Drug resistant Gram positives Dr Subramanian S MD MNAMS AB Infectious Diseases Infectious Diseases Consultant Global Health City, Chennai
Flash news! Carbapenem resistant Gram negatives! Vancomycin resistant Staph! Ceftriaxone resistant gonococcus! MDR tuberculosis Drug resistant HIV! Fluconazole resistant Candida!
Why? Lack of suspicion and identification Inappropriate agent or inadequate dosing Advances in microbial resistance Abuse of drugs over the counter and in veterinary setting Dry drug pipeline
Where are Gram pos infections? Skin and soft tissue infections Dental and ENT infections Pulmonary infections Osteomyelitis Septic arthritis Endocarditis Meningitis
Gram positives! 57 year old with squamous cell cancer of oesophagus presented with fever, cough and chills. X ray confirms pneumonia. Patient dies of septic shock in 3 hours and blood cultures grow GPC 32 year old alcohol abuser with liver disease presents with fever, and altered sensorium. Encephalopathy is suspected. After blood cultures, antibiotics are started. Blood culture shows GPC, but he dies inspite of antibiotics. 80 year old healthy male has lunch at 2 pm. At 4 pm, he is aphasic. He deteriorates quickly, and no infarct is seen on scan. CSF shows GPC. He is improving on antibiotics.
Where is the disease??
Pneumococcal disease
CAP in Indian Adults Prevalence of S.pneumoniae CAP Study Details Total CAP Cases (Adult) Cases with Confirmed Etiology (n) S.pneumoniae +ve CAP (% of n) 2009; Lourdes hosp, Kerela 1 145 110 42.7% KIMS, Bengaluru 2 100 38 26.3% PD Hinduja hosp & BYL Nair hosp, Mumbai 3 100 58 39.7% AMCH, Bijapur 4 50 26 30.8% BMCRI, Bangalore 5 450 165 32.7% SKIMS, Srinagar 6 100 29 3.4% CMC, Ludhiana 7 233 108 25.9% IGMCH, Shimla 8 70 53 35.8% 1. Menon RU et al. J Fam Med Primary Care 2013;2:244-9. 2.Mythri S et al. IOSR-JDMS.2013;12(2):16-9. 3. Dagaonkar et al. Am J Respir Crit Care Med. 2012;185:A6060 (poster). 4. Abdullah BB et al. ISRN Pulmonology, 2012. 5. Ramamurthy et al. JEMDS. 2013;2(12):2123-30. 6. Shah BA et al. Lung India. 2010;27(2): 54-7. 7. Oberoi et al. JK Science. 2006;8(2):79-82. 8.Bansal S et al. Indian J Chest Dis Allied Sci. 2004;46 :17-22.
Acute Bacterial Meningitis (Community) Prevalence of S.pneumoniae ABM Mani R et al. Indian J Med Microbiol. 2007 Apr;25(2):108-14.
Pneumococcal disease incidence
Pneumococcal mortality
Disease specific mortality
Co-infection: Influenza Virus and S.pneumoniae Co-infection Impacts Disease Severity S. Pneumoniae +ve: 125 times increased odds of severe influenza (95% CI: 16.95-928.72; p<0.0001) Palacios G, Hornig M, Cisterna D et al. PLoS One. 2009 Dec 31;4(12):e8540.
Pneumococcus in India Mostly suffering from denial! Estimated 136,000 deaths in under 5 in year 2005; 106 per 100,000 Western countries have axed this with vaccination Drug resistance unheard of a decade ago Emerging studies show more resistance than earlier!
Has PPV induced a sizeable impact on IPD in the US? Has PPV induced a sizeable impact on IPD? Cases/100,000 population 120 PCV7 introduced* Age group <5 5-17 18-49 50-64 65 100 80 60 40 20 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 PPV23 in use since 1987 Year Pilishvili T et al. J Infect Dis. 2010;201:32-41.
Quinolone resistance in S.pneumoniae in Canada Chen et al NEJM 1999
Restriction policy can work Heavy macrolide use in 80s in Finland Erythromycin resistant S.pneumoniae rose from 8% to 13% High use regions had high resistance Education on this done NEJM 1997;337
Reduction in resistance
S. Pneumoniae Antimicrobial Resistance in India Study ANSORP 1 (2008-09) Shariff et al 2 (2007-10) Molander et al 3 (2007-11) Antibiotic S % I % R % S % I % R % S % I % R % Penicillin 100 0 0 95 0 5 95.5 2.9 1.6 Erythromycin 82.6 0 17.4 80 0 20 86.4 2.5 11.1 Ceftriaxone 95.6 4.4 0 - - - - - - Ciprofloxacin NA NA 0 42 35 23 - - - Cotrimoxazol e 0 8.7 91.3 17 1.5 82 12.7 13.1 74.2 1. Kim SH et al. Antimicrob Agents Chemother. 2012 Mar;56(3):1418-26. 2. Shariff M et al. J Infect Dev Ctries. 2013 Feb 15;7(2):101-9. 3. Molander V et al. BMC Infect Dis. 2013 Nov 9;13(1):532.
Drug resistance in SP Study Penicillin non susceptibility IBIS 1999 1.3% BMC ID 2007-2011 4.5% IJMR 2007-2013 5.2% Penicillin resistance is an independent and powerful predictor of mortality in patients with S.pneumoniae infection.
SSTI Cellulitis, folliculitis, furuncle, carbuncle, necrotizing fasciitis etc Most are due to Staph and Strep Gram negs in diabetic foot, post op, bites, penetrating injuries etc
Nosocomial Pathogens By Infection Type Pneumonia UTI BSI SSI S. Aureus 19% 2%. 16% 20% Coag (-) staph 2% 4% 31% 14% Enterococcus 2% 16% 9% 12% Pseudomonas 17% 11% 3% 8% Other gram (-) 29% 45% 17% 23% C. albicans <5% 8% 5% 3% Jernigan, J. Cecil s Textbook of Medicine
Proportion of SSTIs (%) 40 30 20 Causes of SSTIs: SENTRY programme 1998 2004 Staphylococcus aureus is the leading cause of SSTIs worldwide 50 38 45 S. aureus P. aeruginosa E. coli Enterococcus spp. Enterobacter spp. β-streptococcus CoNS Klebsiella spp. 10 12 11 6 5 5 5 4 11 7 9 5 4 3 4 0 Europe North America SENTRY is a surveillance programme which evaluated over 12000 isolates over 7 year period in Europe, North America and Latin America Moet GJ et al. Diagn Microbiol Infect Dis 2007;57:7 13
Shifting epidemiology of serious infections SCOPE surveillance study 1995 2002 Nosocomial bloodstream infections & mortality due to S. aureus Wisplinghoff H et al. Clin Infect Dis 2004;39:309 317
Resistant isolates (%) The MRSA threat MRSA isolates among ICU patients in the US 1 MRSA isolates from bacteraemia patients in England and Wales 2 70 60 50 40 30 20 10 US England and Wales 0 1995 1996 1997 1998 1999 2000 2001 2002 Year 2003 2004 1. Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance System. MRSA among ICU patients, 1995 2004. http://www.cdc.gov/ncidod/dhqp/pdf/ar/icu_restrend1995-2004.pdf 2. Johnson AP et al. J Antimicrob Chemother 2005;56:455 462
The MRSA threat Indian Scenario Of the 739 cultures of S. aureus, 235 (32%) has been found to be multiply resistant with the individual figures of resistance being 27% - Mumbai 42.5% - Delhi & 47% - Bangalore MRSA is emerging to be a significant problem pathogen - Journal of Post. Grad. Med. 1996
Indian data on MRSA INSAR 2013 (2008-9) Study Outpatient Ward ICU 28% 46% 45% Bathalapalli 2012 65% 71% Bangalore 2015 52% 62% Most of these studies DO NOT report vanco MIC!!
The MRSA threat: India Risk factors for MRSA Srinivasan etal, Indian Journal of Medical Microbiology vol. 24, No. 3, 2006
Disease Manifestations due to Staphylococcus aureus Wounds Skin ulcers Pneumonia Intravenous line infections S. Antibiotic aureus selection Deep abscesses (Often with bacteraemia) Infective endocarditis Bacteraemia Osteomyelitis
MRSA : Treatment Options Vancomycin Teicoplanin Linezolid Daptomycin Tigecycline Dalfopristin/quinupristin Clindamycin Cotrimoxazole Investigational agents Telavancin (approvable) Dalbavancin Oritavancin PBP-2a targeted -lactams (ceftobiprole, ceftaroline)
Vancomycin reducing susceptibility A new clinical problem - VISA first reported in Japan in 1996 - VRSA first reported in USA in 2002 Still a rare phenomenon and both have different resitance mechanisms Resistance has been related to increased Vancomycin use globally BUT in about 50% of cases Vancomycin was not used
Vancomycin MIC creep for MSSA and MRSA strains
Vancomycin Creeping MIC levels Increasing MIC for staphylococcus 2004) 3 - Shifting MIC - lesser than 0.5 µg/ml to >1 µg/ml (from 2000 to 1.Steinkraus G et al. J Antimicrob Chemother 2007;60:788 794, Clin Microbiol Infect 2008; 14 (Suppl. 2): 3 9 2.Soriano A et al. Clin Infect Dis 2008;46:193 200 3 data from US
Vancomycin Creeping MIC levels Increasing MIC for staphylococcus - Shifting MIC - lesser than 0.5 µg/ml to >1 µg/ml (from 2000 to 2004) 3 *Inappropriate therapy defined as empirical therapy to which the MRSA strain was resistant 1.Steinkraus G et al. J Antimicrob Chemother 2007;60:788 794, Clin Microbiol Infect 2008; 14 (Suppl. 2): 3 9 2.Soriano A et al. Clin Infect Dis 2008;46:193 200 3 data from US
No. of Days (median) Vancomycin Creeping MIC levels 25 20 P=0.02 21 15 10 10.5 Low MIC (<1.5) High MIC (>1.5) 5 0 Length of stay (median) 2 fold increase in LOS with High Vanomycin MIC in MRSA infection 1 1.8 fold increase in mean Hospital Cost with High Vanomycin MIC 2 1. T. P. Lodise et al Antimicrob agents chemother 2008, p. 3315 3320 2. Maclayton, D. O. et al, Clinical Ther. 28, Number 8, 2006 LOS = Length of Stay
Vancomycin Creeping MIC levels 12 10 8 P=0.17 11 6 4 Low MIC (<1.5) High MIC (>1.5) 2 0 1 Recurrence within 60 days Patients with higher Vancomycin MIC had a higher likelihood of recurrence 1 1. T. P. Lodise et al Antimicrobial agents and chemotherapy, Sept. 2008, p. 3315 3320 2. Maclayton, D. O. et al, Clinical Therapeutics/Volume 28, Number 8, 2006
High Vancomycin MIC and clinical failure
Log 10 CFU/g Bactericidal activity is rapid 12 11 10 9 8 7 6 5 4 3 2 1 0 8 16 24 32 40 48 56 64 72 Time (h) Growth control Nafcillin Vancomycin Linezolid Cubicin Daptomycin Kern WV. Int J Clin Pract 2006;60:370 378
Daptomycin efficacy in CRBSI 80 70 60 50 P=0.04 68 40 30 20 10 0 32 Overall responce Vancomycin Daptomycin Daptomycin had improved overall response in more patients in comparison to vancomycin More that 3/4 th of the patients had clinical resolution within 2 nd day of Daptomycin therapy Anne-Marie Chaftari et al, Int J Antimicrob Agents :36 (2010) 182 186