The disposition and metabolism of meropenem in laboratory animals and man

Meropenem is a new carbapenem antibiotic which possesses a broad spectrum of antibacterial activity against many of the pathogens responsible for pediatric bacterial infections. In order to define meropenem dosing guidelines for children, an escalating, single-dose, pharmacokinetic study at 10, 20, and 40 mg/kg of body weight was performed. A total of 73 infants and children in four age groups were enrolled in the study: 2 to 5 months, 6 to 23 months, 2 to 5 years, and 6 to 12 years. The first patients enrolled were those in the oldest age group, who received the lowest dose. Subsequent enrollment was determined by decreasing age and increasing dose. Complete studies were performed on 63 patients. No age-or dose-dependent effects on pharmacokinetic parameter estimates were noted. Mean pharmacokinetic parameter estimates were as follows: half-life, 1.13 ؎ 0.15 h; volume of distribution at steady state, 0.43 ؎ 0.06 liters/kg; mean residence time, 1.57 ؎ 0.11 h; clearance, 5.63 ؎ 0.75 ml/min/kg; and renal clearance, 2.53 ؎ 0.50 ml/min/liters kg. Approximately 55% of the administered dose was recovered as unchanged drug in the urine during the 12 h after dosing. No significant side effects were reported in any patients. By using the derived pharmacokinetic parameter estimates, a dose of 20 mg/kg given every 8 h will maintain plasma meropenem concentrations above the MIC that inhibits 90% of strains tested for virtually all potentially susceptible bacterial pathogens.

Section: Methodsmentioning

confidence: 99%

Sequential, single-dose pharmacokinetic evaluation of meropenem in hospitalized infants and children

Blumer

Reed

Kearns

et al. 1995

“…Studies with rats have shown that DHP-I activity in the brain is negligible (33), approximately 6.4-and 3,000-fold less than in the muscle and the lungs, respectively (17). Since the fraction of cilastatin (16 to 66%) that reaches the cerebrospinal fluid (CSF) is about 3-fold that of meropenem (6 to 20%) in mammals with inflamed meninges (34)(35)(36)(37)(38), the site of infection in this model would have increased M:C ratios with respect to the actual proportions injected subcutaneously. It provides greater protection of meropenem without further increasing the dose of cilastatin and, therefore, is a more sensible model to determine therapeutic equivalence with the mouse.…”

Section: Neutropenic Guinea Pig Soleus Infection Model (Sepsis By Thementioning

confidence: 99%

Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Agudelo

Rodríguez

Peláez

et al. 2014

e Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.

“…The drawback of MEM-CLA is that it requires intravenous access. The advantages are tolerable side effects (31), low plasma protein binding (32), and good lung penetration (33).…”

mentioning

confidence: 99%

Meropenem-Clavulanic Acid Has High In Vitro Activity against Multidrug-Resistant Mycobacterium tuberculosis

Forsman

Giske

Bruchfeld

et al. 2015

We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi-and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/ liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB. Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is unrelentingly increasing worldwide. As MDR/XDR-TB is notoriously difficult to treat, already approved drugs, such as trimethoprim-sulfamethoxazole, are being investigated as treatment options (1). The activity of penicillin against Mycobacterium tuberculosis was investigated in the 1940s (2), but ␤-lactams were deemed ineffective. However, it was later shown that the ␤-lactamase BlaC causes the hydrolysis of ␤-lactam antibiotics (3-6). This hydrolysis can be inhibited by the ␤-lactamase inhibitor clavulanic acid (CLA), which irreversibly inactivates BlaC (6, 7). Meropenem (MEM) is a ␤-lactam antibiotic of the carbapenem group. Even though MEM is a relatively poor substrate for BlaC (8), MEM on its own shows conflicting evidence regarding antituberculous activity (9-12). Hence, the combination meropenem-clavulanic acid (MEM-CLA) is an interesting treatment alternative for drug-resistant TB, but there is a lack of in vitro and in vivo studies for this combination. The aim of this study was to investigate the in vitro effect of MEM-CLA against M. tuberculosis, predominantly MDR/XDR-TB isolates.Using Middlebrook 7H10, 94 M. tuberculosis isolates were studied. The isolates consisted of clinical isolates and isolates submitted to the Public Health Agency of Sweden for proficiency drug susceptibility testing, with all isolates being globally sourced. A total of 68 isolates showed sufficient growth to be studied further, and they were categorized into three resistance groups consisting of 36 MDR-TB, 13 XDR-TB, and 19 with mixed resistance patterns (non-MDR/XDR-TB). Strain H37Rv (ATCC 27294) was used as the control. Middlebrook 7H10 agar (Becton Dickinson AB, Stockholm, Sweden) enriched with 10% oleic acid-albumindextrose-catalase (OADC) and 5% glycerol was prepared in 14-cm petri dishes, each dish containing 60 ml of agar. A stock solution was prepared by diluting MEM with water, and then applied in serial two-step dilutions, reaching a final antibiotic concentration range of 0.002 to 512 mg/liter of MEM. CLA was added to all dishes at a concentration of 64 mg/liter in order to ensure a sufficient concentration of the ␤-lactamase inhibitor throughout the whole experiment. Due to the short half-life of CLA in solid media (1.4 days) (13), the concentration of CLA after the first week of our experiment was expected to be around 2 mg/liter, similar to the concentration of CLA seen in seru...