1. Massimo Antonelli, MD Dept. of Intensive Care & Anesthesiology Università Cattolica del Sacro Cuore Rome - Italy Antibiotics: The old and the new

2. Major sites of infection in medical ICU n= 13,592 Richards MJ, et al. Infect Control Hosp Epidemiol 2000; 21: 510-515

3. Facts Multi-resistant germs are common Antimicrobial resistance increases over time Inadequate therapy is associated with Mortality Can we adopt specific strategies to decrease resistance ?

4. Most Frequently Reported Pathogens from ICU Patients with Nosocomial Pneumonia 1. Pseudomonas aeruginosa 2. Staphylococcus aureus 3. Enterobacter spp. 4. Klebsiella pneumoniae 5. Acinetobacter spp. Richards MJ et al. Crit Care Med 1999; 887-892.

5. S. aureus —The Most Frequent Isolate in EPIC Study Vincent JL, et al. JAMA 1995;274:639-644. Vincent JL. Int Care Med 2000;26:S3-S8.

6. MRSA Pneumonia: Infection-Related Mortality

7. Multiresistant bacteria are a problem in VAP 7.7S. pneumoniae % of all isolatesOrganism 3.1MSSA 8.4H. influenzae 11.8A. baumannii 11.8MRSA 31.7P. aeruginosa Rello J. Am J Respir Crit Care Med 1999; 160:608-613. (n = 321 isolates from 290 episodes)

8. Acinetobacter baumannii Resistance in 118 ICUs of 5 European Countries 16%5%9% Imipenem 81%75%78% Ciprofloxacin 51%10%36% Amikacin 58%75%44% Pip/taz 76%81%70% Ceftazidime Spain PortugalFranceAntibiotic Pip/taz=piperacillin/tazobactam Hanberger H et al. JAMA 1999;281:67-71.

9. Variables indipendently associated with VAP caused by “Potentially Resistant” bacteria *.0251.2-14.24.12Broad-spectrum antibiotics (Y/N).00033.3-55.013.46Prior antibiotic use (Y/N).0091.6-23.16.01Duration of MV before VAP episode  7 d (Y/N) p Value95% CIOdds Ratio Variable Trouillet JL., et al. AM J RESPIR CRIT CARE MED 1998; 157: 531-539 * Discriminant value (AUC) = 0.89

10. Facts Multi-resistant germs are common Antimicrobial resistance increases over time Inadequate therapy is associated with Mortality We may adopt specific strategies to decrease resistance: antibiotic rotation ?

11. ICU Patients Non-ICU Patients Source: NNIS Data. Clin Chest Med. 20:303-315. Antimicrobial Resistance in Nosocomial Infections Gram-Negative Pathogens

12. ICU Patients Non-ICU Patients Source: NNIS data. Clin Chest Med. 20:303-315. Antimicrobial Resistance of Nosocomial Infections Gram-Positive Pathogens

13. Facts Multi-resistant germs are common Antimicrobial resistance increases over time Inadequate therapy is associated with Mortality We may adopt specific strategies to decrease resistance: antibiotic rotation ?

14. Mortality Associated With Initial Inadequate Therapy In Critically Ill Patients With Serious Infections in the ICU 0%20%40%60%80%100 % Luna, 1997 Ibrahim, 2000 Kollef, 1998 Kollef, 1999 Rello, 1997 Alvarez-Lerma,1996 Initial appropriate therapy Initial inadequate therapy *Mortality refers to crude or infection-related mortality Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Ibrahim EH et al. Chest 2000;118L146-155. Kollef MH et al. Chest 1999; 115:462-474 Kollef MH et al. Chest 1998;113:412-420. Luna CM et al. Chest 1997;111:676-685. Rello J et al. Am J Resp Crit Care Med 1997;156:196-200. Mortality*

16. Reducing Inadequate Therapy Antibiotic Management Through Practice Guidelines 0 2 4 6 8 10 12 14 16 18 Duration of Antibiotic Therapy Length of ICU Stay ICU Admission to Discharge Total Length of Stay Number of Days Computer-Generated Regimen Physician-Generated Regimen *P<0.001. † P<0.003. † * * * Evans, et al. N Engl J Med. 1998;338:232.

17. Risk Factors for Resistance in VAP Use of antibiotics within 15 days 1 Duration of hospitalization 2 Duration of mechanical ventilation > 7 days 1 1 Trouillet J-L et al. Am J Respir Crit Care Med 1998;157:531-539. 2 Lautenbach E et al. Clin Infect Dis 2001;32:1162-1171.

18. Facts Multi-resistant germs are common Antimicrobial resistance increases over time Inadequate therapy is associated with Mortality We may adopt specific strategies to decrease resistance: antibiotic rotation ?

19. Antimicrobial Resistance: Key Prevention Strategies Optimize Use Prevent Transmission Prevent Infection Effective Diagnosis & Treatment Pathogen Antimicrobial-Resistant Pathogen Antimicrobi al Resistance Antimicrobial Use Infection Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Susceptible Pathogen

20. Key Prevention Strategies  Prevent infection  Diagnose and treat infection effectively  Use antimicrobials wisely  Prevent transmission Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Clinicians hold the solution!

21. 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults 1.Vaccinate 2.Get the catheters out 3.Target the pathogen 4.Access the experts 5.Practice antimicrobial control 6.Use local data 7.Treat infection, not contamination 8.Treat infection, not colonization 9.Know when to say “no” to vanco 10.Stop treatment when infection is cured or unlikely 11.Isolate the pathogen 12. Break the chain of contagion Diagnose and Treat Infection Effectively Prevent Infection Use Antimicrobials Wisely Prevent Transmission 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

22. Use Antimicrobials Wisely Step 6: Use local data Fact: The prevalence of resistance can vary by local, patient population, hospital unit, and length of stay. Actions: know your local antibiogram know your patient population  Link to: NCCLS Proposed Guidance for Antibiogram DevelopmentNCCLS Proposed Guidance for Antibiogram Development 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

23. Risk factors for Early Onset Pneumonia Incidence % 14,6 30 41,7 19 29,2 25 13,6 30,6 14,7 8,7 26,9 46,7 8,2 33,3 Age <= 40 Age 41-65 Age > 65 Males Females Multiple trauma Head trauma Pulmonary contusion No pulmonary contusion AIS 1^ AIS 2 AIS 3 MV > 24 h MV <= 24 h or none 01020304050 * p-value < 0.05, chi-square test or Fisher's exact test ^ 1: thorax 4, abdomen 4, abdomen > 9 * * * Antonelli, 1994, Chest; 105:224-28

25. Fact: A major cause of antimicrobial overuse is “treatment” of colonization. 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults Use Antimicrobials Wisely Step 8: Treat infection, not colonization

26. Invasive Bronchoscopic Diagnostic Tests Reduce Antimicrobial Use in Suspected VAP* Invasive Non-invasive Diagnosis Antimicrobial-free11.0 7.5 p <.001 days (at day 28) Mortality16.2% 25.8% p =.022 Fagon JY, et al: Ann Intern Med 2000;132:621-30 *413 patients; 31 intensive care units 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults Step 8: Treat infection, not colonization

27. Impact of Hand Hygiene on Hospital Infections YearAuthorSettingImpact on Infection Rates 1977Casewell adult ICUKlebsiella decreased 1982Makiadult ICUdecreased 1984Massanariadult ICUdecreased 1990Simmonsadult ICUno effect 1992Doebbelingadult ICUdecreased with one versus another hand hygiene product 1994WebsterNICUMRSA eliminated 1995ZafarnurseryMRSA eliminated 1999Pittet hospitalMRSA decreased ICU = intensive care unit; NICU = neonatal ICU MRSA = methicillin-resistant Staphylococcus aureus  Link to: Improving hand hygieneImproving hand hygiene 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults Step 12: Contain your contagion Source: Pittet D: Emerg Infect Dis 2001;7:234-240

29. ROTATION ?

30. Kollef Ann Intern Med. 2001;134:298-314. The evidence

31. Antibiotic rotation in the ICU : 10 Reviews, No RCT, 4 cohort studies

32. ANTIMICROBIAL RESISTANCES ANALYSIS EXPERT SYSTEM FOR DECISION SUPPORT Computer Assistance in Infection Control

33. SURELY NEGATIVE SURELY POSITIVE MISSING DATA PHYSICIAN VALIDATED COMPUTER SUGGESTED

35. RESISTANCES 2000 - 2001

36. When to start Sandiumenge, Intensive Care Med 2003 on line 1. Antibiotic therapy should be started immediately Impact of microbiological investigation on guiding and de-escalating therapy 2. Antibiotic choice can be targeted, in some cases, on direct staining 3. The antibiotic regimen must be modified in the light of microbiological findings Dose and duration 4. Prolonging antibiotic treatment does not prevent recurrences. What microorganism should be covered 5. Patients with COPD or >1 week of ventilation should receive combination therapy, due to the risk of VAP due to Pseudomonas aeruginosa 6. MSSA should be strongly suspected if GCS<8. MRSA is not expected in the absence of prior antibiotic administration

37. 7. Therapy against yeasts is not required, even in the presence of Candida spp colonization 8. Vancomycin administration for MRSA-related VAP (and for other Gram–positive pneumonias) is associated with a very poor outcome Choice of initial agent 9. Guidelines should be regularly updated and customized to local patterns 10. The specific choice of agent should be based on the regimen to which each patient has been exposed previously Sandiumenge, Intensive Care Med 2003 on line