Professor of Chemotherapy Department of Preclinical and Clinical Pharmacology University of Florence Researching field Pharmacokinetics, Pharmacodynamics of antimicrobial, antifungal and antitumoral drugs Academic Activities Vice-President of the Italian Society of Chemotherapy, member of the Council of the Italian Society of Microbiology and of the Italian College of Pharmacology Professor Teresita Mazzei
Antimicrobial therapy in critically ill septic patients from the pharmacokinetic/pharmacodynamic view Teresita Mazzei Department of Preclinical and Clinical Pharmacology University of Florence, Italy
Correct use of antibiotics Main parameters Microbiological aspects (susceptibility, resistance) Pharmacological aspects (pharmacodynamics, pharmacokinetics, patients) Therapeutics index (efficacy/toxicity)
PHARMACOKINETICS SERUM LEVELS elimination dose absorption distribution metabolism TISSUE LEVELS dose optimisation PHARMACODYNAMICS high serum or tissue levels low or absent serum or tissue levels PK PD CORRELATION (T>MIC AUC/MIC C max /MIC) MIC MBC Killing PAE PA-SME TOXICITY EFFICACY RESISTANCE
Patterns of bactericidal activity Time-killing curves for P. aeruginosa ATCC 27853 CONCENTRATION-DEPENDENT TIME-DEPENDENT 10 Tobramycin Ciprofloxacin Ticarcillin 10 10 8 8 8 6 6 6 4 2 0 4 2 0 0 2 4 6 8 0 2 4 6 8 W.A. Craig et al., 1991, modified 4 2 0 64xMIC 16xMIC 4xMIC MIC 1/4xMIC Control 0 2 4 6 8 hours
PK-PD correlations Concentration (mg/l) 40 30 20 10 C max /MIC Aminoglycosides Fluoroquinolones Daptomycin AUC/MIC Vancomycin Teicoplanin Tigecycline MIC 0 T > MIC Betalactams Linezolid PAE 0,5 10 0 8 16 24 Hours
Conditions affecting the pharmacokinetics of antibiotics and possible solutions Critically ill patients Variations in extracellular fluid Variations in renal clearance Increased if: pleural effusion ascites mediastinitis Increased if: drug abuse burns hyperdynamics Decreased if: renal imapairment fluid therapy oedema post-surgical drainages haemodynamically active drug leukaemia dialysis hypoalbuminaemia hypoalbuminaemia Antimicrobial dilution or loss Consider dosage increase Enhanced antimicrobial renal excretion Consider dosage increase Reduced antimicrobial renal excretion Consider dosage decrease Pea F et al., Clin Pharmacokinet, 2005
Hydrophilic antibiotics Lipophilic antibiotics Beta-lactams Penicillins Cephalosporins Carbapenems Monobactams Glycopeptides Aminoglycosides Macrolides Fluoroquinolones Linezolid Tetracyclines Chloramphenicol Rifampicin Limited volume of distribution Inability of passively diffusing through plasmatic membrane of eukariotic cells Inactivity against intracellular pathogens Renal elimination as unchanged drug Large volume of distribution Free diffusion through plasmatic membrane of eukariotic cells Activity against intracellular pathogens Elimination after liver metabolization Pea F, Viale P e Furlanut M, Clinical Pharmacokinetics, 2005
BETALACTAMS OXAZOLIDINONES GLYCOPEPTIDES AMINOGLYCOSIDES FLUOROQUINOLONES
BETALACTAMS and OXAZOLIDINONES Time-dependent (T > MIC) Short PAE
BETALACTAMS T > MIC Relationship between the change in log 10 CFU per thigh or lung for various pathogens following 24 h of therapy with different doses of penicillins ( ), cephalosporins ( ), and carbapenems ( ) PENICILLINS CEPHALOSPORINS CARBAPENEMS Andes D & Craig WA, Int J Antimicrob Agents, 2002
BETALACTAMS PK-PD parameters and clinical outcome in 87 hospitalized pts with various infections treated with ceftriaxone, cefepime or piperacillin RECOVERY FAILURE % time above MIC 97 ± 8.9 71.5 ± 20.5 % time above MIC (unbound) 94.5 ± 11.7 58.1 ± 27 AUC above MIC (mg h/l) 1209.7 ± 646.2 658.2 ± 282.8 AUC 24 /MIC (h) 8246.2 ± 20272 142.4 ± 99.7 C max /MIC 798.1 ± 1870 26.2 ± 21.6 C max /MIC 132.7 ± 356.8 0.5 ± 0.9 Sàbada B et al., Clin Microbiol Infect, 2004
PK of ceftriaxone (2g IV) in critically ill patients Total plasma ceftriaxone concentrations of individual patients over 24 h following iv administration renal failure MIC (8 mg/l) Joynt GM et al., J Antimicrob Chemother, 2001
Impaired taget site penetration of betalactams may account for therapeutic failure in patients with septic shock PIPERACILLIN 4g Plasma Interstitial fluid free concentration in plasma (mg/l) healthy volunteers (n. 6) septic pts (n. 6) concentration in interstitium (mg/l) muscle of healthy volunteers adipose tissue of healthy volunteers muscle of septic pts adipose tissue of septic pts time after infusion (min) time after infusion (min) Joukhadar C et al., Crit Care Med, 2001
Ceftazidime 4g/day IV continuous infusion* in 8 ICU patients 100 80 60 day1 day2 day3 40 AUC** = 902.1 613.8 673.2 20 MSSA MIC 90 = 16 mg/l P. aeruginosa MIC 90 = 8 mg/l 0 E. coli MIC 90 = 0.5 mg/l 0 6 12 18 24 30 36 42 48 54 60 66 72 serum concentration AUIC = AUC 24 /MIC * day1 = 1g IV bolus + 3g continuous infusion ** mg/l h
Concentrations data for seriously ill pts receiving betalactams by bolus or continuous infusion Drug Mean C max (mg/l) Mean C min (mg/l) Mean C ss (mg/l) Bolus Bolus Infusion C ss (infusion)/ C min (bolus) Ceftazidime 89 19 47 2.4 Ceftazidime 124 25 30 1.2 Ceftazidime 91 4 19 4.8 Ceftazidime 120 ~ 5 40 8 Ceftazidime - 19 63 3.3 Cefepime 233 5 41 8.2 Apalcillin 70-80 ~ 6 27 4.5 Piperacillin 227 5 18 3.6 C max = peak concentration; C min = trough concentration; C ss = steady-state concentration Roberts JA et al., Int J Antimicrob Agents, 2007
Penetration of β-lactam antibiotics into various tissues when administered by continuous or bolus administration Drug % Tissue penetration Bolus Infusion Ceftazidime (in peritoneal exudate) 35% 56% Apalcillin (in bronchial secretions) Patients received bolus or continuous dosing for 3 days then switched to the other mode of dosing Day 3, 11.8% (bolus then infusion) Day 5, 5.7% (infusion then bolus) Day 3, 2.2% (bolus then infusion) Day 5, 9.8% (infusion then bolus) Roberts JA et al., Int J Antimicrob Agents, 2007
Randomized controlled studies comparing outcome during continuous infusion (CI) and intermittent administration (Int) (I) Study Drug and regimen (dose X 24 h) N CI/ N Int Indication Outcome Remarks Bodey et al., 1979 Nicolau et al., 2001 Georges et al., 2005 Hanes et al., 2000 Cefamandole (+carbenicillin 5g every 6h) 12g CI vs 3g every 6h Ceftazidime (+tobramycin 7mg/kg daily) 3g CI vs 2g evry 8h Cefepime (+amikacyn 15mg/kg daily) 4g CI vs 2g every 12 h Ceftazidime 60mg/kg CI vs 2g every 8h 74/92 FUO NS P= 0.03 in favour of CI for infections in pts with persistent neutropenia 17/18 HAP NS Lower dose during CI 26/24 ICU NS 17/15 HAP NS Lower dose during CI Mouton JW & Vinks AA, Curr Opin Crit Care, 2007
Randomized controlled studies comparing outcome during continuous infusion (CI) and intermittent administration (Int) (II) Study Drug and regimen (dose X 24 h) N CI/ N Int Indication Outcome Remarks Van Zanten et al., 2007 Lau et al., 2006 Roberts et al., 2007 Buijk et al., 2002 Cefotaxime 2g CI vs 1g every 8h Piperacillin/tazobactam 12/1.5g CI vs 3/0.375g every 6h Ceftriaxone (+ undefined other antibiotics) 2g CI vs 2g every 24h Ceftazidime 4.5g CI vs 1.5g every 8h 47/46 COPD NS Lower dose during CI 130/132 IAI c NS 29/28 ICU NS P= 0.008 in favour of CI in a priori analysis after logistic regression P= 0.02 in favour of CI for proven bacterial eradication 12/6 ICU NS Mouton JW & Vinks AA, Curr Opin Crit Care, 2007
Mean serum concentration of imipenem (*) and meropenem ( ) 1g IV infusion (+s.d.) in two groups of ICU patients mg/l 1000 PK parameter Imipenem (10 pts) Meropenem (10 pts) C max (mg/l) 95.8 (50.5) 46.6 (14.7) < 0.01 P t1/2β (h) 2.0 (0.3) 2.1 (0.6) n.s. AUC 0-00 (mg/l.h) 226.4 (85.3) 99.5 (23.9) < 0.01 100 Vd (l) 16.4 (3.6) 25.0 (4.1) < 0.01 Cl tot (ml/min) 105.6 (26.6) 191 (52.2) < 0.01 10 1 0 2 4 6 8 hours Novelli A et al., Clin Pharmacokinet, 2005
PK/PD of linezolid after intermittent or continuous infusion 20 Intermittent Continuous Concentration (mg/l) 15 10 5 * * ** ** * ** ** ** 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Parameter Group I Group C AUC/MIC 92.2 ± 45.2 a 103.03 ± 39.8 a T > 4 mg/l MIC (%) > 85% 4 mg/l = Susceptibility breakpoint 2 mg/l = for Staphylococcus spp. and Enterococcus spp. 3/8 (40%) 8/8 (100%) *p< 0.05 **p< 0.01 Time (h) Novelli A et al., Int J Antimicrob Agents, 2007
GLYCOPEPTIDES Time-dependent (T > MIC or AUC/MIC) Long PAE
Pharmacodynamics of vancomycin in 108 pts with S. aureus nosocomial RTI Odds ratios for clinical success Characteristic Odds ratio 95% Cl P-Value AUC 24 /MIC value 350 7.19 1.91, 27.3 0.0036 MSSA as pathogen 3.88 1.10, 14.8 0.0359 Single lobe involvement 6.32 1.56, 25.6 0.0099 Baseline serum albumin* 3.73 1.09, 12.8 0.0364 Baseline CL CR ** 1.04 1.01, 1.07 0.0154 * per 1 g/dl ** per 1 ml/min Moise-Broder PA et al., Clin Pharmacokinet, 2004
Teicoplanin in pts with acute leukemia and febrile neutropenia Plasma concentrations during the overall treatment period in the standard (400mgx3 ev. 12h 400mg/die) and the high dosage groups (800+400mg/d1 600+400mg/d2 400mgx2) Plasma teicoplanin concentration (mg/l) High dosage (n=22) Standard dosage (n=11) Duration of therapy (h) Pea F et al., Clin Pharmacokinet, 2004
AMINOGLYCOSIDES Concentration-dependent (C max /MIC or AUC/MIC) Very long PAE
Aminoglycosides Postantibiotic effect (PAE)* (h) of tobramycin and gentamicin Organisms Tobramycin Gentamicin 2xMIC 4xMIC 2xMIC 4xMIC MSSA (4) 9.3 ± 0.8 b 9.8 ± 0.4 a 5.1 ± 0.9 b 7.5 ±1.7 a MRSA (4) 4.4 ± 1.2 a 6.0 ± 1.3 b 2.3 ± 1.1 a 2.4 ± 0.9 b E. coli (4) 2.8 ± 0.7 7.2 ± 2.2 a 2.7 ± 0.6 3.8 ± 0.3 a K. pneumoniae (4) 8.9 ± 1.0 b 10.3 ± 0.6 b 4.9 ± 0.8 b 6.1 ± 0.6 b E. cloacae (4) 3.4 ± 0.7 6.9 ± 0.8 b 2.5 ± 0.8 4.7 ± 0.4 b P. mirabilis (4) 7.9 ± 0.5 b 10.9 ± 1.7 b 5.7 ± 0.3 b 6.9 ± 0.8 b P. aeruginosa (4) 6.1 ± 0.2 b 9.5 ± 1.3 b 2.8 ± 1.2 b 5.1 ± 1.9 b ( ) no. isolates * bacteria were exposed to antibiotics for 2h. Results are expressed as mean ± SD of data from at least 4 experiments a = P < 0.05 b = P < 0.01 Tobramycin vs Gentamycin ANOVA test A. Novelli et al., J Chemother, 1995
AMINOGLYCOSIDES C max /MIC Relationship between the maximal peak plasma level to MIC ratio and the rate of clinical response in 236 patients with Gram-negative bacterial infection treated with aminoglycosides (gentamicin, tobramycin or amikacin) R.D. Moore, J. Infect. Dis., 1987
Summary of the results of 9 meta-analyses of studies comparing once daily aminoglycoside administration with multiple daily doses Reference No. of trials n. pts TOXICITY EFFICACY Nephrotoxicity Ototoxicity Galloe et al., (1995) 16 1200 OD = MD OD = MD OD > MD (NS) Barza et al., (1996) 21 3091 OD < MD a OD = MD OD > MD (NS) Ferriol-Lisart et al., (1996) 18 2317 OD < MD (NS) OD < MD (NS) OD > MD Hatala et al., (1996) 13 1200 OD < MD (NS) OD < MD (NS) Munckhof et al., (1996) 20 2881 OD < MD OD = MD OD > MD Freeman et al., (1996) 15 OD = MD OD > MD a Zaki Ali & Goetz (1997) 26 2035 OD < MD MD < OD (NS) OD > MD Bailey et al., (1997) 22 2500 OD < MD (NS) OD = MD Hatala et al., (1997) 4 422 OD < MD (NS) OD = MD a More than one method of meta-analysis was used and significance depended on method of analysis Barclay ML et al., Clin Pharmacokinet, 1999
Aminoglycosides PK in critically ill haematology-oncology patients Manny RP, Hutson PR. Aminoglycoside volume of distribution in haematology-oncology patients. Clin Pharm. 5: 629-632; 1986 Higa GM, Murray WE. Alterations in aminoglycoside pharmacokinetics in patients with cancer. Clin Pharm. 6: 963-966; 1987 Hary L et al. Pharmacokinetics of amikacin in neutropenic patients. Curr Ther Res. 46: 821-827; 1989 Zeitany RG et al. Increased aminoglycoside dosage requirements in hematologic malignancy. Antimicrob Agents Chemother. 34(5): 702-708; 1990 Davis RL et al. Amikacin pharmacokinetics in patients receiving high-dose cancer chemotherapy. Antimicrob Agents Chemother. 25: 944-947; 1991 Kosirog JL et al. Aminoglycoside forecasting in neutropenic patients with cancer. Clin Pharmacokinet. 24: 79-87; 1993 Tod M et al. Population pharmacokinetic study of amikacin administered once or twice daily to febrile, severely neutropenic adults. Antimicrob Agents Chemother. 42(4): 849-856; 1998 Romano S et al. Population pharmacokinetics of amikacin in patients with haematological malignancies. J Antimicrob Chemother. 44: 235-242; 1999 Yombi JC et al. Key pharmacokinetic parameters of isepamicin in febrile neutropenic cancer patients and in women with acute pelvic inflammatory disease. J Chemother. 17(5): 521-526; 2005
FLUOROQUINOLONES Concentration-dependent (C max /MIC or AUC/MIC) Long PAE
FLUOROQUINOLONES AUC/MIC Relationship between the change in log 10 CFU per thigh or lung for various pathogens following 24 h of therapy with different doses of various fluoroquinolones S. pneumoniae Other pathogens Andes D & Craig WA, Int J Antimicrob Agents, 2002
Relationship between ciprofloxacin AUIC and bacterial eradication rates (74 pts with RTI in ICU) 100 % of patients remaining culture-positive 75 50 25 0 0 2 4 6 8 10 12 14 Days of therapy AUIC < 125 AUIC 125-250 AUIC > 250 A. Forrest et al., Antimicrob. Ag. Chemother., 1993
Levofloxacin Probabilities of successful outcome Clinical (134 pts)* Microbiological (116 pts)** 1 1 0,9 0,9 0,8 0,8 Probabilily 0,7 0,6 0,5 Probabilily 0,7 0,6 0,5 0,4 0,3 0,2 Urinary tract infection Pulmonary infection Skin and soft tissue infection 0,4 0,3 0,2 0,1 0 Break Point = 12.2 0,1 Break Point = 12.2 0 0 10 20 30 40 50 0 10 20 30 40 50 Peak/MIC ratio Peak/MIC ratio * 7 failures ** 5 persistent organisms Preston S.L. et al., JAMA 1998
LEVOFLOXACIN DOSAGE AND PATHOPHYSIOLOGICAL SITUATIONS (10 ICU pts with VAP) Plasma levofloxacin concentration (mg/l) 10 500 mg BID in VAP-ICU 8 6.5 5 3 2 1 0.8 0.65 0.5 0 4 8 12 16 20 24 Pea F. et al. Clin Pharmacokinet 2003; 42: 589-598 Time (hours)
AUIC vs resistance 100 Probability of remaining susceptible 75 50 25 AUC < 100 AUC > 101 0 0 5 10 15 20 Days from initiation of therapy J.K. Thomas, AAC, 42:521-527, 1998
Conclusions (I) Pharmacological research is going from the bench to the bedside Important clinical data are demonstrating that outcome is dependent on PK-PD parameters Clinicians must improve their PK-PD knowledge to obtain the best efficacy in the antimicrobial treatment of patients
Conclusions (II) The pathophysiological changes occurring during sepsis (i.e. endothelial damage, increased capillary permeability, third spacing, acid-base status, serum proteins and organ function) are known to influence drug PK and PD, expecially of water-soluble drugs such beta-lactams, glicopeptides and aminoglycosides Therefore, the serum and tissue concentrations achieved when drugs are administred at the same dosages suggested for healthy volunteers are often suboptimal but sometimes can be too high (organ failure) In conclusion, in order to optimize antibacterial regimens to achieve clinical cure in patients with sepsis we must consider many aspects that are mainly changes in PK-PD parameters and patient s pathophysiology