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18. antibiotic use in the ic ul

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Yerragunta Tirumal

This document discusses antibiotic use and resistance in the ICU. It notes that 30-40% of ICU patients have or develop nosocomial infections, with antibiotics commonly used empirically, definitively, or prophylactically. While appropriate antibiotic choice and timing can reduce mortality from infection, clinical trials have not proven this due to flaws in study design. Widespread antibiotic use leads to increased resistance, seen most prominently in India with extended-spectrum beta-lactamase producing bacteria. The document advocates for more responsible antibiotic use through early culture and de-escalation of therapy once pathogens are identified, in order to curb rising antibiotic resistance in the ICU.

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Antibiotics in the ICU Ram E. Rajagopalan, MBBS, AB (Int Med) AB (Crit Care) Department of Critical Care Medicine SUNDARAM MEDICAL FOUNDATION Chennai Choice, Resistance, Pharmacokinetics & Pharmacodynamics
Nosocomial Infection Between 30-40% ICU patients have or develop infection About ½ of these are nosocomial Prevalence is very variable between different kinds of units Lung Urine Wound Bacteremia Other
Bacteriologically confirmed (true positive) “Anticipated” infection Clinically suspected infection Antibiotic use in the ICU Empirical Rx Definitive Rx Prophylactic Rx
Indications for antibiotics ~ 60% of patients in a general ICU receive antibiotics Unproven 'Infection' 28% Proven Infection 59% Prophylaxis 18% Bergmans et al JAC 1997; 39: 527-35
IncisionTime Time of Prophylactic dose RateofWoundInfection Antibiotic Prophylaxis Only for “clean-contaminated” & some “clean” wounds Appropriate cover; No value for additional doses One dose.. ..one hour before.. ..incision SURGICAL WOUND
Antibiotic Use & Resistance Habarth et al. Circulation 2000; 101: 2916-21 ….but prolonged ABP was an independent risk factor for bacterial resistance (AOR 1.6; 95%CI: 1.1-2.6) 2641 CABG patients; 4-yr. observ. cohort Either < or > 48 hr antibiotic prophylaxis 0 10 20 30 40 %ofsugicalinfections <48 hour >48 hour
Systemic Antibiotic Use 0 5 10 15 20 25 30 35 0 5 10 15 20 Days of ventilation %withVAP No Abx Prior Abx Resistant Ps. aeroginosa; Acinetobacter 19% 65% ARRD 1989; 139:877–84. Ventilator Associated Pneumonia
Policy on Prophylaxis Limit antibiotic prophylaxis to surgical wounds; ideally one pre-op. dose Avoid for Preventing pneumonia in intubated pts Preventing bacteremia from CV lines Preventing UTI from a Foley‟s catheter #1 Prevention Cure
Empirical Antibiotics Suspected Infection Empirical Treatment Infection: Subsequently confirmed by bacteriology Infection: not confirmable (false negative) No infection (SIRS) ? Over treatment 25-40% 60-75% ICEM Yearbook 2003; 218-228.
Assumptions for use of Empirical Antibiotics Nosocomial infection increases (attributable) mortality Antibiotic treatment reduces mortality Early administration of correct antibiotic improves survival Adverse effects are less than the benefits of treatment
Is death attributable to NI? NI Treat Don‟t Treat Is there a difference? Yes No NI kills Patient dies of critical illness Definition: Mortality caused by an infection (in excess of mortality in a similarly ill patient without infection).
Does Rx improve survival? 35 Clinical Trials identified None placebo controlled Only 2 double-blind No “Gold Standard” antibiotic Mainly comparing antibiotic regimens Mainly “equivalence” trials NO DIFFERENCE BETWEEN AGENTS Where are the Emperors clothes? ICEM Yearbook 2003; 219-28.
Is death attributable to NI? Cohort of ICU Patients NI No NI Rx No (appropriate) Rx Severity of illness is a confounder; May be adjusted by case-control studies or Multivariate (regression) analysis About 25% attributable mortality Definition: Difference in death rates between infected & uninfected patients after adjusting for confounders
Attributable Mortality Nosocomial Attributable Infection mortality All Nosocomial Infection 20% (2.8-44) Blood-stream 25% (4.4-47.3) Vent. Assoc. Pneumonia 25% (7.8-42) Urinary Tract NoneChest 2001; 120:2059–93
Effect of Appropriate Choice Luna et al; Chest 1997; 111: 676-85. 0 10 20 30 40 50 60 70 80 90 100 No Rx Correct Rx Incorrect HospitalMortality(%)
Effect of Appropriate Timing 0 10 20 30 40 50 60 70 80 90 100 Early Late None Correct Incorrect HospitalMortality(%) Luna et al; Chest 1997; 111: 676-85.
Timing and Mortality Iregui et al Chest 2002; 122:262–8 No Delay 12.5 + 4.2 h Delay 28.6 + 5.8 h TimefromDxofVAP(h) 20 40 n=107 Delay increased hospital mortality 2.5x & VAP attributable mortality 3.5x
Design Flaws VAP Rx Culture + Culture - Appropriate Inappropriate ? Colonization by resistant bugs & subsequent adverse outcome 25% 75%
Making the Choice Appropriately timed, appropriately chosen antibiotic can save lives…….so…. ….which antibiotic(s)? Focused Rx with narrow spectrum (or) Gorillamycin + Supersporin + King-Kongopenem?
CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen Pseudomonas (46) 30% (13/44) 24% (11/46) 23% (10/43) 36% (16/44) 46% (21/46) 60% (26/44) 64% (7/11) Klebsiella ESBL (38) 0% (0/38) 5% (2/38) 26% (10/38) 35% (13/37) 32% (12/38) 37% (14/38) 80% (8/10) E Coli ESBL (36) 0% 3% (1/36) - 58% (21/36) 53% (19/36) 67% (24/26) 82% (9/11) Acinetobacter (15) 8% (1/12) 31% (4/13) 73% (8/11) 75% (9/12) 55% (6/11) 36% (4/11) 100% (3/3) Proteus (18) 72% (11/15) 11% (2/18) 11% (2/18) 67% (12/18) 100% (15/15) 87% (13/15) 100% (2/2) Non-ESBL (K+Ec) (15) 100% (15/15) 93% (14/15) - 100% (15/15) 100% (10/10) 100% (10/10) 100% (2/2) Antibiogram ™: SMF ICU Nosocomial Pathogens,
Antibiotics & Resistance Widespread use of antibiotics leads to the selection of antibiotic resistant strains Archibald et al; ICARE Clin Inf Dis 1997; 24: 211-15 Evidence: Resistant organisms are more common amongst inpatients ICUs (with highest use) have highest rates of resistance 0 5 10 15 20 25 30 35 40 45 50 %ResistantOrganisms MRSA MRSE Pseud CTZ VRE Inpatient Outpatient p <0.01 for all comparisons
“De-escalation” Chest 2002; 122:2183–2196. De-escalate Rx Lab confirmed Initial Rx wide-spectrum Suspect infection Culture-based de-escalation can reduce resistance
Policy on Empirical Rx a. Empirical Rx can be justified in ICU b. Abx. choice based on local patterns c. Initial Rx should be wide-spectrum d. De-escalate based on culture result As choice is based on local susceptibility & de-escalation needs culture results CULTURE prior to antibiotics is MANDATED! #2
Policy for Definitive Therapy Critically ill patients have microbiological colonisation of normally sterile sites Treat true infection Aviod antibiotics for colonised patients ! #3
Microbe Culture in VAP Probability 1 2 3 4 5 6 VAP Log CFUs No VAP CCM 2003; 31: 2544 – 51. Routine culture of sputum Does not differentiate infection vs. colonization Quantitative or semi-quantitative cultures are needed
Responsible Use  1. Identify the site of infection  2. Know your bacteria  3. Maximise efficacy / minimise toxicity  Appropriate dose ; PK-PD understood  Drug level monitoring  Duration #4
Identify Site SMF ICU 2001 0 5 10 15 20 25 30 35 40 45 Pneumonia Bacteremia Urinary Tract Pseudomonas Klebsiella E. Coli Proteus Staph aureus Enterococcus
CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen Pseudomonas (46) 30% (13/44) 24% (11/46) 23% (10/43) 36% (16/44) 46% (21/46) 60% (26/44) 64% (7/11) Klebsiella ESBL (38) 0% (0/38) 5% (2/38) 26% (10/38) 35% (13/37) 32% (12/38) 37% (14/38) 80% (8/10) E Coli ESBL (36) 0% 3% (1/36) - 58% (21/36) 53% (19/36) 67% (24/26) 82% (9/11) Acinetobacter (15) 8% (1/12) 31% (4/13) 73% (8/11) 75% (9/12) 55% (6/11) 36% (4/11) 100% (3/3) Proteus (18) 72% (11/15) 11% (2/18) 11% (2/18) 67% (12/18) 100% (15/15) 87% (13/15) 100% (2/2) Non-ESBL (K+Ec) (15) 100% (15/15) 93% (14/15) - 100% (15/15) 100% (10/10) 100% (10/10) 100% (2/2) Antibiogram ™: SMF ICU Nosocomial Pathogens
Extended Spectrum Beta Lactamase (Klebsiella) 0 2 4 6 8 10 12 14 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 PercentResistance 7x
The ESBL “Plague”  Plasmid-mediated resistance Very high frequency in Indian Hospitals MYSTIC study; Mathai et al Diag Mic Inf Dis 2002; 44: 367-77. ~70% of E. coli / Klebsiella all over India >50% in Anna Nagar „community‟ >80% in SMF ICU Cross-species transmission amongst enterobactereaciae Wide resistance to all beta-lactams including cephalosporins
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
What provokes ESBL Resistant Organisms? Chest 2001; 119: 397S - 404S Chest 2001; 119: 391S - 396S AJRCCM 2000; 162:1610-16 J Hosp Infect 2003 ; 53: 39-45 JAMA 1999; 281: 517-23 Are there identifiable risk groups? Prior 3rd Gen Ceph. Poor Functional Status High APACHE score >5 days in ICU Decubitus ulcers Instrumentation Community wide use of ciprofloxacin or co-trimoxazole
Does „ESBL‟ kill? Case control 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
Treating „ESBL‟: Chest 2001; 119: 391S - 396S. Diag Mic Inf Dis 2002; 44: 367-77. Carbepenems are drugs of choice Avoidance of all 3rd gen. Cephalosporins Traditional choices for „serious‟ gram negative infections In-vitro sensitivity may be spurious 4th Generation Ceph. may be effective B-lactam / lactamase inhibitors; recommended but have high rates of resistance Aminoglycoside, quinolone resistance common
Minimizing ESBL Resistance Restriction of Ceftazidime alone is not effective Hospital- wide restriction of 3rd generation cephalosporins Use of B-lactam/ lactamase inhibitor for empirical therapy Good infection control measuresJAMA 1998; 280: 1233-7
MDR Acinetobacter Increasing prevalence and outbreaks Gram negative “cocco-bacillus” Ventilator Associated Pneumonia Bacteremia Secondary meningitis / ventriculitis Skin infections Endocarditis CAPD-peritonitis TEM1 / CARB mutation ESBL Oxa- beta lactamase Carbepenemase A/G, quinolone resist
Environmental Sources of Acinetobacter  Bed rails  Bedside tables  Ventilators  Infusion pumps  Mattresses  Pillows  Patient monitors  X-ray view boxes  Curtain rails  Curtains  Equipment carts  Sinks  Ventilator circuits  Floor mops Infect Control Hosp Epidemiol. 2003;24: 284-95
Risk Factors for Acinetobacter Ventilator Assoc. Pneumonia  Age  Chronic lung Dx  Immunosupress.  Prior antibiotic Rx  Invasive Device  Prolonged ICU stay Bloodstream Infection  Respiratory failure  Prior Antibiotics  Invasive device ________________________________________________ 72% of BSI has a lung sourceCID; 2001; 33: 939-46
Impact of Acinetobacter in the ICU Outcome Group Any infection Pneumonia Mortality Cases 58% 70% Controls 15% 17% Attributable mortality 43% 53% Risk ratio for death 4.0 (CI951.9-8.3) 4.0 (CI951.6-10.2) Length of stay (median) Cases 23 days 23 days Controls 10 days 10 days Excess LOS 13 days 13 days Crit Care Med 1999;27:1794-1799. 48 patients 1:1 case control study
Impact of A. baumanii Resistance Outcome Group All Imipenem (R) Mortality Cases 40% 44% Controls 28% 24% Attributable mortality 12% P=NS 20% P=NS Length of ICU stay (median) Cases 35 days Controls 37 days Excess ICU LOS -2 days P=NS Crit Care Med 2003;10:2478-2482. Historical cohort study; 60 patients with A. baumanii VAP matched 1:1 to Controls
Acinetobacter: Rx Options Carbepenem (if no resistance) Colistin / Polymixins (aerosol?) Sulbactam (ampi-sulb; cefperazone-sulb) 66 33 21 86 37 47 47 0 20 40 60 80 100 Amp/sulb Pip Cefotaxime Imipenem Cipro Gent TMP/SMX MDR, A. baumani Is resistant to chlorhexidine J Hosp Infect 2002;51:106-113. TSN Database
Quinolne Resistant Pseudomonas Aeroginosa 0 5 10 15 20 25 30 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 PercentResistance 3x
Carbepenem Resistant P. aeruginosa Increasing prevalence Amp C mechanism; beta lactams induce J Carbepenem resistance: Mutational porin channel loss Acquired metalo-beta-lactamases (integrin) Treat: Colistin, Aminoglycoside, Quinolone, 4th G Cephalosporin Prevent: ? multi-agent Rx of all ICU P. aeruginosa
Methicillin Resistant Staphylococcus Aureus 0 10 20 30 40 50 60 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 PercentResistance
How About MRSA? Quite common; VAP, bacteremia Risk factors: Age, severity of illness, prior antibiotic use, instrumentation* Attributable mortality (>MSSA) debatable Prefer Vancomycin for Rx even in VAP or severe CAP; equivalent efficacy @ to linezolid *Ann Intern Med. 2002; 136: 834-44 @ J Anti Chemo 2003; 51(S2): ii27-35
Pharmacokinetics: Vd Pharmacokinetics is altered and variable in critically ill Volume of distribution (Vd) can change significantly in any individual with changing fluid balance Vd is vastly different between patients Implication: Regardless of organ dysfunction most drugs need to be “loaded” at normal or higher doses. Drug level measurement would be ideal Surgery 1998; 124: 73-8 J. Chemother 1995; 7: 45-9 Intens Care Med 2001; 27: 363-70 Ant Ag & Chemo 2002; 46:1557-60 Intens Care Med 2004; 30: 2145–56
Clearance: Renal Function Increased Vd : Due to fluid retention J Vd and Renal failure = K clearance Calculated Creatinine clearance / GFR** MDRD or Cockraft-Gault method are poor : in acutely ill with changing renal funct : severe muscle wasting Measured values ideal CRRT similar to GFR ~35 ml/min* CVVHD clears < 50 Da molecular weight CVVF clears larger molecules (>1100 Da) *Intens Care Med 2004; 30: 2145–56 **N E J Med 2006; 354: 2473-83
Clearance: Liver Function Liver function does not affect most antibiotic clearances significantly Hypoalbuminemia may increase free antibiotic levels, but again the effect is modest and does not affect treatment Chloramphenicol, clarithro, erythro, clinda, metronidazole, nafcillin, tetracycline… may need some dose adjustmentIntens Care Med 2004; 30: 2145–56
Pharmacodynamics MBC MIC BacterialCountatsiteAntibioticConc. Post Ab Effect Pharmacodynamics: Defines the Interaction of the drugs and the microbes Inf Dis Clin NA 2004; 18: 451-65
Concentration Dependent MBC MIC BacterialCountatsiteAntibioticConc. Peak AUC Indicators of efficacy: Peak / MIC ratio AUC / MIC ratio Inf Dis Clin NA 2004; 18: 451-65 Agents: Quinolones Amphotercin Aminoglycosides Metronidazole
Time Dependent MBC MIC BacterialCountatsiteAntibioticConc. Time > MIC Inf Dis Clin NA 2004; 18: 451-65 Indicators of efficacy: Time above MIC Preferably > 50% Agents: Penicillins Cephalosporins Carbepenems Glycopeptides Macrolides Linezolid
Value of PK / PD Better Drug Dosing: Once-a-day aminoglycoside therapy Better interpretation of antibiotic levels- improved responses Population studies allows better identification of MIC breakpoints Better dosing to minimize emergence of resistance
Duration of Treatment What is the optimal duration of antibiotic administration? Guarantee cure Minimize cost Minimize resistance Should resistant strains be subjected to longer treatment courses? JAMA 2003; 290: 258-98
0 1 2 3 months 0 1 2 3 months 0 1 2 3 months Restrict Rotate Heterogeneous use Gorillamycin Supersporin Kingkongopenem
Rotation Strategies to Reduce Resistance Abx 2 Abx 3 Abx 1 Resistance Abx 1 Presumed that the decline in resistance with antibiotic cessation would be at least as fast as the emergence of resistance. Time
 None of the evidence is “clean”  Mainly observational cohorts  Some studies are of a single scheduled change (not rotation)  Associated confounders:  Antibiotic restriction policies  Infection prevention strategies  Often evaulate nosocomial infection alone not colonisation rates  RCTs are needed Rotation: The Evidence? Gerding et al AAC 1991; 35: 1284-90 Koleff et al AJRCCM 1997; 156: 1040-8 Gruson et al AJRCCM 2000; 162: 837-43 Raymond et al CCM 2001; 29: 1101-8 Toltzis et al Paediatrics 2002; 110: 707-11
Strategies to Reduce Resistance Restriction, Rotation, ?Rubbish… Resistance Abx 2 Abx 3 Abx 1Abx 1 Resistance emerges fast (with antibiotic use) but…… declines slowly (with cessation of use)* Antibiotic cycling is inferior to “heterogeneous” use** *Austin et al Proc Nat Ac Sci 1999; 96:1152-56 **Bonhoeffer et al Proc Nat Ac Sci 1997; 94: 12106-11
The Power of BacteriaAge: Bacteria 3,500,000,000 years (2000x) Eukaryotes 1,800,000,000 years (1000x) Multicellulars 580,000,000 years (300x) Australopithecus 4,000,000 years (2x) Homo erectus <2,000,000 years (1) Antibiotic use 60 years (0.00003x) 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” !!! They are ubiquitous and indestructible Gould SJ. Life‟s Grandeur; Vintage (Pub), 1997.

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18. antibiotic use in the ic ul

  • 1. Antibiotics in the ICU Ram E. Rajagopalan, MBBS, AB (Int Med) AB (Crit Care) Department of Critical Care Medicine SUNDARAM MEDICAL FOUNDATION Chennai Choice, Resistance, Pharmacokinetics & Pharmacodynamics
  • 2. Nosocomial Infection Between 30-40% ICU patients have or develop infection About ½ of these are nosocomial Prevalence is very variable between different kinds of units Lung Urine Wound Bacteremia Other
  • 4. Indications for antibiotics ~ 60% of patients in a general ICU receive antibiotics Unproven 'Infection' 28% Proven Infection 59% Prophylaxis 18% Bergmans et al JAC 1997; 39: 527-35
  • 5. IncisionTime Time of Prophylactic dose RateofWoundInfection Antibiotic Prophylaxis Only for “clean-contaminated” & some “clean” wounds Appropriate cover; No value for additional doses One dose.. ..one hour before.. ..incision SURGICAL WOUND
  • 6. Antibiotic Use & Resistance Habarth et al. Circulation 2000; 101: 2916-21 ….but prolonged ABP was an independent risk factor for bacterial resistance (AOR 1.6; 95%CI: 1.1-2.6) 2641 CABG patients; 4-yr. observ. cohort Either < or > 48 hr antibiotic prophylaxis 0 10 20 30 40 %ofsugicalinfections <48 hour >48 hour
  • 7. Systemic Antibiotic Use 0 5 10 15 20 25 30 35 0 5 10 15 20 Days of ventilation %withVAP No Abx Prior Abx Resistant Ps. aeroginosa; Acinetobacter 19% 65% ARRD 1989; 139:877–84. Ventilator Associated Pneumonia
  • 8. Policy on Prophylaxis Limit antibiotic prophylaxis to surgical wounds; ideally one pre-op. dose Avoid for Preventing pneumonia in intubated pts Preventing bacteremia from CV lines Preventing UTI from a Foley‟s catheter #1 Prevention Cure
  • 9. Empirical Antibiotics Suspected Infection Empirical Treatment Infection: Subsequently confirmed by bacteriology Infection: not confirmable (false negative) No infection (SIRS) ? Over treatment 25-40% 60-75% ICEM Yearbook 2003; 218-228.
  • 10. Assumptions for use of Empirical Antibiotics Nosocomial infection increases (attributable) mortality Antibiotic treatment reduces mortality Early administration of correct antibiotic improves survival Adverse effects are less than the benefits of treatment
  • 11. Is death attributable to NI? NI Treat Don‟t Treat Is there a difference? Yes No NI kills Patient dies of critical illness Definition: Mortality caused by an infection (in excess of mortality in a similarly ill patient without infection).
  • 12. Does Rx improve survival? 35 Clinical Trials identified None placebo controlled Only 2 double-blind No “Gold Standard” antibiotic Mainly comparing antibiotic regimens Mainly “equivalence” trials NO DIFFERENCE BETWEEN AGENTS Where are the Emperors clothes? ICEM Yearbook 2003; 219-28.
  • 13. Is death attributable to NI? Cohort of ICU Patients NI No NI Rx No (appropriate) Rx Severity of illness is a confounder; May be adjusted by case-control studies or Multivariate (regression) analysis About 25% attributable mortality Definition: Difference in death rates between infected & uninfected patients after adjusting for confounders
  • 14. Attributable Mortality Nosocomial Attributable Infection mortality All Nosocomial Infection 20% (2.8-44) Blood-stream 25% (4.4-47.3) Vent. Assoc. Pneumonia 25% (7.8-42) Urinary Tract NoneChest 2001; 120:2059–93
  • 15. Effect of Appropriate Choice Luna et al; Chest 1997; 111: 676-85. 0 10 20 30 40 50 60 70 80 90 100 No Rx Correct Rx Incorrect HospitalMortality(%)
  • 16. Effect of Appropriate Timing 0 10 20 30 40 50 60 70 80 90 100 Early Late None Correct Incorrect HospitalMortality(%) Luna et al; Chest 1997; 111: 676-85.
  • 17. Timing and Mortality Iregui et al Chest 2002; 122:262–8 No Delay 12.5 + 4.2 h Delay 28.6 + 5.8 h TimefromDxofVAP(h) 20 40 n=107 Delay increased hospital mortality 2.5x & VAP attributable mortality 3.5x
  • 18. Design Flaws VAP Rx Culture + Culture - Appropriate Inappropriate ? Colonization by resistant bugs & subsequent adverse outcome 25% 75%
  • 19. Making the Choice Appropriately timed, appropriately chosen antibiotic can save lives…….so…. ….which antibiotic(s)? Focused Rx with narrow spectrum (or) Gorillamycin + Supersporin + King-Kongopenem?
  • 20. CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen Pseudomonas (46) 30% (13/44) 24% (11/46) 23% (10/43) 36% (16/44) 46% (21/46) 60% (26/44) 64% (7/11) Klebsiella ESBL (38) 0% (0/38) 5% (2/38) 26% (10/38) 35% (13/37) 32% (12/38) 37% (14/38) 80% (8/10) E Coli ESBL (36) 0% 3% (1/36) - 58% (21/36) 53% (19/36) 67% (24/26) 82% (9/11) Acinetobacter (15) 8% (1/12) 31% (4/13) 73% (8/11) 75% (9/12) 55% (6/11) 36% (4/11) 100% (3/3) Proteus (18) 72% (11/15) 11% (2/18) 11% (2/18) 67% (12/18) 100% (15/15) 87% (13/15) 100% (2/2) Non-ESBL (K+Ec) (15) 100% (15/15) 93% (14/15) - 100% (15/15) 100% (10/10) 100% (10/10) 100% (2/2) Antibiogram ™: SMF ICU Nosocomial Pathogens,
  • 21. Antibiotics & Resistance Widespread use of antibiotics leads to the selection of antibiotic resistant strains Archibald et al; ICARE Clin Inf Dis 1997; 24: 211-15 Evidence: Resistant organisms are more common amongst inpatients ICUs (with highest use) have highest rates of resistance 0 5 10 15 20 25 30 35 40 45 50 %ResistantOrganisms MRSA MRSE Pseud CTZ VRE Inpatient Outpatient p <0.01 for all comparisons
  • 22. “De-escalation” Chest 2002; 122:2183–2196. De-escalate Rx Lab confirmed Initial Rx wide-spectrum Suspect infection Culture-based de-escalation can reduce resistance
  • 23. Policy on Empirical Rx a. Empirical Rx can be justified in ICU b. Abx. choice based on local patterns c. Initial Rx should be wide-spectrum d. De-escalate based on culture result As choice is based on local susceptibility & de-escalation needs culture results CULTURE prior to antibiotics is MANDATED! #2
  • 24. Policy for Definitive Therapy Critically ill patients have microbiological colonisation of normally sterile sites Treat true infection Aviod antibiotics for colonised patients ! #3
  • 25. Microbe Culture in VAP Probability 1 2 3 4 5 6 VAP Log CFUs No VAP CCM 2003; 31: 2544 – 51. Routine culture of sputum Does not differentiate infection vs. colonization Quantitative or semi-quantitative cultures are needed
  • 26. Responsible Use  1. Identify the site of infection  2. Know your bacteria  3. Maximise efficacy / minimise toxicity  Appropriate dose ; PK-PD understood  Drug level monitoring  Duration #4
  • 27. Identify Site SMF ICU 2001 0 5 10 15 20 25 30 35 40 45 Pneumonia Bacteremia Urinary Tract Pseudomonas Klebsiella E. Coli Proteus Staph aureus Enterococcus
  • 28. CTZ Cipro Oflox Amik Cef Sul Pip Taz Imepen Pseudomonas (46) 30% (13/44) 24% (11/46) 23% (10/43) 36% (16/44) 46% (21/46) 60% (26/44) 64% (7/11) Klebsiella ESBL (38) 0% (0/38) 5% (2/38) 26% (10/38) 35% (13/37) 32% (12/38) 37% (14/38) 80% (8/10) E Coli ESBL (36) 0% 3% (1/36) - 58% (21/36) 53% (19/36) 67% (24/26) 82% (9/11) Acinetobacter (15) 8% (1/12) 31% (4/13) 73% (8/11) 75% (9/12) 55% (6/11) 36% (4/11) 100% (3/3) Proteus (18) 72% (11/15) 11% (2/18) 11% (2/18) 67% (12/18) 100% (15/15) 87% (13/15) 100% (2/2) Non-ESBL (K+Ec) (15) 100% (15/15) 93% (14/15) - 100% (15/15) 100% (10/10) 100% (10/10) 100% (2/2) Antibiogram ™: SMF ICU Nosocomial Pathogens
  • 30. The ESBL “Plague”  Plasmid-mediated resistance Very high frequency in Indian Hospitals MYSTIC study; Mathai et al Diag Mic Inf Dis 2002; 44: 367-77. ~70% of E. coli / Klebsiella all over India >50% in Anna Nagar „community‟ >80% in SMF ICU Cross-species transmission amongst enterobactereaciae Wide resistance to all beta-lactams including cephalosporins
  • 31. 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
  • 32. What provokes ESBL Resistant Organisms? Chest 2001; 119: 397S - 404S Chest 2001; 119: 391S - 396S AJRCCM 2000; 162:1610-16 J Hosp Infect 2003 ; 53: 39-45 JAMA 1999; 281: 517-23 Are there identifiable risk groups? Prior 3rd Gen Ceph. Poor Functional Status High APACHE score >5 days in ICU Decubitus ulcers Instrumentation Community wide use of ciprofloxacin or co-trimoxazole
  • 33. Does „ESBL‟ kill? Case control 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
  • 34. Treating „ESBL‟: Chest 2001; 119: 391S - 396S. Diag Mic Inf Dis 2002; 44: 367-77. Carbepenems are drugs of choice Avoidance of all 3rd gen. Cephalosporins Traditional choices for „serious‟ gram negative infections In-vitro sensitivity may be spurious 4th Generation Ceph. may be effective B-lactam / lactamase inhibitors; recommended but have high rates of resistance Aminoglycoside, quinolone resistance common
  • 35. Minimizing ESBL Resistance Restriction of Ceftazidime alone is not effective Hospital- wide restriction of 3rd generation cephalosporins Use of B-lactam/ lactamase inhibitor for empirical therapy Good infection control measuresJAMA 1998; 280: 1233-7
  • 36. MDR Acinetobacter Increasing prevalence and outbreaks Gram negative “cocco-bacillus” Ventilator Associated Pneumonia Bacteremia Secondary meningitis / ventriculitis Skin infections Endocarditis CAPD-peritonitis TEM1 / CARB mutation ESBL Oxa- beta lactamase Carbepenemase A/G, quinolone resist
  • 37. Environmental Sources of Acinetobacter  Bed rails  Bedside tables  Ventilators  Infusion pumps  Mattresses  Pillows  Patient monitors  X-ray view boxes  Curtain rails  Curtains  Equipment carts  Sinks  Ventilator circuits  Floor mops Infect Control Hosp Epidemiol. 2003;24: 284-95
  • 38. Risk Factors for Acinetobacter Ventilator Assoc. Pneumonia  Age  Chronic lung Dx  Immunosupress.  Prior antibiotic Rx  Invasive Device  Prolonged ICU stay Bloodstream Infection  Respiratory failure  Prior Antibiotics  Invasive device ________________________________________________ 72% of BSI has a lung sourceCID; 2001; 33: 939-46
  • 39. Impact of Acinetobacter in the ICU Outcome Group Any infection Pneumonia Mortality Cases 58% 70% Controls 15% 17% Attributable mortality 43% 53% Risk ratio for death 4.0 (CI951.9-8.3) 4.0 (CI951.6-10.2) Length of stay (median) Cases 23 days 23 days Controls 10 days 10 days Excess LOS 13 days 13 days Crit Care Med 1999;27:1794-1799. 48 patients 1:1 case control study
  • 40. Impact of A. baumanii Resistance Outcome Group All Imipenem (R) Mortality Cases 40% 44% Controls 28% 24% Attributable mortality 12% P=NS 20% P=NS Length of ICU stay (median) Cases 35 days Controls 37 days Excess ICU LOS -2 days P=NS Crit Care Med 2003;10:2478-2482. Historical cohort study; 60 patients with A. baumanii VAP matched 1:1 to Controls
  • 41. Acinetobacter: Rx Options Carbepenem (if no resistance) Colistin / Polymixins (aerosol?) Sulbactam (ampi-sulb; cefperazone-sulb) 66 33 21 86 37 47 47 0 20 40 60 80 100 Amp/sulb Pip Cefotaxime Imipenem Cipro Gent TMP/SMX MDR, A. baumani Is resistant to chlorhexidine J Hosp Infect 2002;51:106-113. TSN Database
  • 43. Carbepenem Resistant P. aeruginosa Increasing prevalence Amp C mechanism; beta lactams induce J Carbepenem resistance: Mutational porin channel loss Acquired metalo-beta-lactamases (integrin) Treat: Colistin, Aminoglycoside, Quinolone, 4th G Cephalosporin Prevent: ? multi-agent Rx of all ICU P. aeruginosa
  • 45. How About MRSA? Quite common; VAP, bacteremia Risk factors: Age, severity of illness, prior antibiotic use, instrumentation* Attributable mortality (>MSSA) debatable Prefer Vancomycin for Rx even in VAP or severe CAP; equivalent efficacy @ to linezolid *Ann Intern Med. 2002; 136: 834-44 @ J Anti Chemo 2003; 51(S2): ii27-35
  • 46. Pharmacokinetics: Vd Pharmacokinetics is altered and variable in critically ill Volume of distribution (Vd) can change significantly in any individual with changing fluid balance Vd is vastly different between patients Implication: Regardless of organ dysfunction most drugs need to be “loaded” at normal or higher doses. Drug level measurement would be ideal Surgery 1998; 124: 73-8 J. Chemother 1995; 7: 45-9 Intens Care Med 2001; 27: 363-70 Ant Ag & Chemo 2002; 46:1557-60 Intens Care Med 2004; 30: 2145–56
  • 47. Clearance: Renal Function Increased Vd : Due to fluid retention J Vd and Renal failure = K clearance Calculated Creatinine clearance / GFR** MDRD or Cockraft-Gault method are poor : in acutely ill with changing renal funct : severe muscle wasting Measured values ideal CRRT similar to GFR ~35 ml/min* CVVHD clears < 50 Da molecular weight CVVF clears larger molecules (>1100 Da) *Intens Care Med 2004; 30: 2145–56 **N E J Med 2006; 354: 2473-83
  • 48. Clearance: Liver Function Liver function does not affect most antibiotic clearances significantly Hypoalbuminemia may increase free antibiotic levels, but again the effect is modest and does not affect treatment Chloramphenicol, clarithro, erythro, clinda, metronidazole, nafcillin, tetracycline… may need some dose adjustmentIntens Care Med 2004; 30: 2145–56
  • 49. Pharmacodynamics MBC MIC BacterialCountatsiteAntibioticConc. Post Ab Effect Pharmacodynamics: Defines the Interaction of the drugs and the microbes Inf Dis Clin NA 2004; 18: 451-65
  • 50. Concentration Dependent MBC MIC BacterialCountatsiteAntibioticConc. Peak AUC Indicators of efficacy: Peak / MIC ratio AUC / MIC ratio Inf Dis Clin NA 2004; 18: 451-65 Agents: Quinolones Amphotercin Aminoglycosides Metronidazole
  • 51. Time Dependent MBC MIC BacterialCountatsiteAntibioticConc. Time > MIC Inf Dis Clin NA 2004; 18: 451-65 Indicators of efficacy: Time above MIC Preferably > 50% Agents: Penicillins Cephalosporins Carbepenems Glycopeptides Macrolides Linezolid
  • 52. Value of PK / PD Better Drug Dosing: Once-a-day aminoglycoside therapy Better interpretation of antibiotic levels- improved responses Population studies allows better identification of MIC breakpoints Better dosing to minimize emergence of resistance
  • 53. Duration of Treatment What is the optimal duration of antibiotic administration? Guarantee cure Minimize cost Minimize resistance Should resistant strains be subjected to longer treatment courses? JAMA 2003; 290: 258-98
  • 54. 0 1 2 3 months 0 1 2 3 months 0 1 2 3 months Restrict Rotate Heterogeneous use Gorillamycin Supersporin Kingkongopenem
  • 55. Rotation Strategies to Reduce Resistance Abx 2 Abx 3 Abx 1 Resistance Abx 1 Presumed that the decline in resistance with antibiotic cessation would be at least as fast as the emergence of resistance. Time
  • 56.  None of the evidence is “clean”  Mainly observational cohorts  Some studies are of a single scheduled change (not rotation)  Associated confounders:  Antibiotic restriction policies  Infection prevention strategies  Often evaulate nosocomial infection alone not colonisation rates  RCTs are needed Rotation: The Evidence? Gerding et al AAC 1991; 35: 1284-90 Koleff et al AJRCCM 1997; 156: 1040-8 Gruson et al AJRCCM 2000; 162: 837-43 Raymond et al CCM 2001; 29: 1101-8 Toltzis et al Paediatrics 2002; 110: 707-11
  • 57. Strategies to Reduce Resistance Restriction, Rotation, ?Rubbish… Resistance Abx 2 Abx 3 Abx 1Abx 1 Resistance emerges fast (with antibiotic use) but…… declines slowly (with cessation of use)* Antibiotic cycling is inferior to “heterogeneous” use** *Austin et al Proc Nat Ac Sci 1999; 96:1152-56 **Bonhoeffer et al Proc Nat Ac Sci 1997; 94: 12106-11
  • 58. The Power of BacteriaAge: Bacteria 3,500,000,000 years (2000x) Eukaryotes 1,800,000,000 years (1000x) Multicellulars 580,000,000 years (300x) Australopithecus 4,000,000 years (2x) Homo erectus <2,000,000 years (1) Antibiotic use 60 years (0.00003x) 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” !!! They are ubiquitous and indestructible Gould SJ. Life‟s Grandeur; Vintage (Pub), 1997.