1. Nabil Abuchala, MD, FCCP King Faisal Specialist Hospital & Research Center The Use of Antibiotics in ICU Getting It Right From Start To Finish: The Role of DE-ESCALATION THERAPY ™ DE-ESCALATION THERAPY and the pinwheel symbol are trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.

2. 2 A10123S What Is Initial “Inadequate Therapy”?

3. 3 A10123S Myth There is time to start with one therapy and then escalate later, if needed. Fact Inadequate initial antimicrobial therapy increases mortality. Changing from inadequate to appropriate therapy may not decrease mortality. Initially delayed appropriate antibiotic therapy (IDAAT) is inadequate therapy. Kollef MH et al. Chest 1999;115:462-474. Ibrahim EH et al. Chest 2000;118:146-155. Iregui M et al. Chest 2002;122:262-268. Initial “Inadequate Therapy” In Critically Ill Patients with Serious Infections

4. 4 A10123S Defining Initial Inadequate Therapy The antibiotic did not cover the infecting pathogen(s) The pathogen was resistant to the antibiotic Dosing was not adequate Combination therapy was not used, if indicated. 1 Kollef MH et al. Chest 1999;115:462-474. 2 Ibrahim EH et al. Chest 2000;118:146-155. Initial therapy is considered to be inadequate if:

5. 5 A10123S Inappropriate Antimicrobial Therapy: Prevalence Among ICU Patients Source: Kollef M, et al: Chest 1999;115:462-74 Community-acquired infection Hospital-acquired infection Hospital-acquired infection after initial community-acquired infection Inappropriate Antimicrobial Therapy (n = 655 ICU patients with infection) Patient Group Percent Inappropriate

6. Initial Inadequate Therapy in VAP *Includes patients with HAP and VAP. Kollef MH et al. Chest 1999;115:462-474. Luna CM et al. Chest 1997;111:676-685. Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Rello J et al. Am J Resp Crit Care Med 1997;156:196-200. % Patients Receiving Initial Inadequate Therapy 02040 Rello 97 Alvarez-Lerma 96 Luna 97 Kollef 99 26%* 35% 34% 24%

7. 7 A10123S Does Inadequate Therapy Result from Antibiotic Resistance? Inadequate therapy is more likely if antibiotic resistance is present, and antibiotic resistant organisms are more commonly associated with inadequate therapy (adapted from Kollef). Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138. % Inadequate Treatment of VAP

8. 8 A10123S 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 adequate therapy Initial inadequate therapy *Mortality refers to crude or infection-related mortality. Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Kollef MH et al. Chest 1999; 115:462-474 Kollef MH et al. Chest 1998;113:412-420. Ibrahim EH at al. Chest 2000;118:146-155. Luna CM et al. Chest 1997;111:676-685. Mortality*

9. 9 A10123S What Constitutes Initial Appropriate Therapy?

10. 10 A10123S Initial Appropriate Therapy Empiric broad-spectrum therapy initiated at the first suspicion of serious infection. Selection of antibiotic to ensure adequate coverage of all likely pathogens. Factors to consider when defining appropriate therapy: Microbiologic data Monotherapy vs. combination therapy Dose and dosing frequency Penetration Timing Toxicity Risk of influencing resistance Prior antibiotic use Kollef MH et al. Chest 1999;115:462-474.

11. 11 A10123S Factors in Selecting Initial Appropriate Therapy Patient features: Choose empiric therapy based on site and severity of infection, and physician assessment of the likelihood for deterioration and mortality. Local susceptibility and epidemiology: Choose empiric therapy to cover the likely infecting pathogens based on patterns while considering prior antibiotic therapy. Initial antibiotic therapy dosing and duration: Choose initial empiric therapy that will deliver enough antibiotic to the site of infection and be well-tolerated (consider antibiotic penetration). Combination vs. monotherapy: Initial antibiotic choice should give broad enough coverage, avoid emergence of resistance, and have the potential for synergy if necessary.

12. 12 A10123S Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539. Optimizing Combination Therapy in Critically Ill Patients Using Local Susceptibility Data All patients were ventilated > 7 days, and had received prior antibiotic therapy. 050607080 Aztreonam+ amikacin + vancomycin Piperacillin-tazobactam + amikacin + vancomycin Ceftazidime + amikacin + vancomycin Imipenem + amikacin + vancomycin % susceptibility 90100

13. 13 A10123S Timing

14. 14 A10123S Importance of Timing of Antibiotic Administration 107 patients with VAP in a medical ICU All patients received an antibiotic shown to be active in vitro against the bacteria –33 patients received treatment that was delayed for  24 hours (28.6  5.8 hours) (classified as receiving IDAAT) –74 patients received treatment timely within 24 hours (12.5  4.2 hours) Risk factors for hospital mortality Iregui et al. Chest 2002;122:262–268

15. 15 A10123S Appropriate Early Antibiotic Therapy Reduces Mortality Rates In Patients With Suspected VAP Iregui et al. Chest 2002;122:262–268 Mortality (%) Hospital mortalityMortality attributed to VAP 0 60 80 20 40 p<0.01 p<0.001 Initially delayed antibiotic treatment Early appropriate antibiotic treatment

16. 16 A10123S Antibiotic Pharmacology and the Pharmacodynamics of Bacterial Killing

17. 17 A10123S Pharmacodynamic Parameters In Vivo Potency T>MIC C max :MIC AUC:MIC Concentration Time MIC 0 PAE

18. 18 A10123S Pharmacodynamic Parameters Predection of outcome Parameter correlating with efficacyCmax:MICAUC:MICT>MIC AntibioticAminoglycosidesAzithromycin Fluroquinolones Ketolides Linezolid Daptomycin Tigecycline Carbapenems Cephalosporins Macrolides Penicillins Organism killingConcentration- dependent Time-dependent Therapeutic goalMaximize exposure Optimize duration exposure

19. 19 A10123S Dandekar PK et al. Pharmacotherapy. 2003;23:988-991. Meropenem 500 mg Administered as a 3 h Infusion Extends the Time Over the MIC vs a 0.5 h infusion MIC 02468 0.1 1.0 10.0 100.0 Concentration (mcg/mL) Time (h) Rapid Infusion (30 min) Extended Infusion (3 h) Additional T>MIC gained

20. 20 A10123S Meaningful Outcomes of Appropriate Therapy

21. 21 A10123S Meaningful Outcomes of Appropriate Therapy Stops progression of disease Saves lives Reduces hospital length of stay Is more cost effective

22. 22 A10123S Antibiotics and Sepsis: Necessary But Not Sufficient for Survival Outcome: Stopping Progression of Disease Appropriate antibiotics decrease evolution to severe sepsis by ~50% Infection Inflammation/Coagulation Activation Kreger BE et al. Am J Med 1980;68:332-43. Meehan TP et al. JAMA 1997;278:2080-4. Opal SM et al. Crit Care Med 1997;25:1115-24. Pittet D et al. Am J Respir Crit Care Med 1996;153:684-93. Simon D et al. Crit Care Clin 2000;16:215-31. Courtesy of the National Initiative in Sepsis Education. Copyright © 2002 Thomson Advanced Therapeutics Communications™ (ATC) and Vanderbilt University School of Medicine. All rights reserved.

23. 23 A10123S Kreger BE et al. Am J Med 1980;68:332-43. Meehan TP et al. JAMA 1997;278:2080-4. Opal SM et al. Crit Care Med 1997;25:1115-24. Pittet D et al. Am J Respir Crit Care Med 1996;153:684-93. Simon D et al. Crit Care Clin 2000;16:215-31. Appropriate antibiotics reduce mortality by 10%-15%; mortality remains 28%-50% Severe Sepsis Death Courtesy of the National Initiative in Sepsis Education. Copyright © 2002 Thomson Advanced Therapeutics Communications™ (ATC) and Vanderbilt University School of Medicine. All rights reserved. Antibiotics and Sepsis: Necessary But Not Sufficient for Survival Outcome: Stopping Progression of Disease Appropriate antibiotics decrease evolution to severe sepsis by ~50% Infection Inflammation/Coagulation Activation

24. 24 A10123S Appropriate Therapy Leads to Lower Mortality in Gram-Negative Sepsis <0.00149% (47-51%) 28% (22-32%) Total <0.00129% (23-31%) 10% (0-13%) Non-fatal <0.00167% (63-72%) 42% (39-45%) Ultimately fatal NS85% (71-100%) 84% (80-86%) Rapidly fatal P-value Mortality without appropriate therapy Combined data (range) Mortality with appropriate therapy Combined data (range) Underlying Disease Bochud P-Y et al. Intensive Care Med 2001;27:S33-S48. Outcome: Saving Lives

25. 25 A10123S Multiple Outcomes: Saving Lives, Reducing Length of Stay and Cost-Effectiveness Percent Case-Control Analysis 46 Resistant* cases matched to 113 Susceptible** cases Matched on site of infection and LOS prior to infection Resistant vs. Susceptible infections: $79,300 vs. $40,400 P = 0.06 P < 0.001 Cosgrove SE et al. Arch Intern Med 2002;162:185-190. Outcome: Saving Lives, Reducing Length of Stay, Improving Cost-Effectiveness *Third-generation cephalosporin-resistant Enterobacter isolates in subsequent cultures **Third-generation cephalosporin-susceptible Enterobacter isolates in subsequent cultures

26. 26 A10123S Meaningful Outcomes: Length of Stay 33 resistant cases matched with 66 non-resistant controls by species, infection site, infection date. Case patients had a longer median LOS than controls subsequent to infection: 11 vs 7 days respectively (Odds ratio 1.76; 95% CI 1.17-2.64; P= 0.01) Lautenbach E et al. Clin Infect Dis 2001;32:1162-1171. Outcome: Reducing Length of Stay

27. 27 A10123S Meaningful Outcomes: Hospital Charges Case patients had 2.9 fold higher median hospital charges subsequent to infection than control patients (95% CI, 1.76-4.78; P<0.001) Lautenbach E et al. Clin Infect Dis 2001;32:1162-1171. Outcome: Improving Cost-Effectiveness

28. 28 A10123S Which Patients Are Candidates For Initial Aggressive Antibiotic Therapy?

29. 29 A10123S Patients Who May Benefit From Empirical Broad-Spectrum Antimicrobial Therapy Critically ill patients with serious infections: Hospital-acquired pneumonia (HAP) Ventilator-associated pneumonia (VAP) Bacteremia Severe sepsis Severe community-acquired pneumonia Meningitis

30. 30 A10123S What are the Principles in Choosing the Initial Appropriate Empiric Therapy? Stage 1

31. 31 A10123S DE-ESCALATION THERAPY  Stage 1 Administering the broadest-spectrum antibiotic therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay) Stage 2 Focusing on de-escalating as a means to minimize resistance and improve cost- effectiveness

32. 32 A10123S Principles Consider unit-specific antibiograms in choosing initial appropriate therapy. Certain antibiotics promote resistance to other classes of antibiotics. –Choose agents that minimize resistance. –Consider the impact of outpatient antibiotic therapy on in-patient antibiotic resistance. Choose combination therapy in appropriate settings, such as Third-generation cephalosporins for Enterobacter.

33. 33 A10123S Acinetobacter Resistance in North and Latin American ICUs 19.8%9.9%3.0%Imipenem 49.4%69.9%27.1%Ciprofloxacin 40.9%62.5%8.2%Amikacin 42.9%51.2%15.7%Pip/taz 48.6%63.6%19.8%Ceftazidime Antibiotic North America* 1 Latin America 1 Europe 2 *Canada and the United States Pip/taz=piperacillin/tazobactam 1 Gales AC et al. Clin Infect Dis 2001;32(Suppl 2(:104-113. 2 Fluit AC et al. Clin Infect Dis 2000;30:454-460.

34. 34 A10123S KFSH/MSICU 2005 Gram Negative Organisms Bacteremia & Pneumonia

35. 35 A10123S Antibiotic Susceptibility of Resistant Klebsiella pneumoniae Paterson DL. IDSA 1998.

36. 36 A10123S Piperacillin-sensitive and Piperacillin–resistant P. aeruginosa VAP Epidemiologic investigation of ICU patients who developed VAP caused by P. aeruginosa, with 34 isolates being piperacillin resistant and 101 being piperacillin sensitive. Independent risk factors for piperacillin resistance: –Underlying fatal medical condition –Initial disease severity –Previous fluoroquinolone use. “Restricted fluoroquinolone use is the sole independent risk factor for PRPA* VAP that is open to medical intervention.” *Piperacillin-resistant P. aeruginosa Trouillet JL et al. Clin Infect Dis 2002;34:1047-1054.

37. 37 A10123S 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.

38. 38 A10123S Treatment Outcome for ESBL-Producers Paterson DL. IDSA 1998. 8Imipenem 36Quinolones 44Beta-Lactams 71No active antibiotics % Mortality Treatment Initial appropriate therapy should be administered empirically if there is any suspicion that an infection is due to an ESBL-producing strain.

39. 39 A10123S Using Third- and Fourth-Generation Cephalosporins Against ESBL Producers Cephalosporins may not be effective against K. pneumoniae bacteremia Many labs do not seem to be able to detect ESBL- producing Enterobacteriaceae. Suboptimal clinical responses have been observed when third- and fourth-generation cephalosporins are used to treat ESBL-producing organisms. Paterson DL et al. J Clin Microbiol 2001;39:2206-2212.

40. 40 A10123S All patients were ventilated > 7 days, and had received prior antibiotic therapy. Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539. Combination Therapy in Critically Ill Patients with VAP 050607080 Aztreonam+ amikacin + vancomycin Piperacillin-tazobactam + amikacin + vancomycin Ceftazidime + amikacin + vancomycin Imipenem + amikacin + vancomycin % susceptibility 90100

41. 41 A10123S Carbapenems: A Good Choice for Initial Appropriate Therapy in ICU Patients with Serious Infection Broad-spectrum activity Proven efficacy Low potential for resistance Good tolerability

42. 42 A10123S Principles and Specifics of De-Escalating Stage 2

43. 43 A10123S DE-ESCALATION THERAPY  Stage 1 Administering the broadest-spectrum antibiotic therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay) Stage 2 Focusing on de-escalating as a means to minimize resistance and improve cost- effectiveness

44. 44 A10123S General Principles When Considering De-Escalating Identify the organism and know its susceptibilities; recognize any limitation in the available microbiology support system (e.g., length of time to receiving antibiogram). Assess and potentially modify initial selection of antibiotics based on organism susceptibility report. Make the decision in the context of patient improvement on the initial regimen. Individualize the duration of therapy based on patient factors and clinical response. Singh N et al. Am J Respir Crit Care Med 2000;162:505-511. Dennesen PJW et al. Am J Respir Crit Care Med 2001;163:1371-1375. Ibrahim EH et al. Chest 2000;118:146-155. Luna CM et al. Chest 1997;111:676-685.

45. 45 A10123S How To Optimize De-Escalating: Use of Clinical Parameters To Modify or Stop Antibiotic Therapy Use of the Clinical Pulmonary Infection Score (CPIS) to attempt to identify patients in whom antibiotic therapy can be stopped after 3 days. Factors in the calculation of the CPIS*: –Temperature –Blood leukocytes –Tracheal secretions –Oxygenation –Pulmonary radiography –Progression of pulmonary infiltrate –Culture of tracheal aspirate Score  6 (pneumonia unlikely) Score  6 (treat as having pneumonia) *The first five criteria were used to calculate initial CPIS; all 7 were use to calculate a repeat score on day 3. Singh N et al. Am J Respir Crit Care Med 2000;162:505-511.

46. 46 A10123S How To Optimize De-Escalating: Use of Clinical Parameters To Modify or Stop Therapy Evolution of the CPIS correlated with mortality. PaO 2 /FIO 2 ratio was the best correlate of clinical response and outcome. Luna CM et al. Crit Care Med (in press). 4 5 6 7 VAP-3VAPVAP+3VAP+5VAP+7 CPIS Survivors (n=31) Non-Survivors (n=32) All (n=63) Therapy Serial CPIS Measurements to Determine the Outcome in VAP Days

47. 47 A10123S How To Optimize De-Escalating: Use of Protocol Therapy in VAP (1) Application of a clinical guideline for treatment of VAP shown to increase the initial administration of adequate antimicrobial treatment and decrease the overall duration of antibiotic treatment. Before (n=50) and after (n=52) comparison of VAP management with initiation of protocol. Protocol: –Clinical diagnosis of VAP with tracheal aspirate or bronchial cultures. –Before period: therapy as per treating physician. –After period: patients with VAP received antibiotic treatment according to treatment guidelines; empiric treatment for P. aeruginosa; MRSA with vancomycin, imipenem/ciprofloxacin (selected based on local susceptibility data). –Modify therapy per culture after 24-48 hours depending on the clinical course of the patient. –Try to STOP therapy after 7 days unless clinically indicated otherwise. Ibrahim EH et al. Crit Care Med 2001; 29: 1109-1115.

48. 48 A10123S How To Optimize De-Escalating: The Role of Protocol Therapy in VAP (2) Mean APACHE II = 25.6, Mean CPIS = 6.7 ** * *P<0.030 **P<0.001 *** Before period (14.8+8.1 days; After period (8.6+5.1 days) Adapted from Ibrahim EH et al. Crit Care Med 2001; 29: 1109-1115. %

49. 49 A10123S When microbiologic data are known, narrow antibiotic coverage Kollef M. Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH., eds. Antimicrobial Optimization: Concepts and Strategies in Clinical Practice. New York:Marcel Dekker Publishers, 2005:41-64.

50. 50 A10123S Treatment Duration

51. 51 A10123S Treatment Duration? Uncomplicated UTIs –Depends on antibiotic (Single dose: gatifloxacin; 3 days: ciprofloxacin, TMP/SMX; 7 days: nitrofurantoin, oral cephalosporins) Endocarditis (4- 6 weeks) Osteomyelitis (4-6 weeks) Catheter-related infections? Depends on organism –S. epidermidis and line removed: 5-7 days, line not removed, 10-14 days –S. aureus: 14 days +/- TEE

52. 52 A10123S Pneumonia –Hospital/healthcare-associated with good clinical response: 8 days (unless etiologic pathogen is P. aeruginosa, ~10-14 days) –Assumes active therapy administered initially Treatment Duration

53. 53 A10123S No. at risk 197187172158151148147 204194179167157151147 8 vs 15 Day Treatment of VAP No difference in outcome except if P. aeruginosa involved Probability of survival Days after Bronchoscopy P=0.65 Antibiotic regimen 8 days 15 days JAMA 2003 290:2588

54. 54 A10123S Treatment Duration of Community-Associated Pneumonia : No Consensus Guidelines –IDSA (2000)—treat Streptococcus pneumoniae until afebrile 72 hours; gram negative bacteria, Staphylococcus aureus, “atypicals” =  2 weeks –Canadian IDS/TS (2000) = 1–2 weeks –ATS (2001)—standard is 7–14 days, but with new agents, may shorten duration (ie, 5–7 days for outpatients) –BTS (2001)—subject to clinical judgment (7–21 days) Evidence –“The precise duration of treatment … is not supported by robust evidence”–BTS –“Not aware of controlled trials”–IDSA Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382. Mandell LA, et al. Clin Infect Dis. 2000;31:383-421. British Thoracic Society. Thorax. 2001;56 (Suppl 4): iv1-iv64. American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-1754.

55. 55 A10123S Meningitis (Tunkel et al. Clin Infect Dis 2004;39:1267-84) –Neisseria meningitidis (7days) –Haemophilus influenzae (7 days) –Streptococcus pneumoniae (10-14 days) –Streptococcus agalactiae (14-21 days) –Aerobic gram negative bacilli (21 days) –Listeria monocytogenes (  21 days) Treatment Duration

56. 56 A10123S Combination Therapy

57. 57 A10123S When is Combination Therapy Considered Appropriate? Initial empirical “coverage” of multi-drug resistant pathogens until culture results are available (increases chances of initial active therapy) Enterococcus (endocarditis, meningitis?) P. aeruginosa (non-urinary tract = controversial; limit aminoglycoside component of combination after 5-7 days in responding patients) S. aureus, S. epidermidis (Prosthetic device infections, endocarditis)-Rifampin/gentamicin+ vancomycin (if MRSA or MRSE) or antistaphylococcal penicillin Mycobacterial infections HIV

58. 58 A10123S Conventional (three-times daily regimen) Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655 Concentration (mg/L) 0 0 8 8 14 4 4 6 6 10 12 Time (hours) 0 0 12 24 20 4 4 8 8 16 Once-daily regimen 2 2 Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Optimizes Concentration-dependant Effect on Bacterial Kill

59. 59 A10123S Summary

60. 60 A10123S Summary Initial inadequate therapy: Inadequate initial empiric therapy leads to increased mortality in patients with serious infection. Initial appropriate therapy: Means starting with a broad-spectrum antibiotic and then focusing based on clinical and microbiological data. Broad- spectrum antibiotics should not be held in reserve. Should be based on patient stratification, and local epidemiology and susceptibility patterns. Includes use of appropriate drug, dose, and duration.

61. 61 A10123S Summary (continued) DE-ESCALATION THERAPY  occurs in two stages: Stage 1 - administering the broadest-spectrum antibiotic therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay). Stage 2 - focusing on de-escalating as a means to minimize resistance and improve cost-effectiveness.

62. 62 A10123S An Art in Medicine Balance An Evidence-Based Problem: Mortality with Inadequate Therapy A Theoretical Dilemma: Concern of Resistance with Broad-Spectrum Therapy Evans RS et al. N Engl J Med 1998;338:232-238. Gruson D et al. Am J Respir Crit Care Med 2000;162:837-843. Raymond DP et al. Crit Care Med 2001;29:1101-1108. Clinical evidence showing lack of resistance with heterogeneous use of broad-spectrum therapy: