Witchcraft for Gram negatives Dr Subramanian S MD DNB MNAMS AB (Medicine, Infect Dis) Infectious Diseases Consultant Global Health City, Chennai www.asksubra.com
Drug resistance follows the drug like a faithful shadow. - Paul Erhlich 1854-1915
It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. -Alexander Fleming, Nobel prize lecture, 1945
Alphabet soup ESBL AmpC KPC MBL (NDM) CTX-M OXA Porin loss
Peleg AY, Hooper DC. N Engl J Med 2010; 362:1804-1813
Class A Class B Class C Class D SHV TEM CTX-M PER VEB IMI SME NMC KPC GES BIC IMP VIM NDM KHM SPM GIM SIM AIM DIM AmpC CMY ACT DHA ACC FOX OXA 1-10 OXA 11-15 OXA 23/27, 24/40, 48, 51/66/69, 58, 143 ESBL Carbapenemases Metalo β Lactamases Bush, Jacoby Antimicrob Agents Chemotherap 2010; 54:969-76 Patel, Bonomo. Expert Rev Anti Infect Ther 2011; 9: 555-70
3rd Gen cephalosporins Ceftriaxone breakpoints have been lowered by CLSI Even if it says susceptible, failures are high Pyelonephritis from Thailand: Both clinical (65% and 93%) and microbiological (67.5% and 100%) responses at 72 hours after ceftriaxone treatment were poorer in the ESBL-producing group than in the ESBL-nonproducing group (p < 0.0002)
Cefepime Cefepime not a great choice for ESBL Patients receiving cefepime for an ESBL infection were 9.7 (95% CI: 1.4 68.8) and 28.5 (95% CI: 2.6 306.6) times as likely to have an unsuccessful clinical and microbiological response compared with those with a non-esbl infection in one study
Mortality and Inadequate Therapy in Enterobacter In a study of 129 patients with Enterobacter bacteremia: 63% (7/11) patients who received inadequate therapy died, compared with 17% (9/54) patients who received adequate monotherapy and 16% (10/64) patients who received adequate combination therapy. Administration of a third-generation cephalosporin to patients who developed Enterobacter bacteremia within the past 14 days was significantly more likely to cause emergence of a multiresistant Enterobacter spp. (p<0.001) than was administration of other classes of antibiotics. When Enterobacter organisms are isolated from blood, it may be prudent to avoid third-generation cephalosporin therapy regardless of in vitro susceptibility. Chow JW et al. Ann Internal Med 1991;115:585-590.
Treatment Outcome for ESBL-Producers Initial appropriate therapy should be administered empirically if there is any suspicion that an infection is due to an ESBL-producing strain. Treatment No active antibiotics Beta-Lactams Quinolones Imipenem % Mortality 71 44 36 8 Paterson DL. IDSA 1998.
Frequency distribution of ESBL-positive isolates by country in the Asia-Pacific (AP) region during 2007. Hawser S P et al. Antimicrob. Agents Chemother. 2009;53:3280-3284
Cipro and carbapenems Quinolones are related to carbapenem resistance in Ps.aeruginosa Increased efflux (meropenem and doripenem) and decreased porin entry (all) Reduced Cipro use resulted in reduction in meropenem resistance in Ps.aeruginosa No change in Enterobacteriaeceae or A.baumanii Kohler T AAC:43:424-27 Quayle J AAC 50:1633-41 Lewis JG ICHE 2012; 33(4):368-73
Cipro use Rate of resistant infections per 10,000 patient days by month Panel A: Carbapenem resistant infections Panel B: Cipro resistant infections Panel C: Cefepime resistant infections Lewis JG. ICHE 2012;33(4):368-73
55 year old patient with diabetes is admitted with cholangitis with stones. The biliary stent placed earlier seems to be blocked. Blood culture grows K.pneumoniae. What would you use? Resistant to ampi, ceftriax, ceftaz, cefepime, pip/taz, amp/sulb, amox/clav, ertapenem, Susceptible to amikacin, tigecycline, meropenem, imipenem, gentamicin, colistin
Carbapenem resistant Enterobacteriaceae Multiple mechanisms ESBL with porin loss AmpC with porin loss KPC MBL (NDM) OXA Combinations Consider potencies, drug levels, toxicities Strict contact isolation
NDM among outpatients Stool samples among 200 distinct patients in Rawalpindi, Pakistan 64 carbapenemase positive isolates; all NDM Species E.coli: 30/64 isolated E.cloacae: 21/64 isolates Prevalence: Inpatient: 19/70 (27.1%) Outpatient: 18/130 (13.8%) Perry et al.j Antimicrob Chemother. Epub July 2011
Microbiology from Asia Chung et al. Am. J. Respir. Crit. Care Med. December 15, 2011 vol. 184 no. 12 1409-1417
Local microbiology Pathogen India Pakistan China Korea Pseudomonas spp Malaysia Taiwan Thailand Philippi nes 20% 15-18% 18% 23% 17.6% 21% 17.8% 42.1% A. baumannii 38% 58.5% 16% 9% 23% 20% 28.2% 13.1% MRSA 5% 18% 16% 23% 11.8% 18% 7.6% K. pneumoniae 23% No data 14% 11% 5.8% 9% 7.7% 26.3% E. coli 6.1% 3.6% 2.8% Enterobacte riaceae 8.2% 8% 3.2% S. maltophilia 11.8% 3.4% Chawla R. American Journal of Infection Control. Vol 36(4), 2008. suppl. S93 S100
Am. J. Respir. Crit. Care Med. December 15, 2011 vol. 184 no. 12 1409-1417 Indian data Acinetobacter resistance to imipenem 86% Resistance rates to ceftazidime, ciprofloxacin, ampicillin-sulbactam, and piperacillin-tazobactam were 78.2%, 80.7%, 75.9%, and 76.7%. Pseudomonas resistance to CPM rising Nosocomial outbreaks of Acinetobacter reported Chung et al. Am. J. Respir. Crit. Care Med. December 15, 2011 vol. 184 no. 12 1409-1417
Acinetobacter resistance
What s in the pipeline Aztreonam/avibactam Plazomycin Eravacycline Nothing before 2020
What s also in the pipeline? Cotrimoxazole resistant meleiodosis Outbreaks of B.cepaceae and S.maltophila Colistin resistance!!