PK/PD Approach to Antibiotic Therapy Review

Page 1 of 6

A PK/PD Approach to Antibiotic Therapy

Introduction Pharmacokinetics (PK) is concerned with the time course of antimicrobial concentrations in the body, while pharmacodyamics (PD) is concerned with the relationship between those concentrations and the antimicrobial effect. Antibiotic dosing regimens have traditionally been determined by PK parameters only. However, PD plays an equal, if not more important, role. In this age of increasing antimicrobial resistance, PD becomes even more important because these parameters may be used to design dosing regimens which counteract or prevent resistance. Discussion The primary measure of antibiotic activity is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro. While the MIC is a good indicator of the potency of an antibiotic, it indicates nothing about the time course of antimicrobial activity. PK parameters quantify the serum level time course of an antibiotic. The three pharmacokinetic parameters that are most important for evaluating antibiotic efficacy are the peak serum level (Cmax), the trough level (Cmin), and the Area Under the serum concentration time Curve (AUC). While these parameters quantify the serum level time course, they do not describe the killing activity of an antibiotic. Integrating the PK parameters with the MIC gives us three PK/PD parameters which quantify the activity of an antibiotic: the Peak/MIC ratio, the T>MIC, and the 24h-AUC/MIC ratio. The Peak/MIC ratio is simply the Cpmax divided by the MIC. The T>MIC (time above MIC) is the percentage of a dosage interval in which the serum level exceeds the MIC. The 24h-AUC/MIC ratio is determined by dividing the 24-hour-AUC by the MIC.

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552

PK/PD Approach to Antibiotic Therapy Review

Page 2 of 6

Antimicrobial Patterns The three pharmacodyamic properties of antibiotics that best describe killing activity are time-dependence, concentration-dependence, and persistent effects. The rate of killing is determined by either the length of time necessary to kill (time-dependent), or the effect of increasing concentrations (concentration-dependent). Persistent effects include the PostAntibiotic Effect (PAE). PAE is the persistant suppression of bacterial growth following antibiotic exposure. Using these parameters, antibiotics can be divided into 3 categories: Pattern of Activity Type I Concentration-dependent killing and Prolonged persistent effects Type II Time-dependent killing and Minimal persistent effects Type III Time-dependent killing and Moderate to prolonged persistent effects. Antibiotics Goal of Therapy PK/PD Parameter 24h-AUC/MIC Peak/MIC

Aminoglycosides Daptomycin Maximize Fluoroquinolones concentrations Ketolides Carbapenems Cephalosporins Erythromycin Linezolid Penicillins Azithromycin Clindamycin Oxazolidinones Tetracyclines Vancomycin Maximize duration of exposure

T>MIC

Maximize amount of drug

24h-AUC/MIC

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552

PK/PD Approach to Antibiotic Therapy Review

Page 3 of 6

For Type I antibiotics (AG's, fluoroquinolones, daptomycin and the ketolides), the ideal dosing regimen would maximize concentration, because the higher the concentration, the more extensive and the faster is the degree of killing. Therefore, the 24h-AUC/MIC ratio, and the Peak/MIC ratio are important predictors of antibiotic efficacy. For aminoglycosides, it is best to have a Peak/MIC ratio of at least 8-10 to prevent resistence. For fluoroquinolones vs gram negative bacteria, the optimal 24h-AUC/MIC ratio is approximately 125. Versus gram positives, 40 appears to be optimal. However, the ideal 24h-AUC/MIC ratio for FQ's varies widely in the literature. Type II antibiotics (beta-lactams, clindamycin, erythromcyin, and linezolid) demonstrate the complete opposite properties. The ideal dosing regimen for these antibiotics maximizes the duration of exposure. The T>MIC is the parameter that best correlates with efficacy. For beta-lactams and erythromycin, maximum killing is seen when the time above MIC is at least 70% of the dosing interval. Type III antibiotics (vancomycin, tetracyclines, azithromycin, and the dalfopristinquinupristin combination) have mixed properties, they have time-dependent killing and moderate persistent effects. The ideal dosing regimen for these antibiotics maximizes the amount of drug received. Therefore, the 24h-AUC/MIC ratio is the parameter that correlates with efficacy. For vancomycin, a 24h-AUC/MIC ratio of at least 125 is necessary (some researchers recommend a ratio of 400 or more for problem bugs).

Outcome studies

Aminoglycoside Pharmacodynamics in Vivo Initial serum peak level Died Survived

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552

PK/PD Approach to Antibiotic Therapy Review

Page 4 of 6

< 5mcg/ml >= 5mcg/ml Moore et al, J Infect Dis 149: 443, 1984

21% 79% 2% 98%

Aminoglycoside Pharmacodynamics in vivo

Moore et al, J Infect Dis 155: 93, 1987

Vancomycin Outcome vs 24h-AUC/MIC ratio 24hAUC/MIC Satisfactory Unsatisfactory ratio < 125 > 125 4 (50%) 71 (97%) 4 2

Hyatt et al, Clin Pharmacokinet 28: 143, 1995

Fluoroquinolone Pharmacodynamics vs S. pneumoniae 24h-AUC/MIC ratio < 33.7 > 33.7 Microbiological Response (64%) (100%)

Ambrose et al, Antimicrob Agents Chemo 10: 2793, 2001

Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552

PK/PD Approach to Antibiotic Therapy Review

Page 5 of 6

Craig et al, Ped Infect Dis 15: 255, 1996

Conclusion PK dosing has shown us that one dose is not appropriate for all patients. Pharmacodynamics shows us that one target level is not appropriate for all patients. We need to evalaute both the serum level data and the MIC, taking into consideration the PD properties of the drug. Numerous outcome studies have shown that class-appropriate PK/PD parameters are excellent predictors of antibiotic efficacy. References 1. Rodvold KA. Pharmacodynamics of antiinfective therapy: taking what we know to the patient's bedside. Pharmacotherapy. 2001 Nov;21(11 Pt 2):319S-330S. [ PubMed ] 2. Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JC. What do we really know about antibiotic pharmacodynamics? Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S. [ PubMed ] 3. Nicolau DP. Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling. J Infect Chemother. 2003 Dec;9(4):292-6. [ PubMed ] 4. Craig Wm. The Role of Pharmacodynamics in Effective Treatment of Community Acquired Pathogens. Advanced Studies in Medicine 2002;2(4):126-134. 5. Li RC, Zhu ZY. The integration of four major determinants of antibiotic action: bactericidal activity, postantibiotic effect, susceptibility, and pharmacokinetics. J Chemother. 2002 Dec;14(6):579-83. [ PubMed ] 6. Frimodt-Moller N. How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents. 2002 Apr;19(4):333-9. [ PubMed ]

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552

PK/PD Approach to Antibiotic Therapy Review

Page 6 of 6

7. Schentag JJ. Pharmacokinetic and pharmacodynamic surrogate markers: studies with fluoroquinolones in patients. Am J Health Syst Pharm. 1999 Nov 15;56(22 Suppl 3):S21-4. [ PubMed ] 8. Wright DH, Brown GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother. 2000 Nov;46(5):669-83. [ PubMed ] 9. Van Bambeke F, Tulkens PM. Macrolides: pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 2001;18 Suppl 1:S17-23. [ PubMed ] 10. Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis. 1998 Jul;27 (1):10-22. [ PubMed ] 11. Ambrose PG, et al. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001 Oct;45(10):2793-7. [ PubMed ] 12. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis. 1984 Mar;149 (3):443-8. [ PubMed ] 13. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987 Jan;155(1):93-9. [ PubMed ] 14. Hyatt JM, McKinnon PS, Zimmer GS, Schentag JJ. The importance of pharmacokinetic pharmacodynamic surrogate markers to outcome. Clin Pharmacokinet. 1995 Feb;28(2):143-60. [ PubMed ]

www.rxkinetics.com Copyright 1984 - 2009, All rights reserved. RxKinetics, Plattsburg, MO 64477

http://www.rxkinetics.com/antibiotic_pk_pd.html

29/05/2552