Alternative Dosing for Meropenem

Muna Said, PharmD   3 minutes




Evidence Behind Alternative Dosing of Meropenem

Inappropriate antibiotic use is a significant concern for healthcare systems worldwide, as it can lead to adverse patient outcomes, promote antibiotic resistance, and impose economic burdens. This issue underscores the importance of implementing strategies such as antimicrobial stewardship to optimize antibiotic use. However, beyond stewardship efforts, there is a cneed to refine dosing strategies to ensure effective treatment while minimizing risks associated with overuse and misuse. [1]

Meropenem, a broad-spectrum antibiotic belonging to the carbapenem class, is a prime example of a drug where dosing strategies are under scrutiny. Traditionally, meropenem has been administered intravenously (IV) at a dose of 1,000 mg every 8 hours (q8h). However, emerging evidence and pharmacokinetic-pharmacodynamic considerations have led to the exploration of alternative dosing regimens, such as administering 500 mg every 6 hours (q6h). The rationale behind these alternative dosing regimens lies in the pharmacokinetic and pharmacodynamic properties of meropenem. Unlike some antibiotics where efficacy correlates directly with plasma concentrations, meropenem's bactericidal activity is primarily dependent on the percentage of time that plasma concentrations remain above the minimum inhibitory concentration (MIC) of the target pathogen (%T > MIC). Consequently, adjusting the dosing regimen to maintain optimal %T > MIC could theoretically achieve comparable clinical outcomes while potentially reducing the risk of adverse effects and the development of resistance. [1]

While some observational and pharmacokinetic studies have provided insights into the equivalence of alternative dosing regimens in terms of pharmacodynamic endpoints, data comparing these regimens are still limited. One retrospective cohort study, conducted in 2009, examined 127 adult patients with neutropenic fever, comparing clinical outcomes among patients treated with alternatively-dosed meropenem 500mg q6h, traditionally-dosed meropenem 1g q8h, and imipenem-cilastatin 500mg q6h following failure or intolerance of cefepime for febrile neutropenia. [1,2]

The results showcased that the primary outcomes of time to defervescence (median 3 vs. 2 vs.3 days), need for additional antibiotics (20% vs. 17% vs. 14%), and time to receipt of additional antibiotics (median 5 vs. 2 vs. 1 days) were not significantly different among the imipenem-cilastatin, traditionally dosed meropenem, and alternatively dosed meropenem groups, respectively. In addition, significant differences in secondary outcomes, which were treatment duration (median 10 vs. 8 vs. 8 days), seizure rate (0% vs 0% vs 0%), in-hospital mortality (5% vs. 7% vs. 7%), and 30-day mortality (13% vs. 7% vs .14%), were not identified among the three groups, respectively. Additionally, no adverse effects on clinical outcomes were observed with the alternative dosage of meropenem, suggesting that alternatively-dosed meropenem was as effective and safe as traditional dosing strategies for febrile neutropenia. [2]

A 2008 prospective, open-label, steady-state pharmacokinetic investigation involving 20 hospitalized patients assessed the steady-state pharmacokinetics and pharmacodynamics of meropenem. These patients were divided into three groups based on estimated creatinine clearance levels and received meropenem 500 mg IV every 6, 8, or 12 hours. Notably, the findings revealed that in groups 1, 2, and 3, the mean maximum serum concentrations of meropenem were 29.2 ± 9.8, 33.2 ± 8.5, and 33.5 ± 4.7 mcg/ml, respectively, while the mean minimum serum concentrations were 2.4 ± 1.1, 3.8 ± 2.7, and 4.9 ± 1.6 mcg/ml. The half-life values were 2.5 ± 0.9, 3.4 ± 1.3, and 6.1 ± 1.4 hours, and the volume of distribution at steady state was 29.3 ± 8.7, 23.8 ± 8.1, and 28.7 ± 8.6 L for groups 1, 2, and 3, respectively. [3]

Across all groups, the cumulative fraction of response exceeded 90% for enteric pathogens and Pseudomonas aeruginosa, and ranged from 82.4% to 85.2% for Acinetobacter species. Pharmacodynamic analyses indicated that these dosing regimens, adjusted for renal function, were acceptable for treating infections caused by enteric gram-negative pathogens and P. aeruginosa. However, further considerations may be needed for Acinetobacter species. [3]

In a 2014 non-randomized pharmacokinetic study involving 9 morbidly obese patients hospitalized in an intensive care unit, meropenem dosing regimens were evaluated. Patients received either meropenem 500 mg q6h or 1 g q6h, infused over 0.5 hour. Pharmacokinetic parameters were estimated using compartmental methods, and Monte Carlo simulations were conducted for various dosing regimens (500 mg q8h, 1 g q8h, 2 g q8h, 500 mg q6h, 1 g q6h; infused over 0.5 and 3 hours). Results indicated that the pharmacokinetics of meropenem in morbidly obese patients were similar to those in other patient populations, except for volume of distribution at steady-state (Vss), which was larger in morbidly obese patients. Despite this difference, standard dosing regimens achieved adequate pharmacodynamic exposures for susceptible pathogens. No adverse events were reported; however, the study's limitations, including the small sample size and lack of data on the penetration of meropenem into specific infection sites, warrant caution in generalizing the findings to broader patient populations. [4]

Lastly, in a 2017 pharmacokinetic study involving 40 patients categorized as non-obese, obese, or morbidly obese, meropenem pharmacokinetics were evaluated. The findings indicated similar pharmacokinetics across all patient groups.  Dosing regimens, including 500 mg q12h, 500 mg q8h, 500 mg q6h, 1 g q8h, or 1 g q6h, achieved adequate pharmacodynamic exposures for susceptible pathogens at certain free drug concentration to MIC values, but higher ƒT>MIC values required prolonged infusions of larger doses. Due to these findings, the study concluded that dosage adjustments based solely on body weight are unnecessary. [5]

Overall, this evidence suggests that meropenem 500 mg q6h demonstrates comparable outcomes to the 1 g q8h regimen, although small sample sizes within studies may limit the power to detect significant differences. The efficacy of the alternative dosing regimen can be theoretically supported by meropenem's pharmacokinetic and pharmacodynamic profile. Additionally, the alternative regimen may offer cost savings in drug acquisition, as it entails a reduction in total daily dose compared to traditional dosing. considerations such as increased workload for pharmacy and nursing staff, as well as patient quality of life, must also be weighed against the potential cost savings. Moreover, due to the limited available data, further confirmation is required through larger prospective studies to corroborate the efficacy and safety of meropenem 500 mg administered every 6 hours as a viable therapeutic option. [1]

References:

  1. Wilby KJ, Nasr ZG, Elazzazy S, Lau TT, Hamad A. A Review of Clinical Outcomes Associated with Two Meropenem Dosing Strategies. Drugs R D. 2017;17(1):73-78. doi:10.1007/s40268-017-0173-0
  2. Arnold HM, McKinnon PS, Augustin KM, et al. Assessment of an alternative meropenem dosing strategy compared with imipenem-cilastatin or traditional meropenem dosing after cefepime failure or intolerance in adults with neutropenic fever. Pharmacotherapy. 2009;29(8):914-923. doi:10.1592/phco.29.8.914
  3. Cheatham SC, Kays MB, Smith DW, Wack MF, Sowinski KM. Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients. Pharmacotherapy. 2008;28(6):691-698. doi:10.1592/phco.28.6.691
  4. Cheatham SC, Fleming MR, Healy DP, et al. Steady-state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit. J Clin Pharmacol. 2014;54(3):324-330. doi:10.1002/jcph.196
  5. Chung EK, Cheatham SC, Fleming MR, Healy DP, Kays MB. Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients. J Clin Pharmacol. 2017;57(3):356-368. doi:10.1002/jcph.812

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