Emerging Infectious Avian Influenza H5N1 Diseases • Endemic in domestic poultry in certain areas • Sporadic human from direct contact 2008 with infected poultry and/or wild birds • Person-to-person spread of H5N1 virus from William E. Maher, MD has been very rare, limited and unsustained Ohio State University Medical Center • No evidence of changes to H5N1 to increased transmissibility to or among humans, but infection seen in some mammals

Emerging Infectious Avian Influenza H5N1 Diseases - Global View

• Update on Avian Influenza A/H5N1 • H5N1 resistant to amantadine and rimantidine, but sensitive to Oseltamivir and • Upsetting the balance Zanamivir • Things that shouldn’t be there • Some Oseltamivir resistant strains reported • Things we weren’t aware of • No available , work in progress • Unanticipated (but maybe not unexpected) changes

1 Epidemiologic Findings in Malaria Human H5N1 Cases Dominican Republic • Thailand, 2004: limited spread in a family from prolonged and • 1999-2000 outbreak, Hurricanes Mitch and George very close contact. No transmission beyond one person. • 2004, Hurricane Jeanne, Punta Cana • Vietnam, 2004: fatal case presented with fever, diarrhea and seizures, and was initially diagnosed as encephalitis. • Heavy rains and flooding, increased mosquitoes • Vietnam, 2005: Infection via ingestion of raw duck . • Malaria-infected migrant workers • Azerbaijan, 2006: teenagers infected by contact with wild dead • 3,000 malaria cases reported in 1999 birds (swans) removing feathers from the birds. • Indonesia, 2006: 8 people in one family were affected, with 7 • 1,500-2,500 malaria cases now reported annually deaths. No further spread outside of the exposed family was documented or suspected. • Europeans in Punta Cana All inclusive resorts, never left the grounds • Vietnam, 2006: high viral concentration and elevated inflammatory cytokine levels in fatal cases. Inflammatory • CDC recommend chloroquine prophylaxis for response appears to be implicated in the pathogenesis travelers to La Altagracia and Duarte provinces.

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO

2003 2004 2005 2006 2007 2008 Total Country death death death death cases deaths cases deaths cases cases cases deaths cases cases s s s s Malaria risk area in

Azerbaijan 0 0 0 0 0 0 8 5 0 0 0 0 8 5 Dominican Republic: Cambodia 0 0 0 0 4 4 2 2 1 1 0 0 7 7 China 1 1 0 0 8 5 13 8 5 3 3 3 30 20 Rural, with highest risk Djibouti 0 0 0 0 0 0 1 0 0 0 0 0 1 0 Egypt 0 0 0 0 0 0 18 10 25 9 7 3 50 22 in provinces bordering Indonesia0 0 0 02013554542371613133108 Haiti. In addition, risk in Iraq00000032000032 Lao all areas of La People's 00000000220022 Democratic Altagracia Province, Republic Myanmar0 0 0 000 0 0 1 0 0010 including resort areas. Nigeria0 0 0 000 0 0 1 1 0011 Pakistan 0 0 0 0 0 0 0 0 3 1 0 0 3 1 Thailand 0 0 17 12 5 2 3 3 0 0 0 0 25 17 Turkey 0 0 0 0 0 0 12 4 0 0 0 0 12 4

Viet Nam 3 3 29 20 61 19 0 0 8 5 5 5 106 52

Total 4 4 46 32 98 43 115 79 88 59 31 24 382 241

2 Malaria in Kingston, Jamaica • Fall 2006, confirmed malaria cases, Kingston, Jamaica where Malaria Great Exuma transmission does not normally occur • Ant malarial drugs recommended. • February 29, 2008 CDC removed temporary recommendation for malaria preventive medication (prophylaxis) for travel to Kingston Jamaica. • Kingston continues to experience rare cases of malaria, but the risk to travelers appears to be minimal.

Recommendations for Celebrities Who Own Travelers to Great Exuma Islands in the Exumas • Repeated instances of chloroquine-sensitive Plasmodium falciparum malaria occurring in travelers to the island of Great Exuma • Nicolas Cage • Ongoing, low-level risk of malaria for people traveling to the island. • Faith Hill and Tim McGraw • CDC recommends that travelers to Great Exuma, Bahamas take chloroquine malaria preventive medication (prophylaxis) • David Copperfield • There is currently no known risk of malaria on other islands of the Bahamas; therefore, • Johnny Depp prophylaxis is not necessary for those islands

3 Chikungunya Fever in Italy Chikungunya Fever in Italy

• In Swahili Chikungunya: illness of the • CHIKV 1st Isolated in Tanzania in 1953 bended walker • African countries, Indian subcontinent, SE Asia. • Fever, arthralgia, myalgia, headache and diffuse maculopapular rash. • Outbreaks: India, Comoros and La Réunion islands in the SW Indian Ocean in early 2005 • Symptoms 4–7 days after bite • During these outbreaks, travelers from • Arthralgia is often severe, persistent industrialized countries became infected with • 12% of patients have chronic arthralgia 3 CHIKV and were still infected on returning home. years after onset of illness • Aedes albopictus—a vector of CHIKV—was introduced a number of years ago and is now • Chikungunya is transmitted by Aedes aegypti widespread in Italy or A. albopictus

85% of the cases were confirmed by either serology or PCR.

Lancet. 2007 Dec 1;370(9602):1805-6 Lancet. 2007 Dec 1;370(9602):1805-6

4 Chikungunya Fever in Italy

• Outbreak of a tropical disease in a non- tropical area • Index case had recently traveled to an endemic area (India) to visit relatives • Vector infestation traced to imported tires from a tire retreading company that had imported used tires infested with mosquito eggs from Georgia, USA. • Other Diseases: Malaria, Yellow Fever, Dengue, ?

MMWR August 10, 2007 / Vol. 56 / No. 31

Dengue in Texas Autochthonous Malaria • Dengue noted in 5 Texas border counties since 1980. • Inadvertent carriage of infective Anopheles mosquitoes by airplane, ship, • Survey in Brownsville, Texas, and baggage, or bilge water may be Matamoros, Tamaulipas, Mexico (n = 600), responsible for these occurrences. in 2004 to assess dengue seroprevalence. • Also, large populations of migrants from • Recent dengue infection was detected in areas highly endemic for malaria may act 2% and 7.3% of residents in Brownsville as human reservoirs for potential and Matamoros, respectively. gametocyte carriers. • Past infection was detected in 40% of • Outbreaks of mosquito borne malaria in Brownsville residents and 78% of areas of New Jersey, New York, and Texas Matamoros residents.

5 Norovirus • Most common cause of infectious gastroenteritis among persons of all ages • Responsible for 50% of all food-borne gastroenteritis outbreaks in the United States • Major problem cruise ships, nursing homes and hospitals • Detected in 35% of persons with sporadic gastroenteritis and in 14% of all children < 3 years old hospitalized for gastroenteritis. • Cause of chronic diarrhea among transplant patients • Diagnostic PCR available at CDC and State Health Dept. • ? Emerging due to lifestyle changes vs. better tests EID Vol 2, No. 1—January-March 1996:37-43

Outbreaks of Acute Gastroenteritis: Settings 2006 Norovirus • Short, self-limited illness Setting Number of Outbreaks • As few as 100 virus particles thought to Cruise ships 37 infectious Long-term care 37 • Stable in the environment and can survive facilities freezing and heating to 60°C (140°F). Restaurants 13 • Transmission to the oral mucosa via hand Hospitals 7 contact with materials, fomites, and environmental surfaces contaminated with feces Colleges 3 or vomitus Parties 3 • May be food borne or waterborne Other 26 • Susceptible to chlorination Total 126

6 Prevention of Norovirus Chagas Disease Transmission Trypanosoma cruzi in The USA • American trypanosomiasis • Endemic to Central and South America • Hand hygiene with alcohol-based hand gels; 9 Romaña’s Sign 9 Megacolon • Disinfect surfaces: 1:10-50 dilution 9 Megaesophagus chlorine bleach 9 Cardiomegaly. • Do not return to work or school for 24 9 Reduvid Bug Vector to 72 hours after symptoms resolve • Rare Transmission 9 IVDA 9 Transfusion Photo courtesy of CDC

Prevention of Norovirus Chagas Disease Transmission Range and Vector

• During outbreaks 9 Use contact precautions Triatoma sanguisuga 9 Avoid sharing staff members between units or facilities with affected patients 9 cluster symptomatic patients 9 instruct visitors on hand hygiene 9 close affected units to new admissions and transfers

Photo courtesy of CDC

7 Chagas Disease

• Cases of Chagas disease reported in the United States 93 in infants in Texas 91 in an infant in Tennessee 91 in a 56-year-old woman in California 91 in Louisiana 2006 • Vector in the USA is Triatoma sanguisuga,

Photograph courtesy South Florida NRC

Chagas Disease Wildlife, Exotic Pets, and Emerging Zoonoses

• T. cruzi has been identified in Photos courtesy of CDC 9>18 species of mammals 9raccoons, opossums, armadillos, foxes, skunks, dogs, wood rats, squirrels, and nonhuman primates • Lack of human cases in USA 9Lack of habitat for the bugs in most US homes 9a preference for animal hosts 9delayed defecation of triatomines found in the US compared with those found in Latin America. ►May 22 – Child hospitalized because of festering lesions, fever, sweats, ocular discharge, and new skin lesions.

8 April, 2003 800 rodents from Ghana

200 Native Prairie Dogs 510 Dormice 53 rope squirrels 47 tree squirrels

2 brush-tailed 50 Gambian porcupines giant rats 100 striped mice Illinois Photos courtesy of CDC Distributor Photos courtesy of CDC

Wildlife, Exotic Pets Monkeypox and Emerging Zoonoses • In 1958, monkeypox was noted as a viral disease that is found mostly in the rainforest countries of central • Petting zoos linked to Escherichia coli and west Africa. Laboratory studies showed that the O157:H7, salmonellae, and Coxiella burnetii virus could also infect rats, mice, and rabbits. • Salmonellosis from a Komodo dragon exhibit • In 1970, monkeypox was identified as the cause of a rash illness in humans in remote African locations. • Twelve elephant handlers infected with M. tuberculosis, and 1 with active disease • In early June 2003, monkeypox was reported among after 3 elephants died of tuberculosis. several residents in the United States who became ill after having contact with sick pet prairie dogs. This is • Human monkeypox related to pet prairie the first evidence of community-acquired monkeypox dogs in the United States.

9 Wildlife, Exotic Pets and Emerging Zoonoses Meningococcemia • Close contacts of persons with • Lyssaviruses in pet bats meningococcal disease have a higher risk for carriage and therefore invasive disease. • Ringworm from African pygmy hedgehogs • Contacts should receive or chinchillas. chemoprophylaxis to eliminate nasopharyngeal carriage of N. meningitidis • Tularemia in commercially traded prairie ASAP. dogs; • Risk of secondary cases is highest immediately after onset of disease • ≈7% of human with salmonella in US are associated with having handled a • Secondary cases rarely occur after 14 days. reptile. • Oral is an effective single dose chemoprophylactic agent.

Attempt to Determine Quinolone-Resistant Reservoir of Marburg Virus Neisseria meningitidis (MARV) Minnesota and North Dakota, • Democratic Republic of the Congo 2007–2008 • A mine associated with a protracted outbreak of • In August 2006, a worker in a day care center Marburg hemorrhagic fever during 1998–2000 in eastern North Dakota died of Group B Meningococcemia • MARV nucleic acid found in 12 bats, 3.0%–3.6% of 2 species of insectivorous bat and 1 species • Children received rifampin, staff ciprofloxacin of fruit bat • Secondary case, January 20071 • Antibody to the virus found in the serum of 9.7% of 1 of the insectivorous species and in 20.5% of 9 Ciprofloxacin-resistant the fruit bat species • 2 unrelated cases, 2008 • Attempts to isolate virus unsuccessful. 9 Ciprofloxacin-resistant

10 Chemoprophylaxis for Meningococcal Disease Plasmodium falciparum with Possible Fluoroquinolone-resistance Malaria and Atovaquone-

Drug Age group Dosage Duration/Route Proguanil Treatment Failure Rifampin <1 mo 5 mg/kg q 12 hrs 2 days PO • Atovaquone Resistance 9 Single point mutation in plasmodial cytochrome b 1 mo to 10 mg/kg q 12 hrs 2 days PO <15 yrs • Therapeutic Concerns >15 yrs 600 mg every 12 hrs 2 days PO 9 Narrow margin for dosing errors with a large parasite load 9 Stress completion of course in a non-immune host Ceftriaxone <15 yrs 125 mg Single IM dose 9 ? Lower drug levels if >100 kg at standard dose. >15 yrs 250 mg Single IM dose • Recrudescent malaria 3-4 weeks after ATQ/PRO Rx 9 Failure likely due to drug resistance Azithromycin <15 yrs 10 mg/kg body weight Single PO dose >15 yrs 500 mg SinglePO dose 9 Quinine plus doxycycline, or artemether/lumefantrine (if available) should be used to treat relapse

Plasmodium falciparum Malaria and Atovaquone-Proguanil Emerging Infectious Diseases 2008 Treatment Failure Challenges in Diagnosis and Management of • Atovaquone/proguanil (Malarone) Invasive Fungal Infections 9Effective Rx: chloroquine-resistant P. falciparum malaria 9Convenient route of administration (oral) Julie E. Mangino, MD 9Short treatment course (three days-12 pills) Ohio State University Medical Center 9Attractive adverse-effect profile

11 Trends in Mortality: Excess Mortality, Invasive Mycoses Length of Stay (LOS), Candidiasis Aspergillosis and Associated Costs 0.8 Invasive Candidemia in the United States

a 0.6 • Excess mortality rates: 10%-49% 0.4 • Excess LOS in hospital: 3.4-30 days Population 0.2 Rate per 100,000 Rate per • Excess costs: $6200-$92,000 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 a Year • Average total cost of candidemia: $44,536

aCrude mortality rate (US) due to candidiasis and aspergillosis. a1997 dollars. Pfaller, Diekema. Clin Microbiol Rev. 2007;20:133-163. Rentz et al. Clin Infect Dis. 1998;27:781-788.

Candida - A High Priority in the ICU: Increased Hospital Bloodstream Infection Pathogens Costs for Candidemia

% BSI Crude Pathogen (n=10,515) Mortality, % a Hospital Stay Coagulase-negative Staph 35.9 (1) 25.7 $37,681 (84.6%) `` Staphylococcus aureus 16.8 (2)a 34.4 Candida species 10.1 (3) 47.1 Enterococcus species 9.8 (4) 43.0 Therapy $4710 (10.5%) Pseudomonas aeruginosa 4.7 (5) 47.9 Adverse Drug Reactions Diagnostic Procedures $610 (1.4%) $1513 (3.4%)

Total Cost of Candidemia: $44,536a aP<.05 for patients in ICU vs non-ICU settings. a1997 dollars. SCOPE data. Wisplinghoff et al. Clin Infect Dis. 2004;39:309-317. Rentz et al. Clin Infect Dis. 1998;27:781-788.

12 Risk Factors for Candidemia Factors Associated With 1 • Central venous catheters C glabrata Infection • Systemic antibiotic exposure •Emergence of C glabrata as an important • Length of stay in ICU >72 hours bloodstream pathogen may not be just a • Major surgery, especially abdominal matter of selection with drug pressure • Pancreatitis 9Nosocomial transmission pattern • Dialysis • Neutropenia 9Patient age (increases with age) • Immunosuppressive agents (steroids, etc) • Changes in mucosal defenses with age • Colonization with Candida species • Colonization by C glabrata (40%, >70 years) • Total parenteral nutrition, hyperalimentation 1Pfaller, Diekema. J Clin Microbiol. 2004;42:4419-4431. 2Lin et al. Antimicrob Agents Chemother. 2005;49:4555-4560.

Distribution of Common Factors Associated With Candida Species C glabrata Infection1 Frequency 1% 1% 3% 9 Underlying diseases 3% C albicans 15% 9 Geographic location (United States > worldwide) 36% C glabrata 2 C parapsilosis 9 Previous exposure to specific C tropicalis • Azoles C krusei C krusei • Piperacillin-tazobactam, Vancomycin, 20% C lusitaniae Other • Anti-anaerobic agents 22% 1Pfaller, Diekema. J Clin Microbiol. 2004;42:4419-4431. Various sources, predominantly IDSA Guidelines: Pappas et al. Clin Infect Dis. 2004;38:161-189. 2Lin et al. Antimicrob Agents Chemother. 2005;49:4555-4560.

13 Number of cases C. albicans vs. Non- albicans in the MICU & SICU 2001-2007 Traditional Diagnosis 20 C. albicans 18 18 Non-albicans • Blood cultures 16 14 13 13 13 9Negative: 50% sensitivity by autopsy data 12 10 10 9 9 9 9Intense research to improve techniques 8 8 8 7 7

NumberCases of 6 6 6 6 5 5 5 5 5 • Biopsies and other cultures 4 4 4 3 3 3 2 2 LIMITED BY 2 9Not always feasible 0 BIOLOGY OF 0 MICU SICU MICU SICU MICU SICU MICU SICU MICU SICU MICU SICU MICU SICU 9Contaminant vs real? THE DISEASE 2001 2002 2003 2004 2005 2006 2007 Year and Type of ICU

Candidemia Cases - MICU - 2001-2007 Candidemia Management: 14 C. albicans 13 C. glabrata Who and When to Treat? C. tropicalis 12 C. parapsilosis C. dubliniensis Asymptomatic, positive C. krusei superficial cultures or beta-D- 10 C. lusitaniae glucan 9 9 Signs and Full-blown 8 Markers symptoms disease 7 No disease Sequelae 6 66 6

Num ber of Cases 555 5

4 4 Prophylaxis Empirical Therapy 3 3 Preemptive

2 2 2 22 Symptomatic, high-risk 2 1 111 11111 febrile patient receiving Asymptomatic, 0 high-risk patient 2001 2002 2003 2004 2005 2006 2007 (chemo, ICU?) Ye ar

14 Use of Beta-D-Glucan Assay An Eye for an Eye… to Diagnose Candidemia

Sensitivity, Specificity, PPV, NPV, • Dilated eye exam Author Population Sampling % % % % Obayashi1 Febrile Single 90 100 59 97 9 All with candidemia patients

Odabasi2 AML / MDS Multiple, 2+ 65 96 57 97 9 Particularly in prolonged fungemia Ostrosky- Hospitalized Single 64 92 89 73 Zeichner3 patients • Endophthalmitis

Mohr4 ICU patients, Multiple, 2+ 100 63 – – surveillance 9 Consider intravitreal treatment / vitrectomy

1. Obayashi et al. Lancet. 1995;345:17-20. 2. Odabasi et al. Clin Infect Dis. 2004;39:199-205. Piek et al. Intensive Care Med. 1988;14:173-175. 3. Ostrosky-Zeichner et al. Clin Infect Dis. 2005;41:654-659. Barza. Clin Infect Dis. 1998;27:1134-1136. 4. Mohr et al. Presented at: 45th ICAAC; Washington, DC. 2005. Abstract M-168. Essman et al. Ophthalmic Surg Lasers. 1997;28:185-194.

Clinical Manifestations Lifelines of Candidiasis • Lines and foreign bodies • Superficial disease: mucous membranes – Thrush, esophagitis, vaginitis, cutaneous syndromes 9 Remove if possible—better outcomes in neutropenic patients, or IV drug users 9 Tunneled catheters are lower risk • Deep organ involvement 9 Neutropenic patients – Candidemia (most common) – Peritoneum, liver, spleen, L-AMB gallbladder (hepatosplenic – CNS (neonates) • Gut vs line? candidiasis to postsurgical – Respiratory tract (rare) collections) 9 Biofilms are important – Cardiac (surgery) – Ocular • Polyenes and echinocandins – Urinary (management issue) – Disseminated candidiasis FLUC (liver/spleen in neutropenics – Arthritis, osteomyelitis, Anaissie et al. Am J Med. 1998;104:238-245. with candidemia) Cole et al. Clin Infect Dis. 1996;22(suppl 2):S73-S88. myositis (long-term treatment) Nucci et al. Clin Infect Dis. 2002;34:591-599. Schinabeck et al. Antimicrob Agents Chemother. 2004;48:1727-1732.

15 Antıfungal Drugs Principles of Managing By Mechanism of Action Invasive Candidiasis

• Membrane disrupting agents: • Evaluate the bug Amphotericin B, Ampho B lipid formulations 9Consider species-specific features • Ergosterol synthesis inhibitors: 9Consider susceptibility testing Azoles: fluconazole, itraconazole, voriconazole • Remove prosthetic devices, if possible • Nucleic acid inhibitor: • Glucan synthesis inhibitors: Echinocandins: • Consider options for antifungal therapy caspofungin, anidulafungin and micafungin

Principles of Managing Revised IDSA Guidelines Invasive Candidiasis for Candidemia

• Consider the source of infection: • Choice of therapy depends on clinical status of the patient and knowledge of species 9Local epidemiology 9Remove all lines, if feasible • Establish the diagnosis • Therapy 9Fluconazole ≥6 mg/kg/d (400 mg), or 9Caspofungin 50 mg/d, anidulafungin 100 mg/d, or 9Repeat cultures, pursue imaging micafungin 100 mg/d, * or 9AMB (0.6-1.0 mg/kg/d for AMB or 3 mg/kg/d for liposomal • Consider the type of patient formulations of AMB) in selected circumstances* 9Treat 2 weeks after last positive blood culture and 9Colonized? Trauma? Neutropenic? Future resolution of signs and symptoms of infection chemo? *Transition to fluconazole, when appropriate, is encouraged once the Candida sp is known and the patient is stable. Pappas et al, guideline revisions in progress.

16 Proposed Approach: The Bottom Line: Immunocompromised Patients Ostrosky-Zeichner, Pappas. Crit Care Med. 2006;34:857-863. Candidemia in the ICU • Epidemiology supports importance of Yeast in blood culture candidemia, particularly in ICU settings

Immunocompromised • Need better diagnostics (transplant, BMT, AIDS) Nonimmunocompromised • Need practical rules to assess risk Start (lipid) polyene and wait for identification (ID) • for:

Endemic Candida 9 Prophylaxis mycosis 9 Preemptive and empirical therapy

Continue (lipid) polyene until stable; consider fluconazole or itraconazole as 9 Traditional therapy appropriate

Proposed Approach: Non-immunocompromised Patients Treatment of Candiduria Ostrosky-Zeichner, Pappas. Crit Care Med. 2006;34:857-863. Do not treat asymptomatic candiduria unless

Yeast in risk factors are present blood culture • Treat • Treatments

Immunocompromis 9 Symptomatic patients 9 Remove “hardware” ed (transplant, Non-immunocompromised 9 Neutropenic patients (stents and/or Foley) BMT, AIDS) 9 Low birth-weight 9 Fluconazole (200-400 Start lipid polyene mg/dl) Hemodynamically Hemodynamically infants and wait for stable, no unstable, identification (ID) 9 Patients with 9 Flucytosine (100mg/kg/d) previous azoles previous azoles urological 9 Lower urinary tract Start fluconazole, Start echinocandin or Endemic manipulations/ infections: AMB bladder 1 Candida wait for ID and 1 mycosis lipid polyene, wait for ID monitor response and monitor response obstructions irrigations (rarely useful) 9 Upper urinary tract No response If good response If no response, Continue lipid polyene until If good response treat infections or clearly complete 14 days from switch to another stable, then consider 14 days from first first negative culture, agent from (pyelonephritis): can use fluconazole or itraconazole resistant 2 negative culture isolate may switch to the above classes azoles and echinocandins fluconazole or 1. Drew et al. Clin Infect Dis. 2005;40:1465-1470. voriconazole if stable 2. Sobel et al. Clin Infect Dis. 2007;44:e46-e49. and susceptible

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