Meropenem - Drug Monograph

Introduction

Meropenem is a broad-spectrum carbapenem antibiotic belonging to the beta-lactam class of antimicrobial agents. It was developed to address the growing need for effective antibiotics against multidrug-resistant Gram-negative organisms while maintaining activity against many Gram-positive and anaerobic pathogens. Meropenem represents a cornerstone therapy for serious infections in hospitalized patients, particularly in critical care settings.

Mechanism of Action

Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis. Like other beta-lactam antibiotics, it binds to penicillin-binding proteins (PBPs) located in the bacterial cell wall, particularly PBP2 in Escherichia coli and PBP1A in Pseudomonas aeruginosa. This binding disrupts the final transpeptidation step of peptidoglycan synthesis, leading to cell lysis and death. Meropenem demonstrates stability against many beta-lactamases, including extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes, though it remains susceptible to hydrolysis by metallo-beta-lactamases (MBLs) such as NDM-1 and VIM.

Indications

Meropenem is FDA-approved for:

• Complicated skin and skin structure infections
• Complicated intra-abdominal infections
• Bacterial meningitis in pediatric patients ≥3 months of age
• Complicated urinary tract infections

Additionally, it is commonly used off-label for:

• Febrile neutropenia in immunocompromised patients
• Hospital-acquired pneumonia and ventilator-associated pneumonia
• Sepsis of unknown origin
• Infections caused by multidrug-resistant Gram-negative organisms

Dosage and Administration

• Adults: 1 g IV every 8 hours (range: 500 mg to 2 g every 8 hours)
• Duration: Typically 7-14 days depending on infection type and severity

• Renal impairment:

- CrCl 26-50 mL/min: 1 g every 12 hours - CrCl 10-25 mL/min: 500 mg every 12 hours - CrCl <10 mL/min: 500 mg every 24 hours

• Hemodialysis: 500 mg every 24 hours (administer after dialysis)
• Elderly: Adjust based on renal function
• Pediatric patients:

- ≥3 months: 20 mg/kg every 8 hours (max 2 g every 8 hours) - Meningitis: 40 mg/kg every 8 hours (max 2 g every 8 hours)

• IV infusion over 15-30 minutes
• Compatible with 0.9% sodium chloride, 5% dextrose, and other common IV solutions
• Do not mix with other medications in the same IV line

Pharmacokinetics

• Absorption: Not orally bioavailable; administered intravenously only
• Distribution: Widely distributed into body tissues and fluids, including cerebrospinal fluid (CSF concentrations reach approximately 20% of plasma levels in inflamed meninges)
• Protein binding: Approximately 2%
• Metabolism: Minimally metabolized by hydrolysis of the beta-lactam ring
• Elimination: Primarily renal excretion (70-80% unchanged in urine)
• Half-life: Approximately 1 hour in patients with normal renal function
• Steady-state: Achieved within 24-48 hours with regular dosing

Contraindications

• Known hypersensitivity to meropenem, other carbapenems, or beta-lactam antibiotics
• History of anaphylactic reactions to beta-lactams
• Patients with meningitis who have demonstrated hypersensitivity to meropenem components

Warnings and Precautions

• Seizures: Has been associated with CNS adverse effects including seizures (0.5% incidence), particularly in patients with renal impairment, CNS disorders, or those receiving higher doses
• Clostridium difficile-associated diarrhea: May range from mild to life-threatening colitis
• Development of drug-resistant bacteria: Prolonged use may result in superinfection
• Interaction with valproic acid: Meropenem reduces valproic acid concentrations, potentially leading to seizure breakthrough
• Pregnancy: Category B - Use only if clearly needed
• Lactation: Excreted in human milk; caution advised when administering to nursing women

Drug Interactions

• Valproic acid/Valproate sodium: Meropenem significantly decreases valproic acid concentrations (50-90% reduction) via inhibition of glucuronidation and possible increased renal elimination
• Probenecid: Competes with meropenem for active tubular secretion, increasing meropenem concentrations (co-administration not recommended)
• Other nephrotoxic drugs: May enhance nephrotoxicity (aminoglycosides, vancomycin)
• Warfarin: Possible enhancement of anticoagulant effect (monitor INR closely)

Adverse Effects

• Diarrhea (4.8%)
• Rash (3.4%)
• Nausea/vomiting (3.1%)
• Injection site reactions (2.4%)
• Headache (2.3%)

• Seizures (0.5%)
• Pseudomembranous colitis
• Hypersensitivity reactions (anaphylaxis, Stevens-Johnson syndrome)
• Thrombocytopenia, eosinophilia
• Hepatitis, hepatic dysfunction
• Acute kidney injury

Monitoring Parameters

• Clinical response to therapy (fever, WBC count, infection markers)
• Renal function (serum creatinine, BUN) at baseline and periodically during treatment
• Liver function tests (ALT, AST, bilirubin)
• Complete blood count with differential
• Seizure activity in susceptible patients
• Signs of superinfection or C. difficile infection
• Prothrombin time/INR in patients on warfarin
• Valproic acid levels if co-administered (strongly discouraged)

Patient Education

• Complete the full course of therapy even if feeling better
• Report any signs of allergic reaction (rash, itching, swelling, difficulty breathing)
• Report severe diarrhea, especially if containing blood or mucus
• Inform all healthcare providers about meropenem use
• Report any unusual tingling, twitching, or seizure-like activity
• Notify provider if pregnant, planning pregnancy, or breastfeeding
• Understand that this medication is administered only in healthcare settings

References

1. FDA Prescribing Information: Merrem® IV (meropenem for injection) 2. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. 3. Lexicomp Online®. Meropenem monograph. Wolters Kluwer Clinical Drug Information. 4. Zhanel GG, et al. Carbapenems in the 21st century: resistance mechanisms and optimal use. Drugs. 2011;71(15):1955-1971. 5. Kuti JL, et al. Pharmacodynamic properties of meropenem against Pseudomonas aeruginosa in patients with nosocomial pneumonia. J Antimicrob Chemother. 2013;68(11):2572-2577. 6. Nicolau DP. Pharmacokinetic and pharmacodynamic properties of meropenem. Clin Infect Dis. 2008;47 Suppl 1:S32-40. 7. Papp-Wallace KM, et al. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011;55(11):4943-4960.