Professor of Chemotherapy Department of Preclinical and Clinical Pharmacology University of Florence

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1 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

2 Antimicrobial therapy in critically ill septic patients from the pharmacokinetic/pharmacodynamic view Teresita Mazzei Department of Preclinical and Clinical Pharmacology University of Florence, Italy

3 Correct use of antibiotics Main parameters Microbiological aspects (susceptibility, resistance) Pharmacological aspects (pharmacodynamics, pharmacokinetics, patients) Therapeutics index (efficacy/toxicity)

4 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

5 Patterns of bactericidal activity Time-killing curves for P. aeruginosa ATCC CONCENTRATION-DEPENDENT TIME-DEPENDENT 10 Tobramycin Ciprofloxacin Ticarcillin W.A. Craig et al., 1991, modified xMIC 16xMIC 4xMIC MIC 1/4xMIC Control hours

6 PK-PD correlations Concentration (mg/l) C max /MIC Aminoglycosides Fluoroquinolones Daptomycin AUC/MIC Vancomycin Teicoplanin Tigecycline MIC 0 T > MIC Betalactams Linezolid PAE 0, Hours

7 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

8 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

9 BETALACTAMS OXAZOLIDINONES GLYCOPEPTIDES AMINOGLYCOSIDES FLUOROQUINOLONES

10 BETALACTAMS and OXAZOLIDINONES Time-dependent (T > MIC) Short PAE

11 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

12 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 ± ± 20.5 % time above MIC (unbound) 94.5 ± ± 27 AUC above MIC (mg h/l) ± ± AUC 24 /MIC (h) ± ± 99.7 C max /MIC ± ± 21.6 C max /MIC ± ± 0.9 Sàbada B et al., Clin Microbiol Infect, 2004

13 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

14 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

15 Ceftazidime 4g/day IV continuous infusion* in 8 ICU patients day1 day2 day3 40 AUC** = MSSA MIC 90 = 16 mg/l P. aeruginosa MIC 90 = 8 mg/l 0 E. coli MIC 90 = 0.5 mg/l serum concentration AUIC = AUC 24 /MIC * day1 = 1g IV bolus + 3g continuous infusion ** mg/l h

16 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 Ceftazidime Ceftazidime Ceftazidime 120 ~ Ceftazidime Cefepime Apalcillin ~ Piperacillin C max = peak concentration; C min = trough concentration; C ss = steady-state concentration Roberts JA et al., Int J Antimicrob Agents, 2007

17 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

18 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

19 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= 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

20 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) (85.3) 99.5 (23.9) < Vd (l) 16.4 (3.6) 25.0 (4.1) < 0.01 Cl tot (ml/min) (26.6) 191 (52.2) < hours Novelli A et al., Clin Pharmacokinet, 2005

21 PK/PD of linezolid after intermittent or continuous infusion 20 Intermittent Continuous Concentration (mg/l) * * ** ** * ** ** ** Parameter Group I Group C AUC/MIC 92.2 ± 45.2 a ± 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

22 GLYCOPEPTIDES Time-dependent (T > MIC or AUC/MIC) Long PAE

23 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 , MSSA as pathogen , Single lobe involvement , Baseline serum albumin* , Baseline CL CR ** , * per 1 g/dl ** per 1 ml/min Moise-Broder PA et al., Clin Pharmacokinet, 2004

24 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 ( mg/d mg/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

25 AMINOGLYCOSIDES Concentration-dependent (C max /MIC or AUC/MIC) Very long PAE

26 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 ± ± 2.2 a 2.7 ± ± 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 ± ± 0.8 b 2.5 ± ± 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

27 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

28 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) OD = MD OD = MD OD > MD (NS) Barza et al., (1996) OD < MD a OD = MD OD > MD (NS) Ferriol-Lisart et al., (1996) OD < MD (NS) OD < MD (NS) OD > MD Hatala et al., (1996) OD < MD (NS) OD < MD (NS) Munckhof et al., (1996) OD < MD OD = MD OD > MD Freeman et al., (1996) 15 OD = MD OD > MD a Zaki Ali & Goetz (1997) OD < MD MD < OD (NS) OD > MD Bailey et al., (1997) OD < MD (NS) OD = MD Hatala et al., (1997) 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

29 Aminoglycosides PK in critically ill haematology-oncology patients Manny RP, Hutson PR. Aminoglycoside volume of distribution in haematology-oncology patients. Clin Pharm. 5: ; 1986 Higa GM, Murray WE. Alterations in aminoglycoside pharmacokinetics in patients with cancer. Clin Pharm. 6: ; 1987 Hary L et al. Pharmacokinetics of amikacin in neutropenic patients. Curr Ther Res. 46: ; 1989 Zeitany RG et al. Increased aminoglycoside dosage requirements in hematologic malignancy. Antimicrob Agents Chemother. 34(5): ; 1990 Davis RL et al. Amikacin pharmacokinetics in patients receiving high-dose cancer chemotherapy. Antimicrob Agents Chemother. 25: ; 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): ; 1998 Romano S et al. Population pharmacokinetics of amikacin in patients with haematological malignancies. J Antimicrob Chemother. 44: ; 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): ; 2005

30 FLUOROQUINOLONES Concentration-dependent (C max /MIC or AUC/MIC) Long PAE

31 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

32 Relationship between ciprofloxacin AUIC and bacterial eradication rates (74 pts with RTI in ICU) 100 % of patients remaining culture-positive Days of therapy AUIC < 125 AUIC AUIC > 250 A. Forrest et al., Antimicrob. Ag. Chemother., 1993

33 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 = ,1 Break Point = Peak/MIC ratio Peak/MIC ratio * 7 failures ** 5 persistent organisms Preston S.L. et al., JAMA 1998

34 LEVOFLOXACIN DOSAGE AND PATHOPHYSIOLOGICAL SITUATIONS (10 ICU pts with VAP) Plasma levofloxacin concentration (mg/l) mg BID in VAP-ICU Pea F. et al. Clin Pharmacokinet 2003; 42: Time (hours)

35 AUIC vs resistance 100 Probability of remaining susceptible AUC < 100 AUC > Days from initiation of therapy J.K. Thomas, AAC, 42: , 1998

36 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

37 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