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Home , Aminopenicillin, Atypical bacteria, Mycoplasma pneumoniae, Telavancin

3/17/19

Super Bugs Need Super Drugs, or Do They? George Dresden, MSN, ACNP, DNP

Objectives ØDetermine which to use based on pharmacodynamic category: time dependent, concentration dependent, time dependent/concentration enhanced ØImprove your prescribing of for with resistance to beta lactams, including . ØAssess for all gram negative and positive bacteria, as well as viral etiologies with secondary bacterial . Recognize, isolate, and treat the superbugs early. ØIn immunocompromised patients test for fungal etiologies, and be prepared to treat them. Differentiate between opportunistic and non-opportunistic systemic infections.

Antibiotic/ Biggest Threats in 2013

Urgent Threats Ø Drug-resistant Shigella Ø -resistant Enterobacteriaeae (CRE) Ø -resistant Staphyococcus aureus (MRSA) Ø Drug-resistant Neisseria Gonorrhoeae Ø Drug-resistant pneumoniae Ø Clostridiodes Difficile Ø Drug-resistant Tuberculosis Serious Threats Ø Multidrug-resistant Acinetobacter Concerning Threats Ø Drug-resistant Campylobacter Ø -resistant Staphylocccus aureus (VRSA) Ø Fluconazole-resistant Candida Ø -Resistant Group A Streptococcus Ø Extended-spectrum Beta-lactamase producing Ø Clindamycin-resistant Group B Streptococcus Enterobacteriaceae Ø Vancomycin-resistant (VRE) Ø Multidrug-resistant Pseudomonas aerginosa CDC is working toward releasing an updated Threats Ø Drug-resistant non-typhoidal Salmonella Report in the Fall of 2019.

1 3/17/19

World Health Organization’s Top 12 Priority

Priority 1: CRITICAL Priority 2: HIGH › Acintobacter baumannii, carbapenem-resistant › , vancomycin-resistant › , carbapenem-resistant › Staphylococcus, methicillin-resistant, vancomycim- intermediate and resistant › Enterobacteriaceae, carbapenem-resistant, ESBL- producing › Helicobacter pylori, -resistant – Klebseilla › Campylobacter spp., fluroquinolone-resistant – Escherichia coli – Enterobacter spp. › Salmonellae, fluroquinolone-resistant – Serratia spp. › Neisseria gonorrhoeae, third generation – Proteus sp. -resistant, fluroquinolone-resistant – Providencia spp – Morganella spp. Priority 3: MEDIUM › Streptococus pneumoniae, penicillin-non-susceptible › Haemophilus influenzae, -resistant › Shigella spp., fluroquinolone-resistant

So, How Did We Get Here? Quick Terminology Review-Take a Nap if this is Old Hat for you › Bacteriostatic-inhibition of bacterial growth › Bactericidal-killing of bacteria › Minimum inhibitory concentration (MIC)-the lowest concentration of antibiotic that completely inhibits growth of the specific organism being tested › Minimum bactericidal concentration (MBC)- the lowest concentration of antibiotic at which bacteria are killed Evidence supports killing when treating endocarditis, meningitis and osteomyelitis, otherwise, inhibition of growth is generally sufficient.

So How Did We Get Here? › Overuse or misuse of antibiotics, i.e. giving antibiotics for a viral (#1 misuse) › Patients not completing courses of antibiotics when they start feeling better, so they get re-infected › Saving antibiotics and sharing them with others or taking them later for a different illness

2 3/17/19

Concentration vs Time-Dependent Killing For an antibiotic to eradicate an organism: – It must bind to its target site(s) in the bacterium – It must occupy an adequate number of binding sites (concentration)

Pharmacokinetic/Pharmacodynamic Parameters Affecting Antibiotic Potency – To work effectively, it must remain there long enough for the metabolic processes of the bacteria to be sufficiently inhibited (Time-Dependent)

Concentration vs Time-Dependent Killing

Antibiotic Pharmacodynamic Categories Time –Dependent Concentration-Dependent Time-Dependent-Concentration (T> MIC) Cmax/MIC or AUC/MIC Enhanced No post-antibiotic effect Strong post-antibiotic effect AUC 24/MIC (for gram-) Moderate post-antibiotic effect Aminoglycosides () Fluroquinolones Clindamycin Erythromycin Metronidazole Vancomycin Amphotericin B Azole antifungals >MIC for 40-50% of dosing AUC/MIC >125 for gram- interval-max killing seen when bacteria, > 25-50 for gram+ time above MIC is at least 70% cocci Cmax/MIC >10. of dosing interval.

DOUBLE COVERAGE

Based on the assumptions Ø The combination provides a broad spectrum of coverage for empiric treatment before knowing the ID and susceptibility of offending Ø The combination may provide additive or synergistic effects against the pathogen Ø The combination of antibiotics may decrease or prevent the emergence of resistant bacteria

3 3/17/19

Beta Lactams

Development of Beta Lactam Resistance › Decreased penetration to the target site – Permeability of the outer membrane no longer allows the antibiotic through such as with Pseudomonas aeruginosa › Alteration of the target site – Penicillin binding (PBPs) may be changed so that they no longer have an affinity for the beta-lactam antibiotics so that the bacterial cell is no longer inhibited. Examples are pneumococci, methicillin resistance in staphylococci, and Haemophilus influenzae. › Inactivation by a bacterial (ESBL) – Chromosomal beta-lactamases – Plasmid-mediated beta-lactamases

How to Use Beta Lactams Effectively Anti-Staphylococcal Penicillin Natural Penicillin › Methcillin › Pen V – Gm+, very narrow spectrum, should be given IV, – Gm+, less effective against gm -, narrow may cause interstitial nephritis spectrum, PO, prone to ß-lactamase (, , rheumatic , › streptococcal skin infections) – Gm+, treatment for PCN-resistant Staphyloocus Amino-Penicillin aureus, very narrow spectrum, should be given IV › › Ampicillin – Gm+, treatment for staphylococcal infections, very – Gm+ & gm -, broad spectrum PO and IV, narrow spectrum, should be given IV prone to ß-lactamase (ear infections, sinusitis, UTI, menigitis) › › – Effective against staphylococci that produce ß- lactamase, very narrow spectrum, should be given – Gm+ & gm -, broad spectrum PO and IV, PO prone to ß-lactamase (skin infection, sinusitis, UTI, streptococcal ) › and – Gm+, and Staphyococci that produce ß- lactamase, very narrow spectrum, should be given PO

4 3/17/19

How to Use Beta Lactams Effectively Anti-Pseudomonal Penicillin Cephalosporin › Pipercillin › 1st generation predominantly active – Gm+ & Gm-, extended spectrum, against Gm+ bacteria, the 3 successive should be given IV or IM if given with generations have increased activity a ß-lactamase inhibitor, against Gm- bacteria, reducing Gm+ further strengthens its effectiveness activity. › › 1st generation: cefalothin, , – Gm- & limited Gm+, mainly useful for , & UTI › 2nd generation: (PO), & › – Mainly Gm-, particularly Pseudomonas aeruginosa, also stenotrophomonas › 3rd generation: , , maltophilia infections & › 4th generation: › 5th generation: ceftaroline

How to Use Beta Lactams Effectively Carbapenems › Broad spectrum beta-lactam › Aztreonam antibiotics. They are highly – Gm+ and Gm- & anaerobic bacteria, resistant to ß-lactamases. broad spectrum, IV, NOT active against MRSA › – Aerobic and anaerobic, Gm+ and ß-lactamase Inhibitors Gm- (including ESBL-producing strains), and Pseudomonas, IV, can › Resemble ß-lactam antibiotic produce seizures at high doses structure, so bind to the ß- lactamase and protect the › antibiotic from destruction – Aerobic and anaerobic, Gm+ and Gm-, ultra broad spectrum, IV › They are most successful when the binding is irreversible › – Gm+ and Gm-, broad spectrum, IV, › 3 Most Important: Clavulanic NOT effective against MRSA acid, , & Tazobactam

Beta-Lactamase Enzyme

5 3/17/19

Why Is It Important To Detect ESBL’s? › The presence of an ESBL-producing organism in a clinical infection can result in treatment failure if the wrong antibiotic is used. › ESBL’s can be difficult to detect because they have varying levels of activity against the cephalosporins. It is crucial to choose wisely which antibiotics to test against. For example, one enzyme may have a minimum inhibitory concentration (MIC) of 4 μg/ml on ceftazidime but have poor activity on cefotaxime with a MIC of 256 μg/ml. › If an ESBL is detected, ALL PENICILLIN’S, CEPHALOSPORINS, AND AZTREONAM SHOULD BE REPORTED AS RESISTANT, even if in vitro test results indicate they have susceptibility.

Metallo Beta-Lacamase › Resistant against a broad spectrum of beta-lactam antibiotics. › This includes those in the carbapenem family. › This particular class is characterized by its ability to hydrolyze carbapenems and by their resistance to available ß-lactamase inhibitors (tazobactam, sulbactam, ) but susceptibility by metal ion chelators (vitamin B12, ascorbic acid). › The most common bacteria that are responsible for this enzyme are Gm- such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa.

Penicillin-under or over utilized? › Penicillin allergy is the most common, reported by up to 15% of hospitalized patients › Clinically-can they be safely given structurally related cephalosporins or carbapenems › Do they need allergy consultation first?

6 3/17/19

Approach to the Patient with a Past PCN Reaction Who Requires Antibiotics

The Penicillins Category Parenteral Agents Oral Agents Natural Penicillins Penicillin G Penicillin V Antistaphylococcal penicillins Nafcillin, oxacillin Dicloxacillin Ampicillin Amoxacillin, ampicillin Aminopenicillins+ß-lactamase Ampicillin-Sulbactam Amoxicillin-clavulanate inhibitors Extended spectrum penicillins Pipercillin, ticarcillin Extended spectrum penicillins+ß- Pipercillin-tazobactam, lactamase inhibitors ticarcillin-clavulanate

Knowledge Affirmation Which of the following antibiotics is NOT a ß-lactam? a. Ampicillin b. Meropenem c. Ceftriaxone d. Vancomycin e. Aztreonam

7 3/17/19

Knowledge Affirmation Which of the following antibiotics is NOT a ß-lactam? a. Ampicillin b. Meropenem c. Ceftriaxone d. Vancomycin e. Aztreonam

Treatment Options for Gram Positive Bacteria

Antimicrobial Agents for Treatment of Infections Caused by Antibiotic Class Antibiotic Antistaphylococcal penicillins Nafcillin, oxacillin 1st generation cephalosporins Cefazolin 2nd generation cephalosporins Cefuroxime 3rd generation cephalosporins Ceftriaxone, cefotaxime 4th generation cephalosporins Cefepime ß-lactam/ß-lactamase inhibitor combinations Ampcillin-sulbactam, pipercillin-tazobactam, ticarcillin-claculanate Carbapenems Imipenem, meropenem, Also sometimes active (not first choice, and only if susceptibilities are known Clindamycin Sulfa drugs -sulfamethoxazole Quinolones Ciprofloxacin, , moxifloxacin Tetracyclines Minocycline, Macrolides Erythromycin, azithromycin Rifamycins Rifampin Aminoglycosides Gentamycin (synergistic dosing) If MRSA and Vancomycin, , ortavancin, Oxazolidinones , tedizolid Streptogramins Quinupristin-dalfopristin -like Tigecycline 5th generation cephaosporins Ceftaroline

8 3/17/19

Treatment for in the Hospitalized Patient

Outpatient Treatment for Beta Lactam Susceptible Streptococcus pneumoniae

Antimicrobial Agents for Treatment of Infections Caused by Streptococcal Species Other than Streptococcal Pneumoniae

Antibiotic Class Antibiotic Natural penicillins Penicillin G Aminopenicillins Ampicillin Aminoglycosides are sometimes Gentamycin added for synergy Clindamycin is added for severe invasive Streptococcus pyrogenes infections Alternatives 1st generation cephalosporin Cefazolin Azithromycin If PCN resistant Vancomycin 2nd generation cephalosporin Cefuroxime 3rd generation cephalosporin Cefotaxime, ceftriaxone

9 3/17/19

IV Treatment for Susceptible Enterococcal Infections

Knowledge Affirmation Each of the following might be appropriate empiric monotherapy for cellulitis EXCEPT: a. Ceftazidime b. Vancomycin c. Oxacillin d. Cefazolin e. Clindamycin

Knowledge Affirmation Each of the following might be appropriate empiric monotherapy for cellulitis EXCEPT: a. Ceftazidime b. Vancomycin c. Oxacillin d. Cefazolin e. Clindamycin

10 3/17/19

Gram Negative Bacteria

Antimicrobial Agents for Treatment of Infections caused by Enterobacteriaceae

Antibiotic Class Antibiotic Escherichia coli, Klebsiella spp., Proteus spp. Aminopenicillins (except Klepseilla spp. and Ampicillin Proteus vulgaris) 1st generation cephalosporin (except for Cefazolin Proteus vulgaris) Sulfa drugs Trimethoprim-sulfamethoxazole Quinolones Ciprofloxacin, levofloxacin, moxifloxacin If resistant to the above antibiotics 3rd, 4th and 5th generation cephalosporins Cefotaxime, ceftriaxone, cefipime, ceftaroline Cephalosporin+ß-lactamase inhibitor Ceftazidime- Monobactam Aztreonam Extended-spectrum penicillins+ß-lactamase Pipercillin-tazobactam, ticarcillin-clavulanate inhibitor Carbapenems Imipenem, meropenem, doripenem, ertapenem +aminoglycoside in serious infections Gentamycin, tobramycin, amikacin

Antimicrobial Agents for Treatment of Infections caused by Enterobacteriaceae Antibiotic Class Antibiotic Enterobacter, Serratia, Citrobacter, Providencia, Morganella spp. Carbapenems Imipenem, meropenem, doripenem, ertapenem Sulfa drugs Trimethoprim-sulfamethoxazole Quinolones Ciprofloxacin, levofloxacin, moxifloxacin 4th generation cephalosporins Cefepime +aminoglycoside in serious infections Gentamycin, tobramycin, amikacin Salmonella enterica, shigella spp. Quinolones Ciprofloxacin, levofloxacin 3rd generation cephalosporins Cefotaxime, ceftriaxone, Macrolides Azithromycin Sulfa drugs Trimethoprim-sulfamethoxazole Yersinia spp. Aminoglygosides Gentamycin, streptomycin Teracyclines Doxycycline Quinolones (Yersenia enterocolitica) Ciprofloxacin Sulfa drugs (Yersenia enterocolitica) Trimethoprim-sulfamethoxazole

11 3/17/19

Antimicrobial Agents for Treatment of Infections Caused by Pseudomonas aeruginosa

Antibiotic Class Antibiotic Extended-spectrum penicillins 3rd generation cephalosporins Ceftazidime 4th generation cephalosporins Cefepime Cephalosporin+ß-lactamase inhibitor Ceftolozane-tazobactam Carbapenems Imipenem, meropenem, doripenem Aztreonam Quinolones Ciprofloxacin, levofloxacin Aminoglygosides Gentamycin, tobramycin, amikacin

The Increasing Resistance of Pseudomonas Criteria for defining MDR, XDR and PDR in Pseudomonas aeruginosa › MDR: Non-susceptible to > 1 agent in > 3 antimicrobial categories › XDR: Non-susceptible to > 1 agent in all but < 2 categories › PDR: Non-susceptible to all antimicrobial agents listed.

MDR: multidrug-resistant; XDR: extensively drug resistant; PDR: pandrug-resistant

12 3/17/19

Treatment of Neisseria species

Neisseria Meningitidis Antibiotic Class Antibiotic Natural penicillins Penicillin G 3rd generation cephalosporins Ceftriaxone, cefotaxime Intolerable to ß-lactam antibiotics Chloramphenicol (unavailable in US) Postexposure prophylaxis Quinolone Ciprofloxacin Rifamycin Rifampin 3rd generation cephalosporin Ceftriaxone

Neisseria gonorrhoeae Antibiotic Class Antibiotic 3rd generation cephalosporin+macrolide Ceftriaxone+azithromycin

Campylobacter Jejuni Infection Treatment

Antibiotic Class Antibiotic Treatment of Choice Macrolides Erythromycin, azithromycin, clarithromycin Quinolones Ciprofloxacin, leofloxacin Alternatives Tetracyclines Tetracycline, doxycycline Aminoglycosides Gentamycin, tobramycin, amikacin +ß-lactamase inhibitor Amoxicillin+clavulanic acid Chloramphenicol

Treatment only indicated for a subset of patients –those with high , bloody or profuse diarrhea, prolonged symptoms, or immunocompromised.

Antimicrobial Agents for Treatment of Infections Caused by Helicobacter pylori

Antibiotic Class Antibiotic Aminopenicillins Amoxicillin Macrolides Clarithromycin Metronidazole Tetracyclines Tetracycline Bismuth subsalicylate (Pepto Bismol) Recommended Regimens *Duration of treatment is generally 2 weeks Amoxicillin+clarithromycin+PPI Metronidazole+clarithromycin+PPI Bismuth subsalicylate+metronidazole+tetracycline+PPI

13 3/17/19

Antimicrobial Agents To Treat Infection from Haemophilus influenzae Antibiotic Class Antibiotic Treatment of Choice Aminopenicillins+ß-lactamase inhibitor Amoxicillin+clavulanate, ampicillin+sulbactam 2nd generation cephalosporins Cefuroxime 3rd generation cephalosporins Ceftriaxone, cefotaxime Also active Tetracyclines Tetracycline, doxycycline Macrolide-like agents Azithromycin, telithromycin Quinolones Ciprofloxacin, levofloxacin, moxifloxacin, Carbapenems Imipenem, meropenem, doripenem, ertapenem Sometimes active Sulfa drugs Trimethoprim-sulfamethoxazole Prophylaxis for serotype B Rifamycins Rifampin

Antimicrobial Agents For Infection Due to Moraxella catarhalis

Antibiotic Class Antibiotic Extended-spectrum penicillins Piperacillin Aminopenicillins+ß-lactamase inhibitor Amoxicillin+clavulanate, ampicillin+sulbactam 2nd generation cephalosporins Cefuroxime 3rd generation cephalosporins Ceftriaxone, cefotaxime Macrolides Azithromycin, clarithromycin Aminoglycosides Gentamycin, tobramycin, amikacin Sulfa drugs Trimethoprim-sulfamethoxazole Quinolones Ciprofloxacin, levofloxacin, moxifloxacin Tetracyclines Tetracycline, doxycycline

Acinetobacter species Infection Treatment

14 3/17/19

Knowledge Affirmation Which of the following antibiotic regimens would be appropriate for a patient with a severe infection caused by Pseudomonas aerugnosa prior to knowledge of the isolate’s susceptibilities? a. Ceftazidime+tobramycin b. Ceftriaxone+gentamycin c. Pipercillin+rifampin d. Ertapenem+amikacin e. Ampicillin+tobramycin

Knowledge Affirmation Which of the following antibiotic regimens would be appropriate for a patient with a severe infection caused by Pseudomonas aerugnosa prior to knowledge of the isolate’s susceptibilities? a. Ceftazidime+tobramycin b. Ceftriaxone+gentamycin c. Pipercillin+rifampin d. Ertapenem+amikacin e. Ampicillin+tobramycin

Anaerobic Bacteria

15 3/17/19

Antimicrobial Agents for Clostridioides (formerly ) spp. (NOT including C. difficile)

Antibiotic Class Antibiotic Treatment of Choice Natural penicillins Penicillin G Metronidazole *For infections with Clostriodiodes perfingens add clindamycin to penicillin

Antibiotic Regimens for the Treatment of Clostridioides difficile Infection

Antimicrobial Agents that may Induce C. Difficile Diarrhea and

16 3/17/19

Anaerobic Gram-Negative Treatment for Infections Caused by Bacteroides, Prevotella, and Porphyromonas spp.

Antibiotic Class Antibiotic First-line agents ß-lactam/ß-lactamase inhibitor combinations Ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanate Carbapenems Imipenem, meropenem, doripenem, ertapenem Metronidazole Second-line agents Clindamycin 2nd generation cephalosporins Cefotetan, Extended-spectrum penicillins Pipercillin Quinolones Moxifloxacin Tetracycline-like agents Tigecycline Chloramphenicol

Knowledge Affirmation Which of the following antibiotics has little activity against anaerobic bacteria? a. Imipenem b. Metronidazole c. Ceftriaxone d. Clindamycin e. Amoxicillin+clavulanate

Knowledge Affirmation Which of the following antibiotics has little activity against anaerobic bacteria? a. Imipenem b. Metronidazole c. Ceftriaxone d. Clindamycin e. Amoxicillin+clavulanate

17 3/17/19

Atypical Bacteria

Treatment for Atypical Bacteria Infections

Mycoplasma pneumoniae Antibiotic Class Antibiotic Macrolide-like agents Azithromycin, Clarithromycin, erythromycin, telithromycin Tetracyclines Tetraclycline, doxycycline Quinolones Levofloxacin, moxifloxacin, gemifloxacin

Legionella species Antibiotic Class Antibiotic First-line agents Macrolides Azithromycin Quinolones Levofloxacin, moxifloxacin Second-line agents Macrolides Erythromycin, clarithromycin Quinolones Ciprofloxacin, gemifloxacin Tetracyclines Doxycycline

Knowledge Affirmation › Which of the following antibiotics does NOT have activity against Legionella pneumonphila? a. Azithromycin b. Levofloxacin c. Moxifloxacin d. Erythromycin e. Pipercillin+tazobactam

18 3/17/19

Knowledge Affirmation › Which of the following antibiotics does NOT have activity against Legionella pneumonphila? a. Azithromycin b. Levofloxacin c. Moxifloxacin d. Erythromycin e. Pipercillin+tazobactam

Myobacteria

Antimicrobial Treatments for Infections Caused by Myobacterium species

Mycobacterium Tuberculosis Active Disease (+rifampin+pyrazinamide+ethambutol) x 2 months, followed by (isoniazid+rifampin) x 4 months Latent Infection Isoniazid x 9 months

Mycobacterium Avium Complex Antibiotic Class Antibiotic Clarithromycin+ethambutol+rifabutin Alternative Agents Macrolides Azithromycin Quinolones Ciprofloxacin, levofloxacin Aminoglycosides Amikacin

19 3/17/19

Antimicrobial Treatment for Myobacterium leprae

Antibiotic Class Antibiotic Dapsone+rifampin+clofaximine Alternative Agents Tetracyclines Minocycline Quinolones Ofloxacin Macrolides Clarithromycin

Knowledge Affirmation All of the following are used to treat patients with tuberculosis EXCEPT: a. Pyrazinamide b. Isoniazid c. Rifampin d. Dapsone e. Ethambutol

Knowledge Affirmation All of the following are used to treat patients with tuberculosis EXCEPT: a. Pyrazinamide b. Isoniazid c. Rifampin d. Dapsone e. Ethambutol

20 3/17/19

Fungal Infections

Antifungal Agents for Candida species

Antifungal Class Antifungal Echinocandins Caspofungin, anidulafungin, micafungin Azoles Fluconazole, voriconazole, posaconazole, itraconazole, isavuconazole Polyene Amphotericin B

• If your patient is not improving on standard antibacterial therapy, despite new negative cultures, look for an underlying fungal infection. • At risk patients include: those with IV lines of catheters, bone marrow transplant recipients, ICU patients , patients with implanted joint prostheses, or who are immunosuppressed. • Mortality of invasive candidiasis is 30%.

Opportunistic Infections-PJP

21 3/17/19

Antifungal Agents for Nonmeningeal Cryptococcal Infection

Treatment for Aspergillosis

Antifungal Class Antifungal Initial Therapy Voriconazole+ echinocandin (NOT fluconazole) If intolerant of voriconazole Amphotericin B or isavuconazole Salvage Therapy Echinocandin Caspofungin, micafungin, anidulafungin Voriconazole, isavuconazole, OR liposomal + amphotericin B Duration of therapy at a minimum is 6-12 weeks. For most immunosuppressed patients it will continue for months to years. If the etiology was endocarditis, the patient should stay on a lifelong azole at a treatment dose.

Questions???? ?

22 3/17/19

References • Antimicrobial fundamental concepts. Obtained from https://www.asp.mednet.ucla.edu/files/view/guidebook/AntimicrobialFundamentalConcepts.pdf

• Blumenthal, K. G., & Solensky, R. (2017). Choice of antibiotics in penicillin-allergic hospitalized patients. www.uptodate.com • CDC. (2018). Antibiotic/antimicrobial resistance (AR/AMR). https://www.cdc.gov/drugresistance/biggest_threats.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fdrugresistance%2Fthreat-report- 2013%2Findex.html

• Cox, G.M. & Perfect, J. R. (2017). Cryptococcus neoformans infection outside the central nervous system. www.uptodate.com

• Hauser, A. R. (2019). Anaerobic bacteria. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA. • Hauser, A. R. (2019). Antibiotics that target the cell envelope. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA.

• Hauser, A. R. (2019). Atypical bacteria. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA

• Hauser, A. R. (2019). Gram negative bacteria. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA. • Hauser, A. R. (2019). Gram positive bacteria. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA.

• Hauser, A. R. (2019). Mycobacteria. In Antibiotic Basics for Clinicians, Wolters Kluwer: Philadelphia, PA. • Kanafani, Z. A. & Kanj, S. S. (2018). Acinetobacter infection: Treatment and prevention. www.uptodate.com.

• Kauffman, C. A. (2018). Management of candidemia and invasive candidiasis in adults. www.uptodate.com

• Kauffman, C. A. (2018). Treatment and prevention of invasive aspergillosis. www.uptodate.com

• Kelly, C. P. , Lamont, J. T. & Bakkan, J. S. (2019). Clostridioides (formerly Clostridium) difficile infection in adults: Treatment and prevention. www.uptodate.com

• Letourneau, A. R. (2017). Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects. www.uptodate.com • Marrie, T. J., & Tuomanen, E. I. (2018). Pneumococcal pneumonia in adults. www.uptodate.com • Melin, J. A., Kunins, L., Givens, J., & Sokol, H. N. (2019). What’s new in hospital medicine. www.uptodate.com

• Quindós-Andrés, G. (2016). Environmental Mycology in Public Health. https://doi.org/10.1016/B978-0-12-411471-5.00006-5

• Quintiliani, R. (2010). Pharmacodynamics of antimicrobial agents: Time-dependent vs. concentration dependent killing. www.antimicrobe.org.

• Sarma, S. C. (2015). Beta Lactam Antibiotics. Presentation. https://www.slideshare.net/saurav9119/beta-lactam-antibiotics-43630735

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