Merovex 500/Merovex 1000 Mechanism of Action

Pharmacological Classification: Antibacterials (Carbapenems).
Pharmacology: Pharmacodynamics: Mode of action: Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Pharmacokinetics: In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500 mg, 1 mg and 2 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1 g doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.
A study of 12 patients administered meropenem 1 g 8 hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 271.
Distribution: The average plasma protein binding of meropenem was approximately 2% and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.
Metabolism: Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.
Adult patients: Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age.
Toxicology: Preclinical safety data: Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2 g/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.
Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1 g/kg.
The IV LD₅₀ of meropenem in rodents is greater that 2 g/kg.
In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.