Antibiotic use in ICU by zad zad

ANTIBIOTIC CHOICE IN THE ICU By

Prof. ABDEL FATTAH ABDEL SATTAR ANESTHESIA & PAIN RELIEF DEPARTMENT NATIONAL CANCER INSTITUTE CAIRO UNIVERSTIY 1

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Topics • • • •

What Is Initial “Inadequate Therapy”? What Constitutes Initial Appropriate Therapy? Timing Antibiotic Pharmacology and the Pharmacodynamics of Bacterial Killing • Meaningful Outcomes of Appropriate Therapy • Which Patients Are Candidates For Initial Aggressive Antibiotic Therapy?

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Topics • What are the Principles in Choosing the Initial Appropriate Empiric Therapy? Stage 1 • Principles and Specifics of De-Escalating Stage 2 • Treatment Duration • Combination Therapy • Empiric Antifungal Therapy in the ICU

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The empiric use of antibiotics is the norm rather than exception in ICU. The physician should be familiar with the suspected organisms for both community and hospital acquired infection. Choice will consider: • The nature of the infection (What organisms are most likely involved) . • Understanding of different antibiotics (spectrum and limitations) • The patient factors (renal or hepatic dysfunction are common in ICU patient) . 4

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What Is Initial “Inadequate Therapy”?

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Defining Initial Inadequate Therapy Initial therapy is considered to be inadequate if: • 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.

1Kollef

MH et al. Chest 1999;115:462-474.

2Ibrahim

EH et al. Chest 2000;118:146-155.

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Initial “Inadequate Therapy” In Critically Ill Patients with Serious Infections 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. 7

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What Constitutes Initial Appropriate Therapy?

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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. 9

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Timing

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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) IDAAT 31%

• Risk factors for hospital mortality

Timely <24 h 69%

Iregui et al. Chest 2002;122:262–268 11

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Appropriate Early Antibiotic Therapy Reduces Mortality Rates In Patients With Suspected VAP Mortality (%) 80

p<0.01

Early appropriate antibiotic treatment Initially delayed antibiotic treatment p<0.001

40 20 0

Hospital mortality

Iregui et al. Chest 2002;122:262â&#x20AC;&#x201C;268

Mortality attributed to VAP 12

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Antibiotic Pharmacology and the Pharmacodynamics of Bacterial Killing

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Pharmacodynamic Parameters In Vivo Potency Concentration

Cmax:MIC

AUC:MIC

MIC T>MIC

PAE

Time 14

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Pharmacodynamic Parameters Predection of outcome Parameter correlating with efficacy

Cmax:MIC

AUC:MIC

T>MIC

Antibiotic

Aminoglycosides Azithromycin Fluroquinolones Ketolides Linezolid Daptomycin Tigecycline

Carbapenems Cephalosporins Macrolides Penicillins

Organism killing

Concentrationdependent

Time-dependent

Therapeutic goal

Maximize exposure

Optimize duration exposure 15

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Antibiotics and Sepsis: Necessary But Not Sufficient for Survival Infection

Appropriate antibiotics decrease evolution to severe sepsis by ~50%

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 ÂŠ 2002 Thomson Advanced Therapeutics Communicationsâ&#x201E;˘ (ATC) and Vanderbilt University School of Medicine. All rights reserved.

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Antibiotics and Sepsis: Necessary But Not Sufficient for Survival Infection

Appropriate antibiotics decrease evolution to severe sepsis by ~50%

Inflammation/Coagulation Activation

Severe Sepsis

Death

Appropriate antibiotics reduce mortality by 10%-15%; mortality remains 28%-50%

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Which Patients Are Candidates For Initial Aggressive Antibiotic Therapy?

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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 19

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What are the Principles in Choosing the Initial Appropriate Empiric Therapy?

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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 costeffectiveness 21

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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.

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Antibiotic Susceptibility of Resistant

Klebsiella pneumoniae

Imipenem Ciprofloxacin Cefepime Amikacin Pip/taz 0% 20% 40% 60% 80%100% Paterson DL. IDSA 1998. 23

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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. 24

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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. 25

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Combination Therapy

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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 27

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Combination Therapy in Critically Ill Patients with VAP Imipenem + amikacin + vancomycin

Ceftazidime + amikacin + vancomycin Piperacillin-tazobactam + amikacin + vancomycin Aztreonam+ amikacin + vancomycin 0 â&#x20AC;˘

70 80 % susceptibility

100

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. 28

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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

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Tygacil (tigecycline) and Vicuron’s dalbavancin

• December 2004 saw the first regulatory filings for approval of two new antibiotics – Wyeth’s Tygacil (tigecycline) and Vicuron’s dalbavancin. • The FDA granted Tygacil Priority Review status on 28 January 2005, recognising that if approved, the drug would be a significant improvement on existing treatments. • The agent is a new class of antibiotic - a glycylcycline - and its approval would make it a first-in-class. 30

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LINEZOLIDS Oxazolidinones group : • They have a novel mechanism →block bacterial protein synthesis at the ribosome at a very early stage. • So, it does not share cross-resistance with other antimicrobial agents • Spectrum→ Identical to Vancomycin. • Major indication → Vancomycin resistance. • Excellent oral bioavailability. 31

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Principles and Specifics of De-Escalating Stage 2

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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. 34

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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.

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Empiric Antifungal Therapy in the ICU • Invasive fungal infections have increased significantly over the last 2 decades. – aging population with life sustaining therapies like renal dialysis – broad spectrum antimicrobial therapy and invasive medical devices – bone marrow transplantation (BMT) & solid organ transplantation (SOT) – intensive chemotherapy for malignancies – HIV/AIDS epidemic. 36

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Invasive Mycosis

Aspergillosis

Candidiasis

MICU or SICU

Barrier immunity

Oncology

Decreasing immunity

SOT or BMT

Barrier plus cellular immunity 37

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Treatment of Invasive Mycosis • Polyenes – Amphotericin B (AmB) or Liposomal AmB (kidney toxicity)

• Azoles – Fluconazole 400-800 mg/day (liver toxicity, CYP450) – Voriconazole (liver toxicity, visual disturbances, CYP450) – Posaconazole (liver toxicity, CYP450)

• Echinocandins

– Caspofungin iv (liver toxicity)

• Combination ex. AmB/ Fluconazole (liver, kidney toxicity)

Choice of agents depends on whether the patient on previous azole prophylaxis, culture results, local fungal sensitivity, colonization, renal or liver disease, presence of drug-drug interactions, presence of hardware, immuno suppresion, site of disease ex. urine. 38

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Summary

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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. Broadspectrum 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.

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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.

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