Introduction

Meropenem was introduced into clinical use worldwide during the 1990s as a parenteral carbapenem. Physically, it is a white or light-yellow crystalline powder (Figure 1) and is available in the trihydrate form with the molecular formula of C₁₇H₂₅N₃O₅S?3H₂O and associated molecular weight of 437.52 g/mol. Meropenem is slightly soluble (5.63mg/mL) in water (unbuffered) with a logP (partition coefficient) value of -0.6 [1].

Meropenem is a beta-lactam antibiotic of the carbapenem class with a broad-spectrum of action and low toxicity. This antimicrobial provides coverage against several microorganisms, being useful and widely prescribed for the treatment of severe and nosocomial infections in hospitalized patients. Meropenem, such as some other traditional antimicrobial agents, is a time-dependent drug and has a bactericidal action that inhibits bacterial cell wall synthesis. For time-dependent drugs, the main parameter associated with therapeutic success is the percentage of time that the levels of antibiotics at the infection site exceed the minimum inhibitory concentration (%fT>MIC) of the pathogen. Thus, the longer blood concentrations remain above MIC, the higher are the chances of increasing clinical therapy success.[2]

Pharmacodynamics and pharmacokinetics profile

Meropenem has broad-spectrum activity and is active against both Gram-positive and Gram-negative bacteria. Its mechanism of action (MOA) prevents bacterial cell wall synthesis by binding and inactivating penicillin-binding proteins. Meropenem enters bacterial cells through outer membrane porin (OMPs). Its bactericidal activity is time dependent; therefore, when the free drug concentrations are above the minimum inhibitory concentration (MIC) during the dosing interval (t>MIC), unsurprisingly, the drug inhibitory effects are more effective. Meropenem is administered through the i.v. route as a 15-30-mininfusion at a dose of 1-2 g (adult dose), three-times daily for 14 days. Meropenem penetrates most body fluids and tissues rapidly and is mainly cleared from the body through the kidneys; thus, dosage adjustment is generally required for patients with impaired renal function. Meropenem is resistant to various hydrolyzing β-lactamases, such as penicillinases and cephalosporinases, owing to its 6-transhydroxyethyl group. In addition, meropenem has intrinsic stability against human renal dehydropeptidase-I (DHP-I), which,interestingly, extensively inactivates imipenem and panipenem,two of the other commonly used carbapenem antibiotics. Also, meropenem has varying PK profiles among different populationgroups [e.g., children with severe infection (4.5-11.8 years),patients with sepsis undergoing continuous renal replacement therapy (CRRT; 68.5±12.3 years), polytraumatized patients undergoing CRRT (33.4±9.8 years), and morbidly obese patients (55.4±10.1 years)]. Therapeutic drug monitoring (TDM) can be used for dosage optimization to overcome interpatient PK variability, enhancing therapeutic effects while decreasing drug toxicity.[1]

Safety profile

Meropenem is a safe and well-tolerated antibiotic and has been commercially available for >25 years. Researchers demonstrated that meropenem, compared with other antibiotics including those from the carbapenem family, has a comparable or better therapeutic effect and safety profile. Martin-Canal et al. Showed that meropenem had higher efficacious for the treatment of neurological infections compared with imipenem (81.8 and 96.0% in the imipenem and meropenem groups, respectively). Harada et al. demonstrated that meropenem could be an appropriate choice for the successful treatment of severe pneumonia caused by ESBL-Kpn. Liu et al.evaluated the efficacy and safety of meropenem and compared it with doripenem in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). The results demonstrated that a higher Sequential Organ Failure Assessment (SOFA) score was observed in the doripenem group compared with the meropenem group. Thus, the data presented reinforce the favorable safety profile of meropenem. The incidence and pattern of adverse events occurring with meropenem were similar to those of the first carbapenem, imipenem/cilastatin,and to those of cephalosporin. The most common adverse events reported for meropenem were diarrhea, nausea/vomiting, and hypersensitivity reactions. Sameed et al. reported that meropenem could cause Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients with type IV penicillin hypersensitivity. Meropenem can cause seizures and other central nervous system disorders, such as focal tremors and myoclonus. In addition, strict adherence to the prescribed dose is required, particularly for patients with known factors, such as a history of seizures, brain lesions, and bacterial meningitis, that make them susceptible to convulsive activity.[1]

References

[1]Raza A, Ngieng SC, Sime FB, et al. Oral meropenem for superbugs: challenges and opportunities. Drug Discov Today. 2021;26(2):551-560. doi:10.1016/j.drudis.2020.11.004

[2]Steffens NA, Zimmermann ES, Nichelle SM, Brucker N. Meropenem use and therapeutic drug monitoring in clinical practice: a literature review. J Clin Pharm Ther. 2021;46(3):610-621. doi:10.1111/jcpt.13369