Emerging ID issues Drug Resistant Bacteria Spreading Viruses
Emerging ID issues: Drug Resistant Bacteria & Spreading Viruses Paul S. Sehdev, MD, MS, FACP, FIDSA Infectious Disease Consultants & The Traveler’s Clinic Providence St. Vincent’s Hospital October 14, 2011
Trends in S. aureus Disease • • • Emergence of MRSA Emergence of VISA Emergence of VRSA Emergence of h. VRSA Community acquired MRSA Resistance to new agents • Linezolid • Daptomycin
Emergence of Methicillin Resistance • • • 1961: 1962: 1980: 1991: 2003: Methicillin introduced MRSA identified 5 -10% hospital isolates MRSA 25% hospital isolates MRSA 64% isolates in NNISS Chambers. Emerg Inf Dis; 7: 178
Methicillin Resistance: Mechanism • Mec. A gene – Encodes a low affinity PBP (PBP 2 a) – Affects all -lactam drugs – 5 types • Variable patterns of drug susceptibilities – Acquired from unknown locus – Mobile transposon-like element – Resistance profiles continue to change
http: //phsnet. phsor. org/laboratory/micro/antibiotics/QTR%204%202008 PSVMCMRSA. pdf
What is an Extended-Spectrum -Lactamase (ESBL)? • Variant of standard TEM & SHV -lactamases • Result of point mutations • Mutated -lactamase has extended spectrum • Degrades 3 rd generation cephalosporins • Transmitted via plasmids • Over 150 ESBLs identified to date • E. Coli & K. pneumoniae Rice LB. Pharmacotherapy. 1999; 19(8 Pt 2): 120 S.
Molecular Basis of ESBLs Amino Acid Position TEM-1 CTZ MIC <0. 12 TEM-12 4 -32 Glu Ser Glu TEM-10 64 Glu Ser Lys TEM-26 >256 Lys Ser Glu Enzyme 102 162 237 Glu Arg Glu Rice LB. Pharmacotherapy. 1999; 19(8 Pt 2): 120 S.
ESBLs Detection Methods: Inhibition by Clavulanic Acid
Inoculum Effect in K. pneumoniae Isolates Containing ESBLs MIC 90 ( g/m. L) % Susceptible 100 107 CFU/m. L 4 % Susceptible 100 16 90 Ceftazidime 1, 024 11 >1, 024 5 Cefotaxime 32 67 >1, 024 5 Ceftriaxone 64 56 >1, 024 0 Cefepime 16 89 >128 0 Pip/Tazo 1, 024 67 >1, 024 22 Antibiotic Meropenem Cefotetan 105 CFU/m. L 0. 06 Thomson KS. Antimicrob Agents Chemother. 2001; 45: 3548.
Therapy of ESBL Infections • Carbapenems best option • Cephalosporins: – In vitro & in vivo discordance – Failure of Ceftazidime in bacteremic patients – Reports of Ceftriaxone & Cefotaxime success • Meningitis and bacteremia • Few patients • Little data • Trimethoprim/ sulfamethoxazole • Aminoglycosides • Fluoroquinolones Wong-Beringer A. Pharmacotherapy 2001; 21: 583.
This is Neisseria gonorrhea
Resistance in N. gonorrhea • Emerged in 1970’s • Penicillin resistance • Tetracycline resistance • DOC in 1980’s became ciprofloxacin • Fluoroquinolone resistance emerged – Asia Hawaii California everywhere else • 2007, CDC recommended cephalopsorins • Ceftriaxone im or cefixime
N. gonorrhea: Cephalosporin Resistance 2000 -2010 www. cdc. gov/mmwr/preview/mmwrhtml/mm 6026 a 2. htm? s_cid=mm 6026 a 2_w#fig 2
New kid on the block: New Delhi metallo-ß-lactamase-1 (NDM-1) • 2009, first report • • UTI after travel to India Isolate was K. pneumoniae Resistant to all beta-lactam drugs E. coli possessing NDM-1 found in patient’s stool • 2010 USA • 3 cases with 3 different organisms • 2011 Cases on all continents • Except Antarctica & S. America
NDM-1 • Encodes for broad spectrum B-lactamase • Resistant to all B-lactam drugs • Sensitive to tigecycline & colistin • Resides on a plasmid • Transferable between bacteria • Within a species • Across species • Prevalence rates • USA low • India 4% of enteric Gram-negative bacilli
Why the easy spread? Horizontal transfer
NDM-1: It’s in the water • Prevalence study from New Dehli, India • September-October 2010 • Sampled water • Seepage (puddles & rivulets) • Public tap water • 221 samples (171 seepage & 50 tap H 2 O • 51 of 171 (29%) & 2 of 50 (4%) positive • 11 different bacteria possessed • Including V. cholera & Shigella species • Huge implications for developing world • Worldwide interconnectedness makes further spread likely http: //www. ncbi. nlm. nih. gov/pubmed/21478057
Containing NDM-1 • This will NOT just go away! • Infection control is paramount • • High index of suspicion Contact isolation Good hand hygiene Active surveillance • Limiting broad spectrum antibiotic use • Reduces “pressure” that enables resistant bugs to thrive • Reserve active agents • Few (no? ) new antibiotics in pipeline
Chickungunya
Chikungunya Background • 1 st described in 1952 – Outbreaks of febrile polyarthritis • Makonde word – “that which contorts or bends up” • • • Virus was isolated in 1953 Spread throughout South-Central Africa Spread to Thailand in 1958 Now, endemic in S. Asia Indian Ocean outbreak ongoing since 2004
Indian Ocean Outbreak Pialoux G, Lancet, 2007; 7: 319 -27
Epicurves Reunion & France Pialoux G, Lancet, 2007; 7: 319 -27
Clinical Manifestations • Primary infection features – Fever 86 -100% – Arthralgias 96 -100% • Hands, wrists & ankles – Headache 47% – Rash 40% • Secondary – Chronic polyarthralgia 5 -10% – Persists for months to years – Mechanism for disease unknown • Mortality <1% Simon F, Med Clin N Am 2008; 92: 1323 -43
Clinical Manifestations Simon F, Med Clin N Am 2008; 92: 1323 -43
Making the Diagnosis Pialoux G, Lancet, 2007; 7: 319 -27
Treatment & Prevention • Supportive therapy • DEET to repel mosquitoes • Vaccine • • • Live attenuated vaccine candidate (TSI-GSD-218) Phase II trials Single dose vaccine 98% developed neutralizing antibody at day 28 85% remained sero-positive at 52 weeks Trials shelved in 2002 • Future uncertain Edelman R, Am J Trop Med Hyg 2000; 62(6): 681 -5
Dengue Viruses • Flavivirus • Single stranded, nonsegmented RNA virus • 4 distinct serotypes • • • Each serotype provides lifelong immunity Infection does not confer cross protection All can cause severe manifestations Can be infected up to 4 times Subsequent infections may be severe • Main reservoir is humans • Non-human primates may be infected
Dengue Disease Burden • • • Most common arboviral disease Endemic in 100 countries 2. 5 billion persons at risk 100 million cases yearly 250, 000 cases of Dengue hemorrhagic fever 25, 000 deaths yearly
Aedes Mosquitoes • • • Highly susceptible to Dengue infection Preferred nourishment is human blood Thrives in urban environments Bites during daytime Bite is nearly imperceptible May bite several people to obtain a blood meal
Spread & Distribution of Dengue http: //www. who. int/csr/disease/dengue/impact/en/
Dengue in Puerto Rico 2009 -11
Dengue Clinical Syndromes • Undifferentiated fever • Classic dengue fever • Severe Dengue – Dengue hemorrhagic fever – Dengue shock syndrome
Classic Dengue Fever • Sudden onset fever • Headache & retro-orbital pain • Severe myalgia & arthralgia • “Break-bone fever” • Skin rash • Appears around time of defervescence • Mild hemorrhagic manifestations • Tourniquet tests • Laboratories • Leukopenia, lymphopenia & thromobocytopenia • Transaminitis
Tourniquet Test Wilder-Smith A and Schwartz E. N Engl J Med 2005; 353: 924 -932
Chikungunya vs. Dengue Chikungunya Dengue Fever Common Rash Day 1 -4 Day 3 -7 Retro-orbital pain Rare Common Myalgia Possible Very common Polyarthritis Very common None Tenosynovitis Common None Hypotension Possible Common Minor Bleeding Possible Common Sequalae Chronic polyarthritis Tenosynovitis Raynaud’s Fatigue
Dengue Hemorrhagic Fever: CDC Case Definition • • • 4 criteria—must meet all Fever Hemorrhagic manifestations Platelet count <100, 000/mm 3 “Leaky capillaries” • Hematocrit >20% above baseline) • Low albumin • Pleural or other effusions
Dengue Shock Syndrome • 4 criteria for DHF plus • Circulatory failure: • Rapid and weak pulse • Pulse pressure < 20 mm Hg • SBP <90 mm. Hg • Duration of shock is short • 12 -24 hours • Supportive care only intervention • Morality ranges from 0. 2%-20% • 2 deaths in USA from 1993 -2000
DHF Mechanism • Antibody mediated enhancement • • Cross reacting Abs bind virus They do no neutralize bound virus Complexes bind Fc receptors Replicate in dendritic cells & macrophages Viral load is increased Killer cells & T-cell are activated “Cytokine storm” ensues Endothelial damage & capillary leakage
Wilder-Smith A and Schwartz E. N Engl J Med 2005; 353: 924 -932
Dengue Prevention • Insect precautions are mainstay • Vaccines – 2 candidates in phase 2 -3 trials • • Both live attenuated viruses Both tetravalent vaccines Immunogenic, but not reactogenic Field trials in planning stages • Vector control • Must be multi-modal
Sehdev P Clin Inf Dis 2002; 35(9): 1071– 1072
Yellow Fever • 1 st outbreak in New World 1648 • Yet, thought to originate from Africa • Global epidemics • 1793: Philadelphia 10% population died • 1878: Mississippi Valley 100, 000 cases • Sanitary measures reduced burden • Serendipitous • Vector was not known at time • Virus isolated in 1927 • Vaccine developed in 1928
Yellow Fever Map 2007 http: //www. cdc. gov/ncidod/dvbid/yellowfever/YF_Global. Map. html
Estimated Disease Burden • 200, 000 cases per year • 30, 000 deaths • Epidemic attack rates • 30 cases per 1, 000 persons • Case fatality rates • 20 -50% in endemic areas • Imported cases rare, but deadly • 6 cases USA & Europe 1996 -2004 http: //wwwn. cdc. gov/travel/yellowbook/ch 4/yellow-fever. aspx
YF Transmission Cycle Monath TP, Lancet ID 2001; 1: 11 -20
Stages of Yellow Fever Monath TP, Lancet ID 2001; 1: 11 -20
Diagnosis & Treatment • Mainstay is serology • Single positive Ig. M • Fourfold rise in Ig. G titer • PCR positive early (days 1 -6) • But, not readily available • Culture is gold standard • Therapy is supportive • Ribavirin has been tried, but doesn’t work • Immunoglobulin not useful
Yellow Fever Vaccine • • • Live, attenuated virus (17 D strain) 95% effective, 10 year protection HA, fever & myalgia Immediate hypersensitivity (1/131, 000) Vaccine associated neurotrophic disease – 16/23 case age < 9 months • Vaccine associated viscerotropic disease – 10 cases since 1996 • Contraindications – Egg allergy & age < 9 months MMWR 2002; 51: RR-17
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