephalosporins 1. 15% 20% 20% 20% 20% 20% • Patients: 128 consecutive patients who sustained 2. 10% anaphylactic shock (n=81) or urticaria (n=47) and 3. 5% had positive results with penicillin skin tests • All patients were skin tested with cephalothin, 4. 1-5% cefamandole, cefuroxime, ceftazidime, 5. <1% ceftriaxone, and cefotaxime • Patients with negative results for the last 4 cephalosporins were challenged with cefuroxime axetil and ceftriaxone (Ann Intern Med 2004; 141: 16-22) 1234510

Cross-reactivity: Penicillin and Cephalosporins Seven days into an empirical course of • 14 patients (10.9%) had positive results on skin ceftriaxone and azithromycin, he experiences tests for cephalosporins respiratory decompensation associated with • All 101 patients with negative results on skin tests increased oxygen requirements and a new for the cephalosporins tolerated cefuroxime axetil infiltrate (i.e. HAP). Multiple blood cultures are and ceftriaxone (tolerability rate, 100%) positive for an aerobic gram-negative rod. (Ann Intern Med 2004; 141: 16-22)

25 Which of the following agents would be the Third-generation Agents best choice in a HAP patient (receiving ceftriaxone) with gram negative bacteremia? (Ceftriaxone): Holes in Gram-

20% 20% 20% 20% 20% negative Spectrum 1. Tigecycline • Citrobacter 2. Cefepime • Acinetobacter 3. Piperacillin- • Pseudomonas (however, ceftazidime tazobactam strong) 4. Imipenem • ESBLs AND Enterobacter 5. Imipenem + • Stenotrophomonas (and/or Serratia) tobramycin

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Gram-negative Activity: Cefepime (Expansion of gram negative spectrum over Cefepime for “susceptible” ESBL ceftriaxone) bacteria

• Enterobacter • Propensity score-matched cohort study • Pseudomonas • When compared with carbapenem therapy, • E. coli (including ESBL-producing isolates) there was a trend toward increased mortality • Citrobacter in the cefepime-treated group: (HR, 2.87, • Klebsiella (including ESBL-producing isolates) 95% CI, 0.88-9.41) (Wang et al. Open Forum Infect Dis 2016 Sep; 3(3): (J Antimicrob Chemother 2014; 69: 871) ofw132)

26 Beta-lactamase inhibitor combinations: Risk of AKI with vancomyin in gram-negative spectrum combination with piperacillin- • Piperacillin-tazobactam approximates ceftazidime in tazobactam or cefepime gram-negative activity (including Pseudomonas) • Piperacillin-tazobactam has similar weaknesses as • Rate of AKI was significantly higher with ceftazidime vs Citrobacter, Acinetobacter, Enterobacter V+PT (81/279; 29%) vs V+C (31/279; 11%) • As with cefepime, BLI combinations are not as • Multivariate analysis: V+PT an independent consistently effective as imipenem/meropenem in the treatment of ESBL-producing organisms predictor for AKI (Hazard ratio=4.27; 95%CI • BLI combinations should not be used as monotherapy in 2.73-6.68) suspected or confirmed severe ceftriaxone-resistant gram-negative infections • Median onset of AKI was more rapid with • Piperacillin-tazobactam may have a role alone or in V+PT (3 days) compared to V+C (5 days) combination therapy in less ill patients (Clin Infect Dis 2017; 64: 116-23)

Carbapenems: gram negative spectrum Fluoroquinolones • Imipenem, meropenem are active vs most gram- negative pathogens (including third-generation • Five years ago fluoroquinolones were among cephalosporin-resistant and ESBL producers those agents (cefepime, penems, aminoglycosides) • Cannot rely upon ertapenem for ceftriaxone-resistant that could logically be used in the treatment of gram negative infection: little to no Pseudomonas or resistant gram negative infection Acinetobacter coverage and less predictable activity vs ESBL (compared with other carbapenems) • The decline in activity vs Pseudomonas, Enterobacter , and E.coli , including ESBL- • Weaknesses: Stenotrophomonas, Pseudomonas aeruginosa (rapid emergence of resistance over time). producers have greatly diminished the role of Carbapenem-resistant Enterobacteriaceae (CRE) are these agents in the monotherapy treatment of third increasingly more common generation cephalosporin-resistant gram negative pathogens

27 Aminoglycosides Aminoglycoside Toxicity • Dose, time related: toxicity with less than 5 days Spectrum: includes ceftriaxone-resistant of therapy has not been consistently demonstrated gram-negative bacilli (Citrobacter, • Nephrotoxicity is generally reversible Enterobacter, Pseudomonas) but less effective • Ototoxicity (both cochlear and vestibular) is more as monotherapy in the treatment of serious often irreversible; elderly are particularly gram negative infection predisposed. Baseline audiometry is mandatory for long-term therapy, especially in elderly • Drug levels do not reliably predict risk for ototoxicity

Two drugs are superior to one in the treatment of serious Pseudomonal infection. Blood cultures return positive for 50% 50% Pseudomonas aeruginosa 1. True 2. False

1210

28 Combination Therapy? 2016 IDSA HAP/VAP Guidelines • In general, combination therapy has not been found to be superior to beta-lactam monotherapy “We suggest prescribing 2 antipseudomonal in the treatment of P.aeruginosa bacteremia, antibiotics from different classes…only in however, there are some exceptions – Aminoglycoside monotherapy is inferior to patients with …risk factor for resistance.” combination and should only be used in combination Prior IV antibiotics with an antipseudomonal beta-lactam – Neutropenic patients should receive combination Septic shock therapy ARDS preceding VAP – In septic patients, a few days of empiric combination therapy and then monotherapy may be the best option Five or more days hospitalization CRRT

The Human Intestinal Microbiome Proportion of patients developing IBD and in Health and Disease antianaerobic antibacterial status • GI tract houses several trillion microbial cells P<0.001 • These organisms represent 9.9 million microbial genes • > 1 billion years of mammalian-microbial evolution has led to interdependency (N Engl J Med 2016; 375: 2369)

(Pediatrics 2012; 130: e794)

29 Antibiotics and Juvenile Antibiotics and Eczema Idiopathic Arthritis • Meta-analysis of observational studies • Nested case-control study in children with involving children and young adults newly diagnosed JIA • Pooled OR: 1.41 (95%CI 1.30-1.53) • Results: associating eczema with antibiotic exposure o Any antibiotic course: OR 2.1 (95% CI 1.2-3.5) • In addition, a 7% increase in eczema risk o One to two courses: OR 1.7 (95% CI 0.8-2.7) for each additional antibiotic course o Three to five courses: OR 2.8 (95% CI 1.4-4.4) received during 1st year of life o > Five courses: OR 3.0 (95% CI 1.6-5.6) ((Br J Dermatol 2013; 169: 083-991) (Pediatrics 2015; 136: e333)

Zinc for the common cold Antibiotics and Type 2 Diabetes • Meta-analysis RCTs comparing oral zinc with placebo or no treatment • Retrospective review of combined Danish • 17 trials with 2121 participants registries: • Efficacy • Increased risk with receipt of antibiotics (OR 1.53 (95% CI 1.50-1.55) – 1.65 day ↓ cold symptoms – ↓ symptoms in adults but not children • Increase risk of diabetes with cumulative • Adverse events load of antibiotics – Bad taste: RR 1.65 (95% CI 1.27-2.16) • Risk up to 15 years before diagnosis – Nausea: RR 1.64 (95% CI 1.19-2.27) (J Clin Endocrinol Metab 2015; Oct;100(10):3633-40. doi: 10.1210/jc.2015-2696) (Can Med Assoc J 2012; 184: E551-61)

30 Zinc and recovery from the Recovery and Zinc Acetate

common cold Day Zinc Placebo Difference NNT

• Review of individual patient data from 3 2 0.902 0.969 0.067 15 randomized, placebo-controlled trials 3 0.677 0.938 0.262 3.8

(N=199 patients) 4 0.471 0.835 0.365 2.7

• Administration of zinc acetate lozenges (80- 5 0.304 0.732 0.428 2.3

92 mg/day elemental zinc) 6 0.186 0.608 0.422 2.4

– Less than 75 mg/day elemental zince less 7 0.108 0.392 0.284 3.5

consistently associated with improvement 8 0.049 0.247 0.198 5.0 – Acetate preferred over gluconate (Hemila et al. Open Forum Infect Dis 2017) Hemila et al. Open Forum Infect Dis 2017

Vicks VapoRub “works”. True or Vicks VapoRub False?

1. True 50% 50% 2. False

31 (A) cough frequency, (B) cough severity, (C) severity of congestion, (D) severity of rhinorrhea, (E) child's ability to sleep, (F) parent's ability to sleep, (G) combined Vicks Vapo Rub for Cold symptom score Symptoms • Eligible patients aged 2 to 11 years with symptoms attributed to URIs characterized by cough, congestion, and rhinorrhea that lasted 7 days or longer • 138 children randomized to Vicks Vapo Rub, petrolatum, or no intervention • Parents massaged into child’s neck and chest 30 minutes before bedtime

Paul, I. M. et al. Pediatrics 2010;126:1092-1099

32 3/2/2018

Travel Medicine Disclosures

David Sears, MD • None Assistant Professor UCSF, Division of Infectious Diseases

Lecture Outline Lecture Outline 1. Why should you know about travel medicine? 1. Why should you know about travel medicine? 2. The pre-travel visit 2. The pre-travel visit 3. Post-travel evaluation 3. Post-travel evaluation

33 1 3/2/2018

What is the magnitude of travel International Travelers related morbidity/mortality? • >1 billion travelers cross international borders • >20% had some health impairment while each year abroad • ~8% will seek medical care while abroad • 74 million United States residents traveled • Infectious diseases are common (~30% of internationally in 2015 travelers to the developing world end up – Almost half traveled to a developing country with an infection)

UNWTO World Tourism Barometer. World Tourism Organization; 2011.Office of Travel and Tourism Industries 2010 Outbound Analysis, US Dept of Commerce 2011

2015 Outbound Analysis: 2015 U.S. Travel and Tourism Statistics http://travel.trade.gov/outreachpages/download_data_table/2015_Outbound_Analysis.pdf Keystone. Travel Medicine 3rd Ed. 2014 Hill. CID 2006; 43; 1499‐1539

Lecture outline Who should seek pre-travel care? 1. Why should you know about travel medicine? 2. The pre-travel visit • Travelers to resource • Travelers with 3. Post-travel evaluation poor settings significant medical issues

34 2 3/2/2018

Pre-Travel Consultation Pre-Travel Consultation

1. Assess the health of the traveler 1. Assess the health of the traveler 2. Assess the risk of travel 2. Assess the risk of travel 3. Educate 3. Educate 4. Vaccinate 4. Vaccinate 5. Prescribe 5. Prescribe

Assess the Health of the Traveler Pre-Travel Consultation Exacerbation of underlying illnesses is the most common cause of fatality in US travelers 1. Assess the health of the traveler Disease Consideration 2. Assess the risk of travel Chronic pulmonary disease 1) If not on O2 but PaO2 <70 give 2L for flight 2) If on O2 then increase by 3. Educate 1-3L/min for flight CAD Delay if recent MI 4. Vaccinate Neurovascular disease Delay if recent CVA Thrombophilic state DVT prevention 5. Prescribe IDDM Letter for needles/syringes Immunosuppression May affect vaccination and prophylactic decisions

35 3 3/2/2018

CDC Yellow Book Assess the Risk of Travel Your resource for assessing geographic and seasonal risk

• Destination(s) • Season • Duration of stay • Planned activities • Accommodations • Purpose of travel

https://wwwnc.cdc.gov/travel/yellowbook/2016/ https://wwwnc.cdc.gov/travel/yellowbook/2018/table-of-contents

Pre-Travel PREP Searchable resource linked to CDC Yellow Book data Pre-Travel Consultation 1. Assess the health of the traveler 2. Assess the risk of travel 3. Educate 4. Vaccinate 5. Prescribe

http://gten.travel/prep/prep

36 4 3/2/2018

Question #1 Educational Topics

The two most common causes of death • Accident prevention among international travelers are: • Insect avoidance a) Cardiovascular disease and malaria • Safe food and water b) Cardiovascular disease and accidents • Altitude c) Accidents and dengue • Safe sex d) Suicide/homicide and dengue • Animal avoidance • Scuba e) Malaria and dengue • Travel insurance

Accidents Account for Nearly Half Educational Topics of All Travel-Related Deaths

• Accident prevention Fatalities in French Travelers 2000-2004 • Insect avoidance • Safe food and water • Altitude • Safe sex • Animal avoidance • Scuba • Travel insurance

Keystone. Travel Medicine 3rd Ed. 2014

37 5 3/2/2018

WEAR A HELMET!!! (or, better yet, don’t ever get on a motorbike) Educational Topics

• Accident prevention • Insect avoidance • Safe food and water • Altitude • Safe sex • Animal avoidance • Scuba • Travel insurance

Which Insect Repellant to Use? Other Strategies

Product Active Complete Ingredient Protection • Apply sunscreen Time before repellant OFF Deep Woods DEET (24%) 302 minutes • Where pants and long Picardin 20% (Sawyer) Picardin (20%) >300 minutes sleeves Sawyer Controlled Release DEET (20%) 234 minutes • Use permethrin- OFF Skintastic DEET (8%) 112 minutes treated clothing OFF Skintastic for kids DEET (4.75%) 88 minutes • Mosquito nets at night Avon Skin So Soft + IR3535 IR3535 (7.5%) 23 minutes Herbal Armor Citronella (12%) 14 minutes

Fradin MS, Day JF. NEJM 2002; 347; 13-18 Roey. PLoS Negl Trop Dis 2014 Dec; 8(12): e3326.

38 6 3/2/2018

Question #2 Dengue Fever • Mosquito vector: Aedes species (primarily daytime feeder) A 42yo man returned from Honduras 17d ago where he visited • Between 50-100 million infections yearly family in the countryside. He presents to Urgent Care with 7d of • Also cases in Africa (likely more in coastal countries of sub-Saharan Africa) fever, HA, mild joint pain, and rash. His fever resolved today but • US dengue: endemic in Puerto Rico, prior outbreaks in FL, HI, TX he noted bleeding in his gums and lightheadedness. Vitals are T36.5, HR 110, BP 88/55, RR 24, SpO2 97%. Exam revealed petechiae and a maculopapular rash over his trunk. A STAT CBC shows WBCs of 2.8, Hgb of 17.5, and Plts of 35K.

The most likely diagnosis is: a) Leptospirosis b) Zika virus c) Dengue virus d) Malaria e) Chikungunya virus

Dengue Fever: Clinical Disease Flushing 3-5 days Dengue rash erythema • Incubation: Short (4-7 days); if symptoms start Morbilliform eruption w/ >14d after exposure unlikely to be dengue 1-2 days post onset petechiae and islands of of symptoms • Clinical Manifestations: sparing – Fever, headache, joint and muscle aches – Nausea and vomiting –Rash • Lab abnormalities: – leukopenia, thrombocytopenia, transaminitis • Dengue Hemorrhagic Fever/Shock – Occurs 3-7 days into illness, often w/ end of fever Pincus. J Am Acad Dermatol 2008; 58; 308-316

39 7 3/2/2018

Chikungunya Fever Chikungunya Fever: Clinical Disease • Mosquito vector: Aedes species (primarily daytime feeder) • No local transmission in the Americas until late 2013; now endemic • US chikungunya: some local transmission in Puerto Rico, FL, and US Virgin Islands • Incubation period 2-4 days (1-14); if symptoms start >14d after exposure unlikely to be chikungunya • Clinical manifestations – Fever + Polyarthralgias 2-4 days later – Rash: ~ 50%, maculopapular • Labs: – Lymphopenia, thrombocytopenia, transaminitis • Severe complications/deaths in elderly

https://www.cdc.gov/chikungunya/pdfs/chik_world_map_04-22-16.pdf

Question #3 A 28yo man comes to your primary care clinic for a routine visit. He returned from 2wks in Cancun with his fraternity bothers 2mo ago. While there he had a brief and mild febrile illness characterized by rash and painful red eyes. He otherwise has no health problems and no complaints. He mentions that he and his wife are planning to start a family.

You advise the patient to:

a) Defer attempts to conceive for 1 more month b) Defer attempts to conceive for 6 more months c) Defer attempts to conceive until HIV testing can be performed d) Commence with unprotected intercourse as long as he has no further signs or symptoms of infection

40 8 3/2/2018

Zika Virus Zika Virus: Clinical Disease • Mosquito vector: Aedes species (primarily daytime feeder) • Local transmission seen previously in TX and FL • Can be transmitted sexually (from men to women or other men, may persist in semen for >6mo) • Incubation period 2-4 days (1-14); if symptoms start >14d after exposure unlikely to be Zika • Clinical manifestations (resolve within 7d) – Fever, rash, arthralgias, non-purulent conjunctivitis – Severe disease (including Guillain-Barre) is rare – Risk of microcephaly if infected while pregnant (95/10,000 neonates compared to ~2/10,000 baseline risk) [Lancet 2016; 387; 2125-2132]

https://wwwnc.cdc.gov/travel/files/zika-areas-of-risk.pdf

Zika Virus: Prevention of Sexual Lab and Clinical Features: Transmission Related to Pregnancy Chikungunya vs. Dengue vs. Zika

Chikungunya Dengue Zika • Infected or at-risk man and pregnant wife: Lymphopenia +++ ++ - condoms for duration of pregnancy Neutropenia + +++ - • Infected or at-risk woman trying to conceive: Thrombocytopenia + +++ + wait 8wks Hemoconcentration - ++ - • Infected or at-risk man trying to conceive: Arthralgia +++ +++ wait 6mo Myalgia + ++ + Hemorrhage - + - Shock - + - Conjunctivitis - - ++ Note: little difference in rates of fever, HA, rash https://www.cdc.gov/zika/geo/countries-territories.html

41 9 3/2/2018

Diagnostics: Chikungunya, Dengue and Zika Antiviral Treatment Options

Chikungunya Dengue Zika* PCR/NAAT <7d sx <7d sx <14d sx IgM All All All

*Guidance differs for pregnant women: https://www.cdc.gov/zika/hc-providers/testing-guidance.html

https://www.cdc.gov/dengue/resources/poster_chikv_denv_comparison_healthcare_providers.pdf

Educational Topics Prevention of Food-Borne Disease • Most studies failed to correlate guideline • Accident prevention adherence to risk of travelers’ diarrhea • Insect avoidance • Safe food and water • Where you eat is way more important than • Altitude what you eat! • Safe sex • Animal avoidance • Scuba • Travel insurance

42 10 3/2/2018

Educational Topics Rabies in the US vs. the Developing World • Accident prevention United States • Exceedingly rare • Insect avoidance • >90% of cases in bats, • Safe food and water foxes, raccoons, and skunks • Altitude • Safe sex Developing World • No good surveillance • Animal avoidance data • Scuba • >90% of exposures and 99% of deaths are from • Travel insurance dogs

Educational Topics Pre-Travel Consultation

• Accident prevention 1. Assess the health of the traveler • Insect avoidance 2. Assess the risk of travel • Safe food and water 3. Educate • Altitude • Safe sex 4. Vaccinate • Animal avoidance 5. Prescribe • Scuba • Travel insurance

43 11 3/2/2018

Vaccine Preventable Diseases Travel-Related Vaccines

• Routine vaccines should be up to date May Be Required Others to Consider – At least 16% of travelers met criteria for MMR vaccine but only 47% were vaccinated (Annals 2017; 167; 77-84) • Yellow fever • Hepatitis A • Required vaccines • Meningococcus* • Hepatitis B • Other travel-related vaccines • Polio* • Typhoid fever • Japanese encephalitis • Rabies vaccine *By Saudi Arabia for pilgrims during the Hajj

Yellow Fever Question #4 Clinical • Transmission: mosquitoes Which of the following vaccines is safe in a • Risk 50/100,000 in W. Africa and patient with DM, HTN, and a cadaveric kidney 5/100,000 in S. America • Sx: ranges from mild fever/HA to transplant on tacrolimus and 15mg of daily biphasic illness w/ multi-organ failure prednisone? • Vaccine: live-attenuated, single dose for most patients a) Rabies (IM) b) MMR (IM) c) Typhoid (oral) d) Varicella (IM) e) Yellow fever (IM) Check WHO Country List of Requirements http://www.who.int/ith/ITH_country_list.pdf?ua=1 CDC Yellow Book 2016

44 12 3/2/2018

Typhoid Fever Other Travel-Related Vaccines

Disease Notes Clinical Meningococcus Travel to the “meningitis belt” (below) or the Hajj • Transmission: food/water Polio Oral and injectable options; travel to countries w/ active/recent transmission (or the Hajj) • Risk: 400 cases annually US Japanese Recommended if staying in rural areas during – Travel #1 risk factor encephalitis transmission season in east and SE Asia • Sx: fever +/- diarrhea (~2/3) Rabies Risk of animal contact +/- no access to rabies +/- sepsis immunoglobulin • Vaccines (50-80% protective): two options – Intramuscular (inactivated) – booster Q2 years – Oral (live attenuated) – booster Q5 years

https://wwwnc.cdc.gov/travel/yellowbook/2018/

Pre-Travel Consultation Prophylaxis and Self-Treatment: Medications for Travelers 1. Assess the health of the traveler • Malaria 2. Assess the risk of travel • Traveler’s diarrhea 3. Educate • Altitude illness 4. Vaccinate • Motion sickness 5. Prescribe • Treatment for common acute conditions

45 13 3/2/2018

Malaria: U.S. Epidemiology Global Epidemiology

• About 1500 cases/yr • The majority of travelers returning to the United States with malaria were… -Foreign-born -Returning to their country of birth to visit family -Not prescribed malaria chemoprophylaxis • 70% from Africa • 70% P. falciparum

Wilson. CID 2007; 44; 1560-1568 WHO: World Malaria Report. Geneva, Switzerland: World Health Organization; 2014

Malaria: Clinical Presentation Malaria: Severe Malaria

• Impaired consciousness • Hypoglycemia (gluc <40) Symptoms Signs/Laboratory Findings (GCS<11) • Acidosis (HCO3 <15) • Fever • Splenomegaly • Prostration • Normocytic anemia (Hgb • Vomiting • Hepatomegaly • > 2 convulsions in 24hrs <7 in adults) • Respiratory distress • Hyperparasitemia (>10%) • Diarrhea • Pallor • Shock (SBP <80 in • Lactate >5 or HCO3 <15 • Headache • Hyperbilirubinemia adults) • Renal failure (Cr >3) • Arthralgia • Thrombocytopenia • Jaundice (t-bili >3) • Dyspnea • Hemoglobinuria • Spontaneous bleeding • Cough • Pulmonary edema • AMS, seizures

JAMA 2010; 304; 2048-1056 WHO: Guidelines for the treatment of malaria 3rd Edition 2010; Geneva, Switzerland

46 14 3/2/2018

Malaria Chemoprophylaxis Returning Travelers: Treatment Drug Areas of use Directions Pros/Cons

Atovaquone/ Daily; Pro: minimal SEs All To select treatment answer proguanil 1 wk post Con: costly the following:  • Severe or uncomplicated? Chloroquine- Weekly; Pro: weekly Chloroquine • Where was the traveler? susceptible 4 wks post Con: GI upset • What is the distribution of Plasmodium species and Pro: cheap, Lepto what are the rates of Daily; Doxycycline All ppx? chloroquine resistance? 4 wks post Con: photosensitivity • Was chemoprophylaxis taken? Pro: cheap, • Pregnancy test? Mefloquine- Weekly; ok in pregnancy Mefloquine • How much do you trust susceptible 4 wks post Con: neuropsych your microscopist? SEs If any doubt about the species or resistance assume the worst: P. falciparum w/ chloroquine resistance!

https://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf

Travelers Diarrhea (TD) Prevention of TD

• #1 travel-related illness: 30-70% of travelers • Prevention • Pathogens: – Avoidance of contaminated food/water – Bacteria 80-90%: ETEC, campy, shigella, • Prophylaxis salmonella – Viruses 10%: Norovirus, rotavirus – Bismuth subsalicylate 2 tabs QID • Course: – Rifaximin 200 mg PO QD-BID (vs. placebo) – Bacterial and viral diarrhea lasts 3-5 days – Longer durations suggests other diseases • TD: 15% vs. 54% in Mexican travelers

DuPont HL. Annals of Internal Medicine 2005; 142; 805-812

47 15 3/2/2018

Lecture Outline (Self) Treatment of TD 1. Why should you know about travel medicine? • Ciprofloxacin: 2. The pre-travel visit – 500 mg PO BID for 1-3 days 3. Post-travel evaluation • Azithromycin: SE Asia, children, pregnancy – 500 mg PO QD x 3 days or 1000 mg PO x 1 • Rifaximin: not for invasive infections – 200 mg PO TID x 3 days • Loperamide: not for invasive infections – Added benefit, use in “emergency”

Top 5 Complaints of Returning Top 5 Complaints of Returning Travelers Leading to MD Visit Travelers Leading to MD Visit

• Fever without localizing findings • Fever without localizing findings • Acute diarrhea • Acute diarrhea • Dermatological disorders • Dermatological disorders • Chronic diarrhea • Chronic diarrhea • Nondiarrheal gastrointestinal disorders • Nondiarrheal gastrointestinal disorders

Freedman. NEJM 2006; 354; 119-130 Freedman. NEJM 2006; 354; 119-130

48 16 3/2/2018

How to Determine Etiology of Fever Question #5 in Returned Traveler A 24yo woman calls you on an after-hours advice line 20 days after returning from a trip building houses in Uganda with her church group. She complains of 2d of fevers and no other symptoms. She took acetaminophen and currently feels much better. While in Uganda she was around cows and goats. She went rafting on the Nile and hiking in Patients need immediate evaluation a forest. She slept under a bed net but did not take malaria prophylaxis. She had one new male sexual partner and did not use condoms. • Destination(s) What do you advise the patient to do? • Incubation period a) Present to urgent care in the morning b) Go to the STI clinic tomorrow for testing including HIV VL • Exposures c) Go to the lab tomorrow – you will order comprehensive diagnostic testing • Exam findings/labs d) Keep track of her fever and notify you immediately if and when it recurs e) Go to the emergency department for evaluation • Prophylaxis/immunizations

Destination: Etiology of Fever by Region Incubation Period 1000 Visited Etiology of fever according to interval after 900 travel

800 2006. NEJM. DO. Freedman

700 Unknown Rickettsia 600

500 Malaria 400 Cases Typhoid 300 EBV/CMV

200 Dengue Dengue

100

0 Carribean C. America S. America Sub‐Saharan South SE Asia Africa Central Asia Wilson. CID 2007; 44; 1560-1568

49 17 3/2/2018

Exposures? Initial Testing • Insect? •Animals? • CBC w/ differential • Fresh water? •LFTs • What did they consume and where? • Blood cultures x 2 • Sick contacts? • Thick and thin blood smear (x2-3 at 12- • Sexual activity? 24hr intervals if suspicion remains) • Drug use? •CXR • Caves? • Additional testing based on history, exam, • Wounds? and initial blood work •Bites?

Top 5 Complaints of Returning 5 Most Common Dermatological Travelers Leading to MD Visit Diagnoses in Returning Travelers

• Fever without localizing findings • Cutaneous larva • Acute diarrhea migrans • Dermatological disorders • Insect bite • Skin abscess • Chronic diarrhea • Superinfected • Nondiarrheal gastrointestinal disorders insect bite • Allergic rash

Freedman. NEJM 2006; 354; 119-130 Ledermen ER. Int J Infect Dis 2008; 12; 593-602

50 18 3/2/2018

Top 5 Complaints of Returning Chronic Diarrhea: Evaluation Travelers Leading to MD Visit • Bacterial culture • Fever without localizing findings • Acute diarrhea • Stool O&P x 3 • Dermatological disorders • Other tests – Giardia antigen • Chronic diarrhea – Stool AFB stain (cryptosporidium, isospora, • Nondiarrheal gastrointestinal disorders etc.) – Stool Cryptosporidium antigen – Stool Entamoeba histolytica antigen

Freedman. NEJM 2006; 354; 119-130

Summary • Travel health risks are dependent on underlying medical conditions as well as itinerary, duration of travel, purpose of travel, and activities • Travelers should be up to date on routine and travel-specific vaccinations • Travelers should be given prophylactic and self-treatment medications as appropriate • Recommend evacuation insurance to travelers, particularly those at high-risk • A febrile returning traveler is a medical emergency • When in doubt, ask the CDC (and your friendly ID consultant)

THANK YOU!!!

51 19

52 Disclosures

. Grant/funding from: Antibacterial Research Leadership Group (NIH), Infectious Diseases Society of America . Consultant: Actelion, Genentech

Clostridium difficile difficulties Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 3.14.2018

Outline New guidelines hot off the press!

. Brief background and epidemiology . Diagnosis . Management—mild, uncomplicated disease . Management—moderate-severe disease . Management—recurrent/relapsed disease . Management—fulminant disease . Prevention

1 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 53 One of CDC’s 3 “Urgent Threats” CDI Background

. Anaerobic, spore-forming gram- . Risk factors: positive bacillus • Antibiotics . Toxins A + B •Age . Multiple strains • Hospitalization • Epidemic strain ID’d 2004 • Acid-suppression • 078 strain 500,000 •IBD . Fecal-oral spread • Tube feeds 3.8 billion . 12% of all HAIs • Host immune factors . Carriage of C. difficile • Chemotherapy • < 3% for healthy adults in community • Female gender • 20% in hospitalized pts • Domestic animals? Retail food? • up to 50% in LTCF

Magill SS et al., NEJM 2014

Epidemiology trends, inpatients Duration, number, and intensity of antibiotics affect risk for CDI Molecular testing era

Epidemic strain

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm Stevens V, et al. Clin Infect Dis 2011; 53: 42-48.

2 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 54 Antibiotic use affects the population risk Spread of CDI in the hospital

Endogenous Asymptomatic carriers 20% carriage Symptomatic cases 30% 25-33%

Other (environmental • Risk for CDI if prior room occupant got antibiotics = HR 1.22 (1.02-1.45) contamination, etc)

Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 Freedberg DE et al. JAMA Intern Med. 2016 Dec 1;176(12):1801-1808

Diagnostic testing CDI overdiagnosis

Glutamate dehydrogenase Ag (GDH) • Bacterial detection • 21% +PCR • Sensitive but not specific • Of these, 44% + toxin • Toxin-/PCR+ • ↓bacterial load Polymerase chain reaction (PCR): • ↓abx • Toxin-producing gene • ↓diarrhea • ↑Sensitivity • No CDI- complications Enzyme immunoassay (EIA) • Protein detection • ↓Sensitivity • ↑Specificity for disease

Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801.

3 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 55 New testing guidance

.Develop institutional guidance on appropriate testing • No tests if on laxatives • Test only if new onset ≥ 3 stools/24 hours .Multistep algorithm preferred over PCR alone • GDH+toxinPCR • PCR+toxin MANAGEMENT .If institution limits testing to high pretest probability testing, PCR alone okay

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Uncomplicated CDI treatment no longer Treatment scenario #1. 63 y/o F recently treated for a UTI with levofloxacin, now having watery stools 4x/day, depends on severity! fever to 38.3, WBC 11K, Cr 1.0. Other vitals stable. PCR .Mild to moderate: Does not meet criteria for severe positive for C. difficile toxin. With what should you treat • Diarrhea ≥ 3 stools/24 hours her? .Severe A. Vancomycin 125 mg po qid • Not well validated B. Vancomycin 500 mg po qid C. Metronidazole 500 mg po tid • IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or Cr ≥ 1.5 D. Fidaxomicin 200 mg po bid • Severe, complicatedNow “fulminant” ‒ Severe plus hypotension, shock, ileus, and/or megacolon

Zar F A et al. Clin Infect Dis. 2007;45:302-307; McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

4 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 56 Initial uncomplicated CDI, severe or RCTs metronidazole vs. vancomycin non-severe 120 .VAN 125 mg po QID x 10 days (up to 14) (strong, p = 0.005NS p = 0.02 NS high) 100 80 .FDX 200 mg PO twice daily x 10 days (strong, 60 MTZ high) Vanco 40 • Favor in patients at high risk for recurrence 20

.If above agents are unavailable, can consider 0 metronidazole x 10-14 days (weak, high) Cure, all Cure, mild-mod Cure, severe Recurrence • Similar findings for recent study of metronidazole vs vancomycin vs tolevamer • Cure not differential with regard to levels of severity • Higher recurrence across the board (20%) • Only vancomycin is FDA-approved

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 Zar F A et al. Clin Infect Dis. 2007;45:302-307; Leffler DA and Lamont JT. NEJM 2015; 372:1539-1548; Johnson S et al., Clin Infect Dis 2014;59(3):345-54

New evidence to support vancomycin What about fidaxomicin? • Bottom line vs. vanco: Similar cure (~88%), lower recurrence (13-15% vs. 25-27% ) • Unclear role in multiply recurrent or severe disease • aRR death vanco vs metronidazole Cure Relapse • Any severity: 0.86; (0.74 Strain to 0.98) Epidemic Same Same • Severe: 0.79 (0.65 to Non-epidemic Same  0.97) Concomitant abx  • NNT to prevent 1 death, Prior CDI Same  severe CDI: 25 Fidaxomicin Vancomycin Metronidazole $2800 $250-680 $22

Louie TJ, et al. NEJM 2011;364:422-431; Cornely et al, Lancet Infect Dis 2012;12:281-8 ; Petrella LA, et al. Clin Infect Dis 2012;55(3):351-7; Mullane et al., CID 2011;53(5):440-7; Corneley et al., CID 2012;55:s154-s161.; Bartsch SM et al., CID 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514.

5 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 57 Real-world fidaxomicin experience Additional considerations

. UK Trust Hospitals .Stop unnecessary antibiotics analyzed pre- and post- .Shorten antibiotic courses information s/p introduction of .Narrow antibiotic spectrum fidaxomicin . Each hospital .Stop acid-suppressive medications when had a different possible (though low quality evidence) approach to rx with fidaxomicin • Esp PPI (e.g. all patients vs. selected populations) .No anti-peristaltic agents until acute sxs improve • A and B: Fidaxomicin used first-line for all • C, E, F, G: Selected episodes • D: Recurrences only

Treatment scenario #2: You are seeing a 62 y/o F who Take-home has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcal osteomyelitis and has .For initial treatment of non-fulminant CDI, developed her second bout of C. difficile colitis. Her first episode was treated with VAN x 10 days. Her WBC VAN 125 mg po QID x 10-14 days for most count is 9 and Cr is 0.3. What should you treat her with? patients .Role of fidaxomicin unclear A. Metronidazole 500 mg po TID x 10 days • Consider if ↑ risk of relapse or need CA B. VAN 125 mg PO QID x 10 days C. VAN taper D. FDX 200 mg po BID x 10 days

6 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 58 First recurrence, non-fulminant CDI Evidence to support VAN taper

.If metronidazole used initiallyVAN 125 .Treatment outcomes from pts in placebo group mg po QID x 10 days (weak, low) with rCDI of 2 RCTs of probiotics (n = 163) .If VAN used initially, two options: .29 got VAN tapers of varying stripes • VAN taper (weak, low) • Man 21.5 +/- 10 days • 31% recurrence compared to 71% of the 10 pts • FDX 200 mg po BID x 10 days (weak, given standard VAN courses (p = 0.01) mod) • Also lower recurrences for VAN pulses .Small numbers, uncontrolled study

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Vancomycin taper Risk for recurrent CDI

.125 mg po 4x daily x 14 days 100% 90% .125 mg po 2x daily x 7 days 80% .125 mg po 1x daily x 7 days 70% .125 mg po every other day x 8 days (4 doses) 60% 50% No recurrence .125 mg po every 3 days x 15 days (5 doses) 40% Recurrence 30% 20% 10% 0% 1st episode 2nd episode 3rd episode

Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis. 2005 Jun 1;40(11):1591-7

7 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 59 Treatment scenario #3. This patient returns one month Second/subsequent recurrence after you have treated her with a 10-day course of PO FDX complaining of ongoing diarrhea. A repeat stool .VAN taper/pulse (weak, low) toxin is positive. What do you do? .VAN 125 mg po QID x 10 days followed by A. VAN followed by rifaximin rifaximin 400 mg po TID x 20 days (weak, B. VAN taper low) C. FDX 200 mg PO BID x 10 days .FDX 200 mg PO BID x 10 days (weak, low) D. Fecal microbiota transplantation .FMT (strong, mod) E. Any of the above • “appropriate antibiotic treatments for at least 2 recurrences… should be tried prior to offering [FMT]”

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

A word on rifaximin chaser ↓↓↓Fecal diversity with rCDI

.Double-blinded single-center RCT of pts with FMT basics CDI .Colonization resistance • Rifaximin 400 mg po TID x 20 days after .Related donors or standard 10-14 dd course VAN or banked stool metronidazole versus placebo • Need to screen for . Recurrence:17/35 (49%) placebo vs. 5/33 (21%) transmissible diseases rifaximin (p = 0.02) .Multiple RCTs have now been done .Guidance document available (Bakken et al)

Chang JY et al. JID 2008; 197: 435-8; Kassam et al., Arch Intern Med. 2012;172(2):191-3. Gough et al., CID 2011;53(10):994- 1002; Bakken JS et al Clin Gastroenterol Hepatol 2011; 9: 1044-49

8 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 60 FMT trial trends The latest on FMT

. 6 published • Multiple previous trials • 3 vs. abx management supported FMT… • But comparator group not • 3 vs. FMT refinements standard of care . Over time, ↓efficacy in RCTs • Phase 2/3 open-label RCT • Stopped early for futility . ↑response to comparator abx • FMT by enema . Might matter whether active • Recurrence: 9/16 (56%) FMT recurrence vs. prior recurrence? vs. 5/12 (42%) taper group . Might need multiple FMTs • 95% CI for Δ CDI with FMT = -2.8% to +47.3% . Vanco taper might be better than we thought? . Commercially-prepared FMT in development

FMT meta-analysis FMT for abx resistance?

.Overall response: • Multiple infusions: 92% (89-94%) • Single infusion: 84% (79-89%) .Just RCTs: • Multiple: 91% (88-94%) • Single: 77% (56-93%)

Millan B et al. Clin Infect Dis 2016;62:1479-1486

9 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 61 FMT via pill? FMT adverse events

. Unblinded noninferiority (15%) multicenter RCT of 117 adults with ≥ 3 episodes of CDI treated with FMT via colo versus pill Common Rare/serious • Stratified by age (65) and immunosuppressed status (15%) .Diarrhea .Procedure-related harms • Median duration of rCDI rx prior to transplant: 2.3-2.4 mths .Cramping • Perforation • Aspiration . Absence of rCDI @ 12 weeks: 51/53 (96%) in capsule group .Belching versus 50/52 (96%) colonoscopy group (per-protocol) .Nausea .Norovirus • Difference: 0% (95% CI, -6.1% to infinity) .Bloating .Bacteremia • Pts with recurrence were retreated with same modality .IBD flare • Sensitivity analyses including LTFU as recurrences still met noninferiority .Unknown long-term effects • Both groups had increased microbial diversity post-transplant • Weight changes • Chronic disease exacerbation

Drekonja D et al. Ann Intern Med 2015;162(9):630-8.

FMT durability Take-home

.Single-center retrospective f/u of all patients receiving FMT .rCDI is a challenge • 137/191 (72%) response rate (additional 26 deceased and .First recurrence: Stratify by initial rx 15 without contact information) • 2/26 (7.7%) of deceased died of rCDI • MetronidazoleStandard VAN course • Median time to f/u: 22 months (range, 3-51) •VANVAN taper or FDX • Most (97%) got PO vancomycin, 53 (39%) also .Subsequently: fidaxomicin • VAN taper . 24/137 (18%) had rCDI post-FMT • VAN course + rifaximin chaser .61/137 (45%) got additional antibiotics •FDX • 43/113 (38%) w/o rCDI vs. 18/24 (75%) w/ rCDI (p < 0.01) • FMT (try above options first)

Mamo Y et al. Clin Infect Dis. 2017 Dec 19. doi: 10.1093/cid/cix1097. [Epub ahead of print]

10 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 62 Treatment scenario #4: 63 y/o F recently treated for a UTI with levofloxacin, now with profuse diarrhea, T 38.7, Fulminant CDI BP 79/50, HR 140, WBC 30K, Cr 3.2, and lactate 3.7. What do you treat her with? .Paucity of data for medical approaches, expert opinion A. Vancomycin 125 mg po qid • VAN 500 mg po QID (strong, moderate) B. Vancomycin 500 mg po qid • IleusVAN 500 mg in 100 cc saline PR QID C. Vancomycin 500 mg PR qid (weak, low) D. Metronidazole 500 mg iv tid • Metronidazole IV (strong, moderate) E. Fidaxomicin 200 mg po bid .Surgical options: F. A+C+D • Subtotal colectomy (strong, moderate) G. B+C+D • Alt: Diverting loop ileostomy (weak, low)

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Total colectomy with end ileostomy Diverting loop ileostomy + colonic lavage .Retrospective cohort pts in ICU for CDI • N = 161 (38 surgery, 123 medical rx) .Indications: Shock (40%), megacolon (29%), no response to med rx (26%), perforation (5%) .aOR death 0.2 (0.1-0.7) colectomy vs. medical rx • WBC > 50K and lactate > 5 conferred very poor . 3/42 (7%) converted to total colectomy (2 for abd compartment sx) prognosis . 79% had ileostomy reverted • More beneficial in age ≥ 65, immunocompetent, WBC ≥ . VS historical colectomy controls, OR for death = 0.24 (0.09-0.63) 20, lactate 2.2-4.9 • 19% died w/i 30 days • 53% died (58% medical rx, 34% surgical) • 14% more died afterwards, all deemed due to underlying illness • Selection bias likely . RCT recruiting (projected end date 2018)

Lamontagne et al., Ann Surg 2007;245(2):267-72. Neal et al. Ann Surg. 2011 Sep;254(3):423-7; discussion 427-9.

11 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 63 FMT for severe disease Multicenter loop ileostomy study Study Population Intervention Outcome Cammarota et al, Subgroup of RCT w/ RCT FMT via colo vs Mortality: 29% (1 Aliment Pharmacol recurrent CDI, N = 7 w/ vanco FMT) .10 centers, 98 patients Ther 2015 pseudomembranes Initial 2 pts 1 FMT Cure: 71% (≥ 2 FMT) Single-center via colo; remainder • 21% LI patients ; trend towards lower FMT q3 days prn APACHE, less vasopressor use, later surgery Fischer et al, Cohort, N = 29 FMT via colo ~qwk Mortality: 7% (both Aliment Severe (10) +/- with intermittent severe/comp) Pharmacol Ther complicated (19) vanco Success: 93% (≥ 2 .Overall mortality 32% (unadjusted, 34% TC vs 2015 Single-center FMT in 55%) 24% LI, p = 0.4) Zainah H et al. Dig Cohort, N = 14 with FMT via NGT, rpt at Mortality: None d/t • Mortality adjusted for confounders, LI 17% vs Dis Sci 2015 severe, refractory CDI 48-72hr if not CDI (29% at 100 dd (43% in ICU) response 2/2 underlying dz) TC 40%; p = 0.002 Single-center Success: 79% (≥ 2 FMT in 21%) • Less blood loss for the LI group Aroniadis et al. J Multicenter cohort FMT mostly via colo Success: 94% (≥ 2 Clin Gastroenterol N = 17 FMT in 6%) • LI group did worse if reoperation needed 2015 76% severe/complicated

FMT for severe disease Take-home for severe, complicated CDI

.Single center retrospective cohort analysis of 111 patients .Use high-dose oral +/- rectal vancomycin • FMT group treated with vanco 2-4 days pre- & 4 days post-FMT .Use IV metronidazole • Clinician discretion whether to offer FMT .Consider surgical intervention early • 66 (59%) underwent FMT; 45 (41%) did not (incl 26 due to clinical improvement on medical rx and 13 due to instability) • Consider diverting loop ileostomy .3 month mortality: 12.1% (8/66) in the transplant group vs .FMT is promising but need more data, multiple FMTs 42.2% (19/45) in the antibiotic group (OR 0.19 [95% CI, may be needed .073–.49]) • Make sure medical therapy has been optimized ‒ Multivariable analysis: FMT OR, 0.13 (95% CI, .04–.44) .Additional therapies (IVIG, other antibiotics) lack data ‒ However, risk of confounding by indication high ‒ No control for systemic antibiotic receipt

Hocquart M et al. Clin Infect Dis. 2017 Aug 24. doi: 10.1093/cid/cix762. [Epub ahead of print]

12 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 64 Treatment scenario #5. You are starting your 70 y/o M patient RCT of probiotics for CDI on 4 weeks of ciprofloxacin for prostatitis. He asks you whether he should take probiotics. How do you counsel him?

A. Probiotics will prevent antibiotic-associated Diarrhea class Probiotic Placebo OR diarrhea, including CDI AAD 159/1470 (11%) 153/1471 (10%) 1.04 (0.83–1.32) B. Probiotics will prevent antibiotic-associated CDI 12/1470 (0.9%) 17/1471 (1.2%) 0.70 (0.34–1.48) diarrhea but not CDI C. Probiotics are useless • No benefit for probiotic • Very low rates of CDI in this population • Majority of patients were receiving amoxicillin/ampicillin or second-generation cephalosoporins (UK study) • Likely underpowered for the CDI outcome

Allen SJ et al., Lancet 2013 Oct 12;382(9900):1249-57

Meta-analysis Approaches to prevent CDI .NNT: 43 (95% CI, 36−58) .Remained significant even when missing data was excluded .Studies limiting people to initiation within first 1-2 days on abx had stronger effect size • Limits UK study (Allen) .IDSA guidelines = insufficient data

Gerding D N , Johnson S. CID 2010;51:1306-1313 Shen NT et al. Gastroenterology. 2017 Jun;152(8):1889-1900; McDonald LC CID 2018

13 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 65 Infection control Identification and isolation of carriers

.Gloves + gowns for duration of diarrhea + 48 h • Universal gloving? .Wash with soap and water .Private rooms • Dedicated commode .Bleach cleaning • All versus known CDI .+/- UV light .Antimicrobial stewardship (possibly PPI stewardship) IDSA: “insufficient data”

Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455 Caroff DA et al. CID 2017 McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Non-toxigenic C. diff for secondary Secondary prophylaxis? prevention 1. Retrospective cohort at two hospitals in Quebec .173 patients with 1st or 2nd episode of CDI w/i 28 days (phase II) aHR 0.59 (0.43-0.80) • 1-2 days after stopping CDI treatment randomized to Rx’d non-CDI Recurrence aHR 1st CDI 0.91 (0.57-1.45) Adult w/ CDI abx within 90 d non-toxigenic C diff (NTCD-M3) vs. placebo (in or outpt) w/i 6 mo aHR recurrence 0.47 (0.32-0.69) Recurrence: • OR 0.3; 95% CI, 0.1-0.7 2. Retrospective cohort St. Louis • Of NTCD-M3 group, 2% for OR 0.12 (0.04-0.4) those colonized vs. 31% if No multivariate analysis not colonized Rx’d non-CDI Recurrence Adult w/ CDI abx within 90 d (inpt) w/i 4 weeks

Gerding DN et al., JAMA 2015; 313(17):1719-1727

14 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 66 Host protection Monoclonal Abs for secondary prevention MODIFY I and II trials

Actoxumab Bezlotoxumab • NNT = 10 • No clear subgroup benefited • Cost may be an issue • Δ sustained cure Bezlotux vs. SOC: 9.7% (4.8-14.5)

Kyne et al., NEJM 2000;342(6):390-7. Lowy et al. NEJM 2010 Jan 21;362(3):197-205.

C diff vaccine? CDI prevention summary

.Remember infection control basics .Role of isolation of carriers evolving .Unclear role for probiotics, unlikely to be a game-changer .Non-toxigenic C. diff is promising .Passive immunity is effective but costly .There may be a role for vaccine in the future .Do not forget good infection control and antimicrobial stewardship practices!

15 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 67 CDI take-home . VAN or FDX preferred for non-fulminant disease . Fulminant disease: PO/PR vancomycin and IV metronidazole • Consider surgery • Maybe FMT . 1st recurrencestratify by initial Rx •VANVAN taper or FDX (standard VAN course if initial rx w/ metronidazole) . Subsequently: • VAN taper • VAN course + rifaximin chaser THANK YOU! •FDX • FMT (try above options first) . Prevention is important

16 2/16/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 68 Disclosures

I have no disclosures Human Papillomavirus Infection

Advances in Infectious Diseases 3/14/2018

Cristina Brickman, MD MSCE Division of Infectious Diseases University of California, San Francisco

2 Human Papillomavirus Infection

Why is infection with Human Papillomavirus (HPV) Relevant? Overview

A. It causes genital ulcers 1. Pathogenesis of human papillomavirus (HPV) B. It causes genital warts and cancer 2. Complications and Management of HPV C. HPV infection and its complications are potentially - Genital warts preventable - Malignancy D. I’m not sure 3. Primary prevention of HPV infection (vaccination) E. B and C

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69 HPV Genome

• Double-stranded DNA • About 8 kbp • Early region: E1, E2, Pathogenesis of HPV Infection E4, E5, E6, E7 proteins • Late region: L1 and L2 capsid proteins • Upstream regulatory region (URR)

Muñoz N, et al. Vaccine 2006; 24(S3): S1-S10

5 Human Papillomavirus Infection 6 Human Papillomavirus Infection

HPV structure HPV types

. > 100 types in humans1 Capsid proteins: L1 - ≥ 10% difference in L1 structure L2 . 40 Infect anogenital and upper respiratory tract - Most common sexually transmitted infection - High-risk or oncogenic: 16, 18 + others . 99.9% cervical cancers, 90% anal cancers, majority

Viral DNA of oropharyngeal, vaginal, penile and vulvar cancers - Low-risk: 6, 11 + others Viral exterior Viral interior . Genital warts

Baker TS et al. Biophys J. 1991;60:1445-1456 1. Brickman CB, & Palefsky JM. Current HIV/AIDS Reports 2015; 12(1): 6-15

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70 HPV Infection & Productive Life Cycle Nomenclature

. Old: Bethesda system1 Assembly - Morphologic continuum: lesions progress from low- & release grade to high-grade disease, and eventually, invasive cancer Late gene - Name varies depending on location of lesion expression & amplification . New: Lower Anogenital Squamous Terminology (LAST) - NO morphologic continuum Early gene - Same name regardless of location expression - E.g. LSIL (low-grade squamous intraepithelial lesion) Dermis and benign OR HSIL (high-grade squamous Normal Epithelium HPV-infected epithelium intraepithelial lesion) and precancerous Moody CA & Laimins LA. Nature Reviews Cancer 2010; 10: 550-560 1. Brickman CB, & Palefsky JM. Current HIV/AIDS Reports 2015; 12(1): 6-15

9 Human Papillomavirus Infection 10 Human Papillomavirus Infection

Mechanisms of HSIL & Carcinogenesis

1. E6 2. E7 3. Viral integration

Adapted from Kuman, RJ ed. 2002 Blaustein’s Pathology of the Female Genital Tract Figure 7.1

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71 E6 leads to p53 Degradation E7 releases E2F

• E6 binds to cellular E6- • E7 binds cellular Rb and Rb E7 + associated protein leads to release of E6 E6-AP E2F • E6:E6-AP complex cellular E2F binds p53 and targets it transcription factor for ubiquitination • E2F stimulates p53 • Ubiquitinated p53 is + transition into S1-phase degraded by cellular of cell cycle proteosome

Cell cycle

13 Human Papillomavirus Infection 14 Human Papillomavirus Infection

Viral Integration Promotes E6 & E7 Viral Integration Promotes E6 & E7 Expression Expression

Episomal HPV DNA Integrated HPV DNA (provirus) Episomal HPV DNA Integrated HPV DNA (provirus)

E2 E2 E2 E2 inhibits E6 & E2 inhibits E6 & E7 expression E7 expression

E6 E7 E6 E7 E6 E7 E6 E7

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72 Viral Integration Promotes E6 & E7 Integration Expression

Episomal HPV DNA Integrated HPV DNA

+ Rb E7 E2F E6 E6-AP

E2 p53 + E2 inhibits E6 & E7 expression E6 E7 E7 E6 E6 Cell cycle E7 E6 E7 E6 E7 Genomic instability

17 Human Papillomavirus Infection 18 Human Papillomavirus Infection

What Determines Activation of these Mechanisms?

. Incompletely understood . HPV type is important . E.g. E6 and E7 of HPV types 16 & 18 have greater affinity for their targets and are more effective in function  more likely to result in HSIL & mutations Complications & Management of HPV . HIV-infection & tobacco important risk factors

1. Brickman CB, & Palefsky JM. Current HIV/AIDS Reports 2015; 12(1): 6-15

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73 Case 1 The patient…

50 year-old man presents to clinic with complaint of a A. May have oropharyngeal cancer and should be “neck mass” x 1 month. In general good health, non- referred to ENT smoker, social history notable for multiple female sexual B. Has pharyngitis and needs a penicillin prescription partners. On exam his right tonsil appears enlarged and there is a firm, fixed 3cm lymph node along the right C. Is too young for head and neck cancer anterior cervical chain. D. What’s the difference between oropharyngeal and head and neck cancer and why does it matter?

21 Human Papillomavirus Infection 22 Human Papillomavirus Infection

Complications of HPV Infection Treatment of Genital Warts1

. Benign Patient-applied Provider-applied Surgical - Genital warts/condylomata acuminata Imiquimod Cryotherapy Excision . 5.6% of 18-59 year-olds at some point1 Sinecatechins Trichloroacetate Fulguration Podophyllotoxin Bichloroacetate Electrocautery . HPV-associated malignancies Pros: Pros: Pros: non-invasive non-invasive good for large lesions - 40,000 new cases in US per year2 Cons: Cons: Cons: . Cervical cancer Unpredictable response Ineffective for large recovery . Oropharyngeal cancer skin irritation lesions . Anal cancer time & commitment Serial visits

1. Dinh TH et al. Sexually Transmitted Diseases. 2008; 35(4): 357-60 2. Viens LJ et al. MMWR 2016; 65(26) 662-666 1. Workowsli KA et al. MMWR 2015; 64(RR3); 1-137

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74 Cervical Cancer Oropharyngeal Cancer (OPC)

• Subset of head and neck cancers1 • Arise from soft palate, back of throat, tonsils and base of the tongue • ≥ 95% are squamous cell-carcinomas

http://globocan.iarc.fr/Pages/Map.aspx 1. Huang SH and O’Sullivan B. Curr Treatment Options Oncol 2017; 18(7): 40

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Tobacco Consumption & Cancer Incidence New Subset of HPV-associated OPC

Overall • Younger, non-smoking men HPV+ • Associated with sexual risk factors HPV‐ • 7.5% absolute rise HPV+ OPC • Primarily HPV 16 • Better prognosis

Sturgis EM and Cinciripini PM. Cancer 2007; 110(7) 1. Chaturvedi AK et al. J Clinical Oncology 2011; 29: 4294-4301

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75 Screening for OPC Anal Cancer

. None! . 90% anal cancers due to hr-HPV, primarily HPV-16 . Do not test patients for oral HPV infection . Risk factors: tobacco, multiple sexual partners, anal receptive intercourse, HIV

1. Brickman CB, & Palefsky JM. Current HIV/AIDS Reports 2015; 12(1): 6-15

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Anal Cancer in the HIV-infected population Anal Cancer in the General Population

Anal Cancer Incidence per 100,000 person-years All Men Women MSM SEER1 1.5 1.1 1.8 Malachek et al.2 5.1 (95% CI 0.0-11.5)

1. Viens LJ et al. MMWR 2016: 65; 661-666 2. Malachek DA et al. Lancet Oncology 2012: 13(5); 487-500 Piketty C 2012 et al. JCO 2012: 30(35); 4360-4366

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76 Anal Cancer Screening

. Performed by obtaining anal cytology and referring for high-resolution anoscopy if abnormal, analogous to colposcopy . For the general population: None! . HIV-infected patients: - HIVMA: MSM, women with a history of receptive anal Preventing HPV Infection intercourse, individuals with a history of genital warts1 - New York State DOH: MSM women with a history of vulvar or cervical squamous intraepithelial lesion, individuals with a history of anogenital warts2

1. Aberg JA et al. CID 2014: 58(1); 1-10 2. http://www.hivguidelines.org/clinical-guidelines/adults/anal-dysplasia-and-cancer

33 Presentation Title 34 Human Papillomavirus Infection

In addition to imiquimod, what else would Case 3 you recommend?

. 20 year-old woman presents to clinic with complaint of “bumps down below” x 2 weeks. She is sexually active A. Start vaccination with Gardasil® or Cervarix® with one male partner and not using condoms. Exam is B. Defer vaccination since she has already been exposed notable for several cauliflower-shaped papules along her to HPV external labia majora consistent with warts/condylomata. C. Imiquimod is unnecessary since we HPV vaccines will treat genital warts if given quickly D. Start vaccination with Cervarix, which does not cover lr-HPV 6 and 11

35 Presentation Title 36 Human Papillomavirus Infection

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77 HPV Vaccines

. 3 HPV vaccines - All contain VLP made up of L1 capsid subunits - Differ by types covered

Gardasil® Cervarix® Gardasil®9

Year 2006 2009 2014

Manufacturer Merck & Co GlaxoSmithKline Merck & Co

HPV types 16, 18, 6, 11 16, 18 16, 18, 6, 11 & hr-types 31, 33, 45, 52, 58

Clinical Trials in Women Clinical Trials in Men

. Per-protocol-analyses1-3: 98% and 100% efficacy . Efficacy in preventing genital warts in all men1 and in respectively in preventing type-specific cervical HSIL preventing anal HSIL in MSM2 and genital warts . Intention-to-treat analyses: 44% and 73% efficacy respectively for type-specific cervical HSIL and genital warts . Conclusion: work great BUT should be given before individual is sexually active - PREVENTATIVE only, not therapeutic

1. Garland SM et al. NEJM 2007;356(19):1928-1943 1. Giuliano AR et al. NEJM 2011;364(5):401-411 2. Group FI et al. NEJM 2007;356(19):1915-1927 2. Palefsky JM et al. NEJM 2011;365(17):1576-1585 3. Paavonen J et al. Lancet 2009; 374(9686): 301-314

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78 Advisory Committee For Immunization How are We Doing? Practices

. HPV vaccination for all males and females1 . Ages: - 11-12 but can start as early as 9 - “Catch-up” females age 13-26 , males aged 21 except MSM & immunocompromised males  extend through age 26 - If < 15, 2-dose series: 0 and 6-12 months - If ≥ 15, 3-dose series: 0, 1-2 months, 6 months

1. Meites E et al. MMWR 2016;65(49): 1405-1408

US HPV Vaccine Uptake Countries with HPV Vaccination Programs

Tdap

MenACWY

HPV female

HPV male

http://www.who.int/immunization/monitoring_surveillance/en/.

Walker TY et al. MMWR 2017: 66(33); 874-881

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79 Conclusions

. Anogenital HPV infection remains extremely common & causes substantial morbidity and mortality

. Low-grade and high-grade lesions are distinct entities and do not reflect a morphologic continuum Thank you!

. VACCINATE children, adolescents and young adults

46 Human Papillomavirus Infection

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80 Notes

Skin Deep - SSTIs Vivek Jain, MD, MAS

81 Notes

Skin Deep - SSTIs Vivek Jain, MD, MAS

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INFECTIONS IN KIDS

TO TREAT OR NOT TO TREAT? I HAVE NOTHING TO DISCLOSE.

Andi Marmor, MD, MSED Professor of Pediatrics University of California, San Francisco Zuckerberg San Francisco General Hospital

Three Common Presentations Case Presentation: Infant with Fever

FEVER DIFFICULTY BREATHING  Xanadu is 2 week old girl with a fever  Fever without a source (SBI)  Pertussis  No symptoms to suggest a source on  Urinary Tract Infections  Community Acquired PNA exam/history  Pharyngitis  VS: T 38.5, P 150, R 40’s, o/w WNL RASH  Exam: well-appearing, no focal findings to suggest source for fever  Infections and Mimickers

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The most likely cause of Xanadu’s fever is:

A. Viral infection B. Urinary tract infection C. Serious bacterial infection (SBI) (bacteremia/meningitis) D. HSV infection THE FEBRILE INFANT

Everything you need to know about Fever without a source (FWS): SBI in febrile infants - on ONE SLIDE Infants <30 days

 2-3% Appearance and lab criteria do not reliably rule out UTI/SBI in this age group E.Coli>GBS>S. aureus 13-18% >enterococcus, S pneumo  Urine, blood, CSF, empiric abx E. Coli recommended Amp/cefotaxime or amp/gentamicin

<1% Listeria vanishingly rare…some recommend E.Coli/GBSS. pneumo treating with cefotaxime alone

Greenhow, 2014

Schwartz, 2009, Gomez 2010, Greenhow, 2014

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Approach to Infant with FWS FWS: Infants 30-90 days no

 UTI still the most common bacterial source, other SBI less likely  Viral source more reliable Named viral syndromes or + rapid viral test (flu, RSV) SBI unlikely Consider testing for UTI  Inflammatory markers (CBC/CRP/PCT) helpful in select infants Well appearing, neg UA AND no viral source

Case Continued

 Since Xanadu is less than 30 days, and has no source for her fever, you obtain a UA/urine cx and blood cultures and perform an LP URINARY TRACT INFECTIONS  Her UA is positive for LE and nitrites (“PYELONEPHRITIS”)  Now what do you do?

85 3 3/2/2018

Risk of UTI in Infants with FWS Who should we test for UTI?

20 Girls  18 All infants with FWS < 3 mo of age 16 Uncirc  Girls > 3 mo of age Boys 14  FWS (>39) and < 24 months Circ 12 Boys  Boys > 3 mo of age 10  Circumcised: FWS (>39) and < 6 mo 8  Uncircumcised: FWS (>39) and < 12 mo 6  4 Additional Risk Factors: 2  Length of fever (> 2 days) 0  Race (non-black) 01 m3m 6m 12m 18m

Diagnostic Dilemmas Treatment

 Collection of urine  Empiric treatment based on local E. Coli resistance  By catheter for: PO cephalexin safe, tasty, narrow spectrum  Infants < 3 mo of age (high risk)  Ill-appearing/getting antibiotics IV if <2 mo, toxic or not tolerating PO  Consider bag collection for: Total course: 7-14 days (for pyelo)  Low-risk infant (circ boy> 3 mo, girl/boy>1 year)  If UA +, consider cath for culture  Imaging after UTI  Results: U/S in infants <3 mo, older kids if recurrent  + UA: start empiric treatment, send for cx Voiding Cystourethrogram (VCUG) only if high  Neg UA: UTI very unlikely, even in young infants grade VUR/obstruction on U/S  Consider sending for culture in high risk neonate

Roberts 2011;Pediatrics128(3):595–610

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What is Zaffre’s “modified Centor Case Continued score?”

 Xanadu’s 6 yo brother Zaffre also has a A. 1

fever, and is complaining of a sore throat B. 2

 His temp is 38.9, he has tender cervical C. 3 LAN and no cough or runny nose D. 4

E. 5

www.accesspediatrics.com

Modified Centor Score Modified Centor Score

 1 point each:  1 point each: Exudate or swelling on tonsils Exudate or swelling on tonsils?? Tender/swollen ant cervical LN’s Tender/swollen ant cervical LN’s Temp > 38C Temp > 38C Cough absent Cough absent Age 3-14 Age 3-14 ______Max score = 5 Score = 4

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What does this mean? Case Presentation: 3 yo with cough

 What is Zaffre’s prior probability of a +  Amaranth is a 3 yo who presents with 2 GAS culture? weeks of cough, keeps her awake, and

A. ~25% occasional post-tussive vomiting

B. ~50%  She has a PMH of bronchiolitis (6 mo) and is up to date for age on vaccinations C. ~75%  VS: T 38.2, P 130, RR 42, O2 sat 95% D. ~90%  Her mother wants to know if this could be “the whooping cough”

Pertussis Epidemiology

Tdap

Acellular pertussis PERTUSSIS

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Phases of Pertussis Pertussis: Clinical Diagnosis

 Cough lasting >2 weeks + 1of the following: PHASE TIME COURSE DESCRIPTION Apnea* Neonates/young Infants Catarrhal 1-2 weeks Mild fever, cough, rhinorrhea Paroxysms of coughing Paroxysmal 1-6 weeks Older infants/children: Older children Paroxysms, whoop, post-tussive Inspiratory “whoop” emesis Post-tussive vomiting (least specific) Young infants: apnea, cyanosis, bradycardia, poor feeding *May occur without cough Convalescent Weeks-Months Improvement in severity and frequency of coughing episodes

Slide courtesy of Ellen Laves, MD cdc.gov/pertussis

Pertussis: Laboratory Confirmation Pertussis: Treatment

 Lab confirmation ONLY in those with  Major benefits: signs/symptoms consistent with pertussis  Prevent severe disease* in those at risk  Posterior NP specimen (not pharynx/ant NP)  Prevent spread to high risk (HR) patient  Empiric treatment: high suspicion and/or HR  PCR for pertussis  Infants <1 year (< 3mo, preemie at highest risk) False positives may occur  Pregnant women near term  Culture + for B. Pertussis  Unimmunized or underimmunized Most SPECIFIC test  Test and treat if +:  Most sensitive in first 3 weeks  HR but low clinical suspicion  Patient LR but has HR contacts cdc.gov/pertussis *Only treatment BEFORE paroxyms may shorten course

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What is the RECOMMENDED next Case Continued step?

 Amaranth’s vaccination status and non- A. Obtain a PA and lateral CXR specific clinical symptoms make pertussis B. Obtain a blood culture and CBC less likely C. Obtain a sputum culture  However, her RR (42) and O2 sat (95%) make you concerned for pneumonia D. Start PO amoxicillin and discharge with Well-appearing, in minimal resp distress close follow up aside from tachypnea E. Start IV cefuroxime and admit Decreased breath sounds with crackles over the LLL

Pediatric CAP: Diagnosis Bradley JS, et al. Clin Infect Dis. 2011

 Clinical Symptoms of acute illness (ie: fever) + resp distress (tachypnea*, retractions, hypoxia) AND PEDIATRIC COMMUNITY Focal lung findings on exam OR on CXR  Imaging ACQUIRED PNEUMONIA Chest x-ray NOT recommended routinely in outpatients Does not distinguish between pathogens (viral, atypical, etc) *MOST SENSITIVE sign

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Pediatric CAP: Labs Pediatric CAP: Causes Bradley JS, et al. Clin Infect Dis. 2011 Bradley JS, et al. Clin Infect Dis. 2011

 Routine lab testing NOT recommended  Based on age, severity, local resistance  Blood cultures: 2 MO TO 5 YRS: OVER 5 YEARS:  Clinically worsening or hosp with mod/severe disease  Viral testing (flu, RSV)  Viral is most common  M. pneumoniae, C.  IF no evidence of bacterial co-infection  < 2 yrs: S. pneumoniae, C. pneumoniae  CBC/CRP Trachomatis  S. pneumoniae  Not recommended  2-5 yrs S. pneumoniae, M.  Testing for Mycoplasma pneumoniae, S. pneumo pneumoniae, H influenzae,  If available, may guide antibiotic selection C. pneumoniae

Community Acquired Pneumonia:

Treatment Bradley JS, et al. Clin Infect Dis. 2011

st  Inpatient or Outpatient 1 line treatment:  Amoxicillin/ampicillin in infants and young children  Macrolide (azithro) in kids > 5  Ill patent or high-level PCN resistance:  3rd generation cephalosporin if suspect S. pneumo VISUAL DIAGNOSIS  Vancomycin if suspicion for MRSA  +Macrolides if suspicion high for M. pneumoniae and C. pneumoniae

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Toddler with fever, refusing po’s drooling… Examples of “atypical coxsackie”

Hand- foot-mouth disease (coxsackie virus) Pediatrics.aapublications.org Eurosurveillance.org

5 yo comes back from camp with fever, cough and runny nose, then Measles develops rash proceeding head to toe

PHASE TIME COURSE DESCRIPTION Prodromal 2-3 days Fever + 3 C’s: cough, coryza (runny nose), conjunctivitis

Exanthem 3-5 days Erythematous macules proceed cranial -> caudal. May become confluent. Koplik spots

Recovery 5+ days Fever subsides and rash fades

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Measles Fast Facts 9 mo old with high fever for 3 d, fever gone then w/rash on chest head

 Droplet/airborne spread, ~90%  2 doses of vaccine = 97% effective  Dx by serology (IgM or rise in IgG) or PCR  High risk = <5yo or >20yo, pregnant, immunocompromised  Severe/fatal complications:  Encephalitis: 1/1000  Resp/neurologic complication: 1-2/1000  Subacute sclerosing panencephalitis (SSPE): rare  No specific treatment (vit A for severe illness) Roseola infantum Typically caused by Human Herpes Virus (HHV) 6 or 7

10 mo old with rash on day 7 of amoxicillin for AOM Amoxicillin Drug Eruption

 Delayed hypersensitivity (T-cell mediated, Type IV) reaction  Morbilliform, often includes palms and soles, day 5-10 of treatment  NOT a drug allergy, and not associated with advancement to anaphylaxis  Allergy = itchy, urticarial, within hours, may progress • Rash started on day 6 of treatment • Started truncally, spread to head and  May affect up to 10% of pedi pts treated extremities, including palms and soles with amox or PCN • Not itchy, otherwise well  Future use of amox NOT contraindicated

From: Consultant 360

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7 yo with fever, sore throat now with dry, diffuse rash most pronounced 5 yo with temp of 39 for 5 days on trunk and face

Group A Streptococcal “Scarlet Fever”

Kawasaki Disease Unusual color names…

 Unknown etiology (?ID?)  Clinical diagnosis: Fever x5d = 4/5 clinical criteria Amaranth Xanadu  Significance: coronary artery aneurysms Zaffre  Treatment: IVIG Incarnadine “Will all great Neptune’s ocean wash this blood clean from my hand? No, this my hand will rather Falu the multitudinous seas incarnadine, C (conjunctivitis) R (rash) A (adenopathy) S (strawberry H (hands and making the green one red.” tongue) feet)

94 12 3/2/2018

References

1. Greenhow TL, et al. The changing epidemiology of serious bacterial infections in young infants. Pediatr Infect Dis Journal 2014; 33(6): 595-599

2. Roberts KB and the Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.” Pediatrics. 2011;128(3): 595–610

3. Lieberthal, A et al. The Diagnosis and Management of Acute Otitis Media. Pediatrics 2012; 131(3): e964-e999

4. Bradley, J. et al. The Management of Community- Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Disease Society of America. Clin Inf Dis. 2011; 53(7): e25-e76

95 13

96 3/2/2018

Update in diagnosis • I have no disclosures and management of UTIs Brian S. Schwartz, MD UCSF, Division of Infectious Diseases

Lecture outline Case • 27 y/o female presents to your clinic with 4 • Challenges in cystitis days of dysuria and frequency. Denies • Complicated UTI/pyelonephritis vaginal discharge or pelvic pain. Urinalysis reveals: • Asymptomatic bacteriuria – 3+ Leukocyte esterase • Recurrent UTIs – 1+ Heme • Pre-op urine screening – 2+ Nitrite • What do you do next?

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Do you obtain a urine culture? Do you give empiric antibiotics? A.Yes A. No B.No B. Nitrofurantoin x 5 days C. TMP-SMX x 5 days D. Ciprofloxacin x 3 days E. Cefazolin x 7 days

When should you get a urine IDSA guidelines for culture for uncomplicated cystitis? uncomplicated UTI • Uncomplicated UTI: culture not needed Goal: Low resistance, low “collateral damage” – Will likely be susceptible E coli •Nitrofurantoin 100 mg PO BID x 5 days • Culture if… •TMP-SMX DS PO BID x 3 days – Complicated UTIs (pyelo) – avoid if resistance >20%, recent usage – Recurrent UTIs – High local rates of resistance •Fosfomycin 3 gm PO x 1

Hooton TM. NEJM. 2012 Gupta K. CID 2011

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Nitrofurantoin in elderly? Safety of nitrofurantoin • Study of older women (mean age 79) in elderly? – Mean GFR was 38 mL/min • Age > 65 years with Dx cystitis • Evaluated for Rx failure on different abx – Other vs. nitrofurantoin • N=13,421 (2007-12) – 130/1989 (6.5%) vs. 516/3739 (13.8%), CI 0.36-0.53 • Evaluated for nitrofurantoin use ≈ lung injury • However, higher Rx failure in high GFR group too • Nitrofurantoin exposure ≠ lung injury • Cipro more effective than nitrofurantoin in all • Chronic use ≈ lung injury (aRR 1.53 [1.04-2.24]) • Failure rate same for nitrofurantoin vs. TMP-SMX Singh N. CMAJ. 2015 Santos JM. JAGS. 2016

Take home on nitrofurantoin and You start TMP-SMX… Day 2 -Urine culture: > elderly? 100K CFU/mL of enterococcus (S - Amox; R- • May be less efficacious TMP-SMX). Clinical: symptoms a little better • Unlikely dangerous for Rx A. Change to amoxicillin • Danger increase for chronic suppression B. Continue present Rx C.Stop all antibiotics

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Utility of the midstream void culture? Utility of the midstream void culture? • E. coli, Klebsiella, S. saprophyticus • > 200 pre-menopausal women w/ dysuria – Strong correlation (102) with catheter specimen • Midstream void and catheter specimen • Mixed culture (86%) – E. coli often in catheter specimen • Cultures positive • Enterococcus and Group B strep (10% cultures) – 99% midstream – Nearly never found in catheter specimens – 61% had E. coli grew from catheter cultures – 74% catheter specimens • Midstream cultures going to change treatment? Hooton TM. NEJM. 2013 Hooton TM. NEJM. 2013

You start TMP-SMX… Day 2 -Urine culture: > How is guideline compliance? 100K CFU/mL of enterococcus (S - Amox; R- TMP-SMX). Clinical: symptoms a little better A.Change to amoxicillin Quinolones B.Continue present Rx Nitrofurantoin TMP-SMX

C.Stop all antibiotics other

Grigoryan. Open Forum Infect Dis. 2015

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Ciprofloxacin TMP-SMX Dis. 2015 Grigoryan.Open Forum Infect Dis. 2015 Grigoryan.Open Forum Infect

Nitrofurantoin Treatment of complicated UTI Dis. 2015 Grigoryan.Open Forum Infect • Complicated Anyone other than a healthy woman without recurrent infections • Empiric therapy (7-14 days): – Non-pregnant: ciprofloxacin/levofloxacin – Pregnant women: Nitrofurantoin or cephalexin

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Treatment of UTI in men Shorter course of antibiotics many be OK in men with UTI? • Diagnosis: • 39,149 Veterans with UTI – Obtain culture – Assess for STDs (urethritis) • Antibiotic duration • Treatment: ≤ 7 days: 35% (median 7 days) > 7 days: 65% (median 10 days) – Quinolone, TMP-SMX favored – Duration 7-14 days • Veterans who received > 7 days: – If recurrent consider prostatitis – No reduction in recurrences, more C. difficile Drekonja DM. JAMA Intern Med. 2013

Oral antibiotics active against ESBL ESBL trends at UCSF Gram negative pathogens 100

80 n=46

% susceptible isolates % 0 2013 2014 2015 Fosfomycin Nitrofurantoin Doxycycline Cipro Amox-clav

Prakash V. AAC 2009

102 6 3/2/2018

Fosfomycin (Monurol) Catheter-associated UTI • Hard to Dx: • Activity against Gram pos and neg – Bacteriuria common – Often unable to give symptoms • FDA approved for Rx of uncomplicated UTI • Pathogens • Treatment for complicated infections: – More resistant GNRs – Candiduria common, most cases don’t treat – 3 gm (mixed in 4 oz H O) Q2 days for 7-14 d 2 • Treatment – Change Foley – Antibiotics 7-14d Hooton TM. Clin Infect Dis. 2010

Recommended empiric Rx of Empiric treatment of pyelonephritis pyelonephritis in a young woman? • Recommended – Cipro 500 mg PO/IV q12 (Levo ok, not Moxi) A. Ceftriaxone 1 gm IV q24 – Ceftriaxone 1 gm IV q24 • Not recommended B. Moxifloxacin 400 mg IV/PO q24 – TMP-SMX C. Nitrofurantoin 100 mg PO q12 – Nitrofurantoin – Cefpodoxime D. Cefpodoxime 200 mg PO q12 • Health-care associated: B-lactam

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Case What do you recommend? • 65 y/o female w/ DM presents to clinic for routine A. No antibiotics indicated evaluation. She has been feeling well. A urinalysis is sent to look for proteinuria and the lab processes B. Ciprofloxacin and await susceptibilities for culture because bacteria are seen C. Repeat culture in 1 week and if bacteria • UA: WBC-0, RBC-0, Protein-300 still present then treat • The next day you are called because the urine culture has >100,000 Klebsiella pneumoniae

Case What do you recommend? • 65 y/o female w/ DM presents to clinic for routine A. No antibiotics indicated evaluation. She has been feeling well. A UA is sent to look for proteinuria and when the B. Ciprofloxacin and await susceptibilities leukocyte esterase is +++, the lab sends culture C. Repeat culture in 1 week and if bacteria •UA: WBC->50, RBC-0, Protein-300 still present then treat • The next day you are called because the urine culture has >100,000 Klebsiella pneumoniae

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Case 1c: What do you recommend?

• 65 y/o female w/ DM presents to clinic for A. No antibiotics indicated evaluation. Complains of dysuria and frequency. A UA and urine culture are sent. B. Empiric ciprofloxacin and await susceptibilities

•UA: WBC->50, RBC-0, Protein-300 C. Repeat culture in 1 week and if bacteria still • The next day you are called because the urine present then treat culture has >100,000 Klebsiella pneumoniae

Answers: Antibiotics? Definition: Asymptomatic bacteriuria 1a. Asymptomatic bacteriuria, no pyuria – no antibiotics indicated • Bacteriuria without symptoms – Midstream: ≥105 CFU/ml 1b. Asymptomatic bacteriuria, with pyuria – Cath: ≥102 CFU/ml – no antibiotics indicated 1c. Cystitis (symptoms and pyuria) • Pyuria is present > 50% of patients – Antibiotics indicated

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Which patient(s) should be treated for Asymptomatic bacteriuria asymptomatic bacteriuria? Pre-menopausal women 1-5% Pregnant women 2-10% A. Patients with T2 paralysis Post-menopausal women, 50-70 yrs 3-9% Diabetics 9-27% B. Patients > 75 years of age Elderly in LTC facilities (women; men) 15-50% Pts with spinal cord injuries 23-89% C. Patient 1 year post renal transplant Pts undergoing HD 28% Pts with indwelling catheters 25-100% D. Patient undergoing TURP Nicolle. CID. 2005

Who should you treat with Who does not benefit from Rx of asymptomatic bacteriuria? asymptomatic bacteriuria? • Premenopausal (non-pregnant) women • Clear benefit • Postmenopausal women – Pregnant women • Institutionalized men and women – Patients undergoing traumatic urologic • Patients with spinal cord injuries interventions with mucosal bleeding (TURP) • Patients with urinary catheters • Possible benefit • Diabetics • Patients > 3 months post renal transplant – Neutropenic Nicolle. CID. 2005 Asscher AW. BMJ. 1969; Abrutyn E. J Am Soc Ger. 1996;

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Treatment of asymptomatic Asymptomatic bacteriuria in renal bacteriuria in diabetic women transplant recipients • Placebo controlled, RCT (N=105) • > 2 mo post transplant + ASB, N=112 • Diabetic women w/ asymptomatic bacteriuria •1° outcome: Pyelonephritis • Intervention: Antimicrobial vs. placebo x 14d – 7.5% vs. 8.4% (OR 0.88, 95% CI 0.22-3.47) •1° endpoint: Time to 1st symptomatic UTI •2° outcomes: C diff, UTI, MDR infx, • 42% Rx vs. 40% placebo, p=0.42 rejection Harding GKM. NEJM 2003; Cai T. Clin Infect Dis. 2015 – No significance difference

The patient with bacteriuria unable to tell you if they have symptoms? Is asymptomatic bacteriuria protective? • 712 women with asymptomatic bacteriuria Symptomatic UTI (%) Follow-up No Antibiotics Antibiotics Stats • No concern for infection = no treatment 3 months 11 (4%) 32 (9%) NS • Concern for infection exists 1. Always look for other sources (blood, lungs, etc.) 6 months 23 (8%) 98 (30%) p<0.0001 2. If no pyuria, do not treat 12 months 41 (15%) 169 (73%) p<0.0001 3. If candiduria, most cases don’t treat

4. If other source identified, stop UTI treatment Cai T. Clin Infect Dis. 2012

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Is asymptomatic bacteriuria protective? Is asymptomatic bacteriuria protective? • 712 women with asymptomatic bacteriuria • 712 women with asymptomatic bacteriuria Symptomatic UTI (%) Symptomatic UTI (%) Follow-up No Antibiotics Antibiotics Stats Follow-up No Antibiotics Antibiotics Stats

3 months 11 (4%) 32 (9%) NS 3 months 11 (4%) 32 (9%) NS

6 months 23 (8%) 98 (30%) p<0.0001 6 months 23 (8%) 98 (30%) p<0.0001

12 months 41 (15%) 169 (73%) p<0.0001 12 months 41 (15%) 169 (73%) p<0.0001

Cai T. Clin Infect Dis. 2012 Cai T. Clin Infect Dis. 2012

Is asymptomatic bacteriuria protective? 65 y/o woman has had 3 UTIs in the • 712 women with asymptomatic bacteriuria last 6 months. What would be your Symptomatic UTI (%) next step to prevent recurrent UTIs? Follow-up No Antibiotics Antibiotics Stats A. Daily suppressive nitrofurantoin 3 months 11 (4%) 32 (9%) NS B. Intra-vaginal estrogen 6 months 23 (8%) 98 (30%) p<0.0001 C.Cranberry tablets 12 months 41 (15%) 169 (73%) p<0.0001 D.Urology consult Cai T. Clin Infect Dis. 2012

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Recurrent UTIs in women Pathogenesis of UTI in women Prevent vaginal • 20-30% will have a recurrent UTI in 6 mo colonization w/ uropathogens • Risk factors: – Frequent sex, spermicide, new partner

st – Genetic: Age of 1 UTI ≤ 15 yrs; Mother h/o UTIs Prevent growth of uropathogens in bladder – Urinary incontinence Correct anatomic/neurologic Scholes D. JID. 2000; Raz R. CID 2000. problems

Prevention of recurrent UTIs Intravaginal estrogen for UTI prevention? • Prevent vaginal colonization w/ uropathogens How does this work? – Avoid spermicide • Alters vaginal mucosa  promotes lactobacillus – Oral probiotics – Reduced pH inhibits growth of enteric flora – Intravaginal probiotics – Intravaginal estrogen (post-menopausal) • Reverses atrophy of uretheral epithelium • Prevent growth of uropathogens in bladder – Improves bladder emptying • Correct anatomic/neurologic problems

Raz R. JID 2001

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Intra-vaginal estrogen Intra-vaginal estrogen Show me the data! Show me the data! •93 post-menopausal women w/ recurrent UTIs % Colonized with organism •RCT (estriol intrvaginal vs. placebo) Pre-Rx Estriol Placebo –0.5 mg estriol QD x 2 wk  2x/wk x 8 mo Lactobacillus 00 •1° outcome: Recurrent UTIs –0.5 (estriol) vs. 5.9 (placebo) UTI/pt-yr; p < 0.001 Enterobacteriaceae 67 67

Raz R. NEJM. 1993 Raz R. NEJM. 1993

Intra-vaginal estrogen Prevention of recurrent UTIs Show me the data! • Prevent vaginal colonization w/ uropathogens % Colonized with organism Pre-Rx  Post-Rx • Prevent growth of uropathogens in bladder – Increase voiding Estriol Placebo – Methenamine hippurate Lactobacillus 061 00 – Cranberry juice – Postcoitol or daily antibiotics Enterobacteriaceae 6731 6763 • Correct anatomic/neurologic problems

Raz R. NEJM. 1993

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Can increasing fluids reduce UTI risk? Methenamine hippurate

• Premenopausal women w/ recurrent UTI • FDA approved for prevention of recurrent UTI • Randomized: +1.5L/d vs. no change (n=140) • Methenamine formaldehyde • Fluid group: more fluid, voids, reduce urine Osms • Reduced UTIs in women with no renal tract •1° outcome: recurrent UTIs episodes in 12 m abnormalities – RR 0.24, (95% CI 0.07 to 0.89) – 1.6 vs.3.1; OR .52, 95% CI (0.46-0.6), p<0.01 Hooton TM. ID Week. Oct 2017 Cochrane Review. 2012

Cranberry Juice to prevent UTIs Finally put to cranberry to rest… How does it work? • RCT, placebo controlled • Inhibits adhesions produced by E. coli • Subjects: 185 women >64 years • Only vaccinium berries • Intervention: 2 cranberry tabs daily (= 20 oz juice) – Cranberry, blueberry, lingonberry, huckleberry • Outcomes: • Lots of studies done Cranberry Placebo P value Bacteriuria + 29% 29% P=.98 • Many different formulations, many different Pyuria endpoints Sympt UTIs 10 12 NS Raz R. CID. 2004 Juthani-Mehta M. JAMA. 2016

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Postcoital antibiotics Intermittent self-administration of antibiotics TMP-SMX Placebo • RCT in college N=16 N=11 • Healthy women with ≥ 2 UTIs in past 12 mos women • Given sterile cups and Rx for levofloxacin • Intervention: x 6 months • 172 episodes of self-initiation performed –½ TMP-SMX SS vs. – 84% micro confirmed placebo post-coitol 2 (13%) 9 (82%) UTI • Conclusion: self-treatment can be successful Gupta K et al Ann Int Med 2001;135:9 Stapelton A. JAMA. 1990

Continuous antibiotic prophylaxis Prevention of recurrent UTIs • Highly efficacious • Prevent vaginal colonization w/ uropathogens • Studied regimens: – TMP-SMX: 1/2 SS tab nightly or SS 3X/week • Prevent growth of uropathogens in bladder – TMP: 100 mg nightly – Nitrofurantoin: 50-100mg nightly • Correct anatomic/neurologic problems • Associated with antibiotic resistance • 30% have recurrence 6 mo after stopping Nicolle LE. Infection. 1992

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When to evaluate for anatomic abnormalities Management of Recurrent UTIs* in women with recurrent UTIs? Pre-menopausal Post-menopausal • Rads and cystoscopy unrevealing in most cases Avoid spermicide Intra-vaginal estrogen • Red flags suggesting that a urologist is needed Increase fluids (+1.5L/d) Increase fluids (+1.5L/d)

– Hematuria w/o dysuria Methenamine hippurate Methenamine hippurate – Incontinence Post-coitol antibiotics Post-coitol antibiotics – Elevated creatinine – Recurrent Proteus infections (struvite stones) Antibiotic suppression in select cases *Obtain imaging and/or urology evaluation if hematuria w/o Fowler JE. NEJM. 1981; Mogensen P. B J Urol. 1983 dysuria, elevated Cr, incontinence, stones, recurrent Proteus UTI

Does pre-op asymptomatic bacteriuria Summary predispose to prosthetic joint infections? • Nitrofurantoin is 1st choice for uncomplicated • RCT 471 pts for hip replacement cystitis, TMP-SMX ok too • Be aware of ESBL E. coli and limited Rx options •Pyuria+ culture+  randomized • Asymptomatic bacteriuria should be treated in • Treatment vs. placebo for bacteriuria select patients only • Results: • Think about non-antibiotic Rx 1st for recurrent – No reduction in prosthetic joint infections (PJI) UTIs, such as intra-vaginal estrogen, fluids – No correlation of urine culture and PJI organisms

Cordero-Ampuero J. Clin Ortho Relay Res. 2013

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[email protected]

114 18 No financial disclosures HIV in 2018

UCSF’s 39th Annual Advances in Infectious Diseases: New Directions for the Clinic and the Hospital March 14, 2018

Monica Gandhi MD, MPH Medical director, “Ward 86” HIV Clinic, ZSFG Professor of Medicine, Division of HIV, Infectious Diseases, and Global Medicine,

Outline

History of HIV Epidemiology: • Global • U.S. • San Francisco HIV testing: History and Epidemiology • When and how often? HIV Prevention: • Where are we in 2018? HIV Treatment and a glimpse of the Cure • Where are we in 2018?

115 1 First Clinical Descriptions of AIDS ARS: How many people are currently living with HIV worldwide? MMWR

1. 15 million 2. 20 million 3. 30 million 4. 37 million 5. 50 million

Where did it come from?

5 major lineages of primate lentiviruses Where did HIV come from?

HIV – “lentivirus”, subgroup of retroviruses • Lentivirus means SLOW virus (long interval between 1) Chimpanzees; gorillas initial infection and onset of serious symptoms)

2) Monkeys; Mandrills

3) African green monkeys; baboons

4) Sooty mangabeys

5) Sykes’ monkeys Hahn BH. AIDS as a Zoonosis: Scientific and Public Health Implications. Science 2000

116 2 So major types of HIV closest to various SIV How did these viruses get from strains there to here? HIV‐1 HIV‐2

Pandemic 7 subtypes (A‐G) strain (90% of Group M Group N Group O Group P world infections) SIV from sooty SIV from chimpanzees SIV from gorillas mangabeys

First theory – “The River” What was the cross over event? The River: A Journey to the Source of HIV and AIDS (Edward Hooper, 1999) Likely “bushmeat” trade‐ Polish scientist competing hunting primates for food with Sabin for first oral polio Hunters and other highly vaccine (Sabin won) exposed populations: many Scientist (Koprowski) administered his vaccine to 1 SIV strains incorporated million people in Belgium‐ General human population controlled Africa – one cross over event and Likely not reason (wrong primate; wrong timing) but SPREAD due to social led to greater safety with disruption, colonization, city primate cells growth

1Plotkin SA. CHAT oral polio vaccine was not the source of human immunodeficiency virus type 1 group M for humans. Clin. Infect. Dis 2001 Hahn BH. AIDS as a Zoonosis: Scientific and Public Health Implications. Science 2000;

117 3 To know when – we need to go back in When did it get to us? time and get human specimens!

Outbreak in region of origin difficult to 1213 plasma specimens distinguish from tropical diseases from Kinshasa, DRC, UW, Case report (Lancet, 1959) 1959 • 25 year old man (naval seaman) • “Severely emaciated”, “Remorseless anal HIV‐1 found in 1 patient lesion”, pneumonia, ulcer eating into upper (“Bantu male”, ZR59) lip “Phylogenetic analysis” • Post‐mortem revealed cytomegalovirus and • ZR59 and SIV in pneumocystis in the lungs chimpanzees • Pathologists from Manchester Royal • ZR59 and modern human Infirmary (Lancet 1983) said specimens HIV+ strains • Methods questioned, apologies to fiancee’ Estimated HIV entered demanded, no more tissue available humans ~1930 Hahn BH. Science 2000;

The rest is West African history Found another human specimen! No city in region before 1910 had population > 10,000 Lymph node in paraffin found, adult female, Kinshasa (and other) Time to the most populations  in 2nd half of 20th Kinshasa, 1960 “DRC60” recent common ancestor (1884- C. (trade, colonial)

DRC60 very different than 1924) – period of Kinshasa HIV slow growth ZR59 HIV‐1 M from Cameroon brought by traveler down‐river to Family tree constructed, Kinshasa – entered urban sexual rate of mutation City, founding date network and spread calculated By 1960’s, ~2000 people Ancestor of HIV‐1 M infected in Africa probably entered humans x 1000) ( Population 1884‐1924 By 1970s, first probable outbreak in Kinshasa (OIs seen) Worobey M. Direct evidence of extensive diversity of HIV‐1 in Kinshasa by 1960. Nature 455 (October 2008) Worobey M. Nature. 10/08

118 4 What happened from there? Global HIV prevalence in adults, 1985 Carried from West to Eastern Africa in ’70’s Spread fast in E. Africa, epidemic form in early ’80’s • Labor migration (35% truck drivers positive Uganda ’88) • High ratio of men urban centers, sex trade, STDs • Low status of women, low rates circumcision • 85% Nairobi sex workers infected by ‘86) By mid and late ’80’s, on to sub‐Saharan Africa • Tanzam road between Tanzania and Zambia

Piot P. Retrospective seroepidemiology of AIDS virus infection in Nairobi UNAIDS/WHO 1985 populations. Journal of Infectious Diseases 1987

Global HIV prevalence in adults, Global HIV prevalence in adults, 1995 2005

UNAIDS/WHO 1995 UNAIDS/WHO 2005

119 5 When to Begin Treatment for asymptomatic patients - U.S. guidelines – 2012 HIV Infection Prior to 3/12, start when CD4 count <500

ART is recommended for all HIV‐positive individuals

Universal ART policy adopted in San Francisco through HIV Division leadership (Havlir, Hare) and SFDPH January 2010 More than any time in history; 52% women; Children Infected (perinatally) DHHS. Guidelines for the use of antiretroviral agents in HIV‐1 infected adults and adolescents; Available Increased from 110,000 (2015) to 160,000 (2016) at: http://aidsinfo.nih.gov; May 2015

When to Begin Treatment for asymptomatic patients – WHO guidelines– September 30, 2015

HIV Infection Prior to 9/30/15, start when CD4 count <500

ART is recommended for all HIV‐positive individuals

Prioritize CD4 <350 or stage 3, 4; pregnant and breastfeeding women; all children especially < 1 year

World Health Organization. Guidelines on when to start antiretroviral therapy and on pre‐exposure prophylaxis for HIV. September 30, 2015

120 6 ARS: If goal of 90:90:90 is 73% virologic suppression, where are in 2018

1. 44% 2. 55% 3. 66% 4. 73% 5. 84% 6. 100% ‐ the world is right and just

Rates of Adults and Adolescents Living with Diagnosed HIV Infection, by Area of Current UNAIDS targets Residence, Year‐end 2015 — United States and 6 Dependent Areas N = 988,955 Total Rate: 364.3

Note. Data are based on address of residence as of December 31, 2015 (i.e., most recent known address).

Right to Health 12/1/17

121 7 Risks in U.S. cluster with poverty, disempowerment HIV, especially in women clusters with poverty1,2; interpersonal violence3; incarceration4‐7; self‐esteem, alcohol/drugs8

1Amidora. STDs 2006; 2CDC Surveillance 2011; 3Wyatt. Am J Public Health 2002; 4Doherty. JAIDS 2009; 5Doherty. Am J Public Health 2007; 6Adimora. Am J Public Health 2007; 7Khan. J Urban Health 2009; 8Forna. J Natl Med Assoc. 2006

In SF, better outcomes, but not in homeless

Testing and Prevention

SFDPH HIV Epidemiology Annual Report 2016

122 8 What is the most common way that we Case test for new HIV infection in the U.S.?

A 34 year old MSM in San Francisco recently 1. HIV EIA followed by confirmatory Western Blot exited 10 year monogamous relationship 2. Rapid EIA followed by confirmatory Western Blot He was HIV‐negative 2 years ago but hasn’t been 3. HIV RNA level tested since and has had new sexual partners th (insertive, condomless) x 3 over past 2 months 4. 4 generation HIV Ab/Ag test followed by confirmatory/differentiation Needs HIV testing and has heard of the blue pill for protecting himself 5. p24 antigen

Lab‐based 4th generation HIV Test Lab Markers of HIV Infection • Faster, cheaper than RNA Blood sample • Can run individual or batched samples • HIV 1 Antibodies Serologic dynamics of HIV infection • 2H for negative test • HIV1 gp160 (gp120 • 4H if preliminary positive + gp41) • HIV 2 Antibodies • P24 protein (“antigen”)

If +, confirmed by differentiation At SFGH, use immunoassay Architect Ag/Ab followed by Geenius (signal/cut‐off ratio elevated in Architect suggestive of true infection even when Ab negative)

Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014

Family Planning National Training Centers ∙ Supported by Office of Population Affairs Slide courtesy Oliver Bacon MD, Chris Pilcher MD (J Clin Invest); Jensen T. JCM 2015

123 9 U.S. Preventative Services Task ARS: What is the most effective modality Force of HIV prevention in RCTs?

Recommendations changed April 2013 1. Male and female condoms • Routine testing once for everyone age 15‐65 2. Circumcision (“grade A” recommendation) 3. HIV vaccine • Paved way for coverage under ACA 4. Pre‐exposure prophylaxis Repeat testing based for • 5. Treating HIV‐infected individuals Those higher risk for HIV infection Those actively engaged in risky behavior Those living in high‐prevalence setting‐ test and test often Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine, April 30, 2013

What is the most effective modality of Focus on pre‐exposure prophylaxis: HIV prevention in RCTs? PrEP

1. Male and female condoms Giving an HIV‐negative individual a pill (daily, or 2. Circumcision coitally?) to prevent HIV infection 3. HIV vaccine Only agent approved: Tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC) 4. Pre‐exposure prophylaxis Approved by FDA 2012, guidelines by CDC, 5. Treating HIV‐infected individuals recommended by WHO 2015 1. HPTN052 – 96% reduction with treatment 2. Partner Study‐ no transmission if undetectable 3. Opposites Attract‐ no transmission 16,889 condomless sex acts; 343 MSM

124 10 Event‐based or intermittent PrEP IPERGAY Extension Study

TDF/FTC with dosing around the time of sex in MSM 361 MSM; 18 pills/month; 97% reduction in new HIV infections with intermittent PrEP (compared to control arm of IPERGAY RCT) Only if PrEP is taken on by primary % of Adults with PrEP Indicationcare providers can we expand this No. of Adults with PrEP Indication Condomless sex increased from 77% to 86% (STIs didn’t increase, but 30 600,000 have in other studies with PrEP) – Community is doing this!! 24.7 492,000 25 needed prevention tool 500,000 468,000 2‐24 hours before sex: 2 tabs

20 18.5adequately: 400,000 24 hours after 1st dose: 1 tab 15 PrEP advice line at Ward 86: 300,000 (415) 206‐2453 48 hours after 1st dose: 1 tab 10 200,000 157,000 115,000 5 100,000 Monday Tuesday Wednesday Thursday Friday Saturday Sunday 0.2 0.6 0 0 MSM PWID Hetero. Men Hetero. MSM PWID Hetero. Hetero. Ongoing risk: continue 1 tab daily until 48 hours after last exposure Women Men Women Slide courtesy of Catherine Koss MD Molina JM. Lancet HIV 2017.

Being on the Correct Side of History

Treatment and Cure

125 11 The history of ARV approvals- the ascent of the integrase inhibitor and the descent of EFV/Atazanavir Dolutegravir Elvitegravir

WHEN TO DELAY THERAPY

Hardly EVER (TB meningitis, Golconda other space-occupying lesions with inflammation, cryptococcal meningitis)

2012 2013

DHHS Guidelines for the Use of Antiretroviral Ascent of the integrase inhibitor Agents in Adults and Adolescents Living with HIV October 17, 2017 • Three and one imminent

Bictegravir

Dolutegravir

Elvitegravir

Raltegravir

126 12 ARS: What are the brand names of the Currently available SPCs two single pill combinations for Picture of SPC Drugs in SPC Approval Food effects date treatment of HIV coming soon? TDF/FTC/efavirenz 2006 Food  levels (Atripla®) 1. Symuca™ and Juluza ™ TDF/FTC/rilpivirine 2011 Take with solid (Complera®) meal (390kcal) 2. Symtuza™ and Juluca™ TDF/FTC/elvitegravir/ 2012 Take with food 3. DoluRil™ and Darquad™ cobicistat (Stribild®) (373kcal) 4. Symcap™ and Juluca™ ABC/3TC/dolutegravir 2014 Food  levels (Triumeq®) 5. Gesundheit TAF/FTC/elvitegravir/ 2015 Take with food cobicistat (Genvoya®) (373kcal) TAF/FTC/rilpivirine 2016 Take with solid (Odefsey®) meal (390kcal)

SPCs to come out in few months

Dolutegravir/rilpivirine: SWORD trials, for patients to switch to without history of much failure

Darunavir/cobicistat/TAF/FTC: First PI‐based SPC, works with lots of prior resistance

127 13 Cure research initiative

Thank you Strategies being pursued to Diane • Early ART may be curative Havlir MD • Stem cell transplants to reduce reservoir and Division of HIV, • Drugs to flush out HIV from latent reservoirs Infectious • Vaccines to enhance host clearance Disease, and Barriers anticipated Global • Current ART not fully suppressive Medicine, SFGH • No high through‐put reliable assays to examine reservoir • Flush out drugs may not work as monotherapy

128 14 Disclosures

Overview of Hepatitis B & C: I have received research grant support to UCSF Current Concepts and Changing related to HCV from the following: paradigms • AbbVie • Gilead Annie Luetkemeyer • Merck Division of HIV, ID & Global Medicine • Proteus UCSF • ACTG (NIH)

Overview Glossary • DAA: Directly Acting Agents • HCV (i.e. oral HCV drugs) – Screening and selection of patients to treat • Fibrosis Staging: Metavir F0‐F4 – Changing treatment landscape • HCV Genotype: strain of HCV (1‐6), not a drug – Life after HCV cure resistance test • HCC screening • SVR: Sustained virologic response: undetectable HCV • HBV RNA 12‐24 weeks after stopping treating (SVR12= cure – New HBV vaccine in vast majority) – HBV reactivation • APRI: AST:Platelet ratio, provides estimate of fibrosis – New HBV agents • FIB‐4: Fibrosis estimate that includes age, AST,ALT, Plts

https://www.hepatitisc.uw.edu/page/clinical‐calculators/fib‐4

129 1 Your patient

• 30 yo man, HCV Ab+, establishing care with you 3 0‐19 yrs • PMH: depression 2.5 20‐29 yrs

• Meds: paroxetine, Methadone maintenance x 3 years 2 30‐39 yrs with intermittent IDU and smoked methamphetamine 40‐49 yrs 1.5 50‐59 yrs • Social history 60+ yrs – Prior IDU heroin 1 – Alcohol‐ few beers/day, binge drinks on occasion 0.5 Reported cases/100,000 population – Sexually active with men (MSM), condoms use inconsistent 0

Year New HCV infections tripled over 5 years, reaching a 15 year high

Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

HCV screening guidelines • CDC: “Baby Boomers” and those with risk factors HCV Ab+: next steps or exposure • Confirm viremia with HCV RNA • Resurgence of HCV epidemic in young patients. • Screen and vaccinate if lack immunity to HAV & HBV • Reduce alcohol consumption • May be cost effective to offer universal screening • Reduce forward transmission risk – Drug use – avoid sharing needles or nasal straws – Sexual counseling: MSM or HIV infected partner – Household precautions: no shared toothbrushes or razor • Fibrosis Assessment : serologic markers (ex: APRI, Fibrotest) and/or imaging – Impacts decision to screen for HCC and varices – Affects treatment response, choice of therapy, and treatment initiation timeline

CDC HCV Screening guidelines, Barocas CID 2018 • HCV Genotype: 1‐6, determines choice of therapy (for now)

130 2 Case #1 continued ARS Question • Would you offer HCV treatment to this non‐cirrhotic HCV RNA: 3 million IU/ml patient, with ongoing alcohol use & intermittent • Genotype 1a substance use? • AST 35/ALT 33 Alb 3.9. INR 1.1 Platelets 210 1) No, I would not treat until evidence of advanced fibrosis or frank cirrhosis as no benefit • HIV Ab negative APRI= (AST/AST ULN)/Plts 2) No, I am worried about reinfection via MSM route • APRI= 0.4 (suggests non‐cirrhotic) 3) Yes, I would pursue treatment now if he is motivated to be treated • HAV Immune 4) Yes, but only after he demonstrates 6 months of • Hep B S Ab neg, S Ag neg, Core Ab Positive sobriety from speed and alcohol • Ultrasound: no evidence of cirrhosis 5) No, because I can’t get access to HCV medications for my patients

Whom to treat What about alcohol? • Alcohol and HCV are negatively synergistic • Data support successful interferon‐based HCV treatment in active drinkers “Treatment is recommended for all patients with chronic HCV infection, except those with • Benefit of HCV cure despite continued alcohol short life expectancies that cannot be in most patients (Russell 2012, Costenin 2013) remediated by treating HCV, by • Successful HCV cure can be a springboard for transplantation, or by other directed therapy. other positive health changes. Patients with short life expectancies owing to liver disease should be managed in Take-home: Counsel regarding alcohol reduction consultation with an expert.” but don’t withhold treatment due to alcohol use www.hcvguidelines.org alone

131 3 ACLD- advanced ACLD- advanced chronic liver dz chronic liver dz

Backus AASLD 2017 Ioannou AASLD 2 Backus AASLD 2017 Ioannou AASLD 2

Treating Active Injection Drug Users Reinfection: IDU & MSM

OASIS Methadone clinic, HCV PILOT STUDY (n=35) cases  Substantial on- averted treatment substance use  97% SVR in those who completed  NO reinfections at one New HCV cases Liver decompensation Liver transplant year. Sylvestre AASLD 2017 Dore AASLD 2017

Cirrhosis Liver cancer Liver related death • ≈ 96% cure rate in HCV+ methadone clinic attendees, many with active ongoing substance use Jiang AASLD 2017, Dore AIM 2016 Chaillon AASLD 2017

132 4 Reinfection: IDU & MSM California Medi‐Cal Guidelines OASIS Methadone clinic, • PILOT STUDY (n=35) Fibrosis stage 2 or greater  Substantial on- – Many options: Fibroscan, Fibrosure, APRI/FIB‐4, treatement substance use Fibrometer, biopsy)  97% SVR in those who completed Or, any of the following regardless of extent of fibrosis :  NO reinfections at one year. Sylvestre AASLD HIV Coinfection Other liver disease ( e.g. NASH) 2017 Dore AASLD 2017 Diabetes (Type 2) MSM with high risk sexual practices Active injection drug use ESRD on hemodialysis TAKE HOME: Reinfections happen but are not a HCC with life expectancy > 1 yr Women of childbearing age who wish reason to withhold treatment to get pregnant “If you aren’t seeing reinfections, you aren’t treating the high risk populations we have to reach” HBV Coinfection Porphyria cutana tarda pre/post transplant Debilitating fatigue Cryoglobulinemia with vasculitis or renal complications Chaillon AASLD 2017 http://www.dhcs.ca.gov/Documents/Hepatitis%20C%20Policy.pdf

HCV Arsenal & Principals of therapy

www.hcvguidelines.org

133 5 Treatment-Naive Genotype 1a Without Cirrhosis Glecaprevir/Pibrentasvir (G/P) Recommended and alternative regimens listed by evidence level and alphabetically for: Treatment-Naive Genotype 1a Patients Without Cirrhosis • “Mavyret” RECOMMENDED DURATION RATING • Pangenotypic (GT 1‐6)

Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) • 3 pills/once daily 12 weeks I, A for patients without baseline NS5A RASsa for elbasvir • 8 weeks for treatment naïve, non‐cirrhotic (including HIV), Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 12 weeks cirrhotics 8 weeks I, A mg)b • Can be given with CrCl < 30 and in ESRD Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 12 weeks I, A mg) • No need for HCV resistance testing or for ribavirin • Activity against some HCV resistant strains Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 • Do not use in decompensated liver disease(Child‐Pugh Class mg) for patients who are non-black, HIV-uninfected, and whose HCV 8 weeks I, B RNA level is <6 million IU/mL B or C) Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 12 weeks I, A • Least expensive! Wholesale acquisition cost mg) (WAC) of 26,400 for 8 weeks. a Includes genotype 1a resistance-associated substitutions at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance. b This is a 3-tablet coformulation. Please refer to the prescribing information.

Sofosbuvir/Velpatasvir Common Drug Interactions • Check drug interactions • “Epclusa” – University of Liverpool HCV drug interactions • Approved for genotypes 1‐6 • Statins • 1 pill once a day x 12 weeks for most cases • Best for CrCl > 30 (some data to support in renal failure) • Generally do not need HCV resistance testing or • Acid blockers Ribavirin – Avoid altogether with SOF/VEL if possible • Can be used in decompensated hepatic disease • If necessary, do not exceed 20 mg omeprazole, give 4 hours • Side effects: headache, nausea, fatigue after SOF/VEL – All current DAA’s generally well tolerated – Unlikely to be clinically significant interaction with G/P • Wholesale price: $74,760 • Compatible with many HIV regimens as well as methadone and buprenorphine https://www.hep-druginteractions.org/ Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435.

134 6 #3:SOF/VEL/VOX High cures rates attainable in • “Vosevi” previously “special” populations • 12 weeks, one pill daily • HIV+ • For treatment failures (including NS5a • Renal failure including HD failures)‐ high cure rate • Decompensated liver disease • Cannot be used in decompensated liver • Post transplant disease • Active alcohol and substance use

Back to our patient After the cure…

• Insurance approves G/P x 8 weeks • HCV Ab may remain positive for life • You work with his methadone counselor to co‐ – Future HCV screening will need to be HCV RNA administer his HCV treatment with methadone • Counsel about Reinfection • Your pharmacist checks in with him every 2 weeks – Drug use: shared needles, injecting equipment regarding adherence (“works”), straws used for snorting • Week 4 lab check: – Sexual contact through men having sex with men – HCV RNA at week 4 is < limit of detection, LFTs have (MSM): risk highest in HIV+ men but occurs in HIV‐ normalized • If cirrhotic, continue to screen for hepatocellular • 12 weeks after completing treatment, HCV RNA is carcinoma with q 6‐12 month imaging EVEN IF undetectable ‐> Cured! markers of cirrhosis regress.

135 7 HCC Surveillance: U/S +/‐ AFP HCC Surveillance: HCV every 6 months 3. Should we screen in HCV+ pts with F3 fibrosis? • Ultrasound reasonable screening‐ do not need to start Yes! with CT/MRI • Essential to adequately stage fibrosis prior to HCV tx • Rising incidence over past 20 years – Nearly 50% of pts with F3 fibrosis on pre‐treatment Fibroscan – Estimated 39,230 cases and 27,170 deaths in 2016 (≥9.5 kPa) will have post‐SVR Fibroscan <9.5 kPa – Aging HCV+ population, increasing NAFLD – Fibroscan and other non‐invasive fibrosis surrogates have not been validated in post‐SVR pts – Incidence expected to rise until 2030 – Limited evidence comparing post‐SVR biopsy with Fibroscan • High risk groups: shows you will underestimate fibrosis stage if you rely on post‐ – Cirrhosis (any cause) SVR results • 5 UCSF pts with ≥F3 fibrosis on post‐SVR biopsy: 3 (60%) had post‐SVR – Chronic HBV in certain groups. Fibroscan <9.5; 1 of these developed HCC post‐SVR (Price et al , • Observational studies in cirrhosis: screening associated unpublished data) • DON’T stop HCC screening on basis of improvement in with improved survival, detection of early‐stage HCC fibrosis if initially ≥ F3 Heimbach J, AASLD Practice Guidelines, 2017.

HCC Surveillance: Chronic HBV HCC Surveillance: Chronic HBV

Surveillance recommended 1. How should we approach HCC screening in patients HBV Population Group Threshold incidence for Incidence of HCC with HIV/HBV? efficacy of surveillance Surveillance recommended What about Caucasian pts? Cirrhosis 0.2‐1.5%/yr 3‐8%/yr HBV Population Group Family h/o HCC 0.2%/yr Incidence higher than without family history Cirrhosis Asian male >40 years 0.2%/yr 0.4‐0.6%/yr Family h/o HCC Asian female >50 years 0.2%/yr 0.3‐0.6%/yr

African/North American Blacks 0.2%/yr Occurs at earlier age Asian male >40 years Benefit uncertain Asian female >50 years Males <40, Females <50 0.2%/yr <0.2%/yr African/North American Blacks Benefit uncertain Males <40, Females <50

Bruix J, AASLD Practice Guidelines, 2011. Bruix J, AASLD Practice Guidelines, 2011.

136 8 HCC Surveillance: Chronic HBV HCC Surveillance: Chronic HBV

1. How should we approach HCC screening in patients 1. How should we approach HCC screening in patients with HIV/HBV? with HIV/HBV?

Surveillance recommended What about Caucasian pts? Surveillance recommended What about Caucasian pts? HBV Population Group ─ If no cirrhosis and chronic inactive HBV HBV Population Group ─ If no cirrhosis and chronic inactive HBV (long‐term normal ALT, low HBV DNA) (long‐term normal ALT, low HBV DNA) “the incidence of HCC is probably too “the incidence of HCC is probably too Cirrhosis Cirrhosis low to make surveillance worthwhile” low to make surveillance worthwhile” Family h/o HCC Family h/o HCC ─ However… “additional risk factors have ─ However… “additional risk factors have to be taken into account including older to be taken into account including older Asian male >40 years age, persistence of viral replication, co‐ Asian male >40 years age, persistence of viral replication, co‐ Asian female >50 years infection with HCV or HIV, or presence Asian female >50 years infection with HCV or HIV, or presence African/North American Blacks of other liver disease” African/North American Blacks of other liver disease” Benefit uncertain ─ …“Caucasian pts with active HBV are Benefit uncertain ─ …“Caucasian pts with active HBV are Males <40, Females <50 likely at risk for HCC and should be Males <40, Females <50 likely at risk for HCC and should be screened” screened” Bruix J, AASLD Practice Guidelines, 2011. Bruix J, AASLD Practice Guidelines, 2011.

New HBV vaccine Who needs this? • HEPLISAV: HBV • FDA Approved for ≥ 18 yrs old vaccine with an • More injection site reactions adjuvant to • Wholesale price: 230.00 vs. 170‐180.00 for improve response, Standard HBV vaccines given at week 0 & 4 • May be good option for older and/or more immunosuppressed patients • Those in a hurry or at risk for non‐completion: – 2 doses, completed in a month (compared to standard 3 dose, 6 month series) • ? Use in prior non‐responders?

Medical Letter, Issue 1539, 1/18

137 9 Slide 38 HBV Viral Life Cycle

HBsAg pos

Entry Budding ER

HBV reactivation Minus Pl us Reverse Recycling strand transcri ptase strand synthesis synthesis P protein pre- Repair genomic cccDNA S, C, P,e synthesis RNA Nucleus

Transcription Host RNA pol RNA packaging (encapsidation) Transl ati on

Slide 39 Viral Life Cycle- “latent or recovered” HBV Risk of HBV reactivation Immune system considers this “recovered” BUT cccDNA is template for viral replication

HBsAg neg ER Anti-HBs Anti-HBc

cccDNA

Nucleus

• Notably: High dose steroids, rituximab, TNF‐alpha blockers, chemotherapy Bessone WJG 2016

138 10 HBV reactivation with DAA HBV reactivation • FDA warning about risk of HBV reactivation during HCV treatment : 24 cases • Mechanism with HCV treatment‐ ? Viral – none on HBV active treatment before HCV treatment interference • Transaminitis on therapy weeks 4‐8 of HCV – HCV can have known suppressive effect on HBV in treatment dually infected patients – 2 died, 1 transplant, 3 decompensated • Check HBV serologies before HCV treatment or – Transaminitis mistakenly attributed to DAA initially (8) immunosuppressive therapy(HBsAb, sAg, core • Baseline HBV serologies: Ab) – HBV DNA detectable: 7 • Consider adding “HBV Core Ab (+)” to the – HBsAg(+), DNA (‐): 4 – HBsAg(‐), DNA (‐): 3 problem list so not overlooked by other – HBV serologies unknown: 10 providers

http://www.fda.gov/Drugs/DrugSafety/ucm522932.htm CJ Chu Journal of Gastroenterology and Hepatology 23 (2008) 512–520

• Entecavir or Tenofovir preferred over lamivudine for those at higher risk DiBisceglie Hepatology 2015 https://iecho.unm.edu/sites/unm/dow

139 11 Resources HBV: What is on the horizon? • AASLD HBV treatment guidelines: http://www.aasld.org/sites/default/files/guideline_documents/ChronicHepati tisB2009.pdf Mechanism Drug Virus life cycle Entry inhibitors Myrcludex • EASL HBV management guidelines: (antivirals) http://www.easl.eu/_clinical‐practice‐guideline/issue‐8‐april‐2012‐revised‐ Polymerase inhibitors TAF, CMX‐157, AGX‐1009, clinical‐practice‐guidelines‐on‐the‐management‐of‐chronic‐hepatitis‐b Besifovir, Lagociclovir Capsid blockers GLS‐4, NVR 3‐778 • AASLD/IDSA HCV Guidelines: Release inhibitors Rep‐2139, Rep‐2165 http://www.hcvguidelines.org cccDNA cleavage CRISPR/Cas9, TALENS, ZFNs • University of Liverpool HCV Drug interaction (gene editing) database: http://www.hep‐druginteractions.org Transcription ARC‐520, ARC‐521 inhibitors • (RNA interference) Patient education resources Innate immunity GS‐9620, Birinapant http://www.hepatitis.va.gov/provider/hcv/index.asp

Host immune response Adaptive immunity Therapeutic vaccines (GS‐ (immunomodulators) 4774), Engineered T cells

Soriano V, Expert Opin Investig Drugs, 2017.

• Than Backup slides

Thank you!

140 12 HB core Ab HBsAb HBsAg Interpretation Action NEG POS NEG Vaccinated, No Action HBV infection: Dynamic & Lifelong Immune

NEG NEG NEG Not HBV infected Vaccinate for HBV Latent HBV (S Ag negative, POS NEG POS Active HBV • Check HBV DNA core Ab+) infection • Treat HBV according to guidelines (US) • Consider treatment even if low/undetectable HBV DNA (EASL) • Monitor transaminases (q 4 weeks)

POS NEG NEG Possible occult • Check DNA infection • Consider treatment if DNA+ (EASL) • Vaccinate (if DNA negative)

POS POS NEG Immune recovery • Monitor transaminases on therapy • Consider HBV reacvaon if ↑

HBV infection: Dynamic & Lifelong HBV infection: Dynamic & Lifelong

Latent HBV Latent HBV (S Ag negative, (S Ag negative, core Ab+) core Ab+)

• HIGH DNA • HIGH DNA • Normal • Elevated AST/ALT AST/ALT •S Ag+ •S Ag +

141 13 HBV infection: Dynamic & Lifelong HBV infection: Dynamic & Lifelong

Latent HBV Latent HBV • DNA (-) (S Ag negative, (S Ag negative, • Normal core Ab+) core Ab+) AST/ALT

• Low/no DNA • Normal AST/ALT •S Ag+

Indications for HBV treatment

Treat HBV DNA threshold Compensated cirrhotics HBV DNA > 2000 IU

Decompensated cirrhotics Any detectable DNA

Immune Active (E Ag Positive or HBV DNA > 2000 IU, AST > 2x Negative) ULN (DNA threshold varies by guideline)

EASL Guidelines 2012, AASLD Guidelines 2009

142 14 2/26/2018

Disclosures

. I have no disclosures.

Top Curbside Consult Questions in ID

39th Annual Advances in Infectious Diseases March 2018

Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF

Learning Objectives Roadmap

At the end of this talk, you will be able to: . A Brief Word on Curbsides vs. Formal Consults

. Describe the situations in which formal in‐person . Case‐Based Approach to the Top Curbside Consult consultation is preferred over curbside consultation Questions in ID . Outline an approach to common ID questions that arise in the inpatient and outpatient setting

143 1 2/26/2018

Curbsides vs Formal Consults Are Curbsides Okay?

. Need to balance patient safety, provider workload, Curbsides education • Information inaccurate Study of 47 curbsides vs. or incomplete in 51% formal consults . Curbside volume in ID • Medicine consult . In the literature: 20‐120 curbsides/month • Curbside  formal . UCSF Medical Center: 60 curbsides/mo (15 hours/mo) consult by a colleague Formal Consults • Changed Rx in 60% • Curbsided providers (36% “major changes”) . Impossible in most practices to convert all curbsides could not look in chart • If info was into formal consults inaccurate/incomplete then it changed Rx in

92% (45% “major Grace et al, Clin Infect Dis 2010, 51:651. Wachter, B. "The Dangers of Curbside Consults... and Why We Burden et al, J Hosp Med 2013, 8:31. changes”) Need Them."Wachter's World. 29 Apr. 2013.

Is This An Appropriate Curbside? Is This An Appropriate Curbside?

What is the dose of ertapenem when the CrCl is <30? 1. Yes

2. No

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Is This An Appropriate Curbside? Is This An Appropriate Curbside?

1. Yes

2. No

Is This An Appropriate Curbside? Is This An Appropriate Curbside?

Theoretically, if a patient has mild cystitis due to VRE 1. Yes that is sensitive to doxycycline, can I use that drug to treat a VRE UTI? 2. No

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What is an Appropriate Curbside? The Special Case of S. aureus Bacteremia

. The Goldilocks of Curbside Consultation . Benefit of ID consultation versus no consultation . Not too simple: the answer can be easily looked up .adherence to quality indicators for SAB: . Not too complicated: the answer requires nuanced clinical . Getting an echo, repeat blood cultures judgment or interpretation of a lot of data . Improved antibiotic choice and duration . Just right: Hypothetical, factual question .removal of prosthetic devices/source control .detection of metastatic foci of infection . We also tell our ID Fellows that it .mortality (by 20‐50%) should probably be a consult if: . You need to look up the answer . It’s early in the year . The team calls you back several times Saunderson et al, Clin Micro Infect 2015, 21:779. Forsblom et al, Clin Infect Dis 2013, 56:527. Bai et al, Clin Infect Dis 2015; 60:1451. Paulsen et al, OFID 2016. Vogel et al, J Infection 2016; 72:19.

Curbsides for S. aureus Bacteremia? Curbside #1

. Curbside consult is associated with: 55 y/o woman in the ICU after a . Less identification of deep infectious foci complicated spinal surgery. She . Less likely to receive the proper duration of therapy remains intubated, spikes a fever on POD#3 and is pan‐cultured. .90d mortality by > 2‐fold compared to formal consult . She has thick secretions and a new CXR infiltrate. . Formal consult for SAB is preferred if available . Sputum is growing MRSA. . UA (catheter): 11‐20 WBC, Ucx positive for VRE.

Forsblom et al, Clin Infect Dis 2013, 56:527.

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Do You Need to Treat the VRE? Asymptomatic Bacteriuria

1. Yes ASB = (+) urine culture AND no signs/symptoms of UTI

2. No

3. Not sure

Asymptomatic Bacteriuria is COMMON! Hazards of ASB Treatment

. Seen in up to: . Side effects of antibiotics . 25% of elderly, diabetic, or HD patients . 50% of patients in long term care facilities .  risk of Cdiff . 25% of patients with short‐term catheters, ~100% with long‐term catheters .  risk of resistance . Of positive urine cultures obtained on the wards after hospital admission  ~90% are ASB . May increase risk of recurrent UTI by getting rid of “good” interfering bacteria

Nicolle et al, Clin Infect Dis 2005, 40:643. Leis et al, Clin Infect Dis 2014, 58:980 Cai et al, Clin Infect Dis 2012;55(6):771. Cai et al, Clin Infect Dis 2015;61(11):1655..

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Exceptions: Who With ASB Should Be Treated? What About Patients Undergoing Arthroplasty?

. Pregnant women . ASB is not associated with: .risk pyelo, premature delivery . Risk of joint infection from the organism in the urine . Risk of post‐operative UTI . GU procedures w/mucosal bleeding .post‐procedure bacteremia/sepsis . Pre‐op screening and treatment of ASB is not recommended . Immunosuppressed patients? . Renal transplant in the first 3 months? . Neutropenia?

Nicolle et al, Clin Infect Dis 2005, 40:643. Sousa et al, Clin Infect Dis 2014;59:41. Duncan, Clin Infect Dis 2014;59:48. Lamb et al, Clin Infect Dis 2017, 64:806.

The Heart of the Problem How To Distinguish ASB vs. UTI?

. It’s Hard to Ignore a Positive Culture Does the UA help? Does the organism help?

• Only if negative • No, the same organisms . Proof of concept study: • Pyuria is very common in cause ASB and UTI (even . At Mount Sinai, 90% of inpatient urine cultures were ASB, ASB, but the absence of WBC Pseudomonas and ESBL) and 50% were treated with ABx suggests an alternative dx • Always order a UA when . They stopped reporting (+) urine cultures in the EMR ordering a urine culture . Results: . The % of ASB that was treated dropped by 80% . No untreated UTIs and no sepsis Use clinical context: does the patient have signs/symptoms of UTI?

Nicolle et al, Clin Infect Dis 2005, 40:643. Tambyah et al, Arch Intern Med 2000, 160:678. Lin et al, Arch Int Med 2012, 172:33. Leis et al, Clin Infect Dis 2014, 58:980.

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What if I Can’t Assess Symptoms? How to Interpret Urine Studies in a Patient With a Foley or AMS

Alternate Diagnosis Likely? How to define UTI in patients with a catheter or AMS? (Signs/ sx of other illness present)

Yes No Do not order Send U/A, U/A, urine cx urine cx Surrogate signs/symptoms that are No other source of infection consistent w/ UTI AND (i.e., diagnosis of exclusion) U/A, urine cx U/A (+), • Fever, rigors, AMS, malaise U/A (‐), urine U/A (+), urine (‐) cx (+) cx (+) urine cx (‐) • Flank pain, CVAT, pelvic pain • Acute hematuria Do not treat for UTI Asymptomatic Treat for UTI Do not treat bacteriuria (If no alternate dx • Spinal cord injury: spasticity, identified) autonomic dysreflexia, unease

Nicolle et al, Clin Infect Dis 2005, 40:643. Slide courtesy of Catherine Liu.

ASB vs. UTI: Take‐Home Points Curbside #2

. ASB is common, especially in catheterized patients A 75 y/o F with neurogenic bladder and history of prior UTI is admitted with confusion, fever, and a 2d history . Pyuria ≠ UTI, but its absence points to a different source of suprapubic pain and dysuria.

. ASB does not require therapy except for: UA shows >50 WBC/hpf and urine culture grows E. coli. . Pregnancy . Urologic procedures Blood cultures are negative. She improves on empiric . Neutropenia, renal transplant <3 mo? ertapenem and is ready for discharge. Susceptibilities come back and the E. coli is an ESBL producer. . To diagnose a UTI in a patient with a catheter or who cannot report symptoms, the patient must have: Do I need to send her home on ertapenem or are there . Signs and symptoms compatible with UTI . No other source for infection (i.e., diagnosis of exclusion) any oral options?

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Which Oral ABx Has the Best Efficacy in ESBL UTI? Oral Options for ESBL E. coli in the Urine

1. Fosfomycin Antibiotic % Sensitive in vitro Ciprofloxacin 4‐36 2. Nitrofurantoin TMP‐SMX 22‐43 Amoxicillin/Clavulanate 11‐70 3. Minocycline Nitrofurantoin 58‐94 Fosfomycin 91‐100

4. Cephalexin Caveat: susceptibilities for ESBL Klebsiella are lower for both fosfomycin (~54‐80%) and nitrofurantoin (14%)

Prakash et al, AAC 2009, 53:1278. Liu et al, J Micro Immunol Infect 2011, 44:364. Kumar et al, Infect Dis Res Treat 2014, 7:1. Meier et al, Infect 2011, 39:333. Kresken et al, IJAA 2014, 44:295. Fournier et al, Med Mal Infect 2013, 43:62. Rodriguez‐Bano, Arch Intern Med 2008, 168:1897. Linsenmeyer, AAC 2016, 60:1134.

Data for Oral ABx in E.coli ESBL Cystitis (Outpatient) What if the Patient has Pyelonephritis?

. Small study in community‐acquired pyelonephritis Fosfomycin Nitrofurantoin Amoxicillin/clav showing non‐carbapenem = carbapenem • 1‐3 doses  94% cure • 14d  69% cure • 5‐7d  93% cure • No pyelo/bacteremia • No pyelo/bacteremia • MIC not routinely done • Avoid if CrCl<60 . But, non‐carbapenem group: • Dose at 3gm PO qod x 3 . Mostly aminoglycoside or pip/tazo (or improvement) . Had much lower rates of bacteremia

. Bottom line: could consider orals in very select circumstances without bacteremia, but no data

Falagas et al, Lancet ID 2010, 10:43. Rodriguez‐Bano, Arch Intern Med 2008, 168:1897. Pullukcu et al, Int J Antimicrob Agents 2007, 29:62. Reffert and Smith, Pharmacotherapy 2014, 34:845. Park et al, J Antimicrob Chemother 2014, 69:2848.

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Oral Options for ESBL UTI: Take‐Home points Curbside #3

. Most data is for E. coli ESBL (limited data for Klebsiella) A 65 y/o man with ESRD on HD through a tunneled right IJ line is admitted with fever and found to be . For mild‐moderate cystitis: . Oral ABx choice dictated by susceptibilities bacteremic on both line and peripheral cultures with . Consider susceptibility testing for fosfomycin if possible Klebsiella pneumoniae. Line culture turned positive 4 . Caution with nitrofurantoin given poor clinical cure rates hours before the peripheral culture, indicating the line . Would not use orals if the patient is clinically ill, has as the source. He has very poor access options. Do we bacteremia, or cannot be followed closely have to take out the line? . In very select cases of mild pyelonephritis without bacteremia, could consider orals, but there is no data (and can’t use fosfomycin or nitrofurantoin)

Do You Have to Change the Line? CLABSI: Diagnosis

1. Yes, it’s a GNR . Clinical findings at exit site in <3%

2. No, you can consider line salvage . Catheter tip culture: . (+) peripheral bcx and > 15 cfu/plate from catheter tip . 80% sensitive, 90% specific . But >80% of catheters removed unnecessarily

Mermel et al, Clin Infect Dis 2009, 49:1. Safdar and Maki, Crit Care Med 2002, 30:2632.

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CLABSI: Differential Time to Positivity When to Remove the Line

. Allows for diagnosis without removing the line Complicated Infections Virulent Organisms

. Culture from line + peripheral blood at the same time 1. Severe sepsis 1. Staphylococcus aureus 2. Persistent bacteremia 2. Pseudomonas (>72h of appropriate ABx) . CLABSI = blood culture drawn from central line turns 3. Septic thrombophlebitis 3. Candida positive at least 2 hrs before the peripheral culture 4. Exit site or tunnel infection 5. Metastatic infection: . Test characteristics endocarditis, osteomyelitis . 85‐95% sensitive . 85‐90% specific . Not as good for Candida (b/c slow‐growing)

Liñares, Clin Infect Dis 2007, 44:827. Bouza et al, Clin Infect Dis 2007, 44:820. Bouza et al, Clin Microbiol Infect 2013, 19: E129. Safdar et al, Ann Intern Med 2005, 142:251. Mermel et al, Clin Infect Dis 2009, 49:1

Line Management for Other Organisms How to Retain an Infected Line (Line Salvage)

Less aggressive with line removal . Which patients? . Uncomplicated infections Organism PICC/Short‐term CVC Tunneled Cath/Port HD Catheter . Not for exit site infections or virulent organisms Coag‐negative Remove or retain Remove or retain Remove, retain, or . Only studied in long‐term catheters staphylococci guidewire exchange . How to treat? Enterococcus Remove Remove or retain Remove, retain or guidewire exchange . Give systemic ABx + antibiotic lock therapy for 7‐14 d . Get surveillance blood cultures (1 wk after Abx stop) Other GNRs (not Remove Remove or retain Remove, retain or Pseudomonas) guidewire exchange

Use clinical judgment based on: • Severity of infection • Access options (talk to renal!) • Risk of line removal/replacement Mermel et al, Clin Infect Dis 2009, 49:1 Mermel et al, Clin Infect Dis 2009, 49:1

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What is Antibiotic Lock Therapy? Line Salvage with Antibiotic Lock Therapy

. Goal is to get supra‐therapeutic ABx Overall Success Rate (%) Abx Lock Efficacy by Organism (%) concentrations to penetrate biofilms 100 100 90 90 80 . Logistics >90% 80 . Work with pharmacy and nursing 70 70 80% 80% . Mix with heparin, dwell times are variable but usually <48h 60 60‐75% 60 . Common Abx: 50 50 . Gram positives: linezolid, vancomycin, cefazolin 40 40 . Gram negatives: ceftazidime, ciprofloxacin, gentamicin 30 30‐45% 30 40‐55% 20 20 10 10 0 0 Systemic Systemic Line CoNS GNRs S.aureus Abx Abx + Lock removal

Mermel et al, CID 2009, 49:1 Aslam et al. JASN 2014;25:2927. Fernandez‐Hidalgo and Almirante, Expert Rev Anti‐Infect Ther 2014, 12:117. Ashby et al, Clin J Am Soc Nephrol 2009, 4:1601. Beathard, JASN 1999, 10:1045.

What About Guidewire Exchange? Line Management: Take‐Home Points

. Goal is to eliminate biofilm . Physical exam findings are insensitive for diagnosis of CLABSI . How good is it? . Limited data, mostly HD catheters . All lines should be removed for: . Seems at least equal to ABx lock (~70% cure), maybe better . Any complicated infection . Likely better than ABx lock for S. aureus . S. aureus, Pseudomonas, or Candida

. When to use? . Line management for other organisms depends on . If HD catheter removal is clearly indicated but not feasible line type (lower barrier to remove line for short term (especially for S. aureus) catheter > long‐term catheter > HD catheter) . If you want to salvage an HD line but can’t use lock therapy . Use antibiotic lock when possible for line salvage

Robinson et al, Kidney Int 1998, 53:1792. Shaffer, Am J Kid Dis 1995, 25:593. Mokrzycki et al, Dial Transpl 2006, 21:1024. Aslam et al. JASN 2014;25:2927

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Curbside #4 She Should Finish a Treatment Course With:

A 45 y/o woman with diabetes is admitted with 1. Ceftriaxone IV x 14 days pyelonephritis. Her urine and 2 blood cultures are positive for pan‐sensitive Klebsiella pneumoniae. She was treated empirically with ceftriaxone and has improved 2. Ciprofloxacin PO x 14 days (defervesced, normalized her WBC count, resolution of symptoms). 3. Ciprofloxacin PO x 7 days When can she change to PO therapy and how long do we need to treat for? 4. Cephalexin PO x 7 days

I want to use cephalexin because this is the most narrow antibiotic – is this okay?

When is it Ok to Change to PO Therapy? RCTs on Short Course Therapy for Pyelonephritis

. Meta‐analysis of early‐switch (days 1‐4) vs late Study ABx Results Patients Bacteremia Talan et al Cipro 500mg PO bid x 7d Uncomplicated 5% switch (days 7‐10) to PO therapy showed no 2000 superior to TMP‐SMX 1 DS PO pyelo difference in clinical outcome bid x 14d . Studies included beta‐lactams, TMP‐SMX, cipro . Caveat: 6 of the 8 studies were in children Peterson et al Levo 750mg PO qday x 5d = Uncomplicated 2% 2008 cipro 500mg PO bid x 10d and complicated pyelo . Bottom line: when is it ok to change to PO? Sandberg et al Cipro 500mg PO bid for 7d = Uncomplicated 27% . When susceptibilities are known 2012 cipro 500mg PO bid for 14d pyelo . When patient has defervesced and clinically improved

Vouloumanou et al, Curr Med Res Opin 2008, 24:3423. Talan et al, JAMA 2000, 283:1583. Peterson et al, Urology 2008, 71:17. Sandberg et al, Lancet 2012, 380:48.

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Short Course Therapy for Pyelonephritis Treatment Recommendations for Pyelonephritis

. Recent systematic review of short vs long course therapy Uncomplicated Pyelo (IDSA) Complicated Pyelo for pyelonephritis . Fluoroquinolones . No guidelines exist . Cipro 500mg PO bid x 7 days (A‐I) . Patients . Most would treat for 7‐14 days as . Levo 750mg PO daily x 5 days (B‐II) . 8 RCTs, 2515 patients per uncomplicated pyelo . Uncomplicated and complicated pyelo . TMP‐SMX . If urogenital abnormalities, . Most studies compared fluroquinolones . TMP‐SMX 1 DS PO bid x 14 days (A‐I) consider treating for 14 days . 3‐29% of patients bacteremic . Beta‐lactams . Results . Oral beta lactam x 10‐14 days (B‐III) . Short course (≤7d) = long course (>7d) . Lower efficacy than other regimens . If bacteremia would be wary as . Exception: Micro cure rates in short course were lower in pts serum levels will be lower than can w/urogenital abnormalities be achieved with FQ or TMP‐SMX

Eliakim‐Raz et al, J Antimicrob Chemother 2013, 68:2183. Gupta et al, Clin Infect Dis 2011, 52:e103..

PO Therapy for Pyelonephritis: Take‐Home Points Curbside #5

. Ok to change to PO therapy once the patient is improving clinically

. First choice oral therapy is a fluoroquinolone 23 y/o woman with Takayasu arteritis on prednisone . Duration in most cases can be short (≤7 days) with a who needs escalation of immunosuppression to fluoroquinolone infliximab. She has had an indeterminate QuantiFERON (QFT) x 2, negative PPD, and no lung pathology on chest CT. She is US‐born and has no . Duration should be longer with TMP‐SMX (14 days) known TB exposures or other risk factors. Should she and beta‐lactams (10‐14 days) and the latter should be treated for latent TB infection (LTBI)? be used with caution in patients with bacteremia

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An Indeterminate QFT Means: QuantiFERON Interferon Gamma Release Assay (IGRA)

1. Intermediate probability of LTBI

2. Borderline/equivocal result Incubate Measure IFN‐γ by ELISA 3. Low level positive result

1) Nil tube: Negative control 4. The test didn’t work 2) TB antigen tube: • ESAT‐6 + CEP‐10 • Not in BCG or most NTM 3) Mitogen tube: Positive control

Definition of an Indeterminate Assay How Common is an Indeterminate QFT?

. HCWs and TB Screening Programs: 1% Indeterminate = TEST FAILURE . Tertiary care inpatient settings: 20%

Positive control (mitogen) Negative control (nil) had too didn’t work much background IFN‐γ

>85% of indeterminate results

Fabre, Open Forum Infect Dis 2014. Lucet al al, Infect Contrl Hosp Epi 2015, 36:569. Simpson et al, J Immigrant Minorty Health 2013, 15:686.

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Reasons for an Indeterminate QFT Indeterminate QFT and Immunocompromise

Test Factors Patient Factors 70 60 60 . Volume of blood drawn . Immunocompromise . Suboptimal handling impairs ability of T cells to 50 . Delays from blood draw to produce IFN‐γ in response 40 to mitogen incubation step 30 20 20 15 15 10

% indeterminate results 5 1 0 HCWs HIV HIV SLE SOT/HSCT Critical (CD4<100) illness

Cho et al, Lupus 2016; 0:1. Huang et al, Sci Rep 2016; 6:19972. Sester et al, Am J Respir Crit Care Med 2014, Pai et al, Clin Micro Rev 2014, 27:3. 190:1168. Leutkemeyer et al, Am J Respir Crit Care Med 2007, 175:737.

How to Manage Indeterminate QFT? Indeterminate QFT: Take‐Home Point

. If high risk patient  repeat and/or perform a PPD . Indeterminate QFT = test failure due to failure of either the positive (most likely) or negative control . Repeat QFT . May eliminate possibility of lab‐related factors . Many will still be indeterminate (40‐70%) . Consider waiting until CD4 is higher or immunosuppression is decreased

. In a high risk patient, use epidemiologic risk factors, clinical history, chest imaging

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Roadmap Revisited Thanks For Your Attention!

. Remember the Goldilocks Rule for curbsides and . Questions? avoid them in S. aureus bacteremia if possible

. Top Curbside Consult Questions in ID 1. Asymptomatic bacteriuria: Don’t treat (3 exceptions) 2. Oral Abx for ESBL cystitis: Fosfomycin has best data 3. Line management in CLABSI: remove for virulent organisms and complicated infections 4. Oral therapy for pyelo: best data for short course therapy is with fluoroquinolones 5. Indeterminate QFT = test failure

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Disclosures

. I have no disclosures.

Herpesviruses

39th Annual Advances in Infectious Diseases March 2018

Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF

Learning Objectives Roadmap

By the end of this talk, you will be able to: Case‐based approach to: 1. Recognize the key clinical features of the most . HSV‐1 common herpes virus infections. . HSV‐2 (non‐genital infections) . VZV 1. Describe the important principles of diagnosis and . CMV management of common herpes virus infections . EBV

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Case #1 The next best test is:

A 28 year old man presents 1. Throat swab for VZV DFA with fever and severe sore throat after returning from his honeymoon. He has mild 1. Throat swab for HSV PCR anterior cervical LAN and the oral exam shown. The rest of his exam is normal. 2. Throat swab for CMV PCR

Tests for Group A Strep, 3. Tonsillar biopsy to r/o lymphoma acute HIV, and EBV are negative.

Photo courtesy of Matt Russell.

Oral HSV: Primary Infection Case #2

. Children/young adults, HSV‐1 A 30 year old man presents to clinic complaining of “fever . Symptomatic in 10‐30%: blisters” for the past 24 hours. . Gingivostomatitis He has moderate pain but . Pharyngitis/tonsillitis ‐ may not have vesicles! mostly feels a great degree of . Systemic sx (can look like mono) stress and embarrassment . Duration of symptoms 10‐14d about the lesions. This is his 5th episode in the last year. . Oral antivirals  duration of sx . ACV 200mg PO 5x/day x 7 days . Valacyclovir 1gm PO bid x 7 days

Ardino and Porter, J Oral Pathol Med 2008; 37:107. McMillan et al, Pediatr Infect Dis J 1993; 12:280. Ireland, Oxford Dictionary of Dentisty 2010. Cernik et al, Arch Intern Med 2008; 168:1137. Photo courtesy of Laura Pincus.

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Oral antivirals Recurrent Oral HSV: Herpes Labialis

1. Shorten the time for lesions to heal . Almost always HSV‐1 . Recurrences in 20‐40% of HSV‐1 (+) 2. Are effective as suppressive therapy . 1.5 recurrences/year

3. Both #1 and #2 . Triggers: . Fever, URI . UV light exposure (sun) 4. Have no treatment effect . Emotional stress, fatigue . Immunosuppression . Oral/facial surgery or trauma . Menstruation

Cernik et al, Arch Intern Med 2008; 1168:1137. Ardino and Porter, J Oral Pathol Med 2008; 37:107.

Oral HSV Reactivation in Immunocompromised HSV: Diagnostics

*Oral HSV is often a clinical diagnosis. May need to confirm if immunocompromised, severe, atypical, or not responding to Rx.

Test Sensitivity Specifcity Take home points

Culture Vesicle 70‐90% 100% Moderate sensitivity Ulcer 30‐40% Takes 1‐2 days Crusted 20‐30%

DFA Vesicle 70‐90% 99% Rapid (hours) Ulcer 30% Slight  sensitivity c/w culture Crusted 10%

PCR ~90% overall 99% Most sensitive test

Mosely et al, J Clin Microbiol 1981; 13:913. Wald et al, J Infect Dis 2003; 188:1345. Van Wagoner and Hook, Curr Infect Dis Rep 2012; 14:175. Lafferty et al, J Clin Microbiol 1987; 25:323.

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Oral HSV: Treatment Oral HSV: Take Home Points

Episodic therapy . Primary HSV‐1 can be a cause of pharyngitis in young .  time to heal by 0.5‐2.5 days (does not abort lesions) adults (and may not present with vesicles) . Antivirals: . Acyclovir 200mg PO 5x/day x 5 days . HSV PCR of a lesion is the most sensitive diagnostic . Valacyclovir 2gm PO bid x 1 day test for mucocutaneous herpes infections Suppressive therapy .  recurrences by 40‐50% (if ≥4‐6 recurrences/year) . Oral antivirals have a modest treatment effect: they . Not known if can  oral HSV‐1 shedding or transmission can shorten healing time and be used as suppressive . Antivirals: therapy to prevent recurrences . Acyclovir 400mg PO bid . Valacyclovir 500mg or 1000mg PO daily

Cernik et al, Arch Intern Med 2008; 168:1137.

Case #3 What Would You Do With His Antibiotics?

55 year old man is brought in by his 1. Stop acyclovir neighbor for bizarre behavior for 12 hours. He is found to be febrile and has a witnessed seizure in the ED. 2. Change acyclovir to ganciclovir MRI is shown. He is started on vancomycin, ceftriaxone, and acyclovir and is tapped 24 h later. 3. Continue acyclovir

Lumbar puncture: . 50 WBC (89% lymphs), 50 RBC, protein 80, glucose 78 . CSF culture is NGTD . PCR is negative for HSV and VZV

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The HSV PCR May Be Negative Because: HSV Encephalitis

1. He got 24 hours of acyclovir . Epidemiology/Clinical: . Accounts for 10‐20% of encephalitis 2. It’s not a sensitive test . >90% due to HSV‐1, most reactivation (HSV2 rare, in ICH) . Fever, personality change, seizures, focal neuro findings

3. It’s early in the disease course . CSF studies: . WBCs: lymphocytic pleocytosis (median 130 cells) Can be normal in . RBCs: elevated <500 up to 15% . Mildly  protein (median 80 mg/dl), normal glucose

Whitley et al, JAMA 1982, 247:312. Whitley et al, JAMA 1989, 262:234. Tang et al, Clin Infect Dis 1999, 29:803. Domingues et al, Clin Infect Dis 1997, 25:86.

HSV Encephalitis: Diagnosis and Rx HSV Aseptic Meningitis

. CSF PCR: . 1st episode in primary genital HSV‐2 (women>men) . 96% sensitive, 99% specific . May have false (‐) in the first 3d  if suspicion is high re‐tap . Recurrences: . ACV has little effect on PCR (+) within the first 5 days of therapy . 20‐30% of patients will have at least 1 recurrence . Mollaret’s = repeated self‐limited episodes +/‐ skin lesions . MRI: temporal/frontal lobe involvement in 90% . Antivirals needed? . Treatment: . Consider ACV 10 mg/kg q8h or valacyclovir 1gm PO tid x 7‐ . ACV 10mg/kg IV q8h x 14‐21 days 14d (some data for benefit in immunocompromised) . Can check HSV PCR at d14 to define duration . Suppressive therapy not effective to prevent recurrences

DeBiasi and Tyler, Clin Microbiol Rev 2004, 17:903. Tyler, Herpes 2004, 11 Suppl 2: 57A Tyler, Herpes 2004, 11 Suppl 2: 57A. Aurelius et al, Clin Infect Dis 2012, 54: 1304. Berger and Houff, Arch Neurol 2008, 65:596. Noska et al, Clin Infect Dis 2015;60:237.

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HSV Neuro Complications: Take‐Home Case #4

. HSV encephalitis is usually caused by HSV‐1 and 64 y/o man on prednisone affects the frontal/temporal lobes 20mg/d for autoimmune hemolytic anemia presents with a painful progressive rash . CSF HSV PCR is very sensitive for HSV encephalitis: on his left leg in the L4 and L5 . There can be false (‐) within the first 3 days of symptoms dermatomes. . ACV has little effect on sensitivity within the first 5 days He is admitted with concern for disseminated zoster. . HSV meningitis is a complication of primary genital herpes from HSV‐2 and can be recurrent Acyclovir is started but he still has new lesions on day 2

The Most Likely Diagnosis Is: Zoster: Key Clinical Features

1. Disseminated zoster . 80% have prodrome (lasts 2‐3 days)

. New vesicles appear for 2‐4 days 2. Resistant zoster (antivirals  new lesions by 1‐2 days)

3. Uncomplicated localized zoster . Overlap into adjacent dermatomes in 20% (normal variation in innervation) 4. Herpetic whitlow . PHN: pain lasting >3 months after zoster episode, occurs in 10‐20%

Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1.

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To confirm the dx, the most sensitive test is: Cutaneous VZV: Diagnostics

• Zoster is often a clinical diagnosis (~90% accurate). 1. VZV DFA • May need to confirm if immunocompromised, severe/disseminated (e.g., hospitalized), atypical, or not responding to Rx.

2. VZV culture Test Sensitivity Specifcity Take home points

Culture 60‐75% 100% Takes 1‐2 weeks to grow Usually not done

DFA 90% 95% Rapid if in‐house (hours)

PCR 95% 99% Most sensitive test Not always available

Dworkin et al, CID 2007; 44 (Suppl1): S1. Helgason et al, Eur J Gen Pract 1996; 2:12. Kalman and Laskin, Am J Med 1986, 81:775.

Which is the Best Choice to  the Risk of PHN? Zoster Treatment: Antivirals

1. Prednisone . Benefits of therapy .duration new lesion formation by 1‐2 days 2. Valacyclovir .severity and duration of acute pain and rash .risk of PHN (inhibits viral replication, neural damage)

3. Valacyclovir and prednisone . Who to Treat? . ≥50 years, mod‐severe pain/rash, immunocompromised . Consider in all as benefit ( PHN) likely outweighs risk

Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Chen et al, Cochrane Database Syst Rev 2010; Issue 12.

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Timing of Therapy Antiviral Options

. Timing: . Drug options: . All RCTs initiate therapy within 72 hours . Acyclovir 800 mg PO 5x/day, valacyclovir 1gm PO tid . Starting at >72h hasn’t been well studied (?benefit up to 7d) . Duration 7‐10 days . Immunocompromised: treat until all lesions crusted given risk of relapse . If a patient presents at >72 hrs, would still treat if: . Presence of new vesicles (indicates ongoing viral replication) . . Cutaneous, motor, ocular, neurologic complications When to admit patients for IV acyclovir? . . Advanced age, severe pain (since these are risks for PHN) Disseminated disease or CNS/eye complications . . Immunocompromised Severely immunocompromised patients with localized disease (to prevent dissemination) . V1 zoster (VZV ophthalmicus) . Consider in VZV ophthalmicus (V1 zoster)

Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1.

Steroids in Acute Zoster Case #5

. 3 RCTs all show that addition of steroids to ACV: 75 y/o man with well . Accelerated healing, reduced pain, improved QOL controlled HIV presents to . But no decrease in PHN clinic with a rash over his R eye in the V1 distribution . So when to consider steroids? associated with conjunctival . Moderate to severe pain injection. . Facial nerve paralysis . No contraindications to steroid use . Regimen: Prednisone 60 mg/d then taper over 10‐21 d

Wood et al, N Eng J Med 1994; 330:896. Whitley et al, Annals Int Med 1996; 125:376. Esmann et al, Lancet 1987; 330:126. Chen et al, Cochrane Database Syst Rev 2010; Issue 12.

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How Would You Treat Him? VZV Ophthalmicus

1. High dose PO valacyclovir and close follow‐up . Defined as zoster in the V1 distribution

2. Admission and IV acyclovir . Without Rx, 50% will develop eye complications . Conjunctivitis . Anterior uveitis . Necrotizing retinitis . Keratitis . Corneal ulcer . Orbital apex syndrome

Harding et al, Br J Ophthalmol 1987.

VZV Ophthalmicus: Management Case #6

. Ophtho consult for those with: A 59 year old man with SLE on . Eye symptoms cellcept and prednisone (10 . Lesions on the tip or side of the nose mg/day) presents with diffuse vesicular rash. VZV DFA is . Immunocompromised positive and he is started on high dose acyclovir. He still has . Antivirals: new lesions on HD#4. . Treat all patients irrespective of duration of symptoms . Intravenous ACV if immunocompromise Hutchinson’s or eye involvement sign

Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1

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What Would You Do? Disseminated VZV

1. Continue ACV and monitor for visceral involvement . = lesions outside the primary or adjacent dermatomes

2. Change to foscarnet given concern for resistance . Usually immunocompromised, occurs by viremic spread to skin

. Patients may have new lesions for up to 2 weeks Treatment . Patients are at high risk for • Total duration 7‐14 days pneumonitis, hepatitis, DIC • Use IV at least 7 days and until all lesions are crusted

Cohen, NEJM 2013, 369:255. Pergam et al, Am J Transplantation 2013.

Another Complication of VZV: Encephalitis VZV: Take Home Points

. Usually occurs in immunocompromised patients . DFA or PCR are the diagnostic methods of choice for cutaneous zoster . Clinical: . HA, fever, AMS, seizures . Rash present in only 2/3 of cases . Steroids provide no additional benefit to antivirals in  risk of PHN . CSF profile: . Lymphocytic pleocytosis (median 110 cells/mm3) . Admit patients for IV acyclovir if they are severely . Elevated protein, glucose normal to slightly low immunocompromised or have disseminated/CNS . Positive VZV PCR (sensitivity 80‐100%, specificity 98%) . Positive VZV IgG (more sensitive than PCR, especially if chronic) disease

. Treatment: Acyclovir 10‐15 mg/kg IV q8 h for 10‐14 days

Gilden et al, NEJM 2000. Pahud et al, J Infect Dis 2011, 203:316. Tunkel et al, CID 2008, 47:303.

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Case #7 What Antibiotics Should You Start?

47 year old M with no PMH is 1. TMP‐SMX alone admitted with fever and respiratory distress. CT shows prominent GGO. HIV Ab test is 2. TMP‐SMX plus ganciclovir positive and CD4 is 56. BAL is performed and is positive for 3. TMP‐SMX plus acyclovir PCP.

BAL is also positive for CMV 4. TMP‐SMX plus IVIG culture. Plasma CMV PCR is positive at 970 IU/mL.

Approach to CMV Infections Symptomatic CMV in Immunocompetent Patients

Define the Host . Clinical: viral syndrome, abnormal LFTs

. Diagnosis (if testing is done): Immunocompetent Immunocompromised . Positive CMV IgM (but beware false positives) Primary infection Primary or reactivation . Can be elevated for > 4‐12 mo after infection, during reactivation, or polyclonal stimulation (e.g. during acute EBV infection) Asymptomatic or “heterophile • Asymptomatic viremia . Negative or low avidity IgG (‐) mononucleosis” • CMV syndrome • End‐organ disease Diagnosis by serology Diagnosis by tissue biopsy, . Treatment: supportive Supportive Rx only blood PCR, culture Usually anti‐CMV therapy

Navalpotro et al, J Clin Virol 2006; 35:193. Wreghitt et al, Clin Infect Dis 2003; 37:1603. Wreghitt et al, Clin Infect Dis 2003; 37:1603.

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CMV Infection in Immunocompromised Patients CMV End‐Organ Disease: Examples

CMV Infection CMV Colitis • Fever, diarrhea (+/‐ bloody), abdominal pain

Asymptomatic CMV Syndrome End‐Organ Disease Viremia

Asymptomatic Fever plus bone • Neuro: Encephalitis, Retinitis marrow suppression • Pneumonitis (leukopenia and/or • GI: Colitis>Esophagitis thrombocytopenia) • Others: hepatitis, nephritis, CMV Pneumonitis myocarditis, pancreatitis • Fever, mild to severe Plasma CMV PCR (+) Plasma CMV PCR (+) Plasma CMV PCR (+) respiratory failure (GI can be compartmentalized) Treatment depends Treat all patients Treat all patients on host

CMV in HIV+ Patients CMV Treatment

. Asymptomatic viremia in up to 35% pts w/CD4<200 . IV vs PO? . IV ganciclovir if severe infection, high viral load (e.g., >1 million copies/mL), poor oral absorption . Most common end‐organ disease: . PO valganciclovir okay for mild‐moderate disease . Retinitis . GI (colitis > esophagitis) . How long to treat? . Pneumonitis is rare: BAL+ for CMV in ~50% of . 2‐3 weeks and until PCR negative (check weekly) patients (without CMV pneumonitis) . May consider secondary prophylaxis in selected patients

Durier et al, Clin Infect Dis 2013;57:147. Deayton et al, Lancet 2004; 363: 2116. Hayner et al, Chest 1995;107;735. Miles et al, Razonable et al, Am J Transplant 2013; 13:93. Asberg et al (VICTOR study group), Am J Transplant 2007; 7:2106. Chest 1990;97;1072. CDC/NIH/HIVMA Guidelines for the prevention and treatment of OIs in HIV‐infected adults, 2015.

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Case #8 Review Question: What is the Diagnosis?

57 year old woman s/p renal transplant 4 months 1. Asymptomatic CMV viremia prior who has been off her CMV prophylaxis (valganciclovir) due to leukopenia. She presents to 2. CMV syndrome clinic with fatigue and fever to 39.1 and is found to have pancytopenia. She has no other localizing signs/symptoms. 3. CMV end‐organ disease

Labs: . WBC 1.0 (previously 2.5) . Platelets 81 (previously normal) . CMV viral load in the plasma is 56,000 IU/mL

CMV: Take‐Home Points Case #9

. Define your host: immunocompetent or 22 y/o woman presents with fever, sore throat, and immunocompromised (HIV vs transplant/other) cervical lymphadenopathy for 2 days. Heterophile antibody test is negative. . Determine which type of CMV infection your patient has: . Asymptomatic viremia . CMV syndrome . End‐organ disease

. HIV+ patients are a special category: . Commonly have asymptomatic viremia . Can have severe end‐organ disease (retinitis, GI most common) . Rarely have pneumonitis despite frequent +BAL for CMV

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The Sensitivity of Heterophile Ab in 1st Week is: Case #10

A 28 year old man with no PMH is admitted with fever 1. 25% to 39.6, diffuse lymphadenopathy, and pancytopenia. 10 days prior he had a sore throat (now resolved) for 2. 50% which he was prescribed azithromycin.

3. 75% His EBV testing is as follows: ‐ Monospot positive 4. >90% ‐ EBV IgM negative, IgG positive ‐ EBV PCR negative

The Most Likely Diagnosis is: EBV

1. Acute EBV infection (Mononucleosis) . 75% of US is seropositive by age 18

2. Prior EBV infection and a different acute process . Clinical: . Incubation period 4‐6 weeks . <18 y/o: Most are asymptomatic or nonspecific illness . >18 y/o: Most are symptomatic . Infectious mononucleosis = classic triad of sore throat, cervical lymphadenopathy, fever

Balfour et al, J Infect Dis 2013; 207:80.

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Diagnosis of IM: Heterophile Antibody (Monospot) Diagnosis of IM: EBV Serologies

X‐reactivity EBV IgM IgM IgG IgG + (VCA) VCA VCA EBNA EBV IgG (VCA) Acute ++/−− Infection Prior Patient’s blood: IgM Sheep or horse EBV IgG −+ + Agglutination Infection against viral antigens RBCs (EBNA)

• Sensitivity 85‐90% st st . Sensitivity: 90‐95% after 1 week, but only 75% in the 1 week • Specificity >95% . Specificity: 94%. False (+): infections (CMV, Toxo, acute HIV), malignancy, autoimmune (SLE) Weeks . *No longer recommended by the CDC given false (+) and (–)*

Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Luzuriaga and Sullivan, N Engl J Med 2010; 362:21.

Diagnosis of IM: EBV PCR Diagnosis of IM: CBC with Differential

. Not a lot of data . Absolute lymph count > 4,000 x 106/L . Sensitivity 84% . Positive early on, usually undetectable by week 3 . Specificity 94%

. 2016 meta‐analysis of 4 small studies in kids/young . Atypical lymphs >10% adults: . Sensitivity 75% . Pooled sensitivity: 80% . Specificity 92% . Pooled specificity: 95%

. May be helpful when other tests are inconclusive

Jiang et al, J Med Virol 2016; 88:871. Berth et al, J Clin Virol 2011; 50:184. Bauer et al, J Med Virol 2005; 75:54. Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Vouloumanou et al, Curr Opin Hematol 2012; 19:14. Biggs et al, Laryngoscope 2013, 123:2401.

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Complications of EBV Infection Mononucleosis: Treatment

. Hematologic 25‐50% . Neurologic 1‐5% . Steroids?  Not for all, maybe in select cases . Hemolytic anemia . Guillain–Barre syndrome . Cochrane review 2015: “insufficient evidence to the . Thrombocytopenia . Facial paralysis efficacy of steroids for symptom control…lack of research . Aplastic anemia . Aseptic meningitis on the side effects and long‐term complications” . TTP/HUS . Encephalitis . Consider short course to treat severe complications (e.g., . DIC . Transverse myelitis upper‐airway obstruction) . Trigger for HLH . Peripheral neuritis . Splenic rupture . Optic neuritis . Antivirals?  NO, multiple RCTs show no benefit

Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Rezk et al, Cochrane Database Syst Rev 2015, issue 11. Balfour et al, J Clin Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Virol 2007; 39:16.

EBV Take Home Points Thank You!

. Monospot testing can lead to false negatives and . Questions? false positives and is no longer a recommended test

. Serology is 85‐90% sensitive

. PCR is positive early on with overall 80% sensitivity

. Lymphocytosis and atypical lymphs can be an important clue to diagnosis

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Respiratory Viral Infections: Disclosures Focus on Influenza • Roche Molecular Diagnostics Advances in Infectious Diseases • Spouse is consultant March 2018

Bryn A Boslett, MD Division of Infectious Diseases University of California, San Francisco

Outline Case 1

• Respiratory viral illness overview 34yo woman with history of migraine presents to clinic in June with “cold symptoms” for 2 days – runny nose, watery eyes, mild cough and sore • Influenza throat. Exam remarkable for temp 100.4F (38C), rhinorrhea, clear lungs. • Clinical presentation What is the most likely etiology? • Diagnostics • Treatment 1. Group A Strep (GAS) • Prevention 2. Influenza • Respiratory syncytial virus 3. Respiratory syncytial virus (RSV) • If there is time! 4. Rhinovirus 5. Seasonal allergies 3

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Epidemiology of Respiratory Viruses Respiratory Viral Comparison

20 Winter Spring Summer Fall Rx Adenovirus 18 Influenza Influenza NAIs 16 PIV 14 RSV Ribavirin + IVIG * RSV 12 Rhinovirus 10 Parainfluenza None

# of Patients # of 8

6 Adenovirus Cidofovir*

2 Rhinovirus None

0 Coronavirus None * = immunocompromised

Teichtahl et al. Chest.1997;112:591-596.; Marx et al. Clin Infect Dis.1999;29:134-140.; Couch et al. Am J Med. 1997;102:2. (MDACC); slide courtesy of Michael Ison, MD and Catherine Liu, MD Ruuskanen et al.Lancet. 2011 Apr 9;377(9773):1264-75.

Case 1 continued… The Case for antibiotic stewardship

What is your next step? • Overuse of antibiotics is the single most important driver in antibiotic resistance 1. Obtain a CXR • Most antibiotics prescribed in the US are for acute respiratory tract infections – many of 2. Obtain respiratory virus testing which do not require antibiotics 3. Obtain a rapid strep test for GAS • Physician and patient education, computerized 4. Start antibiotics (azithro, doxycycline, etc) clinical decision support, and financial 5. Supportive care recommendations incentives have historically produced only modest reductions in prescription rates

JAMA. 2009;302(7):758-766; JAMA Intern Med. 2013;173(4):273-275.

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Outpatient antibiotic use, 2000 - 2010

• Broad-spectrum antibiotic prescriptions doubled, 2000 – 2010 • 30% of prescriptions deemed unnecessary

Nature 472, 32 (07 April 2011); doi:10.1038/472032a Shapiro DJ et al. J Antimicro Chemotherapy, 2013.

RVP for Antimicrobial Stewardship? Procalcitonin (PCT)

• Prospective observational study in Montreal, Canada • Peptide released from cell during • 800 inpatients with respiratory symptoms were tested by a 12- bacterial infections virus respiratory panel (RVP) over 3 consecutive winters – Correlated with infection severity – Assay takes ~30 min to run • Primary endpoint: change in antimicrobials • Results: RVP turn-around time was <24 hours. 53% positive for • Two main uses found to be influenza; 10% for other viruses. effective in studies: • Positive RVP for influenza correlated antibiotic de-escalation, – Prevention of initiation of but results not significant. Other viruses had no impact. antibiotics (outpatient/ED) – Shortened duration of antibiotics • Suspicion of pneumonia on chest radiography was only (ICU) significant correlation – Most data exists for respiratory J. Clin. Endocrinol. Metab. 79 (6): 1605–8. tract infections Lindscheid P et al. Endocrinology 2003; 144:5578‐84. Semret, M et al. J Infect Dis. 2017 Nov 15;216(8):936‐944. doi: 10.1093/infdis/jix288. Christ‐Crain M, Mueller B. Swiss Med Wkly 2005; 135: 451‐460.

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PCT effect on antibiotic prescribing Case 2

68yo man with history of diabetes presents to clinic in January Setting Abx initiation Abx duration, days complaining of fever, cough and malaise. Temp of 102.2F (39C), HR 100, median (IQR) other VS normal. His lungs are clear. What is your next step? Overall 64% vs 84% 7 (4–10) vs 10 (7–13) Outpatient* 23% vs 63% 7 (5–8) vs 7 (6–8) 1. Obtain respiratory virus testing ED 73% vs 88% 7 (4–10) vs 10 (7–12) 2. Obtain a CXR ICU 100% vs 100% 8 (5–15) vs 12 (8–18) 3. Start oseltamivir (Tamiflu®) 4. Start antibiotics (azithro, doxycycline, etc) *Mainly trials of URI, bronchitis, COPD exacerbation 5. All of the above

Mitsuma SF et al. Clin Infect Dis 2013; 56(7):996-1002 6. Some combination of the above Schuetz P etal. Arch Int Med 2011; 171(15):1322-31

Epidemiology of Respiratory Viruses You decide to order a diagnostic assay

20 for viral infection. Adenovirus 18 Influenza 16 PIV The best possible test would be: 14 RSV 12 Rhinovirus 1. Direct fluorescence antibody (DFA) 10

# of Patients # of 8 2. Rapid antigen detection 6 3. Respiratory viral PCR 4 4. Viral culture 2

Couch et al. Am J Med. 1997;102:2. (MDACC); slide courtesy of Michael Ison, MD and Catherine Liu, MD

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Diagnostics Comparison Diagnostic sampling

• Upper tract samples: Viral Culture PCR DFA Rapid Ag -NP aspirates or swab > nasal swab > throat swab -Collect samples preferably within 5 days of onset (shedding is after 5d) Sensitivity +++ +++ ++ + • Lower tract samples: Turn‐around Slowest Fast Fast Fastest -Collect both upper and lower tract specimens in critically ill patients! -Lower tract can be (+) even if viral shedding is no longer detectable in the upper tract

Case 2 continued… Radiology Findings: NOT diagnostic!

You send an NP swab for rapid antigen detection AND a respiratory viral PCR, which will take two days. You also obtain a CXR, shown here.

Viral infections come with diverse CXR possibilities: normal, consolidation, diffuse infiltrates, etc 20 www.radiology.vcu.edu

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Case 2 continued… Based on what we know about this current influenza season, what is the most likely influenza subtype in The rapid antigen test is negative for influenza A and B. Your next step: our patient?

1. Azithromycin x 5 days 1. Influenza A (H1N1)pdm09 2. Oseltamivir while awaiting full PCR result 2. Influenza A (H3N2) 3. Send home with strict return instructions 3. Influenza A (H7N9) 4. Send to the ED for admission 4. Influenza B

Two days later, respiratory PCR (+) for influenza

H3N2

FluView, CDC, accessed FEB 18, 2018. FluView, CDC, accessed FEB 18, 2018.

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Questions I’ve been asked about influenza Vaccine Effectiveness (VE), 2017-18 season this year… • Interim VE estimates of 17% from Canada, 10% from Australia 1) I heard that the flu shot didn’t work this year. Should I • In US, 4,562 children and adults with acute respiratory illness enrolled still be vaccinated? during November 2, 2017–February 3, 2018, at five outpatient study sites • Overall interim vaccine effectiveness of the 2017–18 seasonal influenza vaccine for preventing medically attended, laboratory-confirmed influenza virus infection was 36% – 25% for A(H3N2) – 67% for A(H1N1)pdm09 – 42% for influenza B virus • Protection rates higher for children 6mo – 8yo (VE = 59%) • Data limited to outpatient setting (ie, less severe cases)

25 Flannery B, Chung JR, Belongia EA, et al. Interim Estimates of 2017–18 Seasonal Influenza Vaccine Effectiveness — United States, February 2018. MMWR Morb Mortal Wkly Rep 2018;67:180–185.

Questions I’ve been asked about influenza Effect of Prior Vaccination? this year… • Prior studies have suggested that prior-season vaccination may influence the effectiveness of current-season vaccination 1) I heard that the flu shot didn’t work this year. Should I • Meta-analysis of 20 observational studies including data on vaccine still be vaccinated? effectiveness for four vaccination groups: current season only, prior YES!!!!! season only, current + prior season, and neither season • Patients vaccinated in both season had 25% higher VE for H1N1, but only no significant difference for H3N2 • No change in VE for patients vaccinated in one season versus both • Patients receiving vaccine in either or both seasons had increased protection against all strains of influenza compared to those with no vaccination

Ramsay, LC. BMC Med. 2017 Aug 21;15(1):159. doi: 10.1186/s12916‐017‐0919‐0; McLean HQ, et al. Clin Infect Dis. 2014 Nov 15;59(10):1375‐85. doi: 28 10.1093/cid/ciu680. Epub 2014 Sep 29.

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Questions I’ve been asked about influenza How is influenza spread? this year… • 142 confirmed cases of influenza in college students • Examined 30 mins of natural 2) Besides the vaccine, what else can I do to avoid getting breathing, prompted speech, sick? spontaneous coughing and sneezing on day 1, 2 and 3 after symptom onset • Assessed the infectivity of detected influenza RNA in aerosols

29 30 Yan J, et al. Proc Natl Acad Sci U S A. 2018 Jan 30; 115(5): 1081–1086.

Results - Aerosolized transmission may be a risk Questions I’ve been asked about influenza this year… • Infectious virus detected in 39% of fine-aerosol samples collected during 30 min of normal tidal breathing 2) Besides the vaccine, what else can I do to avoid getting • Cough was prevalent and was a strong predictor of virus sick? shedding into both coarse and fine aerosols. -Tell friends/family/colleagues to STAY HOME • BUT, cough was not necessary for infectious aerosol when ill -Avoid sick contacts generation (culturable virus found in half of all cough-free -Wash hands frequently samplings). -Wear N95 mask? -Consider NAI prophylaxis if clear exposure history AND high-risk patient (more later…)

31 32 Yan J, et al. Proc Natl Acad Sci U S A. 2018 Jan 30; 115(5): 1081–1086.

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Case 3 Complications of Influenza

You are paged regarding a patient of yours who was admitted overnight to • Influenza viral pneumonia the ICU. He is a 72M with COPD who had fevers and cough x 1 week, now positive for influenza A by rapid testing. In addition to broad-spectrum • Common in those hospitalized with influenza antibiotics, you would recommend: • Severe! Up to 20% mortality

1. No antiviral treatment – he is outside • Secondary bacterial pneumonia of the treatment window • Difficult to distinguish clinically 2. Oseltamivir 75 mg PO BID x 5 days • Influenza “primes” lung tissues for bacterial superinfection 3. Oseltamivir 150 mg PO BID x 10 days  direct viral damage, disrupts mucus barrier, upregulates adherence receptors 4. Peramivir 600 mg IV x1 • S. pneumoniae, S. aureus > S. pyogenes > H. influenzae, gram (-) rods 5. Zanamivir 10 mg inhaled BID x 5 days

Chertow and Memoli, JAMA 2013, 309:275. MMWR 2009, 58:1. Jain et al, Clin Infect Dis 2012, 54:1221.

Available treatments for Influenza Neuraminidase comparison

• Adamantanes: amantadine, rimantidine • M2 ion channel blockers – prevents viral uncoating Drug Adult dose Renally Intubation Contraindictions Adverse effects adjust? OK? • Influenza A only Oseltamivir 75mg PO Q12 Yes Yes None N/V (10%), • Resistance widespread = Not Reliable x 5d headache • Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir Zanamivir 10mg INH No No Resp disease Cough, Q12 x 5d (COPD, asthma) bronchospasm • Drugs of choice Peramivir 600mg IV x1 Yes Yes None Diarrhea (8%), • Active against A + B neuropsych • Resistance low (~1%) since 2009

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Conflicting Data Timing, Duration, Dose

• Multiple observational trials show  illness duration, hospitalizations and • Greatest benefit ≤ 48 hrs, but potential benefit > 48 hrs pneumonia for all groups with NAIs • 48 hrs chosen based on healthy outpatient data • 2014 Cochrane meta-analysis: No impact on hospitalization, not enough data • Observational studies: Antivirals improved outcomes up to 5 days after on complications. Excluded many high-risk groups. symptom onset However… • 2015 meta-analysis (most complete data from manufacturer): •  duration of illness by ~24 hrs for laboratory-confirmed infection •  antibiotic prescription for lower respiratory tract infection (8.7 vs 4.9%) •  risk of hospital admission for any cause (1.7 vs 0.6%)

Jefferson et al, Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965. Dobson et al, Lancet 2015, Jan 29.; Kelley and Cowling, Lancet 2015, Jan 29.; Kaiser et al, Arch Intern Med 2003, 163:1667. Kumar AJT 2009; Casper Blood 2010; SE Asian CID Network BMJ 2013; Lee CID 2013

Survival by Time of Antiviral Initiation, 2009 Timing, Duration, Dose H1N1 Pandemic, California •2 RCTs in 2013 of high vs regular dose oseltamivir x 5d: •Hospitalized kids or adults, immunocompetent, almost all non-ICU •Results: No difference in mortality, ICU admission or intubation, LOS

•2015 retrospective study in 124 ICU patients with influenza: •Patients in the high dose group were sicker at baseline Start Rx while awaiting test results! •No benefit of high dose

•2016 retrospective study in 57 ICU patients with influenza: •Patients in high dose group were sicker •No difference in duration of ventilation, ICU or total hospital LOS *p <.05

Louie J CID 2012; 55: 1198-204 Noel et al, J Intens Care Med. 2016 Mar 18. Welch et al, Intens Care Med 2015; 41:1365.; SE Asian CID Network BMJ 2013; Lee CID 2013

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Influenza Treatment Summary High risk of complications • Who to treat? – All inpatients, and outpatients at high risk of complications • All inpatients – For these high risk groups, treat irrespective of duration of symptoms, as early as • Outpatients with severe disease, or at risk for complications: possible, and do not delay therapy while awaiting lab confirmation • Ages <2 or >65 • Chronic disease (cardiopulmonary, diabetes, liver or kidney • Which drug? disease, etc) – Oseltamivir: drug of choice for most patients • Immunocompromised – Zanamivir: only if no COPD/asthma and not intubated • Pregnant or recent post-partum – Peramivir: if need an IV option • American Indians/Native Alaskans • Morbidly obese (BMI ≥40) • How long? • Residents of chronic care facilities – 5 days for most – Consider 10 days based on severity of illness 41 CDC, Influenza Antiviral Medications: Summary for Clinicians, January 9, 2015.

Hung IFN et al. Chest. 2017 May;151(5):1069‐1080. doi: 10.1016/j.chest.2016.11.012. Adjunctive treatments for influenza

• Prospective open‐label, randomized, controlled trial of clarithromycin‐naproxen‐oseltamivir 30‐day Mortality combination vs usual course of oseltamivir in confirmed influenza A(H3N2) infection • Patients also received 5 days Amox/clavulenate • Primary end point: 30‐day mortality Mean Viral Titer • Secondary end points: – 90‐day mortality – Serial nasopharyngeal aspirate virus titer – Percentage of NAI resistant quasispecies – Pneumonia severity index (PSI) – Duration of hospital stay

– Admission to ICU Pneumonia Severity Index

Hung IFN et al. Chest. 2017 May;151(5):1069‐1080. doi: 10.1016/j.chest.2016.11.012. Days After First Dose

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Hung IFN et al. Chest. 2017 May;151(5):1069‐1080. doi: 10.1016/j.chest.2016.11.012. Questions I’ve been asked about influenza Results and Limitations this year… • Combo rx associated with lower 30d and 90d mortality, lower PSI, fewer resistant viral quasispecies, shorter hospital stay 3) I know I’ve been / will be in contact with someone with • No change in ICU admission, 30d re-admission, or d/c to skilled nursing unit influenza. Can I take something preventative? Scary! • No significant adverse effects reported • Limitations: single center, elderly, hospitalized, onset <72h prior, small sample

Outcome Event Rate RRR (95% CI) NNT (CI) Triple Rx Oseltamivir 30-day 0.9% 8.2% 89% (32-98) 14 (8-49) Mortality 90-day 1.9% 10% 81% (27-95) 13 (7-48) Mortality ICU 1.9% 6.4% 71% (-21-93) Not significant admission 46

NAIs for Prevention? Systematic analysis of NAIs for prevention

• 1. Large tertiary university hospital – Outbreak of 97 cases of flu-like illness in 5 days (48 PCR confirmed) – All hospital workers received full-course NAI (3702 workers) – Mathematical modeling showed reduced infection rate (only 7 new cases) – Several other interventions occurred - isolation, mandatory leave, etc. • 2. Systematic review: 4 meta-analyses examined – Included pre- and/or post-exposure prophylaxis – Settings varied (household transmission, long-term care facilities) – NAIs consistently lowered the odds or risk of symptomatic influenza in all studies.

1. Hagihara M, et al. Intern Med. 2018;57(4):497‐501. doi: 10.2169/internalmedicine.8854‐17. 2. Doll MK, et al. Antimicrob Chemother. 2017 Nov 1;72(11):2990‐3007. doi: 10.1093/jac/dkx271. 1. Doll MK, et al. Antimicrob Chemother. 2017 Nov 1;72(11):2990-3007. doi: 10.1093/jac/dkx271.

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https://www.cdc.gov/flu/professionals/antivirals/summary -clinicians.htm. Accessed Feb 21, 2018. NAIs for Prevention CDC Guidance

• Prophylaxis recommended if: • 3. Study of adverse effects of prophylaxis: – Known exposure to case of influenza within past 48 hours, AND – Single-center study – At high risk of complications during the first two weeks following vaccination – 540 medical staff received NAI post-exposure prophylaxis – Severe immune deficiencies who might not respond to influenza vaccination – Of 411 survey respondents, 22.5% reported adverse effects (GI – Unable to receive vaccination safely upset, headache most common) – Dose is daily, not BID, for 7 days after last known exposure

• CDC guidelines: “In general, CDC does not recommend antiviral • Institutional outbreaks (long-term care homes, hospitals): chemoprophylaxis, but antiviral medications (oseltamivir, zanamivir) may – Continue antiviral chemoprophylaxis for a minimum of 2 weeks, and up to 1 be to prevent influenza in certain situations” week after the last known case was identified. – Antiviral chemoprophylaxis is recommended for all residents, including those 3. Kato H, et al. J Infect Chemother. 2017 Oct;23(10):683‐686. doi: 10.1016/j.jiac.2017.07.008. Epub 2017 Aug 3. who have received influenza vaccination.

Influenza Vaccine Uptake of influenza vaccine amongst healthcare workers (HCW)

• HCW influenza vaccination coverage estimate for the 2016–17 season was 79% (same as prior year) • Rate of 96.7% attained when employers require vaccination – controversial policy • Uptake lowest among medical assistants/aides (69%) and HCW in long‐term care settings (68%) • Offering vaccination at the workplace at no cost was associated with higher vaccination coverage.

Black CL, Yue X, et al. Influenza Vaccination Coverage Among Health Care Personnel — United States, 2016–17 Influenza Season. MMWR Morb Mortal Wkly Rep 2017;66:1009–1015.

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Ding H, Black CL, Ball S, et al. Influenza Vaccination Coverage Among Pregnant Women — United States, 2016–17 Influenza Season. MMWR Morb Mortal Wkly Rep 2017;66:1016–1022. Influenza vaccine in pregnant women Vaccination in the first trimester?

• 2016–17 influenza season: 54% of pregnant women vaccinated • Vaccine Safety Datalink data, electronic records from ~9 million patients to examine 2010-11 and 2011-12 seasons • Recommendation AND offer of vaccine by a primary provider significantly increased uptake • Compared 485 women ages 18-44 who miscarried to 485 women ages 18-44 who didn't miscarry • Refusal linked to concern about harmful effects of vaccine on the fetus • Women vaccinated in 1st trimester with vaccine containing pandemic H1N1, and who had also received the same component the previous year, had an increased risk for spontaneous abortion (SAB) within the 28 days after vaccination (aOR 7.7 vs 1.3) • Median gestational age was 7 weeks

Donahue JG, et al. Vaccine. Volume 35, Issue 40, 25 September 2017, Pages 5314‐5322

Limitations and Take-away Case 4

• Case-control study (observational, cannot determine causation) 28yo woman with AML s/p alloSCT 3 months prior, now presents in • Small numbers overall January with cough and weakness. She is afebrile but hypoxic to 84% on RA, admitted for further care. Rapid PCR testing is positive for RSV. • Rate of spontaneous abortion (SAB) closely follows typical observed rate in 1st trimester • Many cases were vaccinated within a few days of LMP How should she be treated? • Many SAB may be missed, as very early pregnancy may not be recognized 1. Supportive care • SAB cases contained more high-risk women (Age 35 , 2 prior SAB) 2. Inhaled ribavirin ACIP and ACOG continue to recommend vaccination given many other 3. IV ribavirin + IVIG studies (including VSD data) demonstrating safety, and known 4. Oral ribavirin complications of influenza infection in pregnancy 5. Oral ribavirin + IVIG Irving et al. Obstet Gynecol. 2013 Jan;121(1):159‐65; Bratton et al. Clin Infect Dis. 2015 Mar 1;60(5):e11‐9; McMillan et al. Vaccine. 2015 Apr 27;33(18):2108‐17; Chambers et al. Vaccine. 2013 Oct 17;31(44):5026‐32; Moro et al. Am J Obstet Gynecol. 2011 Feb;204(2):146.e1‐7; Moro et al. Am J Obstet Gynecol. 2011 Nov;205(5):473.e1‐9; https://www.cdc.gov/vaccines/acip/meetings/downloads/min‐archive/min‐2015‐06.pdf

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RSV in Adults Treatment of RSV: Ribavirin

• Clinical: • Synthetic guanosine nucleoside analogue that inhibits • Similar active season as influenza nucleic acid synthesis • Wheezing and dyspnea more common • Available in 3 forms: • Aerosolized: previously standard of care • Management: • Toxicity: Bronchospasm, cough, dyspnea • Normal immune system – often URTI, supportive care only • Isolation: Teratogenic, HCW precautions • In immunocompromised setting – LRTI more common, mortality • IV: toxicity  hemolytic anemia, neutropenia, thrombocytopenia rates up to 80% (SCT > solid organ), need to consider Rx • Oral: Now what we use at UCSF, watch for hemolytic anemia

Cesario, Clin Infect Dis 2012, 55:107. Lee et al, Clin Infect Dis 2013, 57:1069. Lee et al, Clin Infect Dis 2013, 57:1069. 57

Outcomes with RSV therapy Other RSV therapies

Prevent URTI  LRTI Prevent Mortality in LRTI • Immunomodulatory therapies • IVIG: efficacy never evaluated by RCT; recommend in leukemia, per Progression URTI  LRTI in RSV Mortality in RSV LRTI European ECIL guidelines 100% 80% 100% 80% • RSV-IG: not available in US 80% 68% 60% 60% • Palivizumab: monoclonal Ab licensed to prevent RSV in high-risk 40% 32% 40% 27% children – no benefit found for RSV treatment 20% 20% •Steroids 0% 0% • Mixed data, generally not recommended

Khanna et al, CID 2008. Kim et al Seminars in Respiratory and Critical Care Medicine 2007 Hirsch et al CID 2013

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RSV Treatment Summary Respiratory Viral Summary

• Upper Respiratory Tract Infection • No treatment for most • Timing: • Consider treatment for solid organ transplants or SCT with high risk • Influenza and RSV – Oct through April, generally features (ie, prior to engraftment, <1 month post-transplant, etc) • Other resp viral illnesses vary by season – some active year-round • Resp viral infections play a significant role in community acquired pneumonia • Lower Respiratory Tract Infection • Ways to Dx: • Treatment for SOT or SCT patients requiring hospitalization for RSV • Resp Viral PCR > DFA > Rapid test • Can consider treating outpatient transplant patients with risk factors (active GVHD, recently post-transplant, etc) • High suspicion = don’t trust (-) test result or normal CXR

Respiratory Viral Summary Thank You!

• Treatment: For influenza, time = life!  In high-risk pts, don’t wait for results. Start a NAI (oseltamivir, others)  Earlier is better, but Rx even >48hrs for inpatients, other high-risk pts • For other resp viral illness, generally no Rx (unless immunocompromised) • Treat RSV in immunocompromised patients with oral ribavirin + IVIG

• Prevention: • Influenza vaccination for all (ages >6mo, no contraindication) • Especially important for healthcare workers, pregnant women

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Lyme Disease Fact and Fiction NO DISCLOSURES

Richard A. Jacobs, M.D., PhD.

Willie Burgdorfer, Ph.D. (1925‐2014) RM Lab in Hamilton, MT Polly Murray who first reported an outbreak of arthritis in 12 children from Old Lyme, CT in 1975—the first description of what would become to be known as Lyme disease.

Author of “The Widening Circle: A Lyme disease Pioneer Tells Her Story”

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Dr. Allen Steere, who at the time was a Rheumatology Fellow Outline at Yale University, was sent to investigate the • outbreak of arthritis. Clinical manifestations In 1977 published a paper on • Diagnosis Lyme Arthritis. (Arthritis and • Therapy Rheumatism 1977;20:7) • Prevention • Controversies

Case Case

• A 35 yo woman is being evaluated for a 6 month h/o • Serologies fatigue, arthalgias without arthritis and memory loss – CDC recommends 2‐stage testing manifest as word‐finding difficulties and • Screening ELISA or IFA—very sensitive but not forgetfulness. The work‐up has been thorough but specific frustrating for both the provider and the patient because answers have not been forthcoming. Finally, –If negative—>no further testing after an exhaustive internet search, she requests that –If positive/equivocal—>confirmatory test Lyme disease serologies be performed. The provider • Confirmatory Western blot reluctantly agrees. –IgM –IgG

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Case Questions

• Serologies return: – Screening test is equivocal • How do you interpret the serologies? –Confirmatory Western blot is IgM (+) • Does she have Lyme disease? and IgG (‐)

Definition “Tick Biology 101”

Lyme disease is a bacterial infection caused primarily by the spirochete Borrelia burgdorferi in the US ( less commonly by B. mayonii in the upper mid‐West) and B. afzelii, and garinii in Europe and Asia (less commonly by B. burgdorferi and rarely by B. speilmanii and B. bavariensis) and is transmitted to humans by the bite of infected Ixodes ricinus complex deer tick. The clinical manifestations can be complex but affect primarily the skin, joints, nervous system and heart

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“Tick Biology 101” “Tick Biology 101” (continued)

• Hard ticks (over 700 species) • Three stages: – Ixodes ricinus complex – Larval—feeds from August to September on – Different geographic distributions white‐footed mouse • Northeastern and upper midwestern states – Nymphal★★‐‐feeds from May through July on – Ixodes scapularis (also called Ixodes dammini) white‐footed mouse • Western states—Ixodes pacificus • Europe—Ixodes ricinus – Adult—feeds on larger mammals, especially deer in the spring and fall • Asia—Ixodes persulcatus

• Soft ticks (over 150 species) ★★ Nymph primarily responsible for disease transmission Most clinical cases occur in the summer months

Tick Biology (continued) Tick Biology (continued)

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Tick Biology (continued) Engorged Tick

Clinical Manifestations Early Localized Disease

• Early Localized Disease • Erythema Migrans – Usually occurs 7‐10 days after the bite – Seen in 70%‐80% of cases – Range 3‐30 days – Begins 7‐10 days after the bite (3‐30 day range) • Early Disseminated Disease – Starts at the site of the the tick bite – Weeks to months after the bite – Slowly expanding (over several days to weeks), flat or slightly raised, erythematous rash that is often • Late Disease described by patients as burning or itching or less – Months to years after exposure commonly, painful – Clears spontaneously over weeks

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Central Clearing

Bulls Eye Rash

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Early Localized Disease Early Localized Disease

• Erythema Migrans • Erythema Migrans –Usually with –Usually accompanied with • Nonspecific systemic symptoms • Nonspecific systemic symptoms – Fatigue – Fatigue – Anorexia – Anorexia – HA “SUMMER FLU” – HA – Myalgias – Myalgias – Fever – Fever • About 40% of patients have spirochetemia

Early Disseminated Disease Early Disseminated Cutaneous Disease (weeks to months) • Cutaneous Manifestations – EM at sites other than the original bite • Neurologic (15% of UNTREATED patients) – Lymphocytic meningitis – Cranial nerve palsies (especially the facial nerve) – Radiculoneuritis • Heart (5% of UNTREATED patients) – Atrioventricular block – Myocarditis (rarely)

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Early Disseminated Cutaneous Disease Early Disseminated Cutaneous Disease

Early Disseminated Disease Late Disease (weeks to months) (months to years) • Cutaneous Manifestations – Arthritis (60% of UNTREATED patients) – EM at sites other than the original bite • Large weight bearing joints • Neurologic (15% of UNTREATED patients) • Often recurrent (70%) – Lymphocytic meningitis – Neurologic – Cranial nerve palsies (especially the facial nerve) • Polyneuropathy – Radiculoneuritis • Encephalomyelits • Heart (5% of UNTREATED patients) – True infection of the neuroaxis – Very rare < 1/106 – Atrioventricular block – More common with B. garinii – Myocarditis (rarely)

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Late Disease (months to years) – Arthritis (60% of UNTREATED patients) • Large weight bearing joints • Often recurrent (70%) – Neurologic • Polyneuropathy • Encephalomyelits – True infection of the neuroaxis – Very rare < 1/106 – More common with B. garinii

Encephalopathy Diagnosis

• Encephalopathy (memory difficulties/cognitive slowing) • Early Disease – Common problem in patients with inflammatory – Clinical Diagnosis diseases – 2‐tier testing only 25% sensitive because of slow – Common background complaint in the general rise in IgM antibodies (1‐2 weeks) and IgG population antibodies (2‐6 weeks) • THESE SYMPTOMS ARE NOT MANIFESTATIONS OF CNS LYME DISEASE IN THE ABSENCE OF SEROLOGIC EVIDENCE OF EXPOSURE

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Diagnosis Diagnosis of Late Manifestations (Steere AC et al. Clin Infect Dis 2008:47:188)

• Late Stages – CDC recommends 2‐stage serologic testing • Sensitivity of 2‐tier testing in late Lyme disease • Screening ELISA or IFA—very sensitive but not is 100% and specificity is 99% specific (syphilis, gingivitis, LYMErix, SLE, RA etc) • “Therefore, current thinking is that all patients –If negative—>no further testing with objective neurologic, cardiac, or joint –If positive/equivocal—>confirmatory test abnormalities associated with Lyme disease • Confirmatory Western blot have serologic response (a + IgG western blot titer) to B. burgdorferi”

New Approaches to Serodiagnosis Commonly Asked Questions

• V1sE C6 peptide ELISA (C6 test) —measures • What is the explanation of an isolated positive antibodies to a protein‐like sequence expressed Western blot IgM? in the sixth invariant region – FALSE POSITIVE – More sensitive in early disease than 2‐stage testing • Can you get Lyme disease more than once? – More sensitive for European strains – Almost always re‐infection • CDC, IDSA and AAN have yet to endorse the test – NOT relapse – Stand alone • Does Lyme disease in pregnancy affect the fetus? – Replace Western blot – Does not predispose to congenital anomalies or fetal demise

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Clues to Diagnosis

• EM occurs 3‐30 days after bite‐‐most commonly in 7‐ 10 days – Early reactions that fade are due to the tick bite and are not EM • Ticks must feed 24‐36 hours to transmit organism • Know prevalence in your area – East Coast 60‐70% infected – West Coast < 5% infected

Clues to Diagnosis

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Prevention Proper Tick Removal

• Light colored protective clothing with shirt tucked into pants and pants tucked into socks • DEET • Permethrin spray for clothes • Tick checks with prompt removal • Antibiotic prophylaxis—200 mg doxycycline – Ixodes tick; fed for 36 hours; tick infection rate >20%; antibiotics given within 72 hours of tick removal

Prevention Back to the Case

• Light colored protective clothing with shirt • A 35 yo woman is being evaluated for a 6 month tucked into pants and pants tucked into socks h/o fatigue, arthalgias without arthritis and memory loss manifest as word‐finding difficulties • DEET and forgetfulness. • Permethrin spray for clothes • Lab tests • Tick checks with prompt removal – ELISA –equivocal – WB—positive IgM and negative IgG • Antibiotic prophylaxis—200 mg doxycycline • NOTE—EXPLANATION OF AN ISOLATED (+) – Ixodes tick; fed for 36 hours; tick infection rate Western blot IgM IS THAT IT IS A FALSE (+) >20%; antibiotics given within 72 hours of tick • IN LATE STAGES OF DISEASE ALMOST ALL HAVE A removal (+) IgG ANTIBODY TITER

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New Lyme‐disease Borrelia spp Controversies in Lyme Disease Identified • Borrelia mayonii – Found in the upper midwestern states – Transmitted by Ixodes scapularis tick • Only a few patients identified – More nausea and vomiting – Higher temperatures – Diffuse rash – High grade spirochetemia • Detected by current 2‐tier testing and C6 test • Responds to standard Lyme disease therapy

Lancet Infect Dis, Feb 5, 2016

Controversies in Lyme Disease How Far Apart Are The Views?

• ILADS/LLMDs • IDSA (Infectious Disease Society of America) • IDSA – Clinical Manifestations • Fatigue – Clinical Manifestations • Low grade fever/hot flashes • Alternate view of the disease • Night sweats • Skin • Sore throat • Swollen glands – LLMDs—Lyme literate physicians • Joints (arthritis) • Stiff neck • Arthralgias/stiffness/less commonly arthritis • Neurologic system • Myalgias – ILADS—International Lyme and Associated Disease • Heart • Chest pain/palpitations • Abdominal pain/nausea Society in US • Diarrhea • Sleep disturbance • Poor concentration and memory • Own set of guidelines • Irritability and mood swings • Depression • Supported by powerful patient advocacy groups • Back pain • Blurred vision/eye pain • Jaw pain – European equivalents • Testicular/pelvic pain • Tinnitus • German Borreliosis Society • Vertigo • Dizziness/lightheadedness • Headaches • Dutch Lyme Association • Cranial nerve disturbances

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How Far Apart Are The Views? How Far Apart Are The Views?

• IDSA • ILADS/LLMDs • IDSA • ILADS/LLMDs – Diagnosis – Diagnosis – Therapy – Therapy • 2‐tier testing – Since there is no definitive test • Longest duration 28 days • Rather than an arbitrary for Lyme disease, laboratory • May need to re‐treat 30‐day treatment course, – 1983 study using “crude” results should not be used to some with persistent the patients clinical (early) assay 94% had a exclude an individual treatment arthritis response should guide positive test – Lyme disease is a clinical duration of therapy diagnosis and tests should be – 2008 article by Steere used to support rather than • Combination and 99% with late disease supersede the physicians sequential therapy that had positive test judgment can last months – Diagnosis of Lyme by 2‐tier confirmation fails to detect up to 90% of cases

How Contentious Is It?

very

Lancet Infect Dis 2011;11:713‐719

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Unvalidated Laboratory Tests Antiscience and Ethical Concerns by “Specialty Laboratories” • Antiscience groups and pseudoscientific practitioners • Urine PCR for tick‐borne pathogens • Using unvalidated laboratory tests • Various specialty laboratories in CA and KS that have been investigated and fined • List current and former ILADS officers sanctioned by state medical boards or reprimanded by federal agencies

Unvalidated Laboratory Tests Unvalidated Laboratory Tests by “Specialty Laboratories” by “Specialty Laboratories”

• Urine PCR for tick borne pathogens • Urine PCR for tick borne pathogens • 11 pathogens from a single patient • 11 pathogens from a single patient – B. burgdorferi, B. miyamotoi, B. recurrentis, A. – B. burgdorferi, B. miyamotoi, B. recurrentis, A. phagocytophilum, B microti, B. divergens, B. phagocytophilum, B microti, B. divergens, B. duncani, B. bacilliformis, B. henselae, B. quintana duncani, B. bacilliformis, B. henselae, B. quintana and E. chaffeensis and E. chaffeensis • Current political climate these positive results

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Unvalidated Laboratory Tests Antiscience and Ethical Concerns by “Specialty Laboratories” • Antiscience groups and pseudoscientific • Urine PCR for tick borne pathogens practitioners • 11 pathogens from a single patient • Using unvalidated laboratory tests – B. burgdorferi, B. miyamotoi, B. recurrentis, A. • Various specialty laboratories in CA and KS phagocytophilum, B microti, B. divergens, B. that have been investigated and fined duncani, B. bacilliformis, B. henselae, B. quintana • List current and former ILADS officers and E. chaffeensis sanctioned by state medical boards or • Current political climate these positive results reprimanded by federal agencies ALTERNATIVE FACTS

Antiscience and Ethical Concerns

• Antiscience groups and pseudoscientific Positive Negative practitioners • Using unvalidated laboratory tests • Various specialty laboratories in CA and KS that have been investigated and fined • List current and former ILADS officers sanctioned by state medical boards or reprimanded by federal agencies

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Prolonged use of antibiotics—months to years Three patients with PICC line sepsis Using “unconventional therapy”—IV garlic

“Lyme Doctor Protection Act”

• A law signed by Governor Andrew Cuomo on December 15, 2014 • The law prohibits the state board of medicine from investigating complaints of substandard care JAMA 2014 “based solely on their recommendation or provision of treatment modality that is currently not universally accepted by the medical profession.” • In NY, “unconventional therapy” is now protected

under law JAMA Internal Medicine January 2015 p 132

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CDC Website Counterpoint

• World Wide Lyme Rally & Protest May 10, 2013 Union Square, NYC—comments by Dr. Kenneth Liegner

Pituitary tumor misdiagnosed as CLD for 3 years

Counterpoint Counterpoint

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Counterpoint Counterpoint

• “Chronic Lyme disease does not exist” • “Chronic Lyme disease does not exist” • There are at least four possibilities to explain • There are at least four possibilities to explain why a person might hold this view: why a person might hold this view: – They can be “dumb as bags of rocks” – They can be “dumb as bags of rocks” – They can be character‐disordered, with exceeding – They can be character‐disordered, with exceeding rigid thinking, impenetrable, circular logic rigid thinking, impenetrable, circular logic – They can be corrupt

Counterpoint Counterpoint

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Counterpoint How Contentious Is It? • “Chronic Lyme disease does not exist” • There are at least four possibilities to explain why a person might hold this view: – They can be “dumb as bags of rocks” – They can be character‐disordered, with exceeding rigid thinking, impenetrable, circular logic – They can be corrupt – They can be sociopaths • One thing is for damn sure: they are truly lousy clinicians Clinical Infectious Diseases 2006;43:1089‐1134

How Contentious Is It? Law Suit Against IDSA

• Blumenthal ended suit in 2008 Shortly after the guidelines were published , then AG Blumenthal sued the IDSA saying the • Blumenthal & IDSA agreed to appoint a new guidelines “severely constrict choices and legitimate diagnosis and treatment options of patients”. committee vetted by both sides to review the data in the recommendations In addition, he accused the IDSA: 1. Several panelist had conflicts of interest • All day open public hearing to offer a forum 2. Panel refused to consider information about CLD 3. Refused to appoint panelists with divergent for alternative views of the diagnosis and views on CLD treatment of Lyme disease – 3 from Lyme advocacy groups – 4 ILADS/LLMDs

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The Final Report‐‐2010 Two Common Scenarios

• The recommendations in the 2006 Guidelines • Scenario 1 were evidence‐based and of the highest – Patient has documented Lyme disease and after scientific quality‐‐ all recommendations therapy continues to have nonspecific symptoms should stand. • Post‐Lyme disease Syndrome (<10%) • The approach to diagnosis and therapy – Antibiotics – multiple RDBPCS • 3mos of abx v placebo —> no difference in symptoms supported by of the International Lyme and st Associated Disease Society (ILADS/LLMDs) was – Persisters—organisms tolerant to 1 line therapy • May respond to other abxs (daptomycin, clofazimine, not evidence‐based and should not alter the cefuroxime) published recommendations – Immunology

• TH17 response with high levels of IL‐23 v usual TH1 response

Two Common Scenarios Some Observations

• Scenario 2 • Spirochetal diseases that affect humans – Relapsing fever (Borrelia recurrentis and other Borrelia spp) – Patient has nonspecific symptoms and no – Leptospirosis (Leptospira species) evidence of exposure to Borrelia burgdorferi i.e. – Syphilis (Treponema pallidum) antibody tests are negative – Lyme disease (Borrelia species) • This is where most of the “philosophical • Diagnosed with antibody studies &/or direct visualization – Relapsing fever—70% by visualization divide” occurs – Leptospirosis—55% by serology – They may have some underlying infection…BUT – Syphilis—95%‐100% by serology • I don’t think it is Lyme disease • Duration of therapy – Relapsing fever—single dose to 10 days • I have seen no evidence that the symptoms respond to – antibiotics Leptospirosis—up to 7 days for severe disease – Syphilis—depends on stage of disease; neurosyphilis 10‐14 days

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Some Questions Poly‐ticks: Blue State versus Red State for Lyme disease‐2004

• With all of the patients with “chronic Lyme disease” treated by LLMDs with long term antibiotics, why has there never been a randomized, double‐blinded controlled study to see if antibiotics are any more effective than placebo?

Poly‐ticks: Blue State versus Red State for Lyme disease‐2004

Lyme Disease/Ixodes tick Bush/Cheney V Kerry/Edwards Southern Tick‐Associated Rash Illness—STARI/ Amblyomma americanum (Lone Star Tick)

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Cutaneous Infections (and their mimickers) Disclosures

I have no conflicts of interest to disclose.

14 I may discuss off-label use of treatments for cutaneous disease.

Kanade Shinkai, MD PhD Associate Professor of Clinical Dermatology University of California, San Francisco

A preview

• Image review: Classic skin presentations of infections (and mimickers). Part 1. Classic cutaneous presentations • Speed rounds: the red leg of infectious diseases (and mimickers)

• Image review: Classic skin presentations of infections (and Part 1. mimickers). Part 2.

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18 year old, immunosuppressed for MCTD Rash not responding to topical steroids

Best first test to be performed in clinic: Best first test to be performed in clinic:

1 Bacterial culture 1 Bacterial culture

2 Viral culture 2 Viral culture

3 Viral direct fluorescence antibody (DFA) 3 Viral direct fluorescence antibody (DFA)

4 Skin biopsy 4 Skin biopsy

5KOH test 5KOH test

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Tinea corporis HIV+ man, CD4 nadir = 4

Trichophyton rubrum Trichophyton mentagrophytes

Microsporum canis (inflammatory) Microsporum audouinii

Diagnosis: KOH Morphology on mold cultures (low yield) Lactophenol plates (higher yield) Skin biopsy (PAS-D)

Most likely infection is: Most likely infection is:

1 Molluscum contagiosum 1 Molluscum contagiosum

2 Cryptococcus neoformans 2 Cryptococcus neoformans

3 Pseudomonas aeruginosa 3 Pseudomonas aeruginosa

4 Herpes simplex virus 4 Herpes simplex virus

5 Penicillium marneffei 5 Penicillium marneffei

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All except for pseudomonas are in the Molluscum contagiosum differential diagnosis in setting of HIV+, CD4<50

1 Molluscum contagiosum: umbilicated papules

2 Cryptococcus neoformans: umbilicated papules

3 Pseudomonas aeruginosa

4 Herpes simplex virus: unusual morphology in immunosuppressed patients

5 Penicillium marneffei: umbilicated papules

Please note: This is not an ARS question

Chronic atopic dermatitis with acute flare Best first test to be performed in clinic:

1 Bacterial culture

2 Fungal culture

3 Viral direct fluorescence antibody (DFA)

4 Skin biopsy

5KOH test

218 4 3/2/2018

Best first test to be performed in clinic: Eczema herpeticum

1 Bacterial culture

2 Fungal culture

3 Viral direct fluorescence antibody (DFA)

4 Skin biopsy

5KOH test

SLE on prednisone, mycophenolate mofetil Best diagnosis is

1 Acne vulgaris

2 Steroid-induced acne/ folliculitis

3 Rash of systemic lupus erythematosus

4 Demodex folliculitis

5 Staphylococcal folliculitis

J Murase, MD

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Best diagnosis is Demodex folliculitis in SCT recipient

1 Acne vulgaris

2 Steroid-induced acne/ folliculitis

3 Rash of systemic lupus erythematosus

4 Demodex folliculitis

5 Staphylococcal folliculitis

Demodex folliculorum, Demodex brevis Bedside test

220 6 3/2/2018

Immunosuppressed liver transplant recipient Most likely infectious cause is

1 Staphylococcus aureus

2 Streptococcus viridans

3 Borrelia burgdorferii

4 Bartonella henselae

5 Vibrio vulnificus

Most likely infectious cause is Immunosuppressed SCT recipient

1 Staphylococcus aureus

2 Streptococcus viridans

3 Borrelia burgdorferii

4 Bartonella henselae

5 Vibrio vulnificus

B Schwartz, MD

221 7 3/2/2018

Most likely cause is Most likely cause is

1 Nocardia asteroides 1 Nocardia asteroides

2 Fusarium oxysporum 2 Fusarium oxysporum

3 Herpes simplex virus 3 Herpes simplex virus

4 Leukemia cutis 4 Leukemia cutis

5 Squamous cell carcinoma 5 Squamous cell carcinoma

Immunosuppressed patient, 3 day ulcer Most likely cause of a rapid-forming ulcer is:

1 Factitial ulcer

2 Pyoderma gangrenosum

3 Herpes simplex

4 Pseudomonas aeruginosa

5 Capnocytophaga canimorsus

Ahronowitz I, Harp J, Shinkai K (2012) Am J Clin Derm, 13: 191-211

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Most likely cause of a rapid-forming ulcer is: Pyoderma gangrenosum

1 Factitial ulcer Inflammatory (not infectious) ulcer with neutrophils Diagnosis of exclusion 2 Pyoderma gangrenosum Violaceous rim, undermined border 3 Herpes simplex Can begin with pustule or “boil” 4 Pseudomonas aeruginosa Pathergy: triggered by (or worsens with) trauma

5 Capnocytophaga canimorsus Associated with: inflammatory bowel disease malignancy (myeloma, IgA) arthritis (connective tissue disease) hepatitis

Ulcer with violaceous border, culture negative

Ahronowitz I, Harp J, Shinkai K (2012) Etiology and management of pyoderma gangrenosum, Am J Clin Derm, 13: 191-211 Ahronowitz I, Harp J, Shinkai K (2012) Etiology and management of pyoderma gangrenosum, Am J Clin Derm, 13: 191-211

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Most likely cause is

1 Acute generalized exanthematous pustulosis

2 Streptococcus viridans

3 Coxsackie A6 virus

4 Herpes simplex virus

5 Varicella zoster virus

Most likely cause is

1 Acute generalized exanthematous pustulosis

2 Streptococcus viridans

3 Coxsackie A6 virus

4 Herpes simplex virus

5 Varicella zoster virus

224 10 3/2/2018

Most common cause of “football” shaped vesiculopustules: 1 Herpes simplex virus

2 Erythema multiforme

3 Coxsackie A16

4 Varicella zoster virus

5 Chilblains lupus

Most common cause of “football” shaped vesiculopustules: 1 Herpes simplex virus

2 Erythema multiforme

3 Coxsackie A16 – Hand, foot, mouth disease

4 Varicella zoster virus

5 Chilblains lupus

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Consult question: eczema management

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Best diagnosis is: Best diagnosis is:

1 Severe atopic dermatitis 1 Severe atopic dermatitis

2Psoriasis 2Psoriasis

3 Drug eruption 3 Drug eruption

4 Retention hyperkeratosis 4 Retention hyperkeratosis

5 Scabies 5 Scabies

Scabies: sarcoptes scabei

Speed rounds: the red leg

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Best diagnosis is:

1 Bilateral cellulitis

2 Bilateral erysipelas

3 Vasculitis

4 Venous stasis dermatitis

5 Pyomyositis

Best diagnosis is: D/dx of the red leg?

1 Bilateral cellulitis • erysipelas • cellulitis 2 Bilateral erysipelas • DVT • vasculitis 3 Vasculitis • pyomyositis • necrotizing fasciitis 4 Venous stasis dermatitis • asteatotic dermatitis • stasis dermatitis 5 Pyomyositis • contact dermatitis

Red Leg: Speed rounds

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No fever, no leukocytosis, bilateral itchy red legs Stasis dermatitis Key features: • bilateral erythema, edema (L>>R) • varicose veins • brawny (golden) hyperpigmentation • no WBC, LAD, lymphangitis

Rx: compression topical steroids

Fever, leukocytosis, red leg Cellulitis

• Unilateral • GAS, Staph aureus • Rapid spread • Toxic-appearing patient • WBC up, LAD, streaking

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Fever, leukocytosis, red leg Erysipelas

• Superficial cellulitis (leg, face) • Strep (GAS > GBS) • F>M • Involves lymphatics • Clue: raised, shiny plaques

Fever, leukocytosis, minimally “red” leg not responding to antibiotics

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Pyomyositis

• bacterial infection of muscle -S aureus (77%), strep (12%) • risk factors: -trauma -travel (tropics) -immunocompromised • Dx: MRI • Rx: surgical drainage psoas, gluteus, quadriceps*

Necrotizing fasciitis Fever, leukocytosis, bilateral “red” legs

• Strep/ staph infection of fascia • post-surgical • 20% mortality • pain out of proportion to exam • rapid spread (minutes to hours) • Dx: MRI • Rx: surgical debridement IV antibiotics

231 17 3/2/2018

No fever, no leukocytosis, but a red leg Vasculitis history of topical neomycin for “rash” • Clue: palpable purpura (bumps!) • favors dependent areas • bilateral • fever, malaise, arthralgias • may involve vessels of other organs -kidneys, joints, gut

Contact dermatitis Red leg: Pearls

• clue: red, angry, weeping, itch>pain Not all red legs are cellulitis • patient looks well • history is key Bilateral cellulitis is rare. Reconsider diagnosis • neomycin is top contact allergen • also: poison oak (rhus) Many treatments for the “red leg” are exclusive topical diphenhydramine

232 18 3/2/2018

Classic cutaneous presentations of infectious diseases (and mimickers)

Part 2.

Superficial proximal onychomycosis due to: Superficial proximal onychomycosis due to:

1 Trichophyton rubrum 1 Trichophyton rubrum

2 Fusarium oxysporum 2 Fusarium oxysporum

3 Candida albicans 3 Candida albicans

4 Penicillium marneffei 4 Penicillium marneffei

5 Pseudomonas aeruginosa 5 Pseudomonas aeruginosa

233 19 3/2/2018

Differential diagnosis includes all but: Differential diagnosis includes all but:

1 Basal cell carcinoma 1 Basal cell carcinoma

2 Pyoderma gangrenosum 2 Pyoderma gangrenosum

3 Leishmania ulcer 3 Leishmania ulcer

4 Squamous cell carcinoma 4 Squamous cell carcinoma

5 Spider bite 5 Spider bite

234 20 3/2/2018

Best next step:

1 Skin biopsy

2 Liquid nitrogen

3 Topical imiquimod cream

4 Podophyllin

5 Reassurance

Pearly pink papules of the penis/ vulva Best next step:

1 Skin biopsy

2 Liquid nitrogen

3 Topical imiquimod cream

4 Podophyllin

5 Reassurance

Bylaite M and Ruzicka T. N Engl J Med 2007;357:691

235 21 3/2/2018

Traveler to Costa Rica 2nd case from Central America

Differential diagnosis for this ulcer: Differential diagnosis for this ulcer:

1 Pyoderma gangrenosum 1 Pyoderma gangrenosum

1 Herpes simplex virus 1 Herpes simplex virus

2 Mycobacterium marinum 2 Mycobacterium marinum

3 Leishmania panamensis 3 Leishmania panamensis

4 Vasculitis 4 Vasculitis

236 22 3/2/2018

Transplant recipient with new “pimple”

Differential diagnosis for this “pimple”: Differential diagnosis for this “pimple”:

1 Acne vulgaris 1 Acne vulgaris

1Zoster 1Zoster

2 Nocardia infection 2 Nocardia infection

3 Contact dermatitis 3 Contact dermatitis

4 Candidiasis 4 Candidiasis

237 23 3/2/2018

Pearls for clinical practice

• Using skin morphology to make the diagnosis

• Keep differential broad: infection & non-infectious causes

• If it scales, scrape it (part I): tinea corporis

• If it scales, scrape it (part II): scabies

• Differential diagnosis of the red leg

Kanade Shinkai ([email protected])

238 24 3/5/2018

I have no disclosures

Fighting Infection in Diabetes

Emily Abdoler, MD Division of Infectious Diseases

GomerBlog. http://gomerblog.com/2018/02/nystatin‐statin/

Outline Outline

• Does DM Increase Risk of Infections? • Does DM Increase Risk of Infections? • Diabetic Foot Ulcers • Diabetic Foot Ulcers • Infections Treated Differently in DM • Infections Treated Differently in DM • Infections Increased in DM • Infections Increased in DM • Other Considerations • Other Considerations

239 1 3/5/2018

Does DM Increase Risk of Infection? Proposed Mechanisms for Increased Infection Risk

Decreased Cell-Mediated Immunity Decreased Leukocyte Function (hyperglycemia)

Normal BMT Vascular Insufficiency Neuropathy Host Day 2

Ischemia Sensory Autonomic  bacterial  abx Tissue injury Urinary growth delivery Retention Impaired immune Disrupted Skin response Barrier

Rajagoplan S CID 2005;40:990‐6. Pozzilli P & Leslie RDG Diab Med 1994;11:935‐41.

Does DM Increase Risk of Infection? Does DM Increase the Risk of Infection?

Surgical Site Infections Adj Odds Diabetes (OR 2.76) Ratio Post-op hyperglycemia (OR 2.02) Lower Respiratory Tract 1.32 - 1.42 Not A1c Infection UTI 1.24 - 1.96 Hospital-Acquired Infections GI 1.4 DM is an independent risk factor (RR 1.76)

Bacterial Skin/MM Infection 1.33 – 1.66 Take-Away: Mycotic Skin/MM Infection 1.34 – 1.44 - DM likely increases the risk of some infections - Relationship of hyperglycemia is unclear

Muller et al CID 2005;41:281‐8. Abu‐Ashour W et al BMC Infect Dis 2018;18. Rodriguez AL et al Am J Infect Contr 2017;45:e149‐56. Latham R et al Infect Contr Hosp Epi 2001;22:607‐12.

240 2 3/5/2018

Outline Diabetic Foot Ulcers

• Does DM increase risk of infections? • Is it infected? • How do you evaluate the infection? • Diabetic Foot Ulcers – General evaluation • Infections Treated Differently in DM – Severity • Infections Increased in DM – Imaging –Culture • Other Considerations • How do you manage the infection? – What organisms should you cover? – Surgical management – Treatment duration

Question #1 Question #1

When should you suspect MRSA could be playing When should you suspect MRSA could be playing a role in a diabetic foot infection? a role in a diabetic foot infection? A. Positive MRSA nasal carriage within last yr A. Positive MRSA nasal carriage within last yr B. Frequent gym use B. Frequent gym use C. Copious purulence C. Copious purulence D. Extreme erythema D. Deep erythema

241 3 3/5/2018

Diabetic Foot Ulcer: Is it Infected? Diabetic Foot Ulcer: Is it Infected?

≥2 classic signs of inflammation or purulence Factors Associated with Infection OR Probe to Bone 6.7 Erythema Warmth Tenderness Ulcer >30 Days 4.7 Swelling/Induration H/o recurrent ulcers 2.4 Traumatic foot wound 2.4 Exclude other causes PVD (in affected limb) 1.9 – 5.5 Trauma Gout Acute Charcot Previous amputation 19.9 Fracture Thrombosis Venous Stasis Neuropathy 3.4 ?Renal insufficiency ?H/o walking barefoot

IDSA Diabetic Foot Infections Guidelines 2012 IDSA Diabetic Foot Infections Guidelines 2012; Lavery LA Diabetes Care 2006;29:1288‐93. Peters EJ et al J Diabetes Complications 2005;19:107‐12

Diabetic Foot Infections: Diabetic Foot Infections: Severity? General Evaluation

IDSA Infection Assess for Severity Description -Arterial & venous insufficiency Uninfected No s/sx of infection Mild Local infection involving only skin & SQ tissue. -Neuropathy Erythema 0.5-≤2 cm Moderate Local infection with erythema >2cm or involving deeper -Biomechanical problems structures. -Severity of infection Severe Local infection + SIRS

IDSA Diabetic Foot Infections Guidelines 2012; Lavery LA et al CID 2007;44:562‐5. IDSA Diabetic Foot Infections Guidelines 2007; Lavery LA et al CID 2007;44:562‐5.

242 4 3/5/2018

Diabetic Foot Infections: Diabetic Foot Infections: Severity? Imaging Evaluation IDSA Infection Predicts risk for: Imaging Severity Hospitalization Osteomyelitis Amputation Uninfected 0% N/A 3% XR for new diabetic foot infections Mild 4% 3% 20% (bony abnl, gas, foreign bodies) Moderate 52% 46% Severe 89% 30-60% 70% MRI if c/f abscess, osteomyelitis

Radionuclide bone scan + tagged WBC scan (If MRI not possible)

IDSA Diabetic Foot Infections Guidelines 2007. Lavery LA et al CID 2007;44:562‐5. Lipsky Diabetes Metab Res Rev 2004;20(Suppl 1):S68‐77. IDSA Diabetic Foot Infections Guidelines 2012

Diabetic Foot Infections: Diabetic Foot Infections: Osteomyelitis Evaluation Culture Evaluation

Diagnostic Tool Sensitivity Specificity Culture FDG-PET Scan 89% 92% No infection = No need for culture WBC Scan (111In-Oxine) 92% 75% If debridement, try to obtain culture WBC Scan (99mTc-HMPAO) 91% 92% Deep Tissue Biopsy/Curettage MRI 93% 75% After debridement & cleansing XR 54% 68% Probe To Bone Drain purulence NO wound swabs Gold Standard: Bone biopsy with pathology and culture Prior to abx if possible Consider inflammatory markers (for monitoring)

Lauri C et al Diabetes Care 2017;40:1111‐20. Lipsky Diabetes Metab Res Rev 2004;20(Suppl1):S68‐77. IDSA Diabetic Foot Infections Guidelines 2012

243 5 3/5/2018

Diabetic Foot Infections: Diabetic Foot Infections: Management Management -Determine care setting When to hospitalize? -Debride (necrotic tissue, callus, etc) -Severe infections -Offload -Moderate infections with complications -Wound Care -Social factors -Antibiotics -Failure of outpatient therapy

IDSA Diabetic Foot Infections Guidelines 2012. Lavery LA et al CID 2007;44:562‐5. IDSA Diabetic Foot Infections Guidelines 2012

Diabetic Foot Infections: Diabetic Foot Infections: What organisms should be covered? What organisms should be covered?

Mild/Moderate Infections Organism(s) Situation Warm climate GNRs -Staph, Strep Severe infections -Not anaerobes or other resistant organism Warm climate Pseudomonas Water exposure Severe Infections Chronic Anaerobes Previously Tx’d Severe Infections H/o MRSA infxn or carriage (last 1y) MRSA Severe Infections ESBL When prevalent***

Lipsky BA et al Arch Int Med 1990;150‐790. IDSA Diabetic Foot Infections Guidelines 2012. Lipsky BA et al. Arch Int Med 1990. IDSA Diabetic Foot Infections Guidelines 2012.

244 6 3/5/2018

Diabetic Foot Infections: Diabetic Foot Infections: Surgical Management Antibiotic Duration Balancing of risks & benefits SSTI Infection Severity Duration -Pt preference? -Surgical target? Mild 1-2 weeks -Chance for function? Moderate 1-3 weeks -Location? Severe 2-4 weeks -Surgical risk? -Prolonged abx risk? -Sepsis/disseminated infection?

Involve vascular surgeon if ischemia

IDSA Diabetic Foot Infections Guidelines 2012 IDSA Diabetic Foot Infections Guidelines 2012

Diabetic Foot Infections: Diabetic Foot Ulcers Antibiotic Duration Take-Aways: Osteomyelitis Duration -Not every ulcer is infected No remaining infection 2-5 days* Residual soft tissue infxn 1-3 weeks* -Infected ulcers need multipronged assessment Residual infected but reliable bone 4-6 weeks** -Obtain deep culture when feasible No debridement & residual infected bone ≥ 3 months** -Mild/moderate are typically 2/2 Staph, Strep

*PO or IV -Surgery requires risk/benefit evaluation **IV -> consider PO -Abx duration varies based on severity

IDSA Diabetic Foot Infections Guidelines 2012

245 7 3/5/2018

Outline Question #2

• Does DM increase risk of infections? A 62yo gentleman with T2DM presents with a 2d history of cough and fevers. He is febrile but • Diabetic Foot Ulcers otherwise stable and is diagnosed with • Infections Treated Differently in DM community-acquired pneumonia. Which is the • Infections Increased in DM most appropriate therapy? • Other Considerations A. Azithromycin B. Levofloxacin C. Doxycycline D. Ceftriaxone + Azithromycin

Question #2 Infections Treated Differently

A 62yo gentleman with T2DM presents with a CAP 2d history of cough and fevers. He is febrile but Empiric therapy: FQ vs. (B-Lactam + Macrolide) otherwise stable and is diagnosed with community-acquired pneumonia. Which is the most appropriate therapy? Coccidioidomycosis A. Azithromycin Treat newly-diagnosed, uncomplicated PNA B. Levofloxacin C. Doxycycline Latent TB infection D. Ceftriaxone + Azithromycin DM is an indication for treatment

IDSA CAP Guidelines 2007; IDSA Cocci Guidelines 2016; SFDPH LTBI Guidelines

246 8 3/5/2018

Outline Urinary Tract Infection A1c =  risk UTI (1 unit = 21% UTI frequency) • Does DM increase risk of infections? Asymptomatic Bacteriuria is common • Diabetic Foot Infections Pre-menopausal women 1-5% • Infections Treated Differently in DM Pregnant women 2-10% • Infections Increased in DM Post-menopausal women, 50-70 yrs 3-9% • Other Considerations Pts with DM 9-27% Elderly in LTC facilities (women; men) 15-50% Pts with spinal cord injuries 23-89% Pts undergoing HD 28% Pts with indwelling catheters 25-100%

IDSA UTI Guidelines 2011. Nicolle CID 2005. Table courtesy Dr. Brian Schwartz.

Urinary Tract Infection Skin & Soft Tissue Infections No treatment for asymptomatic bacteriuria Most commonly due to Staph and Strep RCT: – <10% of cases due to GNRs (same as non-Diabetics) -DM women with asx bacteriuria -TMP/SMX vs Placebo Higher complication rate in DM -40% (placebo) vs 42% (tx) symptomatic UTI – Predisposing factor for necrotizing fasciitis, Fournier’s Higher hospitalization rate in DM Treatment -If DM well-controlled, treat as Tx: Consider abx after I&D of MRSA abscesses uncomplicated? -Otherwise: cipro or levo x7-14d

-If pregnant: nitrofurantoin or cephalexinNicolle CID 2005. IDSA UTI Guidelines 2011. IDSA SSTI Guidelines 2014; Jenkins TC et al J Hosp Med 2014;9:788‐94. Suaya JA et al PLoS ONE 2013;8:e60057.

247 9 3/5/2018

Vulvovaginal Candidiasis Less Common Infections

Likely associated with: Mucor -Glycosuria -36% due to DM - HgbA1c -66% of pts with DM had sinus dz -Blood glucose & glycosuria (even w/o DM) - since 1990s, potentially 2/2 statin

Malignant Otitis Externa ~90% pts have DM -Associated with poor DM control -Typically Pseudomonas

Donders GGG Current ID Reports 2002;4:536‐9. Roden MM et al CID 2005;14:634‐53. Kontoyiannis DP CID 2007;44:1089. Rubin GJ et al Lancet ID 2004;4:34.

Infections Increased in DM Outline

Take-Aways: • Does DM increase risk of infections? -Asymptomatic bacteriuria is common • Diabetic Foot Infections -Don’t treat it! • Infections Treated Differently in DM -SSTIs are likely due to Staph, Strep • Infections Increased in DM -Consider I&D plus abx with all abscesses • Other Considerations -Vulvovaginal candidiasis a/w poor DM control – Vaccinations -Malignant OM a/w poor DM control – Fluoroquinolone therapy

248 10 3/5/2018

Question #3 Question #3

How do the vaccination recommendations How do the vaccination recommendations differ for a 55yo woman with DM compared differ for a 55yo woman with DM compared to a 55yo woman without DM? to a 55yo woman without DM? A. Menactra vaccination recommended A. Menactra vaccination recommended B. Hepatitis B vaccination recommended B. Hepatitis B vaccination recommended C. Hep B and Pneumovax recommended C. Hep B and Pneumovax recommended D. Pneumovax recommended D. Pneumovax recommended

Vaccinations in DM Fluoroquinolones

Age 19-64y FQs have been associated with dysglycemia - 1 dose PPSV23, then: Cohort Study: Macrolides vs FQs - 1 dose PCV13 at 65y (if none previously) -2nd dose PPSV23 Hyperglycemia Hypoglycemia FQ (1y post-PCV13 & 5y after PPSV23) Adj Odds Ratio Adj Odds Ratio Levofloxacin 1.75 1.79 Ciprofloxacin 1.87 1.46 - Hepatitis B series (esp if <60y) Moxifloxacin 2.48 2.13

CDC Immunization Schedule https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html#f7 Chou H‐W CID 2013;57:971‐80.

249 11 3/5/2018

Outline Summary - DM likely increases the risk of some infections • Does DM Increase Risk of Infections? • Diabetic Foot Ulcers - Relationship of hyperglycemia is unclear • Infections Treated Differently in DM - Diabetic Ulcers - Not every ulcer is infected • Infections Increased in DM - Infected ulcers need multipronged assessment • Other Considerations - Obtain deep culture when feasible - Mild/moderate are typically 2/2 Staph, Strep - Surgery requires risk/benefit evaluation - Abx duration varies based on severity

Summary

- Treat differently: CAP, Cocci, LTBI, ?UTIs - Asymptomatic bacteriuria is common Questions? - SSTIs are likely due to Staph, Strep - Consider I&D plus abx with all abscesses - Association with poor DM control - Vulvovaginal candidiasis - Malignant OM a/w poor DM control

GomerBlog http://gomerblog.com/2016/07/epic‐consult‐once‐upon‐a‐time/

250 12 Notes

CAP/HAP/VAP Bradley Sharpe, MD

251 Notes

CAP/HAP/VAP Bradley Sharpe, MD

252 Vaccinations for Adults and Adolescents: An Update Nothing to disclose….

Lisa G. Winston, MD Professor of Medicine, University of California, San Francisco Vice Chief, Inpatient Medical Services and Hospital Epidemiologist Zuckerberg San Francisco General

Diseases/Pathogens with Vaccines Generally Available in the U.S. Key Resource • Tetanus • Hepatitis A • Diphtheria • Haemophilus influenzae type B Centers for Disease Control and Prevention • Pertussis • Human papillomavirus • Measles • Polio http://www.cdc.gov/vaccines/ • Mumps • Influenza http://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/index.html • Rubella • Rabies • Varicella • Typhoid • Meningococcus • Yellow fever • Pneumococcus • Japanese encephalitis • Hepatitis B • Rotavirus • Cholera

253 1 Outline – vaccines to be covered

• Vaccine-related news ▫ Hepatitis A ▫ Yellow fever • New hepatitis B vaccine • Pneumococcal • Meningococcal • Pertussis (Tdap) • Influenza • Varicella (Zoster)

February 6, 2018 - • Human Papillomavirus https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html

Hepatitis A outbreak

• Outbreak in CA, mostly in persons who are Yellow fever vaccine shortage homeless and/or use illicit drugs (injection and • Due to manufacturing problems, currently using non-injection) an imported vaccine ▫ San Diego – 583 cases, 20 deaths (2/23/18) • Available at fewer locations ▫ Santa Cruz – 76 cases, 1 deaths (2/23/18) https://wwwnc.cdc.gov/travel/page/search-for-stamaril-clinics • Recommendation to vaccinate at risk population ▫ Vaccinate occupational groups with close contact • Recent report of New York resident who died from yellow fever acquired in northern Peru – • New - expanded use of hepatitis A vaccine for not vaccinated post exposure prophylaxis • When using IM immune globulin for pre or post https://www.cdc.gov/mmwr/volumes/66/wr/mm6634a5.htm exposure prophylaxis, use higher dose

254 2 New hepatitis B vaccine for adults New hepatitis B vaccine for adults • HEPLISAV-B ▫ Recombinant, adjuvanted vaccine • Consider HEPLISAV-B with ▫ Contains recombinant hepatitis B surface antigen ▫ Diabetes plus novel adjuvant CpG 1018 – ▫ Renal disease oligodeoxynucleotide that enhances B cell and T ▫ Immunosuppression cell responses ▫ Obesity ▫ Given as two doses, one month apart ▫ Older age  Hope for better completion of series ▫ Smokers ▫ Approved for 18 years and older ▫ ? Non-responders ▫ Higher rates of seroprotection than Engerix-B ▫ Higher risk of MI in one study  Post marketing surveillance planned

Pneumococcal Vaccines Pneumococcal 13-Valent Conjugate Vaccine for Adults

• Two vaccines now used routinely in adults 65 • Clinical trial in the Netherlands: 84,496 adults > and older 65 randomized to PCV13 vs. placebo – (CAPiTA • Pneumococcal polysaccharide vaccine trial) ▫ PPSV-23 (Pneumovax); 23 valent ▫ 46% fewer first cases of vaccine type pneumococcal ▫ In use since 1983 community acquired pneumonia (CAP) - ▫ Efficacy against pneumonia in older adults is unclear primary outcome • Pneumococcal protein conjugate vaccine ▫ 75% fewer first cases vaccine type invasive pneumococcal ▫ PCV-13 (Prevnar); 13 valent disease ▫ Recommended for selected adults in U.S. in 2012 ▫ Additionally recommended for 65 and older in 2014 ▫ No difference CAP from any cause ▫ In adults, only one-time dose indicated New Engl J Med 2015; 372:1114-25

255 3 Single dose PPSV-23 (< age 65) Single dose PCV-13 and single dose

Condition PCV-13 PPSV-23 PPSV-23 PPSV-23 (< age 65) single dose single dose revaccinate 5 years after 1st dose Condition PCV-13 PPSV-23 PPSV-23 Heart disease X single dose single dose revaccinate 5 st Lung disease – X years after 1 including asthma dose

Diabetes mellitus X CSF leak X X Alcoholism X Cochlear implant X X Cirrhosis X Cigarette smoking X Long-term care X resident Native populations X with high risk

Single dose PCV-13 and repeat PPSV-23 five years after first dose (< age 65) Sequencing pneumococcal vaccines in Condition PCV-13 PPSV-23 PPSV-23 single dose single dose revaccinate 5 adults years after 1st dose • If PCV-13 and PPSV-23 both indicated, give PCV-13 Sickle cell disease X X X first Asplenia X X X HIV X X X ▫ For 65 and older: wait at least one year before Renal failure X X X administering PPSV-23 Nephrotic syndrome X X X ▫ Wait at least 8 weeks for less than age 65 Leukemia X X X • If PCV-13 and PPSV-23 both indicated and PPSV- Lymphoma X X X 23 has already been administered Multiple myeloma X X X ▫ Wait at least one year before PCV-13 Hodgkin disease X X X Generalized malignancy X X X Solid organ transplant X X X Other immunosuppression XXX

256 4 Meningococcal Vaccines - Who should get MenACWY vaccines? MenACWY • Two tetravalent protein conjugate vaccines (Menactra, Menveo) covering strains A, C, Y, W-135 • Recommended as routine for ages 11 - 18 – ideally given at age 11-12 visit ▫ Menactra: 9 months – 55 years; Menveo – 2 months – 55 years • “Catch up” at high school or college entry if not ▫ Advantages compared to polysaccharide given at age 11-12 vaccine • Second doses now routine for adolescent and  Longer lasting antibody titers teenage vaccinees  Good antibody response to revaccination ▫ Serogroup B not covered by tetravalent vaccines (B, C, and Y circulate in U.S.)

MenACWY vaccine – summary table Who else should get MenACWY vaccine? Risk group Primary series Booster dose • Given to military recruits, travelers/residents with Age 11-18 1 dose, preferred age 11 •Age 16, if primary dose or 12 age 11 or 12 geographic risk, microbiologists •Age 16-18, if primary dose age 13-15 • Other notes: *Also, 1st yr. college •No booster if primary ▫ Vaccination required for pilgrims going to Hajj or Umrah students in residence dose on or after age 16 in Saudi Arabia halls up to age 21 Age 2-55 with 2 doses, 2 months apart Every 5 years complement deficiency or functional or anatomic asplenia Age 2 – 55 with 1 dose Age 2-6: after 3 years prolonged increased risk Age 7 and older: after 5 of exposure years

MMWR. January 28, 2011;60:72-76

257 5 Who else should get MenACWY vaccine? Who else should get MenACWY vaccine?

• In June 2016, ACIP voted to recommend Clusters in New York City and Southern California among men who have sex with men – vaccine may be MenACWY to all HIV-positive persons age 2 recommended before travel months and above ▫ 5 – 24 fold increased risk invasive meningococcal disease ▫ 2-dose primary series, doses given 8-12 weeks apart ▫ Booster dose every 5 years ▫ If Menactra will be used, give PCV-13 first and wait at San Francisco Department of Public Health recommends least 4 weeks before MenACWY MenACWY locally for MSM, especially if multiple partners, partners sought via websites or digital  Expert opinion – data only in infants regarding applications, visit crowded venues such as bars or immune interference with response to PCV-13 parties, smoke, spend time in smoky settings

MMWR 2016;65(43):1189-94

Epidemiology meningococcal disease Recent serogroup B outbreaks linked United States to college campuses

• Incidence of all serogroups has declined • Princeton 2013-2014: 9 cases (1 death) ▫ Decline occurred prior to routine MenACWY • UC Santa Barbara 2013: 4 cases (no deaths) vaccine • University of Oregon 2015: 7 cases (1 death) ▫ In 2013: 564 culture and PCR confirmed cases • Santa Clara University 2016: 3 cases (no deaths) ▫ Historically, only 2-3% of US cases occur in outbreaks, i.e. most cases are sporadic ▫ Serogroup B now causes about 40% of cases in adolescents and young adults

258 6 Two meningococcal serogroup B vaccines Recommendations for MenB vaccines available in US • Recommended for persons 10 years and older at elevated risk due to • Both approved ages 10-25 years ▫ Persistent complement component deficiencies • MenB-FHbp (Trumenba) approved Oct 2014  Including taking drug eculizumab ▫ 2 or 3-dose series (high risk – 3 doses preferred) ▫ Anatomic or functional asplenia ▫ Contains two recombinant factor H binding protein ▫ Routine exposure (microbiologists) antigens ▫ Serogroup B outbreak  One from each subfamily A and B • MenB-4C (Bexsero) approved Jan 2015 ▫ 2-dose series • Additional category B recommendation (individual decision ▫ Contains four components making): MenB vaccine may be given to adolescents and • Cover most but not all serogroup B strains young adults ages 16-23 to provide short-term protection; • Local and systemic reactions common preferred age range 16-18 ▫ More common than with other adolescent vaccines MMWR 2015. 64(22);608-612

Pertussis Vaccine Pertussis Vaccine • Pertussis immunity wanes over time • Peaks every 2-5 years in U.S., including • Vaccine combinations: ▫ 2005, 2010, 2012, 2014 ▫ Childhood DTaP: diphtheria toxoid, tetanus toxoid, and acellular pertussis ▫ Adult/adolescent Td and Tdap: tetanus toxoid and reduced dose diphtheria toxoid +/- reduced dose acellular pertussis antigens

259 7 Acellular pertussis vaccine in adults and Waning immunity after acellular vaccination adolescents – how well does it work?

• 2781 subjects 15 – 65 yrs received reduced • California outbreak 2010: dose acellular pertussis vaccine or hepatitis A ▫ Most pediatric cases were vaccinated as recommended placebo ▫ High levels of disease in pre-adolescents, especially 10- • Followed for 2.5 yrs year-olds J Pediatr 2012;161:1091-6 • Kaiser Permanente study in CA kids: odds of • Based on primary pertussis definition, pertussis increased by 42% per year in the 5 years after vaccine 92% effective completing DTaP New Engl J Med 2012;367:1012-19 • Kaiser Permanente study: ▫ 263,496 persons 8-20 years old who received acellular vs. whole-cell vaccine (at least one dose) ▫ ~ 8.6 relative risk of pertussis for 5 doses acellular vaccine Clin Infect Dis 2013;56:1248-54 Ward et al, NEJM, Oct. 2005

Why is acellular vaccine less protective?

• Fewer antigens • Pertussis rates began increasing in 1980s ▫ Acellular vaccines – up to 5 antigens ▫ Well before acellular vaccines ▫ Whole cell vaccines - ~ 3000 antigens ▫ Priming more robust with whole cell • Rate today estimated 20-fold less than pre- ▫ Different type of T cell response vaccine era and reported rates influenced by • Antigen balance ▫ More testing ▫ High levels of antibody to pertussis toxin may have ▫ More sensitive tests – PCR blocking effect on antibodies to other antigens ▫ False positives, e.g. due to other Bordetella species • Genetic changes in Bordetella pertussis • When acellular vaccine fails in children, illness ▫ Especially pertactin deficiency less severe than in unvaccinated

260 8 Tdap – Recommendations Tdap - pregnancy

• For adolescents, give Tdap instead of Td at • Multiple studies showing Tdap is safe in pregnancy, routine 11-12 yr visit including with short interval between vaccine doses • For adults 19 and older, give single dose Tdap to • Maternal immunization results in high levels of replace a dose of Td pertussis antibody in infants and does not impair • Can be given at any interval from last tetanus- response to DTaP containing vaccine • High vaccine effectiveness (observational) when Tdap given at least 28 days before birth • Recommended for every pregnancy at 27 – 36 • Some debate re exact timing – recent data suggest weeks targeting 27 weeks may be optimal • JAMA 2015;314(15):1581-7 • Clin Infect Dis 2017;64(1):3-8 • JAMA 2014;311(17):1760-9 • Clin Infect Dis 2017;64(1):9-14 • Lancet 2014;384(9953):1521-8 MMWR 2011 / 60(41):1424-26 • Clin Infect Dis 2016;62(7):829-36

Influenza Vaccine Influenza Vaccine – egg allergy • Indicated for all people older than 6 months • Only hives after exposure to egg – any influenza ▫ Unless there is a contraindication… vaccine appropriate for age and health status  Egg allergy – no longer a contraindication • Other reactions to egg (including angioedema and  Severe previous reaction respiratory distress) – any influenza vaccine  Guillain-Barre – relative contraindication appropriate for age and health status; administer in a medical setting with ability to treat allergic reactions • No need to observe for 30 minutes ▫ 15 minutes already recommended for all, especially adolescents (syncope)

MMWR 2016;65:1-54

261 9 2017-18 Influenza Vaccine 2018-2019 likely influenza vaccine

• A/Michigan/45/2015 (H1N1)pdm09-like (new) • A/Michigan/45/2015 (H1N1)pdm09-like (same) • A/Hong Kong/4801/2014 (H3N2)-like (same) • A/Singapore/INFIMH-16-0019/2016 (H3N2)-like (new) • B/Brisbane/60/2008-like (B/Victoria lineage) (same) • B/Colorado/06/2017-like (B/Victoria/2/87 lineage) (new) • For quadrivalent vaccine add: B/Phuket/3073/2013-like (B/Yamagata lineage) (same) • For quadrivalent vaccine add B/Phuket/3073/2013-like (B/Yamagata/16/88 lineage) (same)

Recent Influenza Seasons Interim estimate of effectiveness 2017-2018 influenza vaccine • 2016-17: ▫ Estimated vaccine effectiveness 48% • Based on data 11/2/17-2/3/18 ▫ Influenza A H3N2 (predominant virus): 43% ▫ H3N2 – 25% ▫ Influenza B virus: 73% • 2015-16: relatively mild ▫ H1N1 – 67% ▫ Estimated vaccine effectiveness 59% ▫ Influenza B – 42% ▫ Late peak (March), long duration ▫ Overall – 36% ▫ Vaccine good match for circulating strains • 2014-15: moderately severe ▫ Rate of hospitalization for age 65+ highest since surveillance began 2005-6 ▫ Estimated vaccine effectiveness 19% https://www.cdc.gov/mmwr/volumes/67/wr/mm6706a2.htm

262 10 Challenges with influenza vaccine U.S. virus characterization 2017-2018 • Correctly identifying strain(s) that will circulate • Response affected by multiple factors • Most influenza A viruses circulating are H3N2 ▫ Age ▫ H3N2 viruses show substantial genetic diversity but 98% ▫ First influenza strain encountered (“original of those tested are well inhibited by ferret antisera raised antigenic sin”) against the H3N2 virus in the vaccine, i.e. “a good match” ▫ Subsequent influenza strains encountered, including ▫ H1N1 viruses all belong to same clade and are similar to vaccine strains reference virus in vaccine • Growth of vaccine in eggs: egg-adapted H3N2 strain has a mutation that eliminates a glycosylation site found in circulating H3N2 strains in 2016-2017

PNAS 2017;114(47):12578-83

Influenza vaccines recommended in United States 2017-18 Inactivated, quadrivalent, standard dose - Fluarix Quadrivalent Inactivated standard dose vaccines - Flulaval Quadrivalent -Afluria Quadrivalent(adults by jet injector) given IM - Fluzone Quadrivalent - Fluzone Intradermal Quadrivalent • Quadrivalent: 2 influenza A strains, 2 influenza B Inactivated, quadrivalent, cell culture-based, standard dose strains - Flucelvax Quadrivalent • Trivalent: 2 influenza A strains, 1 influenza B strain Inactivated, trivalent, standard dose - Afluria (adults by jet injector) -Fluvirin Adjuvanted, inactivated, trivalent, standard dose -Fluad Inactivated, trivalent, high dose -FluzoneHigh-Dose Recombinant - Flublok Trivalent and Quadrivalent

263 11 High-dose inactivated vaccine High dose inactivated vaccine

• Trivalent • Studies with clinical outcomes: • Licensed for ages 65 and older ▫ 2-year study with 31,989 participants randomized to • 60 g hemagglutinin per virus strain compared with high dose vs. standard dose: 1.4% vs. 1.9% with 15 g in regular dose confirmed influenza (relative efficacy 24.2%) • Enhanced immune response in those 65 and older New Engl J Med 2014;371:635-45 ▫ Retrospective study at VA 2010-2011; 25,714 veterans and other populations, including people living with high dose, 139,511 standard dose. No difference in HIV hospitalization for influenza or pneumonia, except in • Local reactions (mild to moderate) more common those 85 and older Clin Infect Dis 2015;61:171-6 ▫ Cluster randomized trial in 823 nursing homes 2013- J Infect Dis 2009;200:161-3 2014; respiratory-related hospital admission 3.4% vs. 3.9% Lancet Respir Med 2017 Jul 20 [epub]

Adjuvanted inactivated vaccine Recombinant Influenza Vaccine

• Trivalent • Recombinant vaccine (Flublok) uses baculovirus vectors • MF-59 adjuvant: oil-in-water emulsion of carrying genes that encode for hemagglutinin squalene oil • Vaccine with new antigens can be produced in 6 – 8 • Has been used widely in Europe, licensed in weeks Canada • 2014-2015 influenza season: 8855 participants 50 years • Licensed in U.S. November 2015 for ages 65 and and older received either quadrivalent recombinant older vaccine (45 g HA per strain) or quadrivalent standard • Approved based on safety and immunogenicity vaccine (15 g HA per strain) data • RT-PCR confirmed influenza attack rate 2.2% vs. 3.2% • Clinical trials in progress

N Engl J Med 2017;376:2427-36

264 12 Live Attenuated Influenza Vaccine Additional influenza vaccines licensed (LAIV) in U.S. • Trade name FluMist • Cell culture derived vaccine using canine kidney cells (Flucelvax) • Quadrivalent ▫ Quadrivalent; ages 4+ • Heat sensitive and cold adapted • One vaccine can be administered by jet injector • Approved for healthy persons ages 2 – 49 (Afluria) • Not recommended 2016-17 or 2017-18 ▫ Ages 18-64 • Likely to return 2018-19 based on Feb 2018 • Intradermal vaccine (Fluzone intradermal) ACIP vote ▫ Quadrivalent; ages 18-64; needle one-tenth standard ▫ New H1N1 component length; more local reactions

Influenza vaccination in pregnancy Varicella Vaccine (Varivax)

• Multiple studies with reduction in infant • Recommended for all adults without influenza-like illness (ILI) and confirmed immunity (history of varicella or laboratory influenza after maternal vaccination in evidence) pregnancy • Avoid in pregnancy and with most • Representative study: immunocompromise ▫ Observational study of 249,387 infants in Utah for first • Given as 2 dose series for all ages 6 months of life ▫ Two doses 98% effective in children ▫ 658 infants with laboratory confirmed influenza: 0.84/1000 if mother immunized, 2.83/1000 if mother not immunized • Average annual mortality has declined ▫ Risk reduction 64% ILI, 70% laboratory confirmed 88% overall and 96% under age 50 influenza, 81% influenza hospitalization Shapiro et al, Journal Infect Dis 2011;203:312-15 Marin et al, Pediatrics 2011;128:214-20 Pediatrics 2016;137(6):e20152360

265 13 Varicella Vaccine – Zoster (Zostavax) Varicella Vaccine – Zoster (Zostavax)

Oxman et al, NEJM, June 2005 • Previously recommended as a single dose for • Randomized trial 38,546 adults > age 60 adults age 60 and older ▫ Excluded if history of zoster, immunocompromise • Contraindicated in many, but not all, • Potency much greater (at least 14x) than immunocompromised persons (e.g. okay in vaccine to prevent primary varicella HIV if clinically well and CD4 count > 200) • Zoster incidence reduced by > 50%; post • Follow up subjects in Shingles Prevention Study herpetic neuralgia reduced by > 65% ▫ Efficacy for zoster prevention estimated to last 8 • Injection site reactions common years Clin Infect Dis 2015;60(6):900-9

NEJM 2015;372:2087-96 • 13,900 participants age 70 and older • Phase 3 study; 7698 received vaccine, 7713 placebo • 2 doses adjuvanted subunit vaccine or placebo • Adults 50 and older stratified by age • Follow up 3.7 years • Two dose series • Vaccine efficacy against zoster 89.8% • 6 cases zoster in vaccine group, 210 in placebo group • 23 cases vaccinated vs. 223 cases placebo • Mean follow up 3.2 years • No difference in efficacy by age • 97% efficacy • More injection site and systemic reactions with vaccine • No difference in efficacy by age • Serious adverse events similar • Mild-moderate systemic and local reactions common • Long-term follow up both studies in progress

266 14 Zoster Vaccine Recombinant (Shingrix) Zoster Vaccine Recombinant (Shingrix)

• FDA approved 10/20/17 • No need to screen for history of chickenpox or to do • Contain recombinant glycoprotein E plus a novel laboratory testing • Indicated with chronic medical conditions and low adjuvant (AS01B) • Given as two doses, 2 to 6 months apart dose immunosuppressive therapy, e.g. < 20 mg prednisone daily • Recommended as a routine vaccine for ages 50 ▫ No current recommendations for other and older immunocompromise – pending data ▫ Still give if history of zoster ▫ Revaccinate those who received Zostavax – has been studied after 5 years, wait at least 2 months https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html

https://www.cdc.gov/mmwr/volumes/67/wr/mm6703a5.htm

Human Papillomavirus (HPV) Vaccines Nine-valent HPV vaccine • Genital HPV most common sexually transmitted infection in the U.S. • Protects against 6, 11, 16, 18 plus 31, 33, 45, 52, • Quadrivalent HPV vaccine (Gardasil) 58 (high risk types) ▫ Contains major capsid protein L1 from types 6, 11, 16, 18 ▫ ~ 97% reduction in cervical, vaginal, vulvar pre- ▫ Phased out in 2016 cancers due to types 31, 33, 45, 52, 58 compared • Bivalent HPV vaccine (Cervarix) protects against with quadrivalent vaccine types 16 and 18  5 additional types account for about 20% of cervical ▫ Only licensed in females; limited use in U.S. cancers • Types 16 & 18 associated with 66% cervical cancer • Types 6 & 11 associated with 90% genital warts

267 15 HPV Vaccines Recommendations for Use • Routine vaccination beginning at age 11-12 HPV vaccine: two dose series ▫ Okay to start as young as age 9 • Females: vaccinate through age 26 • October 2016: ACIP and CDC recommended ▫ Use bivalent vaccine (Cervarix), 4-valent vaccine two-dose HPV series if started before age 15 (Gardasil), or 9-valent vaccine (Gardasil 9) ▫ 9 – 14 years olds should receive two doses at least • Males: vaccinate routinely through age 21 6 months apart ▫ Extend to age 26 for MSM or immunocompromise • If started at 15+ years, three doses still needed ▫ Use 4-valent vaccine (Gardasil) or 9-valent vaccine (Gardasil 9) • Okay to continue series with a different vaccine ▫ No need to revaccinate with 9-valent vaccine if series previously completed MMWR 2015;65(11):300-304

HPV Vaccines HPV Vaccine: External Genital Lesions • Excellent efficacy in studies (nearly 100%) in preventing infection with HPV types included in vaccine, if not previously infected • Prevent cervical and anal intraepithelial neoplasia • Greatest benefit before onset of sexual activity / infection with HPV • 4065 healthy men and boys ages 16 – 26 • Randomized, double-blind, placebo controlled • No protection against types with which already • 36 external genital lesions in vaccine group, 89 in infected at time of vaccination placebo group (intent to treat efficacy 60%) • Some partial cross protection against non-vaccine • In seronegative group with all doses received, vaccine serotypes was 90% effective against genital lesions due to HPV types 6, 11, 16, 18 (mostly 6 and 11)

268 16 HPV Vaccines - uptake HPV Vaccines - questions

▫ Relatively expensive • In 2015, 62.8% of girls and 49.8% of boys ages ▫ Not clear what long-term effect will be on risk 13 – 17 had received one of more doses of HPV of cancer vaccine  No recommendation to change cervical ▫ Girls: small improvement; boys: greater increase cancer screening based on vaccination status ▫ Lower than coverage with Tdap and MenACWY MMWR 2016;65:850-58 • HPV infections due to vaccine types are dropping in 14-19 year old girls even with limited uptake J Infect Dis 2013;208:385-93

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Disclosures

• I have no disclosures. CNS INFECTIONS: PEARLS AND PERILS Felicia Chow, MD, MAS Assistant Professor of Neurology March 16, 2018

https://www.intechopen.com/books/novel-aspects-on-cysticercosis-and- neurocysticercosis/epilepsy-and-neurocysticercosis-in-sub-saharan-africa

Learning objectives Neurosyphilis

• Recognize the clinical presentation of common neuroinfectious diseases

• Identify pitfalls of diagnostic testing frequently obtained in the evaluation and management of common neuroinfectious diseases

• Be familiar with the approach to the treatment of common neuroinfectious diseases

Camarero-Temino Nephrology 2013; https://en.wikipedia.org/wiki/Neurosyphilis#/media File:Skull_damage_from_neurosyphilis.jpg

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Stages of syphilis

Question: My patient has neurosyphilis. Does that automatically mean they have late, or like later, or latent syphilis?

Lafond et al. Clin Microbiol Rev 2006

Question: I have a patient whose MRI demonstrated a small acute infarct in the internal capsule. He has hypertension and Answer: Neurosyphilis can occur at any uncontrolled diabetes, and urine tox screen was stage of infection. positive for cocaine. His RPR was 1:64 and was negative 6 months ago. Since strokes in syphilis usually occur as a late presentation and he has many other vascular risk factors, I don’t have to LP him, do I?

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Think meninges, CSF and blood vessels in early syphilis and parenchymal disease in late syphilis

Answer: I would recommend an LP for any patient with a newly positive RPR (or positive RPR of unknown duration) and clinical/radiologic evidence of strokes.

Ghanem CNS Neurosci Ther 2010

Which syphilis patients need an LP?

Question: My clinic patient has uveitis • Any stage of syphilis + neurological symptoms and an RPR of 1:128. Ophtho sent him to • Any stage of syphilis + ocular or otologic disease clinic for neurological evaluation, but he has no neurological symptoms. I don’t • HIV-infected patients PLUS: • Late latent syphilis have to LP him, do I? • Syphilis of unknown duration • Inappropriate serologic response after treatment • Consider for any HIV-infected patient with CD4 <350 cells/mm3 and/or RPR ≥ 1:32

Ghanem Clin Infect Dis 2009

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Beware the ongoing ocular syphilis epidemic

Answer: I would recommend an LP for all • Can occur at any stage of syphilis  most cases now present in early syphilis patients with ocular syphilis. • Can involve ANY ocular structure • Anterior uveitis (iris, ciliary body) • Posterior uveitis (chorioretinitis) • Retinitis, retinal detachment • Optic neuritis

• ~50% of patients with ocular syphilis will have evidence of meningitis in the CSF

• Treatment is the same as neurosyphilis even if CSF is non-inflammatory

• May have residual vision loss despite treatment

Woolston et al. MMWR 2015

No one test has high sensitivity/specificity for neurosyphilis Question: My HIV+ patient, intermittently Test characteristics Notes non-adherent to his ARVs, presented to SERUM Sensitivity: *Titers correspond to disease 1°: 78-86% activity clinic with headaches that are more RPR (non- 2°: Near 100% treponemal 3°/Latent: Varies, ~85% *Used to assess treatment tests) severe than his usual migraines. False positives 1-2%, usually titer <1:8 response  4-fold decline (autoimmune disease, IVDU, TB, considered to be clinically pregnancy, endocarditis) significant

Serum RPR was 1:64. CSF had 20 WBC False negatives in HIV, prozone effect SERUM False positives with other spirochetal *Titers do not correspond to and a mildly elevated protein, but CSF infections, malaria, leprosy disease activity Treponemal VDRL was negative. Could this still be tests False negative in HIV *Most positive for life despite (TPPA, treatment neurosyphilis? FTA-Abs) CSF VDRL CSF VDRL Sensitivity: 30-80%, *CSF VDRL considered “gold Specificity 99% standard” for neurosyphilis CSF Treponemal FTA-Abs/TPPA high sensitivity but low Positive CSF VDRL at any titer = tests specificity neurosyphilis

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Herpes simplex virus CNS infections Answer: Yes, CSF VDRL can be insensitive for neurosyphilis. This absolutely could still be neurosyphilis, and based on the clinical data, I would recommend treating him for neurosyphilis with 2 weeks of Penicillin G (4 million units IV q4 hours).

Question: We have an inpatient who presented with 2 days of fever, headache and confusion. CSF HSV encephalitis with 11 WBC (85%L), protein 75 and glucose 53.

• HSV is the most frequently identified viral etiology of sporadic encephalitis in the US

• Bimodal distribution: 1/3 cases <20 y, 2/3 >40 y

• Case fatality rate >70% if untreated; 1/3 of patients may be significantly disabled despite treatment

• CSF: 5-500 WBC/mm3, normal to moderately elevated protein, glucose typically normal

• Involvement on imaging of the medial CSF HSV 1 PCR negative. Could this still be temporal lobes, insula, and/or inferolateral frontal lobes HSV-1 encephalitis?

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What is the utility of HSV-1 PCR in the CSF? Sensitivity of CSF HSV-1 PCR is lower early in the course of HSV encephalitis

• 54 patients with biopsy- proven HSE underwent HSV-1 PCR from CSF • Sensitivity 98% • Specificity 94%

Lakeman J Infect Dis 1995 Weil Clin Infect Dis 2002

Answer: Yes, this could definitely still be HSV-1 encephalitis. I recommend you Question: The repeat CSF HSV-1 PCR repeat the lumbar puncture, resend an was positive. She received 3 weeks of IV HSV-1 PCR from the CSF and start IV acyclovir but is still quite impaired, far from acyclovir 10 mg/kg every 8 hours as you her baseline. Should we discharge her on await the results. oral antiviral therapy?

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No significant cognitive benefit of oral therapy after IV acyclovir

• 87 HSE patients randomized to valacyclovir Answer: No, unfortunately there is no 2 g TID versus placebo x 90 days evidence that a longer course of oral antiviral therapy after completing IV • Excluded individuals with life expectancy <90 d and acyclovir is beneficial. those who couldn’t take PO

• Primary outcome was survival with no/mild impairment at 12 months

Gnann Clin Infect Dis 2015

Question: We have a 55-year-old man on the inpatient service with no past medical history other Question: CSF demonstrated normal than “possible meningitis” over 5 years ago, who opening pressure with 310 WBC (84% presented with 5 days of fever, chills, malaise and lymphocytes), glucose 40, and protein 91. severe headache. One day prior to presentation, CSF HSV-2 PCR returned positive. What he developed bilateral hip and buttocks pain and paresthesias along with urinary retention. route and duration of acyclovir would you recommend, and should he be On exam, his temperature is 101, and there is discharged on suppressive oral antiviral meningismus. Neurologic exam is notable for therapy? decreased sensation in an S3-S5 distribution.

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• Lumbosacral myeloradiculitis associated most commonly with HSV-2 reactivation

• Typically present with lower back/buttocks pain, paresthesias in lumbosacral distribution and bowel/bladder symptoms • 101 patients with HSV-2 meningitis randomized to

• CSF profile consistent with viral meningitis valacyclovir 500 mg BID or placebo x 1 year after completing treatment for acute meningitis • MRI may be normal or may show root/lower spinal cord edema with enlargement, T2/FLAIR hyperintensity and contrast enhancement

• Treatment: IV acyclovir 10 mg/kg q8h x 2 weeks Eberhardt et al. Neurology 2004 Aurelius et al. CID 2012

• In Year 1, 14 cases of recurrent meningitis in Answer: Although there are no data to guide valacyclovir group (29%) vs. 8 cases in placebo therapy for HSV or VZV meningitis, I generally treat group (16%), p=0.12 severe or complicated cases (e.g., meningo- encephalitis, myelitis, meningoradiculitis), even in • In Year 2, 12 cases in immunocompetent patients, with a full 2-week valacyclovir group (24%) course of IV acyclovir. From the perspective of vs. 4 in placebo (8%), p=0.03 preventing recurrent HSV-2 meningitis, there are no data to support use of long-term suppressive valacyclovir.

Aurelius et al. CID 2012

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Toxoplasmosis Question: Our patient with newly diagnosed HIV infection (CD4 count 90 cells/mm3, viral load 75K) presented with progressive right sided weakness and confusion. Brain MRI demonstrates several ring-enhancing lesions with surrounding edema and mass effect.

https://www.urmc.rochester.edu/libraries/courses/neuroslides/lab3b/slide137.cfm

CNS toxoplasmosis I know the serum • Most common focal brain toxoplasma lesion in HIV+ w/ CD4 < 200 antibody status of in US an HIV+ patient with focal brain • Presentation usually evolves lesions is over weeks to months important. The patient’s serum • TMP/SMX prophylaxis toxo IgM ELISA is reduces risk of negative, so does toxoplasmosis this rule out • Ddx: CNS lymphoma, toxoplasmosis? pyogenic abscess, tuberculoma, cryptococcoma

Tan et al. Lancet Neurology 2012, Laing et al. Int J STD AIDS 1996

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Utility of toxoplasma serology • Toxoplasmosis seropositivity in general population in the US is estimated to be 10-40% Answer: The serum toxoplasma IgG is more informative in an HIV patient in • Toxoplasmosis in HIV is typically reactivation of prior whom you are worried about CNS infection (i.e., IgM antibodies less helpful) toxoplasmosis. Send the IgG and, if safe, • Serum IgG is positive in most HIV patients with CNS do a lumbar puncture and send the CSF toxoplasmosis for toxoplasma PCR.

• CSF toxoplasma PCR is very specific but sensitivity varies

Laing Int J STD AIDS 1996, Correira Trans R Soc Trop Med Hyg 2010, Vidal J Clin Microbiol 2004, Sakamoto Parasitol Int 2014

Toxoplasmosis versus CNS lymphoma in HIV

Toxoplasmosis Primary CNS Lymphoma Clinical Focal s/sx (~75%), HA (~50%), fever Focal s/sx including hemiparesis, Question: Serum toxo IgG was positive. presentation (~50%); sx evolve faster than CNSL aphasia, visual field deficit CSF demonstrated 23 WBC (80%L), 27 At risk with CD4 count <200 At risk with CD4 count <50 Radiologic Basal ganglia, thalamus, grey-white Periventricular, deep white matter RBC, glucose 47 and protein 58. CSF findings junction Can be solitary/few lesions with toxoplasma and EBV PCR are pending. Usually multiple lesions (75%) with solid/homogeneous enhancement; in ring or nodular enhancement patients with HIV, can ring-enhance

What else can help us to distinguish +Mass effect and edema +Mass effect and edema between toxo and CNS lymphoma?

Raffi et al. AIDS 1997

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Toxoplasmosis versus CNS lymphoma in HIV Neurocysticercosis Toxoplasmosis Primary CNS Lymphoma Clinical Focal s/sx (~75%), HA (~50%), fever Focal s/sx including hemiparesis, presentation (~50%); sx evolve faster than CNSL aphasia, visual field deficit

At risk with CD4 count <200 At risk with CD4 count <50 Radiologic Basal ganglia, thalamus, grey-white Periventricular, deep white matter findings junction Can be solitary/few lesions with Usually multiple lesions (75%) with solid/homogeneous enhancement; in ring or nodular enhancement patients with HIV, can ring-enhance

+Mass effect and edema +Mass effect and edema

Treatment Pyrimethamine (w/ leucovorin) and Corticosteroids, methotrexate, sulfadiazine rituximab, XRT, ARVs

AVOID steroids if possible!

Raffi et al. AIDS 1997

Question: My patient, originally from Mexico, was referred for evaluation of a single ring-enhancing right frontal lesion. While in the ED with her husband who was being seen for chest pain, she had a witnessed convulsive spell and was Blood cultures, HIV test, PPD and confused for hours afterward. chest/abdomen/pelvis CT were negative. Serum cysticercal ELISA was also negative. Could this still be cysticercosis?

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Stages of neurocysticercosis Neurocysticercosis (NCC)

• Infection of the nervous Viable cyst system with larval stage of Degenerating cyst the helminth, Taenia solium Dead cyst

• 50+ million people affected worldwide

• One of the most common causes of acquired epilepsy in developing world

Garcia et al. Curr Opin Infect Dis 2003;16:411-419.

Courtesy of HH Garcia

Location, location, location Serological diagnosis of NCC • Enzyme-linked immunotransfer blot • Intraparenchymal (70%) • Sensitivity near 100% for multiple • Cortical (>90%) parenchymal, ventricular, or subarachnoid cysts; specificity 100% • Deep gray matter (5%) • Performs as well (or better) in serum as CSF • Brainstem/infratentorial • Sensitivity much lower in patients w/ single (Uncommon) or calcified lesions (<50%) and higher (100%) for subarachnoid disease • Extraparenchymal (30%) • ELISA • Sylvian fissure • Sensitivity and specificity lower than EITB • Basal cisterns • Sensitivity even lower for single or calcified • Spine lesions (<50%) • Intraventricular • Neither can be used to distinguish prior from active infection

Tsang VC et al. J Infect Dis 1989

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Answer: The epidemiology, clinical presentation and radiology findings are all highly suggestive of NCC, and this is exactly the type of patient in whom the ELISA might be less sensitive. Instead of “We recommend serologic testing with enzyme-linked immunotransfer blot as a confirmatory test in patients with the ELISA, send a serum enzyme suspected neurocysticercosis. Enzyme-linked immunotransfer blot for cysticercosis. immunosorbent assays (ELISAs) using crude antigen should be avoided due to poor sensitivity and specificity.”

White et al. Clin Infect Dis 2018

Question: I saw a patient in clinic, originally from Mexico, currently working as a construction foreman, who complained of 1 month of worsening headaches and several episodes of left Serum cysticercal ELISA was positive. My arm/leg shaking followed confusion. practice is to treat with albendazole + steroids, but dual antihelminthic therapy seems to be all the rage. Is that a good idea for this patient?

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Extraparenchymal NCC Should I treat with dual therapy?

• Less common form of infection w/ proliferating, invasive membranous structures • Double-blind, placebo-controlled RCT

• Associated with more protracted • Inclusion: 1-20 viable cysts course and worse prognosis • Exclusion: Subarachnoid NCC at base of brain, most IV cysts, cysts in brainstem, larger cysts (>30 mm), ocular cysts • Complications, particularly of basal subarachnoid disease, include: • Albendazole + praziquantel vs albendazole vs high-dose • Hydrocephalus and elevated ICP albendazole x 10 days • Vasculitis +/- infarcts and hemorrhages • Primary outcome: Cyst resolution at 6 months

Garcia Lancet Infect Dis 2014

Answer: A recent RCT showing benefit of dual anti-helminthic therapy for NCC patients excluded most patients with subarachnoid disease. Dual antihelminthic therapy is still reasonable in this patient, but steroids should be initiated before starting treatment, and he should be observed carefully for complications (e.g. ICP, seizures).

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Treatment summary Coccidioidal meningitis

CALCIFIED VIABLE DEGENERATING SUBARACHNOID OCULAR CYSTS CYSTS CYSTS CYSTS CYSTS Single lesion: No 1-2 lesions: ABZ +/- PZQ + Surgical albendazole x albendazole x 7- steroids +/- resection antiparasitic 14 d +/- steroids therapy 10-14 d +/- resection  steroids Multiple lesions: often requires Antihelminthic therapy may albendazole + prolonged and result in loss >2 lesions: praziquantel x multiple albendazole + courses of of vision 10-14 d + secondary to praziquantel x steroids therapy inflammation 10-14 d + steroids White et al. Clin Infect Dis 2018 https://microbewiki.kenyon.edu/index.php/Coccidioides_immitis

Question: I am seeing a middle-aged Question: Cocci African American man from Modesto with meningitis is high a 6 week history of progressive headache, on my differential confusion and lethargy. CSF diagnosis. What demonstrates 290 cells/mm3, protein is testing on the 100 and glucose 36. CSF gram stain and CSF is most fungal stains are negative. sensitive to make the diagnosis?

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Coccidioidomycosis

• Most primary infections (pulmonary) are asymptomatic (~2/3)

• CNS dissemination (1%) occurs weeks to months after 1o infection

• Risk factors for extrapulmonary/disseminated disease: • African or Filipino ancestry • Immune compromise (HIV, malignancy, DM, SOT, steroids) • Pregnancy

Imaging: ~66% 50-60% 33% (focal) • Meningeal enhancement • Hydrocephalus • Focal lesion (e.g, infarct, abscess) • Spinal arachnoiditis also common

Drake Neurology 2009, Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006

Performance of Cocci testing in CSF

Answer: If you suspect Cocci meningitis, CSF Parameter Sens (%) Specificity (%) in addition to checking an opening Fungal culture 7 100 pressure, cell count, glucose, protein and Immunodiffusion (ID) 67 99 fungal culture, send a CSF Cocci Complement fixation (CF) 70 100 immunodiffusion, complement fixation and Antigen 93 100 antigen. Antigen, ID, CF 98 99

Kassis Clin Infect Dis 2015, Table adapted from Brian Schwartz Galgiani Clin Infect Dis 2016

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Useful references

Treatment for Cocci meningitis • Marra CM. Update on neurosyphilis. Curr Infect Dis Rep 2009;11:127-134.

st • Weil AA, Glaser CA, Amad Z, Forghani B. Patients with herpes simple encephalitis: rethinking an initial negative polymerase • 1 line: Lifelong fluconazole 400 to 1200 mg/day chain reaction result. Clin Infect Dis 2002;34:1154-57.

• Gnann JW, Skoldenberg B, Hart J et al. Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy. Clin Infect Dis 2015;61;683-91. st • If disease progression on 1 line therapy: • Aurelius E, Franzen-Rohl E, Glimaker M, et al. Long-term valacyclovir suppressive treatment after HSV-2 meningitis: a double- 1. Increase dose of fluconazole as tolerated blind randomized controlled trial. Clin Infect Dis 2012;54:1304-13. • Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescent: 2. Consider another azole (e.g., voriconazole, posaconazole) https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0. 3. Consider IT amphotericin B • Garcia HH, Gonzales I, Lescano AG et al. Efficacy of combined antiparasitic therapy with praziquantel and albendazole for neurocystiercosis: a double-blind randomized controlled trial. Lancet Infect Dis 2014;14:687-95.

• Garcia HH, Nash TE, del Brutto OH. Clinical symptoms, diagnosis and treatment of neurocysticercosis. Lancet Neurol. • Hydrocephalus is a common complication  2014;13:1202-15.

neurosurgery evaluation for shunt • Galgiani JN, Ampel NM, Blair JE et al. Clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 2016;63:e112-46.

• Kassis C, Zaidi S, Kuberski T et al. Role of Coccidioides antigen testing in the CSF for the diagnosis of Coccidioidal meningitis. • Consider adjunctive steroids in patients with vasculitis and Clin Infect Dis 2015;61:1521-26. infarcts • White AC, Coyle C, Rajshekhar V, et al. Diagnosis and treatment of neurocysticercosis: 2017 clinical practice guidelines by the Infectious Diseases Society of America and the American Society of Tropical Medicine and Hygiene. Clin Infect Dis 2018 Feb 22. Epub ahead of print.

Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006

THANK YOU

[email protected]

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Disclosures

Updates in TB for the PCP: No conflicts Opportunities for Prevention

Advances in Infectious Diseases: New Directions for the Clinic and the Hospital March 16, 2017 Pennan Barry, MD, MPH Chief, Surveillance and Epidemiology, California TB Control Branch Assistant Clinical Professor, Division of Infectious Diseases, UCSF [email protected]

Objectives

• Establish importance of testing and treatment for latent tuberculosis infection (LTBI) Part 1: Why test? • Discuss patient populations to be tested • Review testing and treatment options • Discuss diagnosis of active TB

3 4

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Tuberculosis Natural History of TB

Not infected • Mycobacterium tuberculosis • Primary site of infection Exposure to Latent TB infection years Active TB is the lung, but can infectious TB (LTBI) disease disseminate • Person‐to‐person transmission via Rapidly develop inhalation of airborne active TB disease droplets

5 6

TB Cases in the United States Consequences of TB Disease 1982–2016 If TB disease is curable, why is prevention so important? Death 30,000 – ~ 10% of patients with TB do not survive 25,000 Pascopella, Open Forum Infect Dis, 2014

20,000 Disability – After treatment, patients have shorter life expectancy 15,000 9,287 Hoger, Int J Tuberc Lung Dis, 2014; Shuldiner, Int J Tuberc Lung Dis, 2015 10,000 Cost

5,000 – Direct costs in California over 72 million in 2016

CDC, Annual Report, 2015 7 8 Schmidt, et al. MMWR, 2017

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TB Disease vs. Latent How do TB Cases Occur in Tuberculosis Infection (LTBI) California? Progression Importation 80% of LTBI to active disease Active TB disease Latent TB infection TB within 6 months of arrival in US 2015‐2017 Cough, fever, weight loss, No symptoms PREVENTABLE night sweats with LTBI testing and 6% Abnormal chest x‐ray Normal chest x‐ray 2,000 treatment Infectious Not infectious TB cases/yr May progress to active TB disease LTBI test usually positive LTBI test positive Recent Transmission RT recipient 2014‐2016 14%

>2 Million with Latent TB Infection Barriers to TB Prevention Most Unaware and Untreated Patient U.S. Born Non‐U.S. Born • Patient feels well • Perception of risk: uncertain and not urgent • Worried about medicine side effects 0.7 1.8 Million Million Provider • Not considered important clinical problem • Unclear who to test/treat (guidelines are

0% 20% 40% 60% 80% 100% confusing)

11 • Suboptimal tests/treatment options 12

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Part 1: Key Points

• TB disease remains a substantial contributor to morbidity and mortality • Most TB cases in U.S./California are due to Part 2: Who to test? progression of LTBI and are therefore preventable • Patient and provider barriers have impeded adoption in many practice settings

13 14

What is targeted testing? Why not test everyone?

Only test patients who have TB risk factors • Testing populations with low prevalence will result in many false‐positive results

Most persons with a positive test for LTBI Prevalence of Proportion of should be treated latent TB positive tests infection that are false* U.S. born 2.8% 46% Non‐U.S. born 16% 12%

*Calculated using specificity of 97% and sensitivity of 80% CDC, MMWR, 2000 15 Miramontes, PLOS One, 2015 |Pai, Clin Micro Rev, 2014 16

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Proportion of TB Cases by National Origin California, 2016

19% 81% U.S.‐born Born outside U.S.

China Central Philippines America Mexico Vietnam India Other Countries

0% 20% 40% 60% 80% 100%

Risk Assessment https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/TB‐Risk‐Assessment.aspx

• For use by primary care providers • Extensive feedback from diverse providers • Simplicity, clarity over detail • Companion Fact Sheet • Pediatric, University, and Adult versions

https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/TB‐Risk‐Assessment.aspx 20

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Prioritize if necessary US Preventive Services Task Force • Foreign‐born persons with medical risk for progression Recommendation Grade 1. Diabetes mellitus The USPSTF recommends screening for latent 2. Smoker within past 1 year tuberculosis infection (LTBI) in populations that are 3. End stage renal disease at increased risk. 4. leukemia or lymphoma Population 5. Silicosis 6. cancer of head or neck Adults who are at increased risk for tuberculosis: 7. intestinal bypass/gastrectomy • persons born in, or former residents of, countries with increased 8. chronic malabsorption tuberculosis prevalence 9. body mass index ≤20 • persons who live in, or have lived in, high‐risk congregate 10.history of chest x‐ray findings suggestive of previous or inactive settings (such as homeless shelters and correctional facilities) TB (no prior treatment). https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/latent‐ California Department of Public Health, 2016 21 tuberculosis‐infection‐screening Sept 2016. 22

Years in US at TB Diagnosis What about age? California, 2012‒2016 • Younger persons have longer expected life during 7000 which TB progression could occur 6000

• 25‐30% of TB cases in 65+ age group 5000 76% • LTBI prevalence increases with age 4000 • Older age is a risk factor for death if active TB 3000 develops 2000 • No upper limit of age has been set for TB screening 1000 24% Foreign‐born TB Cases 0 0‐5 >6 Years in US CDC Annual Report, 2015 | Miramontes, PLOS One, 2015 | Pascopella OFID 2015 23 24

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Who to Test?: Key Points

• Use a risk‐based approach to testing – Persons with a risk and a positive test should be treated Part 3: How to test?

• Patients should be evaluated for TB risk factors regardless of age or time since entry into the U.S.

25 26

Interferon‐Gamma Release Assays Tuberculin Skin Test (TST aka PPD) (IGRAs) • How to read: – Measure induration (not • QuantiFERON®‐TB Gold (QFT) erythema) at 48‐72 hrs – Reported as positive, negative, or indeterminate – Record millimeters • QuantiFERON®‐PLUS is replacing QFT‐Gold • Positive test: – ≥ 5mm for immunosuppressed • T‐SPOT.TB (T‐Spot) including HIV, recent contacts – Reported as positive, borderline, negative, or – ≥ 10mm for all others with TB indeterminate risk

27 28

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Advantages of IGRA vs TST TST and QFT Specificity

95% • Not affected by BCG vaccination Specificity confidence interval

• Not affected by most non‐tuberculous TST without BCG 97 95–99 mycobacteria TST with BCG 59 46–73 • Interpretation is more objective QFT 96 94–98 • No return visit needed for interpretation of test • Patients and providers may lack confidence in TST results

Menzies, Ann Intern Med, 2007 CDC, MMWR, 2010 | Pai, Clin Micro Rev, 2014 29 Pai, Ann Intern Med, 2008 30

ATS/IDSA/CDC Testing non‐US‐Born Patients Guideline on TB Diagnosis • Using a test with poor specificity will result in • Use IGRA for all >5 yrs (TST acceptable) many false‐positive results • Use a second test if first test is positive in a person with no TB risk (if test required) • Among non‐US‐born patients (prevalence 16%): • Use a second test if first test is negative in a Test % of positive tests person with a high risk for progression (e.g., that are False* TNF‐ alpha, HIV) IGRA 16% TST 72%

*Calculated using specificity of 97% for IGRA, 60% for TST and sensitivity of 80% 31 Lewinsohn, et al, Clin Inf Dis. 2016; DOI: 10.1093/cid/ciw694 32 Pai, Clin Micro Rev, 2014 |Miramontes, PLOS One, 2015

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Diagnosing Latent TB Infection Case • TSTs and IGRAs cannot distinguish between • 35 yo US‐born nurse works in a long term care facility latent TB infection and active TB disease • Contact to active TB cases 3 years ago TST ? Positive ? Active TB positive  completed 9 mo of INH Latent TB infection TST or IGRA disease • Now • Active TB disease must be evaluated – Smear positive, cavitary, INH resistant TB – Review of prior CXR shows “faint irregular 1cm density” in area of current cavity

• Genotype matches prior cases (INH sens)

33 34

RULE OUT ACTIVE DISEASE How to Test?: Key Points BEFORE STARTING LTBI TREATMENT!! • Either IGRA or TST can aid in the diagnosis of • Symptom screen + chest radiograph latent TB infection – IGRA is preferred ! • If abnormal collect sputum: 1. AFB smear and culture 2. TB PCR/Nucleic Acid Amplification Test • Neither test can distinguish between latent TB infection and active TB disease • If sputum collected: – Rule out active disease before treating LTBI – Start empiric treatment for active disease – Or await final culture results before LTBI Rx

35 36

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Prevent TB Study Results

PART 4: How to treat? INH‐RPT INH P‐value N=3,986 N=3,745

Effectiveness 1.9 per 1,000 4.3 per 1,000 Non‐inferior

Completion 82.1% 69.0% P<0.001

Hepatotoxicity 0.4% 2.7% P<0.001

37 Sterling, NEJM, 2011 38

Further Studies of INH‐RPT 12 doses of weekly INH‐RPT

• Children (≥2 yrs) • Advantages: – Non‐inferior to 9 months of INH – Less hepatotoxicity (~ 7x less than INH) • HIV – Greater adherence (82% INH‐RPT vs. 69% INH) – Non‐inferior to 9 months of INH – Unable to receive ART in first 90 days • Disadvantages: • Self‐administered therapy (SAT) – Multiple drug interactions – Non‐inferior to 3HP DOT – Pill burden – Flu‐like / hypersensitivity syndrome (2.2%)

1. Bliven‐Sizemore, Int J Tuberc Lung Dis, 2015, 2. Sterling, Clin Infect Dis, 2015 1. Villarino, JAMA Pediatrics, 2015, 2. Sterling, CROI, 2014, 3. Belknap, Annals Internal Med, 2017 39 40

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4 months of daily Rifampin 9 months of daily Isoniazid (INH)

• Advantages: • Advantages: – Less hepatotoxicity (~5x less than INH) – Efficacy is 60%–90%, depending on duration of treatment – Greater adherence (78% RIF vs. 60% INH) – Fewer drug‐drug interactions

• Disadvantages: • Disadvantages: – Less evidence of efficacy – Adherence: Completion rates <50% – Multiple drug interactions – Hepatotoxicity: Incidence 0.1%, but increases with age • Warfarin, oral contraceptives, methadone, protease – Clinic time required for 9 monthly visits inhibitors, tenofovir alafenamide

Hong Kong Chest Service/Tuberculosis Research Centre, Am Rev Respir Dis, 1992 Villarino, Am J Respir Crit Care Med, 1997 | Menzies, Ann Intern Med, 2008 41 1. Nolan, JAMA, 1999, 2. Smieja, Cochrane Database Syst Rev, 2000, 3. Menzies, Ann Int Med, 2008 42

How to Treat?: Key Points

• INH is traditional gold‐standard, but has low treatment initiation and completion rates Part 5: Diagnosing active TB • Short course regimens have higher completion rates and are less hepatotoxic

• INH‐RPT (12 doses) is as efficacious as INH (9 months)

43 44

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Clinical Presentation: Case Signs and Symptoms • 42 yo man born in the Philippines p/w cough .Cough (dry/productive sputum) 75‐80% x 1 month, 10 pound weight loss .Weight loss 45‐75% • PMH: DM (Hgb A1c=8.0), Tobacco .Fatigue 60‐70% • TST/PPD positive (16mm) 2 years before but .Fever 50‐60% not treated .Night sweats 50‐55% • CXR shows RUL infiltrate, no cavity .Hemoptysis 25‐35% .Pleuritic chest pain .No symptoms 10‐20%

Barnes 1988, Miller 2000 45 46

Radiographic Patterns of Sputum AFB smear Pulmonary TB • Smear positive ≥ 104 bacilli per ml Pattern “Typical” (Reactivation) • Smear AFB amount correlates with Infiltrate Majority of Cases (80%) infectiousness 85% upper • 40‐60% of culture positive cases will be Cavitation Minority of Cases (20%) Rare in children and primary TB smear negative Adenopathy Uncommon More common in children Three smear negative specimens and primary TB does not “rule out” TB! Effusion May be present

47 48

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Xpert MTB/RIF Test Performance What is the Added Value of NAAT? Compared with Culture, U.S. patients • AFB smear (–): – 50‐70% of smear –/culture + cases will be + by NAAT  Sensitivity Specificity start treatment (earlier) – If NAAT (–) likelihood of TB lower 1 Xpert 2 Xperts • Still start treatment if suspicion is high • AFB smear (+): Smear (+) 96.7% 100% – NAAT (+) can confirm TB quickly (59/61) (62/62) – If NAAT (–), prevent falsely diagnosing TB 99.2% (likely NTM if inhibitors ruled out; result repeated) Smear (–) 59.3% 71.4% • Release from isolation (2 Xperts finds all smear +) (16/27) (20/28)

NTCA /APHL Consensus Statement: http://www.tbcontrollers.org/docs/resources/NTCA_APHL_GeneXpert_Consensus_Statement_Final.pdf

Luetkemeyer Clin Infect Dis 2016 Luetkemeyer Clin Infect Dis 2016 50

Use of NAATs! Active TB Diagnosis: Key Points

• NAAT should be used unless results would • Most but not all patients have TB symptoms not impact clinical or public health • Most patients do not have a cavity on CXR management • Use NAATs • Xpert results showing Rif resistance should: • Clinical suspicion is crucial  don’t be afraid – Be confirmed using sequencing and culture of empiric TB treatment – Trigger suspicion for MDR TB (not Rif monoR) • Discuss with state/local TB control program

CDC MMWR October 18, 2013 / 62(41);821‐824 51 52

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Summary of main points

• The majority of active TB in the U.S. arises from latent tuberculosis infection (LTBI) Opportunities for prevention • In all people with positive TB skin test or summary IGRA, rule out active TB disease • Test with an IGRA • Treat with 12 doses of INH + Rifapentine (3HP) or 4 months of rifampin if no contra‐ indications • Call local TB control program with questions

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Acknowledgments References and Resources

Anna Aistrich • California DPH TB Control Branch: http://www.cdph.ca.gov/tbcb Brian Baker – Risk Assessment: https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/TB‐Risk‐Assessment.aspx – INH+Rifapentine Fact Sheet: Shereen Katrak https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document%20Library/TBCB‐INH‐RIF‐LTBI‐fact‐ Jennifer Flood sheet.pdf Tessa Mochizuki • CDC – IGRA Guideline: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf Caitlin Reed – INH+Rifapentine Guideline: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6048a3.htm Gisela Schecter – NAAT Guideline: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5801a3.htm?s_cid=mm5801a3_e Neha Shah – Xpert MMWR: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6241a1.htm • California TB Controllers Association Tambi Shaw – IGRA Guideline: http://www.ctca.org/fileLibrary/file_348.pdf Stephanie Spencer • National TB Controllers Association /Association of Public Health Laboratories Consensus Statement on use of Xpert for release from respiratory isolation: Janice Westenhouse – http://www.tbcontrollers.org/docs/resources/NTCA_APHL_GeneXpert_Consensus_Statement_Final.pdf Kristen Wendorf • ATS/IDSA/CDC Guidelines: – Lewinsohn, et al, Clin Inf Dis. 2016; https://doi.org/10.1093/cid/ciw694 – Nahid, et al, Clin Inf Dis. 2016; https://doi.org/10.1093/cid/ciw376 • TST in 3D: http://www.tstin3d.com/en/calc.html • Curry International Tuberculosis Center (Warmline Consultation Service) [email protected] http://www.currytbcenter.ucsf.edu/ 877‐390‐6682 or 510‐238‐5100 Use the California TB Risk Assessment

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302 14 Disclosures Sexually Transmitted Diseases: Now More than Ever The views expressed herein do not necessarily reflect the official policies of the City and County of San Francisco; Susan S. Philip, MD, MPH nor does mention of the San Francisco Department of Public Health imply its endorsement. Director, Disease Prevention and Control Branch Population Health Division San Francisco Department of Public Health S. Philip has received research support from Roche Assistant Clinical Professor of Medicine Division of Infectious Diseases Diagnostics and GlaxoSmithKline University of California, San Francisco

Overview

 (Very!) Brief US STD Epidemiology

 Sexual History

 Select STDs: Clinical Updates

CDC Treatment Guidelines App for iOS and Android

Available now, FREE! THE guide for STD treatment (accept no competitors)

4 http://www.cdc.gov/std/tg2015/

303 1 San Francisco: STDs Increasing while HIV Diagnoses Decline

1400 4500 Gonorrhea 4000 1200 3500 1000 Syphilis 3000 800 2500

600 2000 HIV 1500

400 # Gonorrhea Cases 1000

# HIV and Early Syphilis Cases 200 500

0 0

Year CDC 2016 STD Surveillance Report SFDPH Population Health Division, Applied Research Community Health Epidemiology and Surveillance Branch

70‐80% of Reportable STDs are diagnosed outside of STD Clinics Many infections are asymptomatic

100%

90% 80% Screening is needed to prevent complications and 70%

60% additional infections

50% – PID, ectopic pregnancy, infertility

40% – Congenital syphilis

30% – Identify candidates for HIV PreExposure Prophylaxis

20%

10%

0% Chlamydia Gonorrhea Primary or Secondary Syphilis

Unknown settings STD Clinics Non STD clinic settings

CDC 2016 STD Surveillance Report

304 2 Persons diagnosed with an STD should be given highest priority for PrEP and other HIV prevention Many infections are asymptomatic

Rectal GC or CT 1 in 15 MSM were diagnosed with HIV within 1 year.* Screening is needed to prevent complications and Primary or additional infections Secondary Syphilis – PID, ectopic pregnancy, infertility 1 in 18 MSM were diagnosed with HIV within 1 year.** – Congenital syphilis No rectal STD or – Identify candidates for HIV PreExposure Prophylaxis syphilis infection

Need to know sexual history to screen appropriately 1 in 53 MSM were diagnosed with HIV within 1 year.* *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

Brief(!) Sexual History is Key Case 1 • Neutral language: At a new patient’s initial visit, you learn he is a gay man – “Do you have sex with men, who has had 3 sex partners in the last year. He feels fine women, or both?” (highest value) and says all STD tests were negative a year ago. In – “What are you doing to prevent addition to an HIV test, what else would you order? unwanted pregnancies or STDs” rather than “You use condoms 1. No additional tests – he is asymptomatic 100%, right?” 2. Urine gonorrhea and chlamydia • Consider adding questions to self‐ 3. Syphilis serology registration materials 4. pharyngeal GC, rectal GC and CT, syphilis serology • Find referral resources for complex 5. I need to know more before deciding trauma or sexual dysfunction

305 3 STD Asymptomatic Screening for Women STD Asymptomatic Screening for MSM

Sexually Active women up to age 25 Screen at least annually, or every 3‐6 mos if high risk • Routine annual chlamydia and gonorrhea screening * • Other STDs and HIV based on risk HIV Syphilis Women over 25 years of age • STD/HIV testing based on risk Urethral GC and CT Rectal GC and CT (if anal sex) Pregnant Women Pharyngeal GC (if oral sex) • Chlamydia • Gonorrhea (<25 years of age or risk) • HIV Hepatitis B surface Ag (frequency not specified) • Syphilis serology Hepatitis C if IDU, born 1945‐65 or transfusion before 1992 • HepB sAg • Hep C (if high risk) HIV + MSM: same as for HIV negative but add Hepatitis C (annually) HIV+ Women • On intake and at least annually: Syphilis, Chlamydia, Anal Cancer – data insufficient for routine screening, some Gonorrhea, and Trichomonas Screening centers perform anal Pap and HRA

* High risk: multiple and/or anonymous partners, CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment drug use, or these risks in patient’s partners

Proportion of asymptomatic rectal and urethral : chlamydial and gonococcal infection among MSM– San Francisco City Clinic, 2011 5% 9% Rectal Infections

91% 95% Summary: Chlamydia Gonorrhea • Use Nucleic Acid Amplification Tests (NAATs) for n=308 N=237 Asymptomatic symptomatic AND asymptomatic patients Urethral 11% Symptomatic • Optimal Specimens: • Women –vaginal swabs (may be self collected) Infections 42% • Men – first catch urine 58% • Extragenital (oropharyngeal, rectal) NAAT not FDA-cleared, 89% but recommended – need lab validation Chlamydia Gonorrhea n=234 n=244 Adapted from Kent, CK et al, Clin Infect Dis July 2005

306 4 Think three site screening! 70-90% of GC and CT infections in MSM would be missed if only urine based screening were done Self‐collected Specimens for GC/CT Screening

• FDA cleared for vaginal swabs! • With lab validation, can use for rectal and pharyngeal swabs – Highly acceptable, similar performance compared to clinician-collected specimens – Self-collection can be performed at laboratory along with blood draw/urine collection or in the exam room before/after the provider visit – May save patient an office visit – May save the provider time

Van der helm, 2009, STD; Sexton, 2013 J Fam Pract; Dodge, 2012 Sex Health Patton CID 2014 Freeman 2011, STD; Alexander 2008, STI; Moncada 2009, STD

Case 2 Case 2: Treatment Options

• You see a 22 year old man with no PMH who presents with 2 1) Ciprofloxacin 500 mg PO x1 days of urethral discharge and dysuria. On exam, he has 2) Cefixime 400 mg PO x1 plus Azithromycin 1 g PO x1 purulent urethral discharge. He has had 3 female partners in 3) Azithromycin 2 g PO x1 the last 3 months. He has a documented history of anaphylaxis to cephalosporins. 4) Gentamicin 240 mg IM x1 plus Azithromycin 2 g PO x1 5) Ceftriaxone 250 mg IM x1 plus Azithromycin 1 g PO x1 • How would you treat him?

307 5 Gonorrhea Treatment is one of Current Recommended Gonorrhea CDC’s key strategies to reducing risk Treatment – any anatomic site of resistant Neisseria gonorrhoeae Ceftriaxone Azithromycin 1g PO x 1 250mg IM x 1 

This is Dual treatment for GC – add the azithromycin regardless of CT result

Alternatives (not recommended for pharyngeal site infections): Cefixime 400mg PO x 1 + Azithromycin 1g PO x 1 Gentamicin 240mg IM x 1 + Azithromycin 2g PO x 1 Gemifloxacin 320mg PO x 1 + Azithromycin 2g PO x 1

Antibiotic Resistance Threats in the United States, CDC 2013 CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

Gonococcal Isolate Surveillance Project (GISP) Disseminated Gonococcal Infection (DGI) Percent of Neisseria Gonorrhoeae Isolates with CDC "Alert" Values for Azithromycin in California GISP STD Clinic Sites, 1992–2016 • Arthritis (monoarticular) in 30%

6 • “Dermatitis‐arthritis syndrome” • Characterized by fever, chills, skin lesions

4 (70%), arthralgias, tenosynovitis • Less commonly, hepatitis, myocarditis,

2 endocarditis, meningitis

Percent of Isolates • Rash characterized as macular or papular,

0 pustular, hemorrhagic or necrotic, mostly on '92 '93 '94 '95 '96 '97 '98 '99 2000 '01 '02 '03 '04 '05 '06 '07 '08 '09 2010 '11 '12 '13 '14 '15 '16 '17 Year distal extremities

Note:“Alert” values are set by CDC as markers to look at possible decreased susceptibility. Azithromycin alerts have MICs ≥ 2.0 μg/mL. No data before 1992. 2015‐2016 data are provisional as of 3/2/2017. STD Clinic Sites:Long Beach (ended participation in 2007), Los Angeles (added in 2003), Orange, San Diego, San Francisco Rev. 09/2017

308 6 DGI Skin Lesions DGI Management

– May require hospitalization – Clinical evaluation for endocarditis and meningitis – Labs • Synovial fluid culture and cell count • Blood cultures x 2 (ask lab eval for GC) – positive in 50% of patients presenting with dermatitis‐arthritis syndrome • Genital, rectal, skin lesion GC testing (culture and NAAT) – Tx: Ceftriaxone 1g IM or IV q 24 hours + azithromycin 1g PO x 1 – Alternative: Cefotaxime OR Ceftizoxime 1g IV q8 hours + azithromycin 1g PO x 1 – Continue IV/IM 24‐48 hours after clinical improvement, then may switch to oral GC agent per sensitivities – Evaluate and empirically treat asymptomatic sex partners for uncomplicated GC Suzaki et al. Internal Medicine 2011

Case 3 Treatment of uncomplicated Chlamydia Adolescents and Adults A 27 year old sexually active HIV+ gay man presents with complaints of severe rectal pain and bleeding. These Recommended regimens (non‐pregnant): symptoms began acutely 3 days ago. He is unable to . Azithromycin 1 g orally in a single dose tolerate anoscopy due to pain but there is evidence of . purulent mucus and blood on external exam. Doxycycline 100 mg orally twice daily for 7 days If you were to pick an empiric treatment regimen today, while awaiting laboratory results, would it be: Recommended regimens (pregnant): . Azithromycin 1 g orally in a single dose 1. Ceftriaxone 250mg IM x 1 + Azithromycin 1g PO x 1 2. Doxycycline 100mg PO bid x 21 days 3. Azithromycin 1 g PO x 1 4. Azithromycin 1g PO qweek x 3 weeks

CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

309 7 Lymphogranuloma venereum (LGV) LGV: Recent shift?

• Caused by specific serovars of Chlamydia trachomatis • In N. America and Western Europe clinical presentation since 2000’s – Serovars L1, L2, L3 shifting to anorectal syndromes in MSM, particularly HIV‐infected • Compared to other serovars of CT, more invasive and virulent, tending to result in systemic • Proctitis disease • Organism travels through lymphatics to multiply within macrophages in regional lymph nodes – Anal pruritus (itching) • Transmission – primarily sexual – Mucous rectal discharge • Rate of transmission unknown • Proctocolitis & hyperplasia of intestinal and • Reservoir not defined peri‐rectal lymphatic tissue • Endemic in many tropical regions, sporadic in N. America and Europe – Symptoms of fever, rectal pain, tenesmus (straining) • Classically in three stages: Primary (painless papule), Secondary – Anoscopy shows diffuse friability and discrete ulcerations (inguinal lymphadenopathy/Buboes), tertiary (strictures, frozen pelvis) – May be mistaken for inflammatory bowel disease

LGV – Primary lesions LGV – Bilateral Inguinal Adenopathy and Ruptured Bubo

• papule • generally painless

groove sign

DOIA 2000

310 8 LGV Proctitis: Diagnosing LGV Proctocolitis: Sigmoidoscopy findings • Primarily by clinical findings/history – severe proctocolitis in MSM is • diffuse friability concerning for LGV • discrete ulceration • May be mistaken for inflammatory bowel disease • Serologic tests can support diagnosis • Rectal CT NAAT will be positive – but does not further specify whether LGV serovars are the cause • Swabs of rectal lesions visualized by anoscopy is better than blind rectal swab • Local or state public health may be able to facilitate molecular confirmation, but likely with time delay.

Treatment of LGV Case 3 38 year old woman, new to your practice, previously injected drugs but none in the past 10 years. HIV and HCV screen negative and she is Recommended: asymptomatic. The lab reports the patient’s syphilis test results are: • Doxycycline 100 mg PO BID x 21 days RPR 1:4 and TPPA+ Your next step? Alternative: • Erythromycin base 500 mg PO QID x 21 days 1. Treat with benzathine PCN 2.4 mu IM x 1 2. Treat with benzathine PCN 2.4 mu IM x 3 Azithromycin 1 g PO weekly for 3 weeks also may be effective 3. Do nothing as this is unlikely to be syphilis based on expected anti‐chlamydial activity but not routinely recommended 4. Perform an LP to rule out neurosyphilis 5. Bring her in for a focused history, physical exam and a pregnancy test Partners within past 30 days of onset of symptoms need evaluation. If w/o symptoms treat: Doxycycline 100 mg BID x 7 days or azithromycin 1g PO x 1

311 9 Syphilis – No Change in 2015 Guidelines Syphilis – No Change in 2015 Guidelines Stage determines Treatment Stage determines Treatment Primary, Secondary & Early Latent: Alternatives (non‐pregnant penicillin‐allergic adults): Primary, Secondary & Early Latent (infection in past 1 year): Doxycycline 100 mg po bid x 14 days • Benzathine penicillin G 2.4 million units IM in a single dose Tetracycline 500 mg po qid x 14 days Ceftriaxone 1 g IV (or IM) qd x 10‐14 d Late Latent and Unknown Duration (infection earlier than 1 year ago): • Benzathine Penicillin G 7.2 million units total, given as 3 doses Azithromycin 2 g po in a single dose* of 2.4 million units each at 1 week intervals Late Latent: Alternatives (non‐pregnant penicillin‐allergic adults): Doxycycline 100 mg po bid x 28 days Neurosyphilis (can occur anytime in the course of infection): Tetracycline 500 mg po qid x 28 days • Aqueous Crystalline Penicillin G 18‐24 million units IV daily administered as 3‐4 million IV q 4 hr for 10 ‐14 d * Should be used only if PCN and doxycycline can’t be used and not in MSM or pregnant women In pregnancy, benzathine penicillin is the only No enhanced efficacy of additional doses of penicillin, recommended therapy. No alternatives amoxicillin or other antibiotics even if HIV infected!

CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

Syphilis Stage Determines Treatment If you cannot ascertain that infection has happened in < 1 year, then must treat for late disease What can help pinpoint timing of infection? Primary Syphilis •Signs or symptoms of primary or secondary •Can recall those symptoms in past year •Contact to a known case in past year •Negative non-treponemal serology (RPR or VDRL) in the past year –This is where routine screening recommendation for MSM and others at higher risk is helpful

312 10 41 Chancres may be multiple, cannot easily distinguish 42 fh

Chancres may be perirectal, not noticed by patient 43 Chancres may be vaginal or cervical, not noticed by 44 ti t

313 11 Secondary syphilis

Chancres may be oral or on lip 45 46

Secondary rash may mimic drug rash or other derm 47 Secondary rash – scrotum 48 diti

314 12 Condyloma lata

Secondary rash – soles of feet 49 Condylomata lata 50

Syphilis – When to LP? Mucosal Lesion • Clinical signs of neurosyphilis – Cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, auditory or ophthalmic abnormalities • Serologic treatment failure • Evidence of active tertiary syphilis (e.g. aortitis and gumma) • HIV positive and late latent syphilis or syphilis of unknown duration

Mucous patch 51 CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

315 13 Consider Ocular Syphilis! Additional Screening after an STD infection

Cluster of four cases Washington State Dec 2014 – Jan 2015 • Women with CT, GC or trichomonas should be All MSM, 75% HIV-infected rescreened at 3 months after treatment. Two patients with permanent visual loss • Men with CT or GC should be rescreened at 3 months Subsequently eight cases identified in San Francisco Dec 2014-March 2015 (75% after treatment. MSM, 88% HIV-infected) • Patients diagnosed with syphilis should undergo follow up serologic serology per current recommendations as Providers should have a high suspicion for well as be screened for other STDs including HIV. syphilis in patients with visual complaints, especially HIV-infected MSM • HIV testing should also be considered in all patients • with a prior STD history Treatment for ocular syphilis is IV PCN as for neurosyphilis even if the CSF lab tests are unremarkable Should also perform pregnancy testing in women diagnosed with an STD

Slide Courtesy I. Park MD, MS CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

Rates of Congenital Syphilis continue to rise Additional Points on Preventing Congenital Syphilis

• Congenital cases are sentinel events for clinical delivery systems AND public health

• Public health prioritizes female partners of male syphilis cases – please prepare patients and encourage them to work with us to ensure partners are treated

• Remember that penicillin is the only acceptable treatment for pregnant women with syphilis – must desensitize if serious true allergy

• Must adhere to strict 7‐day interval for weekly benzathine penicillin in pregnant patients with late latent syphilis (likely OK to extend interval up to 14 days in non‐pregnant adults). If longer than 7 day interval in pregnancy, must restart series.

Bowen MMWR Morb Mortal Wkly Rep. 2015 Nov 13;64(44):1241-5. http://www.cnn.com/2017/03/01/health/syphilis-newborns-partner/index.html accessed March 1, 2017

316 14 Case 4 Case 4 21 year old woman presents to the ED with severe perineal pain, photophobia What would you expect to find from her Herpes Simplex and headache. You see the following on exam: Virus (HSV) serology results?

1. Only HSV‐1 Ab is positive 2. Only HSV‐2 Ab is positive 3. Both HSV‐1 and HSV‐2 Ab results are positive 4. Both HSV‐1 and HSV‐2 are positive

CDC Image Library

Genital Herpes Declining Seroprevalence of HSV‐2 NHANES* 1999‐2016, age 14‐49 • While HSV‐2 is the more common cause, HSV‐1 has increased • Many cases are asymptomatic or atypical! ↓ from 18.0% to 12.1% overall • Primary Genital Herpes (no prior HSV‐1 or HSV‐2) – Can have severe widespread genital ulcers, dysuria, urinary retention, aseptic meningitis • Non Primary first episode genital herpes (serology positive for HSV‐1 or HSV‐2; newly infected with other type) – Fewer lesions, less systemic symptoms • Recurrent Infection – Less severe, usually decrease frequency, intensity, duration over time *National Health and Nutrition Examination Survey National Center for Health Statistics, Data Brief No. 304, 2018.

317 15 Genital Herpes ‐ Diagnosis Genital herpes ‐ treatment

• If lesions – test here first! • First episode • Recurrent episode – – – Acyclovir 400 mg three times per day PCR is test of choice. Acyclovir 400 mg three times x 5 days • Serology is useful in specific instances per day x 7‐10 days – Acyclovir 800 mg twice per day x 5 – Acyclovir 200 mg five times per days – Must be type specific (Glycoprotein G) and use IgG, not IgM day x 7‐10 days – Acyclovir 800 mg three times per day – Patient with history of genital ulcers, but none currently – Valacyclovir 1 g twice per day x x 2 days – Valacyclovir 500 mg twice per day x 3 – Patient’s partner(s) with genital herpes 7‐10 days days – Famciclovir 250 mg three times • – Valacyclovir 1 g once per day x 5 days General screening of the adolescents and adults (including in per day x 7‐10 days – Famciclovir 125 mg twice per day x 5 pregnancy) is NOT recommended days – Famciclovir 1 g twice per day x 1 day – Famciclovir 500 mg once, followed by 250 mg twice daily x 2 days CDC STD Treatment Guidelines 2015; USPSTF JAMA. 2016;316(23):2525-2530 Slide courtesy of Lisa Winston

Genital herpes ‐ suppression Fantastic STD Clinical and CME resource:

• Reduces recurrences by 70‐80% • Long term safety and efficacy documented • Suppressive therapy decreases transmission – Condoms, avoidance of sexual activity with active lesions • Recurrences usually diminish over time; consider discontinuation after a period of suppressive therapy • Regimens – Acyclovir 400 mg twice per day – Valacyclovir 500 mg once per day – Valacyclovir 1 g once per day – Famciclovir 250 mg twice per day

Slide courtesy of Lisa Winston University of Washington, National Network of STD Clinical Prevention Training Centers. http://www.std.uw.edu/

318 16 Thank You! Ina Park Stephanie Cohen Lisa Winston California STD/HIV Prevention Training Center

2015 CDC STD Treatment Guidelines: http://www.cdc.gov/std/tg2015/default.htm

Contact information: [email protected] www.sfcityclinic.org