Applying Pharmacokinetic and Pharmacodynamic Principles to Meropenem
Abstract & Commentary
Synopsis: Comparison of 2 meropenem dosing regimens, 500 mg q 6 h and 1000 mg q 8h, found that the resultant pharmacokinetics and pharmacodynamics were equivalent.Source: Kuti JL, et al. Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts. Am J Health Syst Pharm. 2003;60:565-568.
Meropenem (Merrem) was approved in 1996 for the treatment of a variety of infections. It has both Gram-positive and Gram-negative activity including against Pseudomonas aeruginosa. Similar to other b-lactam antibiotics, meropenem displays time-dependent or concentration-independent killing. The optimal dosing strategy is therefore to maximize the duration above the MIC for susceptible organisms. For meropenem, bacteriostatic effects were observed when drug concentrations remained above the MIC for at least approximately 30% of the dosing interval.
Given this information, Kuti and associates postulated that meropenem dosing of 500 mg every 6 hours may achieve similar pharmacokinetic and pharmacodynamic results when compared to meropenem dosing of 1000 mg every 8 hours. To confirm this, Monte Carlo simulation1 was performed. This is an acceptable method of obtaining dosing comparison data by taking into account patient variability and using published pharmacokinetic data.
To ensure that the above analysis would apply to all susceptible organisms, Kuti et al chose to study Staphylococcus aureus, which has an MIC of 4 mcg/mL. This would represent the "worst-case" scenario. The results of the analysis showed that meropenem dosing of 500 mg every 6 hours achieved a percent time above the MIC of 44, while meropenem dosing of 1000 mg every 8 hours achieved a value of 46. Additionally, meropenem dosing of 1000 mg every 6 hours achieved a percent time above the MIC of 61, while meropenem dosing of 2000 mg every 8 hours achieved a value of 58. From these data Kuti et al concluded that the compared regimens were essentially equivalent and made the appropriate recommendation at Hartford Hospital to use the more frequent dosing scenarios. In the case of meropenem dosing of 500 mg every 6 hours vs 1000 mg every 8 hours, the former regimen was shown to save approximately $38.64 per day, due to less drug being administered. Kuti et al did take into account the additional supply costs associated with 4 vs 3 doses daily.
Comment by Thomas G. Schleis, MS, RPh
The application of pharmacokinetic and pharmacodynamic principles has changed the way in which we now administer many different antibiotics. The observation that aminoglycosides exhibit concentration-dependent killing, as well as have a post-antibiotic effect against many organisms, has resulted in a change from dosing 3 times daily to once daily. This change has resulted in a therapy that is safer and more cost effective, convenient, and efficacious.
Another interesting example is vancomycin. With vancomycin, a number of pharmacokinetic and pharmacodynamic principles need to be considered. Vancomycin exhibits time-dependent killing and theoretically would be best administered as a continuous infusion. Although there have been some studies using continuous infusion, the findings have been equivocal.3-6 In fact, the long half-life of vancomycin, especially in the elderly or patients with renal impairment, becomes the predominant pharmacokinetic principle. This allows for once- or twice-daily dosing. Even with such infrequent dosing, it appears that concentrations above the MIC of susceptible organisms are maintained for most of the dosing interval.2
The beta-lactam antibiotics exhibit time-dependent killing, and it has been suggested that they are best administered as a continuous infusion instead of the more traditional 4-6 doses daily. In some instances, the total daily dose of antibiotic can also be lowered while achieving the same, or even superior, efficacy.2 While meropenem would fit in this category, continuous infusion is not practical given its short stability time once mixed.
Taking into account these dramatic changes in dosing strategies that have occurred by applying pharmacokinetic and pharmacodynamic principles, it is not a great leap of faith to accept the argument presented in this article. The only question is whether the savings are sufficient to offset the additional burden of extra doses of drug being administered. This was not figured into the cost comparison, as it was felt to be a fixed staffing cost while not representing a significant additional burden.
In the outpatient setting the reverse would be true. The proposed change to 4 doses daily could actually result in less reimbursement for the provider and greater inconvenience to the patient. This is a case where the priorities regarding drugs administered in the hospital setting may not apply when considering outpatient administration.
Finally, on a theoretical note, there may be an instance where the preferred dosing strategy of meropenem would be the higher doses given less frequently. Since the bacteriocidal concentrations of meropenem are typically 1-2 times the bacteriostatic concentrations, there could be a situation where a higher dose would achieve bacteriocidal levels and a lower dose would not, but this would certainly be difficult to determine under normal clinical situations.
Editor's Note: Administration of meropenem infusions over 3 hours also improves the likelihood of maintenance of drug levels above the MIC of susceptible pathogens for at least 40-50% of the dosing interval. (2002 ICAAC Abstract A-1388).
1. Thompson KM, et al. Monte Carlo techniques for quantitation uncertainty analysis in public health risk assessments. Risk Anal. 1992;12:53-63.
2. Estes L. Review of pharmacokinetics and pharmacodynamics of antimicrobial agents. Mayo Clin Proc. 1998; 73:1114-1122.
3. Wysocki M, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: Prospective multicenter randomized study. Antimicrob Agents Chemother. 2001;45:2460-2467.
4. Klepser ME, et al. Comparison of bactericidal activities of intermittent and continuous infusion dosing of vancomycin against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. Pharmacotherapy. 1998;18:1069-1074.
5. Di Filippo A, et al. Continuous infusion of vancomycin in methicillin-resistant staphylococcus infection. Chemotherapy. 1998;44:63-68.
6. Pawlotsky F, et al. Constant rate infusion of vancomycin in premature neonates: A new dosage schedule. Br J Clin Pharmacol. 1998;46:163-167.
Dr. Schleis is Director of Pharmacy Services Infectious Limited Tacoma, WA Section Editor, Pharmacology.