Building a Better Mousetrap for Nosocomial Drug-resistant Bacteria: use of available resources to optimize the antimicrobial strategy

Transcription

1 Building a Better Mousetrap for Nosocomial Drug-resistant Bacteria: use of available resources to optimize the antimicrobial strategy Leonardo Pagani MD Director Unit for Hospital Antimicrobial Chemotherapy (UHAC) Antimicrobial Management Program Division of Infectious Diseases Bolzano Hospital Clinic of Infectious Diseases Udine University Villach (A),

2 CURRENT HEALTHCARE SYSTEM Home Care Acute Care Facility Outpatient/ Ambulatory Facility Tranquil Gardens Nursing Home Long Term Care Facility

3 Environments Where Antibiotic Resistance Develops and Their Relationships Nursing Homes Daycare Tertiary Hospitals Community Hospitals Homecare Community Foreign Feedlots Adapted from B. Murray

4 Clinical & Economic Impact of Resistance Clinical impact of resistance will be modulated by: Mechanism of R how much does the MIC change Ability to delivery sufficient antibiotic concentrations to site of infection Dose, penetration,... The cost of failure is HIGH: Mortality LOS & cost of care Cost saved by avoiding treatment failure greater than costs spent by on antimicrobial therapy

5 ! OVERUSE! The desire to ingest medicines is one of the principal features which distinguish man from the animals Osler W. Aecquanimitas, 1920

6 Dangerous macro-organism: organism: MRMS Multi-Resistant Medical Specialist

7 MRMS Resistant to good advice Allergic to professional guidelines Non-compliant with infection control Blind to nosocomial infections Other priorities Missing feeling of accountability

8 My son, My son, if they don t get me, you will become multiresistant

9 THE ANTIMICROBIAL THERAPY PUZZLE ANTIMICROBIAL SITE PATHOGEN BATTERI + MIC PATIENT

10 Defining pharmacokinetics and pharmacodynamics Pharmacokinetics (PK): reflects how a drug is absorbed, distributed and eliminated in the body these factors, along with the dosing regimen of the drug, determine the time course of drug concentration in the serum, tissues and body fluid Pharmacodynamics (PD): the relationship between a drug s serum concentrations and its pharmacological and toxicological effects in other words, PD integrates PK with drug potency (measured by the drug s minimum inhibitory concentration [MIC] against a bacterium) Craig. Clin Infect Dis 1998; 26:1 12

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12 Antimicrobial drugs & pattern of activity Time-dependent Concentration-dependent β-lactams Glycopeptides Oxazolidinones Carbapenems Aminoglycosides Rifampin Quinolones Azalides Usually no PAE Stable, unfloating concentrations over 24 hrs. High PAE Peak over the MIC, regardless of timing

13 PK-PD correlations Concentration n (mg/l) C max /MIC T > MIC Betalactams Oxazolidinones Aminoglycosides Fluoroquinolones AUC/MIC 0,5 10 Vancomycin Teicoplanin Hours PAE MIC

14 Post-antibiotic effect (PAE) The persistent suppression of bacterial growth after exposure to an antibacterial agent Observed for all antibacterials against Gram-positive cocci, such as staphylococci. However, minimal in vivo PAEs for β-lactams with streptococci Moderate to prolonged in vivo PAEs for inhibitors of protein and nucleic acid synthesis (aminoglycosides, quinolones, rifampin, macrolides and tetracyclines) with Gram-negative bacilli Short or no in vivo PAEs for β-lactams with Gram-negative bacilli (only exception: carbapenems with some strains of Pseudomonas aeruginosa)

15 Time-dependent killing with minimal postantibiotic effects Goal of dosing regimen: to optimize duration of antibacterial exposure at the site of infection Major parameter correlating with efficacy is the percentage of the dosing interval for which the serum concentration exceeds the MIC of the drug against the pathogen, or Time above MIC Seen with all β-lactams: penicillins Cephalosporins For these drugs, Time above MIC target for efficacy is > 40 50% of the dosing interval The concentration of drug achieved for > 40 50% is defined as the PK/PD breakpoint Andes et al. Clin Lab Med 2004; 24:

16 β-lactams Relationship between T > MIC and eradication in CFU/ml Log change i T>MIC (% of 24 h) Static effect 2-log kill Maximum effect MacGowan AP, Clin Microbiol Infect, 2004

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18 Ceftazidime PD profile(t>mic) in patients with nosocomial pneumonia (continuous vs. intermittent infusion) Nicolau et al, Clin Drug Invest, g IC/24 h g tid 82% (56-95) 90% MIC = 8 mg/l 1 g tid MIC = 4 mg/l 1 g bid

19 Next dose

20 35 C max 30 Drug concent tration (µg/ml) C min MIC h Time-dependent antimicrobials

21 Dynamic MICs achieved with optimized infusions drug Daily dose MIC reached Pip/tazo 18 g 60 Pen G 18 MU 9 Amoxicillin 12 g 21 Oxacillin 12 g 1 Ampicillin 12 g 28 Ceftazidim 6 g 11 Meropenem 12 g 16

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23 CLSI 2006 New Vancomycin MIC Breakpoints Modification of vancomycin MIC breakpoints for S. aureus criteria 2005 MIC (ug/ml) 2006 MIC (ug/ml) S 4 2 MIC = 4 um/ml now VISA CLSI: Clinical and Llaboratory Standard Institute I (VISA) R (VRSA)

24 Different tissue penetration (PD) of AMs (% tissue-to-plasma ratio) Tissue/fluid Linezolid Teicoplanin Vancomycin ELF (epithelial lining fluid) % % Interstitial fluid 104% 43% - Bone 60% 50-60% 7-13% Muscle 94% 40% 30% CSF 70%* 10% 0-18% Intraperitoneal dialysis fluid 61% 40% 20% A.R. De Gaudio et al Farmaci e Terapia 2002;XIX (Suppl.2): 1-56

25 MIC DRIVEN ANTI STAPHYLOCOCCAL THERAPY OF HAP ADD EMPIRIC ANTISTAPHYLOCOCCAL THERAPY IN PRESENCE OF: 2 major risk factors for MRSA ( >7 days in ICU, previous antibiotic exposure, age > 65 yrs, staph nasal carriage, Gram + cocci at gram stain) or severe sepsis 1 st line standard therapy: vancomycin 15 mg/kg LD followed by 30 mg/kg/q24h by CI + rifampicin 600 mg q24h teicoplanin 12 mg/kg LD followed by 6 mg/kg/24 h + rifampicin 600 mg q24h within 48 hours CULTURE RESPONSE MSSA NO STAPH MRSA MIC < 0.5 mg/l Switch to oxacillin 12g/q24h by CI Stop vancomycin Continue vancomycin and optimize exposure by means of TDM MIC > 1 mg/l Pea F & Viale P. Clin Infect Dis 2006 switch to LINEZOLID 600 mg q12h

26 Concentration-dependent killing with prolonged post-antibiotic effects Goal of dosing regimen: to maximize drug concentration at the site of infection Major parameters correlating with efficacy: AUC/MIC the ratio of the 24-hour area under the curve (free serum drug concentration time curve; AUC) to the MIC and/or C max /MIC the ratio of the peak free serum drug concentration (C max ) to the MIC Seen with: aminoglycosides daptomycin fluoroquinolones amphotericin B For Gram-negative bacteria AUC/MIC target is For Gram-positive bacteria AUC/MIC target is 25 35, or C max /MIC 12 Andes et al. Clin Lab Med 2004; 24:

27 3.5 C max 3.0 Drug concent tration (µg/ml) C min MIC h Concentration-dependent antimicrobials

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31 Antimicrobial Stewardship Program May Help Reduce Antimicrobial Resistance in ICU Jan Dec 2007 Pagani L, et al. Clin Microbiol Infect 2008 surveillance of nosocomial pathogen susceptibilities in significant clinical samples from patients admitted to ICU > hrs. Blood, TBA/BAL, surgical wounds, urine, CSF, drainages,... a) withdrawal of 3 rd -Ceph prophylaxis in critical patients at admission to ICU b) empirical therapy for suspected ICU-acquired infections according to protocols based on local epidemiology data and on pharmacokinetic/pharmacodynamic (PK/PD) criteria c) subsequent regular tailoring of antimicrobial therapy according to microbiologic findings with commitment to streamlining

32 Antimicrobial therapy in the critically ill patients: a review of those patho-physiological conditions responsible for huge pk variability Pea F et al., Clin Pharmacokinet 2005 VARIATIONS OF EXTRACELLULAR FLUID VARIATIONS OF RENAL CLEARANCE Increased if PLEURAL EFFUSION ASCITES MEDIASTINITIS Increased if DRUG ABUSE BURNS HYPERDYNAMICS Decreased if RENAL IMPAIRMENT FLUID THERAPY OEDEMA DRAINAGES HAEMODYNIMICALLY ACTIVE DRUGS LEUKEMIA DYALISIS AGING HYPOALBUMINAEMIA HYPOALBUMINAEMIA Dilution or loss of antibiotic Enhanced antibiotic renal excretion Reduced antibiotic renal excretion Consider DOSAGE INCREASE Consider DOSAGE INCREASE Consider DOSAGE DECREASE

33 RESULTS (i) antimicrobial consumption ATB 2002-DDD 2006-DDD % VAN TEC CIP AMK CAZ AMP/SB PIP/TZ MEM LIN 156*

34 MRSA and ICU Pagani L, et al. Infect Control Hosp Epidemiol 2008; in press

35 RISK ADJUSTED APPROACH to CHOOSE OPTIMAL THERAPY Severity of illness (SIRS / PIRO scale) Organ dysfunction (SOFA score) Age & Co-morbidities (Mc Cabe score) Community vs Hospital acquisition Site-related Microorganism-related risk factors Resistance-related DRUGS CHOICE PK/PD knowledge Physiopathological status Site of infection REGIMENS CHOICE

36 Principles for prescribing Identification of bacterial infection by optimized diagnosis Severity assessment Recognition and incorporation of local resistance data Targeting bacterial eradication (or maximal reduction in bacterial load) Use of pharmacodynamic (PD) indices to optimize choice and dosage Objective assessment of true (overall) costs of resistance and related treatment failure Ball et al. J Antimicrob Chemother 2002; 49:31 40

37 THANK YOU FOR YOUR ATTENTION!