1. 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

2. 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

3. 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

4. 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

5. http://phsnet.phsor.org/laboratory/micro/antibiotics/QTR%204%202008PSVMCMRSA.pdf

6. 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):120S.

7. Molecular Basis of ESBLs Amino Acid Position Enzyme CTZ MIC 102162237 TEM-1<0.12GluArgGlu TEM-124-32GluSerGlu TEM-1064GluSerLys TEM-26>256LysSerGlu Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S.

8. ESBLs Detection Methods: Inhibition by Clavulanic Acid

9. Inoculum Effect in K. pneumoniae Isolates Containing ESBLs Antibiotic MIC 90 (  g/mL) 10 5 CFU/mL% Susceptible 10 7 CFU/mL% Susceptible Meropenem0.061004 Cefotetan11001690 Ceftazidime1,02411>1,0245 Cefotaxime3267>1,0245 Ceftriaxone6456>1,0240 Cefepime1689>1280 Pip/Tazo1,02467>1,02422 Thomson KS. Antimicrob Agents Chemother. 2001;45:3548.

10. 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.

11. This is Neisseria gonorrhea

12. 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

13. N. gonorrhea: Cephalosporin Resistance 2000-2010 www.cdc.gov/mmwr/preview/mmwrhtml/mm6026a2.htm?s_cid=mm6026a2_w#fig2

14. 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

15. 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

16. Why the easy spread? Horizontal transfer

17. 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

18. 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

19. Chickungunya

20. 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

21. Indian Ocean Outbreak Pialoux G, Lancet, 2007;7:319-27

22. Epicurves Reunion & France Pialoux G, Lancet, 2007;7:319-27

24. 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

25. Clinical Manifestations

26. Pialoux G, Lancet, 2007;7:319-27 Making the Diagnosis

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

29. 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

30. 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

31. 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

32. Spread & Distribution of Dengue http://www.who.int/csr/disease/dengue/impact/en/

33. Dengue in Puerto Rico 2009-11

34. Dengue Clinical Syndromes Undifferentiated fever Classic dengue fever Severe Dengue – Dengue hemorrhagic fever – Dengue shock syndrome

35. 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

36. Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932 Tourniquet Test

37. Chikungunya vs. DengueChikungunyaDengue FeverCommonCommon Rash Day 1-4 Day 3-7 Retro-orbital pain RareCommon MyalgiaPossible Very common Polyarthritis None TenosynovitisCommonNone HypotensionPossibleCommon Minor Bleeding PossibleCommon Sequalae Chronic polyarthritis TenosynovitisRaynaud’sFatigue

38. 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

39. 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

40. 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

41. Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932

42. 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

43. Sehdev P Clin Inf Dis 2002;35(9):1071–1072

44. 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

45. Yellow Fever Map 2007 http://www.cdc.gov/ncidod/dvbid/yellowfever/YF_GlobalMap.html

46. 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

47. YF Transmission Cycle Monath TP, Lancet ID 2001;1:11-20

48. Stages of Yellow Fever Monath TP, Lancet ID 2001;1:11-20

49. 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

50. 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