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.

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 Post-Antibiotic 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 Antibiotics Goal of Therapy PK/PD

Parameter

Type IConcentration-dependent killing andProlonged persistent effects

AminoglycosidesDaptomycinFluoroquinolonesKetolides

Maximize concentrations 24h-AUC/MICPeak/MIC

Type IITime-dependent killing and Minimal persistent effects

CarbapenemsCephalosporinsErythromycinLinezolidPenicillins

Maximize duration of exposure

T>MIC

Type IIITime-dependent killing andModerate to prolonged persistent effects.

AzithromycinClindamycinOxazolidinonesTetracyclinesVancomycin

Maximize amount of drug 24h-AUC/MIC

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 dalfopristin-quinupristin 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

< 5mcg/ml 21% 79%

>= 5mcg/ml 2% 98%

Moore et al, J Infect Dis 149: 443, 1984

Aminoglycoside Pharmacodynamics in vivo

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

Vancomycin Outcome vs 24h-AUC/MIC ratio

24h-AUC/MIC ratio

Satisfactory Unsatisfactory

< 125 4 (50%) 4

> 125 71 (97%) 2

Hyatt et al, Clin Pharmacokinet 28: 143, 1995

Fluoroquinolone Pharmacodynamics vs S. pneumoniae

24h-AUC/MIC ratio

Microbiological Response

< 33.7 (64%)

> 33.7 (100%)

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

Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media

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 ]

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 ]

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Table 1. Antibiotic Pharmacodynamic Categories[2]

Time-Dependent (with minimal or no PAE)

Concentration-Dependent (with PAE)

Time-Dependent, Concentration-Enhanced (with

PAE)

Beta-lactamsVancomycin

AminoglycosidesDaptomycinFluoroquinolonesMetronidazoleAzithromycinKetolides

ClarithromycinClindamycinErythromycinLinezolidStreptograminsTetracyclinesTigecycline

Which Antibiotics Are Time- or Concentration-Dependent?

Laura S. Lehman, PharmD

Authors and Disclosures

Posted: 10/24/2007

Question

Could you provide a list of antibiotics that are time-dependent and concentration-dependent, including the new agent tigecycline? Can tigecycline be administered once daily instead of every 12 hours?

Response From the Expert

 

Laura S. Lehman, PharmD Clinical Coordinator, Pharmacy, Carroll Hospital Center, Westminster, Maryland

The pharmacology of antibiotics involves both pharmacokinetic and pharmacodynamic (PD) properties. Pharmacokinetics pertains to drug concentration and time in the host, while pharmacodynamics describes the concentration- and time-dependent interactions of antibiotics against pathogens in the host.[1] We typically think of 2 major PD categories of antibiotics: those with time-dependent bactericidal effect and those with concentration-dependent bactericidal effect. However, a third category has also been described, consisting of antibiotics with both time-dependent and concentration-dependent effects ( Table ).[2]

The time-dependent antibiotics exert optimal bactericidal effect when drug concentrations are maintained above the minimum inhibitory concentration (MIC). Typically, concentrations are maintained at 2 to 4 times the MIC throughout the dosing interval.[1] For these agents, higher concentrations do not result in greater kill of organisms. Furthermore, they tend to have minimal to no postantibiotic effect (PAE).[2]

Concentration-dependent antibiotics achieve increasing bacterial kill with increasing levels of drug. In addition, these agents have an associated concentration-dependent PAE in which bactericidal action continues for a period of time after the antibiotic level falls below the MIC. The peak concentration and area under the concentration curve (AUC) determine efficacy of these antibiotics.[2] For this group of drugs, concentrations of at least 10 times the MIC are needed for optimal bactericidal effect.[3]

The third PD category consists mainly of bacteriostatic antibiotics that have prolonged PAEs. Some of these agents have been classified elsewhere as time-dependent;[1,3] however,

because of the presence of PAE, they also have concentration-dependent features. Efficacy of this group is determined by the 24-hour AUC to MIC ratio (AUC/MIC).[2]

Tigecycline (Tygacil) is a derivative of minocycline, and it is the first glycylcycline antibiotic. There are currently 2 approved indications, for complicated skin and soft tissue infections, and for complicated intra-abdominal infections. An off-label use of tigecycline is the treatment of bronchial secretions in pneumonia.

Tigecycline has a reported mean terminal half-life of 37 to 38 hours.[4] Its PD properties have not yet been fully elucidated, but it appears to have both time- and concentration-dependent characteristics. Its PAE in vivo has been reported as 8.9 hours for Staphylococcus pneumoniae and 4.9 hours for Escherichia coli. [5] Intuitively, on the basis of its long half-life and prolonged PAE, it seems reasonable to question whether tigecycline could be given less often than twice daily. However, according to the manufacturer, a study of the drug's serum and intrapulmonary PD effects in 30 healthy subjects supported a twice-daily regimen for the organisms studied (written communication, Wyeth Pharmaceuticals; August 6, 2007). A literature search revealed no published studies of daily dosing of tigecycline. Daily dosing cannot be recommended at this time.

http://www.medscape.com/viewarticle/563444 junio 26 2011 9 pm