Disclaimer:My Perspective I have neither the intellectual depth nor the luxury of the remote academic view that ID specialists or clinical microbiologists may have……
Intensive Care…….is a “downstream” speciality… …we face the consequences of many therapeutic misadventures!!!
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 StenotrophomonasAssault of the Acronym Burkholderia VISA VRSA…..
Considering whereAntibiotics come from… (not from the friendly neighbourhood drug dealer!)
…& the “Power of Bacteria”… (Historical & Numerical = Genetic)Age:Bacteria 3,500,000,000 years (2000x) = 1yrEukaryotes 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 hrsAntibiotic use 60 years (0.00003x) = 55 secsNumbers:“ The number of E. Coli in the gut of each human being farexceed the number of people that now live or have everinhabited the earth” !!! - Gould SJ; Life’s Grandeur
…antibiotic resistance is Inevitable ! Penicillin Methicillin Penicillin-resistant Methicillin-resistant S. aureus S. aureus S. aureus [1950s] [1970s] (MRSA) Vancomycin  [1990s] Vancomycin Vancomycin- Vancomycin- intermediate- resistant resistant resistant enterococci (VRE)  S. aureus S. aureus (VISA / GISA)
Use Promotes Resistance Urinary E. Coli Resistance vs. Antibiotic Use Usage (DDD/1000/day) % Resistance Antibiotic use is a strong Correlate of ResistanceJAC; DOI: 10.1093/ jac /dkg488 (but not the only factor)
Antibiotics & Resistance 50 p <0.01 for all 45 comparisons % Resistant Organisms 40 35Evidence: 30 InpatientResistant organisms are 25 Outpatientmore common amongstinpatients 20 15ICUs (with highest use) 10have highest rates of 5resistance 0 SA Z SE E CT VR MR MR e ud PsArchibald et al; ICARE Widespread use of antibiotics leads to theClin Inf Dis 1997; 24: 211-15 selection of antibiotic resistant strains
ESBL in the Developing 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
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
Does ‘ESBL’ kill?Case control study from Israel (198 patients)Multivariate analysis;ESBL remains independently associatedwithMortality OR 3.6 (1.4 - 9.5) p <0.008Delayed Rx OR 25.1 (10.5 - 60.2) p <0.001LOS OR 1.56 p <0.001Cost OR 1.57 p <0.003Antimicrob Agents Chemo 2006; 50: 1257-62
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: 484-92Diag Micr ID 2000; 36: 145-52CID 2000; 30: 466-72 Newer studies (? more effective Rx) showCID 2002; 34: 922-9 no difference
MRSA: Attributable Mortality Debated with VAP* Odds of death 2x with MRSA bacteremia vs. MSSAMeta-analysis:31 cohort studies3963 patients2/3 MSSA vs. 1/3MRSAClin Inf Dis 2003; 36:53–9*Anes Clin N A 2004: 22 ; 405 - 35
Risk Factors for MDRO 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 useCID 2001; 33: 939-46Inf Cont Hosp Epi 2009; 30: 1180-5
Approach to Preventing MDRO Factors Early goal-directed Severity of illness…. Rx Device use Avoid Devices Minimise Antibiotic use device-associated infectionCannot justify an“I’m not to blame” Rational & conservativeattitude antibiotic use
CDC: Strategies Is our empirical strategy correct? Administrative SupportWhat is the value of arestricted formulary? Education Antibiotic Use Active Surveillance CultureCulture vs. rapid detection? Isolation Precautions Practicality? Environmental issues Decolonization Mupirocin & SDD?
Assumptions for use ofEmpirical AntibioticsInfection J (attributable) mortalityAntibiotic treatment K mortalityEarly administration of correct antibioticis better than delayed administrationAdverse effects < the benefits of treatment
Attributable Mortality Nosocomial Attributable Infection mortalityDefinition:Mortality caused by an All Nosocomial Infection 20% (2.8-44)infection (in excess ofmortality 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
Is death attributable to 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!
Is death attributable to NI? Cohort of ICU PatientsDefinition:Difference in death NI No NIrates betweeninfected & uninfectedpatients after adjusting Rx No (appropriate) Rxfor confounders Severity of illness is a confounder; May be adjusted by case-control studies or Multivariate (regression) analysis Ideally Propensity modeled
Effect of Appropriate Choice 100 90 Hospital Mortality (%) 80 70 60 50 40 30 20 10 0Luna et al; No Rx Correct Rx IncorrectChest 1997; 111: 676-85.
Effect of Appropriate Timing 100 90 80 Hospital Mortality (%) 70 60 50 40 30 20 10 0Luna et al; Early LateChest 1997; 111: 676-85. None Correct Incorrect
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 shockCID 2007; 45: 329 - 37 Only one study used Propensity scores
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
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!
Current Empirical Rx encourages overuse Suspected VAP Rx 65% 35% VAP No VAP Appropriate Inappropriate ?De-escalated No de- escalation Colonization by resistant bugs & subsequent adverse outcome
VAP: A Decision Analysis 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 strainsChest 1996; 110:1025-34 Limitations: Old data; incomplete info
Strategies to ReduceResistanceCycling Abx 1 Abx 2 Abx 3 Abx 1Resistance TimePresumes that a decline in resistance will occurwith antibiotic cessation (ie, there is a ‘fitness cost’to antibiotic resistance.)
Cycling: The Evidence? None of the evidence is “clean” Mainly observational cohortsGerding et al Some studies are of a single scheduledAAC 1991; 35: 1284-90 change (not cycling)Koleff et alAJRCCM 1997; 156: 1040-8 Associated confounders:Gruson et al Antibiotic restriction policiesAJRCCM 2000; 162: 837-43 Infection prevention strategiesRaymond et alCCM 2001; 29: 1101-8 Often evaulate nosocomial infection alone not colonisation ratesToltzis et alPaediatrics 2002; 110: 707-11 RCTs are needed
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
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 antibioticMath Med & Biol 2005; 22: 187-208 resistance.” and “inappropriately optimized cycles may hinder resistancePNAS 2004 ; 101: 13285–13290 control”
Preventive StrategiesActive Surveillance Cultures + Contact Precautions Identify both colonized & infected patients early Restrict spread by strict infection control processes
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
The RCT; You asked for it! Cluster randomized studyCompliance 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 unchangedN E J Med 2011; 364: 1407-18 40.4+3.3 vs 35.6+3.7 / 1000 patient days (p 0.35)
The VA Initiative“MRSA Bundle” 2007 – 2010; 1.9 million admits ICU / non ICUUniversal nasal survl. 8.3 million patient days; “MRSA Bundle” initiatedContact precautions Universal nasal surveill’nce:Hand Hygiene Chromgenic agar/ PCR“Infection control aseveryone’s + Contact precautionsresponsibility” K ICU MRSA ~62% (relative risk)N E J Med 2011; 364: 1419-30 K Non-ICU MRSA 45%
The Gist: STAR ICU 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 limitedMDRO Gram Value of contact precautions is unsubstantiatednegatives
Decolonization: I am not competent to discuss the merits of Mupirocin to prevent MRSAThe 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?
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 colonizationCID 2006; 43: S70–4 3: Prevents early colonization / VAP
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 = 16BMJ 1998; 316; 1275-85 Best effect in surgical ICU patients
So why not use 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 ICUAJRCCM 2001; 164: 382-88AJRCCM 2001; 164: 338-9 Has been used to combat outbreaks ofAJRCCM 2002; 166: 1029-37 resistant organisms; not in endemic high-Intens Care Med 1999; 25: 1323-6 resistance ICUs
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 AcinetobacterIntersci Conf Antimicrob AgentsChemother. b. Not cost-effective to give SDD to everyone2003 Sep 14-17; 43:abstract no. K-698. c. Requires pre-emptive isolation (quarantine)
More Math Models!The benefit of non-absorbable “antibiotic prophylaxis can only besubstantial if patient-to-patient transmission has already beenreduced to a subcritical level by barrier precautions”…..“a firm theoretical argument against routine use of topicalantimicrobial prophylaxis”
Tackling MDROs! We are facing the consequences of decades of irresponsible use: So control processes will be expensiveBest option: ASC + Contact PrecautionsReal-time surveillance need developmentICU Antibiotic use needs to be reducedProphylactic Abx only work afterprevalence rates are reducedInfection Control Processes remainsupreme
“Antibiotics are a non-renewable resource”…. Laxminarayan & Brown 2001 …..use them wisely!