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![…antibiotic resistance is Inevitable !
Penicillin Methicillin
Penicillin-resistant Methicillin-resistant
S. aureus S. aureus S. aureus
[1950s] [1970s] (MRSA)
Vancomycin
[1997] [1990s]
Vancomycin Vancomycin-
Vancomycin- intermediate- resistant
resistant resistant enterococci (VRE)
[2002] S. aureus
S. aureus
(VISA / GISA)](https://image.slidesharecdn.com/mdrostrategies-130218054016-phpapp01/75/MDRO-Strategies-8-2048.jpg)
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MDRO Strategies
This presentation discusses tackling multiple drug resistant organisms (MDROs) from an intensive care perspective. It notes that intensive care faces the consequences of therapeutic misadventures upstream. The document outlines various definitions of MDROs such as MRSA, VRE, and ESBL gram negatives. It discusses how antibiotic resistance is inevitable due to the power of bacteria and natural selection. Higher antibiotic use correlates with higher resistance rates, particularly in inpatient settings like ICUs. ESBL and other resistant organisms are increasingly prevalent in developing world ICUs compared to developed countries. Studies also show ESBL and VRE infections are associated with higher mortality and costs.
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MDRO Strategies
- 1. This presentation waspresented at Apollo International Forum on Infection Control (AIFIC’ 2013), Chennai The presentation is solely meant for Academic purpose
- 2. Tackling Multiple Drug Resistant Organisms
- 3. Disclaimer: My Perspective Ihave neither the intellectual depth nor the luxury of the remote academic view that ID specialists or clinical microbiologists may have……
- 4. Intensive Care… ….is a“downstream” speciality… …we face the consequences of many therapeutic misadventures!!!
- 5. MDRO Definition “Micro-organisms (predominantly bacteria) that are resistant to one or more classes of anti-microbial agents MRSA VRE ESBL Gram negatives “Pan-resistant” Acinetobacter KPC- Klebsiella pneumoniae VIM-2 / NDM-1 Klebsiella pneumoniae Stenotrophomonas Assault of the Acronym Burkholderia VISA VRSA…..
- 6. Considering where Antibiotics comefrom… (not from the friendly neighbourhood drug dealer!)
- 7. …& the “Powerof Bacteria”… (Historical & Numerical = Genetic) Age: Bacteria 3,500,000,000 years (2000x) = 1yr Eukaryotes 1,800,000,000 years (1000x) Multi-cellulars 580,000,000 years (300x) Australopithecus 4,000,000 years (2x) Homo erectus <2,000,000 years (1) = 5.2 hrs Antibiotic use 60 years (0.00003x) = 55 secs Numbers: “ The number of E. Coli in the gut of each human being far exceed the number of people that now live or have ever inhabited the earth” !!! - Gould SJ; Life’s Grandeur
- 8. …antibiotic resistance isInevitable ! Penicillin Methicillin Penicillin-resistant Methicillin-resistant S. aureus S. aureus S. aureus [1950s] [1970s] (MRSA) Vancomycin [1997] [1990s] Vancomycin Vancomycin- Vancomycin- intermediate- resistant resistant resistant enterococci (VRE) [2002] S. aureus S. aureus (VISA / GISA)
- 9. Selection of Resistance Antibiotic exposure Resistant strains: rare Resistant strains: No survival advantage dominant
- 10. Use Promotes Resistance Urinary E. Coli Resistance vs. Antibiotic Use Usage (DDD/1000/day) % Resistance Antibiotic use is a strong Correlate of Resistance JAC; DOI: 10.1093/ jac /dkg488 (but not the only factor)
- 11. Antibiotics & Resistance 50 p <0.01 for all 45 comparisons % Resistant Organisms 40 35 Evidence: 30 Inpatient Resistant organisms are 25 Outpatient more common amongst inpatients 20 15 ICUs (with highest use) 10 have highest rates of 5 resistance 0 SA Z SE E CT VR MR MR e ud Ps Archibald et al; ICARE Widespread use of antibiotics leads to the Clin Inf Dis 1997; 24: 211-15 selection of antibiotic resistant strains
- 12. Percent Resistance 0 10 20 30 40 50 60 19 89 19 90 19 91 19 92 19 93 19 94 19 95 Aureus 19 96 Resistant 19 97 Methicillin 19 98 19 99 20 00 Staphylococcus
- 13. Percent Resistance 0 2 4 6 8 10 12 14 19 89 19 90 19 91 19 92 19 93 19 94 19 Beta 95 19 96 19 97 19 98 19 Extended Spectrum 99 20 Lactamase (Klebsiella) 00 7x
- 14. Percent Resistance 0 5 10 15 20 25 30 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 Quinolne Resistant 19 98 Aeroginosa 19 99 20 Pseudomonas 00 3x
- 15. ESBL in theDeveloping World Site Location %ESBL Klebsiella E. coli AIIMS, New Delhi1 Tertiary Hospital 80% - Mathai 10 Tertiary Hosps. - >60% KGMC, Lucknow2 Neonatal ICU 86% 64% SMF, Chennai Nosocomial: ICU 84% 82% SMF, Chennai Comm. Acquired: ICU 53% 44% China, Shanghai3 University Hospital 51% 24% Latin America4 SENTRY, Pneumonia 44% 29% 1: Ind J Med Res 2002;115:153-7 2: J Med Microb 2003; 52: 421-5 3: Zhou Yi Xue Za Zhi 2002;82:1476-9 4: Diag Mic Inf Dis 2002; 44: 301-11
- 16. Developing World ICUs International Nosocomial Infection Control Consortium (INICC) 8 Countries; 55 ICUs; 46 Hospitals NNIS (USA) INICC 1992-2004 2002-5 MRSA 59% 84% ESBL 19% 55% Quin. res Pseudo. 29% 59% VRE 29% 5% Ann Int Med 2006; 145: 582-91
- 17. Does ‘ESBL’ kill? Casecontrol study from Israel (198 patients) Multivariate analysis; ESBL remains independently associated with Mortality OR 3.6 (1.4 - 9.5) p <0.008 Delayed Rx OR 25.1 (10.5 - 60.2) p <0.001 LOS OR 1.56 p <0.001 Cost OR 1.57 p <0.003 Antimicrob Agents Chemo 2006; 50: 1257-62
- 18. VRE Implications: Mortality Vancomycin Resistance is: An independent predictor of death in EC bacteremia (OR: 2.1; 95% CI:1.14-3.88) Associated with J all cause mortality (52% vs. 27% in vanco sensitive) An independent predictor of infection related death (OR: 5.2; 95% CI: 1.4-20.0) Ann Int Med 2001; 135: 484-92 Diag Micr ID 2000; 36: 145-52 CID 2000; 30: 466-72 Newer studies (? more effective Rx) show CID 2002; 34: 922-9 no difference
- 19. MRSA: Attributable Mortality Debated with VAP* Odds of death 2x with MRSA bacteremia vs. MSSA Meta-analysis: 31 cohort studies 3963 patients 2/3 MSSA vs. 1/3 MRSA Clin Inf Dis 2003; 36:53–9 *Anes Clin N A 2004: 22 ; 405 - 35
- 20. Risk Factors forMDRO Age / co-morbidity Severity of illness ICU admission Demographic Prior Antibiotic exposure Antibiotic / Prior colonization infection control Exposure to colonized/ infected patient Procedural Invasive Device use CID 2001; 33: 939-46 Inf Cont Hosp Epi 2009; 30: 1180-5
- 21. Approach to PreventingMDRO Factors Early goal-directed Severity of illness…. Rx Device use Avoid Devices Minimise Antibiotic use device-associated infection Cannot justify an “I’m not to blame” Rational & conservative attitude antibiotic use
- 22. CDC: Strategies Is our empirical strategy correct? Administrative Support What is the value of a restricted formulary? Education Antibiotic Use Active Surveillance Culture Culture vs. rapid detection? Isolation Precautions Practicality? Environmental issues Decolonization Mupirocin & SDD?
- 23. Patterns of Antibioticuse in the ICU
- 24. Assumptions for useof Empirical Antibiotics Infection J (attributable) mortality Antibiotic treatment K mortality Early administration of correct antibiotic is better than delayed administration Adverse effects < the benefits of treatment
- 25. Attributable Mortality Nosocomial Attributable Infection mortality Definition: Mortality caused by an All Nosocomial Infection 20% (2.8-44) infection (in excess of mortality in a similarly ill Blood-stream 25% (4.4-47.3) patient without infection). Vent. Assoc. Pneumonia 25% (7.8-42) Chest 2001; 120:2059–93 Urinary Tract None
- 26. Is death attributableto NI? NI Treat Don’t Treat Is there a difference? Yes No NI kills Patient dies of critical illness Unethical to evaluate in this way!
- 27. Is death attributableto NI? Cohort of ICU Patients Definition: Difference in death NI No NI rates between infected & uninfected patients after adjusting Rx No (appropriate) Rx for confounders Severity of illness is a confounder; May be adjusted by case-control studies or Multivariate (regression) analysis Ideally Propensity modeled
- 28. Effect of AppropriateChoice 100 90 Hospital Mortality (%) 80 70 60 50 40 30 20 10 0 Luna et al; No Rx Correct Rx Incorrect Chest 1997; 111: 676-85.
- 29. Effect of AppropriateTiming 100 90 80 Hospital Mortality (%) 70 60 50 40 30 20 10 0 Luna et al; Early Late Chest 1997; 111: 676-85. None Correct Incorrect
- 30. Methodological Issues Systematic review of 51 studies of “appropriate antibiotics” and mortality in bacteraemia No distinction : Empirical vs. definitive Only 16% (8) defined “appropriate” on the basis of in-vitro Cx + route + dose Only 35% looked at attributable mortality Only 21% (7) timed severity of illness measures; but 2 measured it at admission 33% (17) adjusted for septic shock CID 2007; 45: 329 - 37 Only one study used Propensity scores
- 31. Avoiding Overuse: “De-escalation” Suspect infection Initial Rx Multiple drugs wide-spectrum Lab confirmed De-escalate Rx Culture-based de-escalation can reduce resistance Chest 2002; 122:2183–2196.
- 32. Making De-escalation Possible De-escalation is seldom attempted Recent study of VAP* De-escalation only in 22% patients Likely to occur if: 3-4 antibiotics were initially used If adequate cover was initially provided If major pathogen grew on culture *Chest 2006; 129:1210–1218 If culture method was more robust
- 33. Rational De-escalation? Can we use sputum, BAL cytology & culture to make decisions? Probability of VAP +ve -ve BAL with bacteria >95% 25-50% Sputum culture 95% 45% BAL culture 72-95% 50% JAMA. 2007;297:1583-93 No!
- 34. Current Empirical Rxencourages overuse Suspected VAP Rx 65% 35% VAP No VAP Appropriate Inappropriate ? De-escalated No de- escalation Colonization by resistant bugs & subsequent adverse outcome
- 35. VAP: A DecisionAnalysis A decision analysis based on available data suggests: Empirical Rx (using clinical diagnosis) : 66% mortality in the untreated patients 68% mortality in treated patients Reasons for unexpected death with Rx: Diagnostic certainty is low (0.23) Uninfected pts colonize c resistant strains Chest 1996; 110:1025-34 Limitations: Old data; incomplete info
- 36. Gorillamycin Supersporin Kingkongopenem Restrict Cycle Heterogeneous use (Mixing) 0 1 2 3 months
- 37. Strategies to Reduce Resistance Cycling Abx 1 Abx 2 Abx 3 Abx 1 Resistance Time Presumes that a decline in resistance will occur with antibiotic cessation (ie, there is a ‘fitness cost’ to antibiotic resistance.)
- 38. Cycling: The Evidence? None of the evidence is “clean” Mainly observational cohorts Gerding et al Some studies are of a single scheduled AAC 1991; 35: 1284-90 change (not cycling) Koleff et al AJRCCM 1997; 156: 1040-8 Associated confounders: Gruson et al Antibiotic restriction policies AJRCCM 2000; 162: 837-43 Infection prevention strategies Raymond et al CCM 2001; 29: 1101-8 Often evaulate nosocomial infection alone not colonisation rates Toltzis et al Paediatrics 2002; 110: 707-11 RCTs are needed
- 39. Inefficacy of Cycling Restriction, Rotation, ?Rubbish… Abx 1 Abx 2 Abx 3 Abx 1 Resistance The rate of decline of resistance will depend on: the cycling interval & Proc Nat Ac Sci 1999; 96:1152-56 the fitness cost of antibiotic resistance
- 40. Mathematical Models Model simulating hospital patients / NI Bergstrom & Reluga: Cycling and mixing are better than one drug Non-optimal strategies of cycling or mixing degrade effect Even in optimal conditions cycling is not much better than mixing “Cycling is unlikely to reduce either the evolution or the spread of antibiotic Math Med & Biol 2005; 22: 187-208 resistance.” and “inappropriately optimized cycles may hinder resistance PNAS 2004 ; 101: 13285–13290 control”
- 41. Empirical Evidence 44 month, single ICU evaluation of 4 strategies: Patient-specific antibiotic Prioritized antibiotic (cycled) Restricted antibiotic (cycled) Maximal heterogeneity (mixed) Antibiotic heterogeneity: Peterson Index Homogeneity associated with J Carbepenem Res. Acinetobacter : RR 15.5 (5.5–42.8) J Antimic Chemo 2006; J ESBL: RR 4.2 (1.9–9.3) and 57: 1197–1204 J Enterococcus faecalis: RR 1.7 (1.1–2.9).
- 42. Preventive Strategies Active SurveillanceCultures + Contact Precautions Identify both colonized & infected patients early Restrict spread by strict infection control processes
- 43. ASC + Precautions Best studied with MRSA; less with Gm Neg ASC shows benefit in some; inconsistent Mathematical modelling: VRE: Culture (vs. none) K transmit ~40% Culture + isolation K transmit 65% MRSA: Routine cultures are ineffectual ASC can reduce rates Debated: When, how often, Need RCT! Which patients (all vs. at risk) Sites, Methods
- 44. The RCT; Youasked for it! Cluster randomized study Compliance with 10 intervention ICUs (surveillance Cx + barrier) barrier precautions 8 control ICUs (n= 5343 & 3705 respectively) was suboptimal Surveillance cultures on all (reported to Rx grp) MRSA+VRE colonization & infection unchanged N E J Med 2011; 364: 1407-18 40.4+3.3 vs 35.6+3.7 / 1000 patient days (p 0.35)
- 45. The VA Initiative “MRSABundle” 2007 – 2010; 1.9 million admits ICU / non ICU Universal nasal survl. 8.3 million patient days; “MRSA Bundle” initiated Contact precautions Universal nasal surveill’nce: Hand Hygiene Chromgenic agar/ PCR “Infection control as everyone’s + Contact precautions responsibility” K ICU MRSA ~62% (relative risk) N E J Med 2011; 364: 1419-30 K Non-ICU MRSA 45%
- 46. The Gist: STARICU vs. VA While one can decry the deficiencies of observational cohorts; RCTs often underestimate benefits The prime issue: methodology of surveillance STAR: Routine Cx: Median positive ~ 5 days VA: Chromgenic + PCR (“real time”) Extrapolation to Spot-tests for gram negative MDROs limited MDRO Gram Value of contact precautions is unsubstantiated negatives
- 47. Decolonization: I am not competent to discuss the merits of Mupirocin to prevent MRSA The problem of “Dutch” Ideas But am tempted to introduce the Euthanasia Legal drugs concept of Selective Decontamination Legal prostitution of the Digestive Tract (SDD)…… “Going Dutch” A function of living below ….interesting lessons! sea level?
- 48. Methodology of SDD* *Selective Decontamination of the Digestive Tract 1. Oral application of antibiotic: Tobra+ Amphotercin+ Polymixin (Vancomycin added if MRSA is J) 2. NG administration 3. Systemic Antibiotics for 24-48 hr 1 & 2: “Selective”; anaerobes preserved Reduce GI/ Oropharynx colonization CID 2006; 43: S70–4 3: Prevents early colonization / VAP
- 49. Outcomes with SDD Rx Meta analysis 30 RCTs 5727 patients Odds of VAP and death reduced; Rx VAP; OR 0.35 (0.29-0.41) Death; OR 0.8 (0.69-0.93) Death K from 30% to 24% D’amico NNT to prevent one death = 16 BMJ 1998; 316; 1275-85 Best effect in surgical ICU patients
- 50. So why notuse SDD? Rx Resistance? Fear of inducing bacterial resistance Not conclusively established Rx Resistance? Will it work when rate of bacterial resistance is high in an ICU AJRCCM 2001; 164: 382-88 AJRCCM 2001; 164: 338-9 Has been used to combat outbreaks of AJRCCM 2002; 166: 1029-37 resistant organisms; not in endemic high- Intens Care Med 1999; 25: 1323-6 resistance ICUs
- 51. SDD in India? Rx Mathematical Modeling* Maximum effect shown when: a. Colonization pr. with resistant bacteria is low b. All patients at risk are given SDD Rx c. No external source of potential pathogens None of the above can be met in our ICUs a. ESBL ~ 80%; MRSA ~50%; MDR * Bootsma et al Pseudomonas~ 40%; MDR Acinetobacter Intersci Conf Antimicrob Agents Chemother. b. Not cost-effective to give SDD to everyone 2003 Sep 14-17; 43: abstract no. K-698. c. Requires pre-emptive isolation (quarantine)
- 52. More Math Models! Thebenefit of non-absorbable “antibiotic prophylaxis can only be substantial if patient-to-patient transmission has already been reduced to a subcritical level by barrier precautions”….. “a firm theoretical argument against routine use of topical antimicrobial prophylaxis”
- 53. Tackling MDROs! We are facing the consequences of decades of irresponsible use: So control processes will be expensive Best option: ASC + Contact Precautions Real-time surveillance need development ICU Antibiotic use needs to be reduced Prophylactic Abx only work after prevalence rates are reduced Infection Control Processes remain supreme
- 54. “Antibiotics are anon- renewable resource”…. Laxminarayan & Brown 2001 …..use them wisely!