Journal of Antimicrobial Chemotherapy (2001) 47, 500-501
© 2001 The British Society for Antimicrobial Chemotherapy
Correspondence |
Use of the t > MIC to choose between different dosing regimens of ß-lactam antibiotics
a Department of Medical Microbiology, Canisius Wilhelmina Hospital, Nijmegen; b Medimatics, Maastricht, The Netherlands
Sir,
The major pharmacodynamic index correlating with in vitro and in vivo efficacy has been shown to be the time the concentration of an antibiotic remains above the MIC, or in short, the t > MIC.1 This relationship has been shown both in in vitro pharmacokinetic models and numerous animal experiments, and the analysis of clinical trials in humans seems to confirm this.2 This relationship between t > MIC and efficacy is beginning to be used to define or compare dosage regimens in humans. However, there are three major problems with this approach. The first is that, although there is a good relationship between t > MIC and effect, there is no universal agreement on the duration of this time. Should it be 40%, 70% or 100% of a dosing interval? The second problem is the MIC itself. If various dosage regimens of one drug, or even different drugs, are compared with each other with respect to the t > MIC, at which concentration should this be done? Finally, the issue on which we will focus in more detail is the calculation of the t > MIC for different dosage regimens. If a proper comparison is to be made between different regimens, the t > MIC should be calculated. In some recent papers, this approach has been used to compare dosage regimens of the same drug,3,4 or of different drugs.3,5 However, the disadvantage in these publications is that comparisons are made at one concentration only, or at two at the most, which does not furnish a full view of the subject.
A more proper approach, we propose, would be to compare the t > MIC for the various dosing regimens over the whole range of MICs. This would establish a general pic-ture, and enable anyone to draw their own conclusions regarding the comparability of different dosing regimens. Differences and absolute values of t > MIC would be readily visible. An example is shown in the Figure
for various dosing regimens of co-amoxiclav. Recently, a new formulation was introduced, containing 875 mg amoxycillin instead of 500 mg. One of the advantages of this would be that doses of the drug could be administered less frequently. Various claims have been made of equal or almost equal t > MICs at various concentrations (MICs),6 but an overall picture is generally unavailable.
|
), 500 mg q8h; (
), 875 mg q8h; (
), 875 mg q12h.The major disadvantage of this approach, and perhaps one of the reasons that an illustration such as that shown in the Figure
has not been used widely, is that computation of the t > MIC is difficult as soon as calculations involve more than one constant, as is the case in two-compartment models (one for distribution and one for elimination), or drugs given orally (one for absorption and one for elimination). The absorption case is complicated further by two components of the concentration–time curve, one ascending and one descending. These derivations are explicit, which implies that either the various dosing regimens have to be simulated and the t > MIC calculated by hand from the resulting concentration–time relationship, which is a tedious undertaking, or that the use of a numerical approach to solve the equations is necessary. To obtain the t > MIC relationships shown in the Figure, we used an Excel program that was developed for this specific purpose and readily shows the t > MIC–MIC relationship for various dosing regimens. We conclude that to compare various dosing regimens of one or more drugs, a figure showing the t > MIC–MIC relationship would be most helpful, and that the tools to reveal such relationships are now readily available.
Notes
J Antimicrob Chemother 2001; 47: 500–501
* Correspondence address. Streeklaboratorium Medische Microbiologie, Canisius Wilhelmina Ziekenhuis Nijmegen, Weg door Jonkerbos 100, 6532 sz Nijmegen, The Netherlands. Tel: +31-24-3657514; Fax: +31-24-3657516; E-mail: Mouton{at}cwz.nl 
References
1 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26, 1–10.[Web of Science][Medline]
2
.
Andes, D. & Craig, W. A. (1998). In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrobial Agents and Chemotherapy 42, 2375–9.
3 . Drusano, G. L. & Craig, W. A. (1997). Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. Journal of Chemotherapy 9, Suppl. 3, 38–44.
4
.
Woodnutt, G. & Berry, V. (1999). Two pharmacodynamic models for assessing the efficacy of amoxicillin–clavulanate against experimental respiratory tract infections caused by strains of Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 43, 29–34.
5 . Mouton, J. W., Touw, D. J., Horrevorts, A. M. & Vinks, A. A. T. M.M. (2000). Comparative pharmacokinetics of carbapenems: clinical implications. Clinical Pharmacokinetics 39, 185–201.[Web of Science][Medline]
6 . Lode, H. (1999). Amoxicillin/clavulanic acid (875/125 mg). New pharmacodynamic aspects. Deutsches Medizes Wochenschrift 124, 1459–61.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. De Jongh, R. Hens, V. Basma, J. W. Mouton, P. M. Tulkens, and S. Carryn Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection J. Antimicrob. Chemother., February 1, 2008; 61(2): 382 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Pankuch and P. C. Appelbaum Postantibiotic Effect of Ceftobiprole against 12 Gram-Positive Organisms Antimicrob. Agents Chemother., November 1, 2006; 50(11): 3956 - 3958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmitt-Hoffmann, B. Roos, M. Schleimer, J. Sauer, A. Man, N. Nashed, T. Brown, A. Perez, E. Weidekamm, and P. Kovacs Single-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2570 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmitt-Hoffmann, L. Nyman, B. Roos, M. Schleimer, J. Sauer, N. Nashed, T. Brown, A. Man, and E. Weidekamm Multiple-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2576 - 2580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, and N. C. Punt Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141 Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1713 - 1718. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||