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Emerging ID issues:Drug Resistant Bacteria &
Spreading Viruses
Paul S. Sehdev, MD, MS, FACP, FIDSAInfectious Disease Consultants &
The Traveler’s ClinicProvidence St. Vincent’s Hospital
October 14, 2011
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Trends in S. aureus Disease• Emergence of MRSA• Emergence of VISA• Emergence of VRSA• Emergence of hVRSA• Community acquired MRSA• Resistance to new agents
• Linezolid • Daptomycin
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Emergence of Methicillin Resistance
• 1961: Methicillin introduced• 1962: MRSA identified• 1980: 5-10% hospital isolates MRSA• 1991: 25% hospital isolates MRSA• 2003: 64% isolates in NNISS
Chambers. Emerg Inf Dis;7:178
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Methicillin Resistance: Mechanism• MecA gene
– Encodes a low affinity PBP (PBP2a)– Affects all -lactam drugs– 5 types
• Variable patterns of drug susceptibilities– Acquired from unknown locus– Mobile transposon-like element – Resistance profiles continue to change
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http://phsnet.phsor.org/laboratory/micro/antibiotics/QTR%204%202008PSVMCMRSA.pdf
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What is an Extended-Spectrum -Lactamase (ESBL)?
• Variant of standard TEM & SHV -lactamases• Result of point mutations • Mutated -lactamase has extended spectrum
• Degrades 3rd generation cephalosporins
• Transmitted via plasmids• Over 150 ESBLs identified to date• E.Coli & K.pneumoniae
Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S.
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Molecular Basis of ESBLsAmino Acid Position
Enzyme CTZ MIC 102 162 237
TEM-1 <0.12 Glu Arg GluTEM-12 4-32 Glu Ser GluTEM-10 64 Glu Ser LysTEM-26 >256 Lys Ser Glu
Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S.
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ESBLs Detection Methods: Inhibition by Clavulanic Acid
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Inoculum Effect in K. pneumoniae Isolates Containing ESBLs
Antibiotic
MIC90 (g/mL)
105 CFU/mL % Susceptible
107 CFU/mL % Susceptible
Meropenem 0.06 100 4 100
Cefotetan 1 100 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
Thomson KS. Antimicrob Agents Chemother. 2001;45:3548.
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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.
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This is Neisseria gonorrhea
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Resistance in N.gonorrhea
• Emerged in 1970’s• Penicillin resistance• Tetracycline resistance
• DOC in 1980’s became ciprofloxacin• Fluoroquinolone resistance emerged
– AsiaHawaii Californiaeverywhere else• 2007, CDC recommended cephalopsorins
• Ceftriaxone im or cefixime
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N. gonorrhea: Cephalosporin Resistance 2000-2010
www.cdc.gov/mmwr/preview/mmwrhtml/mm6026a2.htm?s_cid=mm6026a2_w#fig2
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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
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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
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Why the easy spread?Horizontal transfer
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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 H2O• 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
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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
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Chickungunya
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Chikungunya Background
• 1st 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
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Indian Ocean Outbreak
Pialoux G, Lancet, 2007;7:319-27
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Epicurves Reunion & France
Pialoux G, Lancet, 2007;7:319-27
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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
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Simon F, Med Clin N Am 2008;92:1323-43
Clinical Manifestations
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Pialoux G, Lancet, 2007;7:319-27
Making the Diagnosis
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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
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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
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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
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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
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Spread & Distribution of Dengue
http://www.who.int/csr/disease/dengue/impact/en/
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Dengue in Puerto Rico 2009-11
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Dengue Clinical Syndromes
• Undifferentiated fever• Classic dengue fever• Severe Dengue
– Dengue hemorrhagic fever– Dengue shock syndrome
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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
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Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932
Tourniquet Test
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Chikungunya vs. DengueChikungunya Dengue
Fever Common CommonRash Day 1-4 Day 3-7Retro-orbital pain Rare CommonMyalgia Possible Very commonPolyarthritis Very common NoneTenosynovitis Common NoneHypotension Possible CommonMinor Bleeding Possible CommonSequalae Chronic polyarthritis
TenosynovitisRaynaud’s
Fatigue
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Dengue Hemorrhagic Fever: CDC Case Definition
• 4 criteria—must meet all• Fever• Hemorrhagic manifestations• Platelet count <100,000/mm3 • “Leaky capillaries”
• Hematocrit >20% above baseline)• Low albumin• Pleural or other effusions
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Dengue Shock Syndrome• 4 criteria for DHF plus• Circulatory failure:
• Rapid and weak pulse• Pulse pressure < 20 mm Hg• SBP <90 mmHg
• 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
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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
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Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932
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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
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Sehdev P Clin Inf Dis 2002;35(9):1071–1072
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Yellow Fever• 1st 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
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Yellow Fever Map 2007
http://www.cdc.gov/ncidod/dvbid/yellowfever/YF_GlobalMap.html
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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/ch4/yellow-fever.aspx
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YF Transmission Cycle
Monath TP, Lancet ID 2001;1:11-20
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Stages of Yellow Fever
Monath TP, Lancet ID 2001;1:11-20
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Diagnosis & Treatment• Mainstay is serology
• Single positive IgM • Fourfold rise in IgG 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
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Yellow Fever Vaccine• Live, attenuated virus (17D 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