What is meropenem?

What is Meropenem?

Meropenem is a broad-spectrum carbapenem antibacterial agent administered intravenously for treating serious bacterial infections caused by susceptible gram-positive, gram-negative, and anaerobic organisms. 1

Chemical Structure and Formulation

Meropenem is a synthetic carbapenem with the chemical name (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. 1

A key structural advantage is the 1-beta-methyl group on the carbapenem moiety, which makes meropenem relatively stable to human dehydropeptidase-I (DHP-I), eliminating the need for coadministration with a DHP-I inhibitor like cilastatin (required with imipenem). 2, 3

Spectrum of Antimicrobial Activity

Gram-Negative Coverage

• Meropenem is particularly valuable for treating infections caused by gram-negative bacilli that produce extended-spectrum β-lactamases (ESBLs) or those that may hyperproduce lactamases (Enterobacter species, Citrobacter species, Serratia marcescens). 4
• Compared to imipenem, meropenem demonstrates superior activity against Enterobacteriaceae and Pseudomonas aeruginosa. 2, 3
• For infections caused by P. aeruginosa, higher doses (1 gram every 8 hours) are recommended. 1

Gram-Positive Coverage

• Meropenem has activity against gram-positive cocci, though it is slightly less active than imipenem against some gram-positive organisms. 2, 3
• Some highly penicillin- and cephalosporin-resistant pneumococci may have reduced susceptibility to meropenem. 5

Anaerobic Coverage

• Meropenem offers anti-anaerobic coverage, which is particularly relevant when treating intra-abdominal infections. 6
• When carbapenems are not used in polymicrobial infections, metronidazole should be added for anaerobic coverage. 6

FDA-Approved Indications

The FDA has approved meropenem for: 1

• Complicated skin and skin structure infections (cSSSI) in adults and pediatric patients ≥3 months
• Complicated intra-abdominal infections (cIAI) in adults and pediatric patients
• Bacterial meningitis in pediatric patients ≥3 months only

Pharmacokinetics

Distribution

• Plasma protein binding is approximately 2%, indicating predominantly extracellular distribution. 1, 7
• Volume of distribution is 21L. 7
• Meropenem achieves excellent tissue penetration in abdominal tissues, bile, cerebrospinal fluid (when inflamed), gynecologic tissues, respiratory tract tissues, and urinary tract tissues. 3

Elimination

• The elimination half-life is approximately 1 hour in patients with normal renal function. 1, 7
• Approximately 70% is excreted unchanged in urine within 12 hours. 1
• A further 28% is recovered as a microbiologically inactive metabolite (ICI 213689). 1, 7
• Fecal elimination represents only approximately 2% of the dose. 1

Dosing

Adult Dosing (Normal Renal Function)

• cSSSI: 500 mg IV every 8 hours (1 gram every 8 hours for P. aeruginosa infections) 1
• cIAI: 1 gram IV every 8 hours 1
• Administration: 15-30 minute infusion or 3-5 minute bolus injection 1

Renal Impairment

Dosage reduction is required in patients with reduced renal function, as the elimination half-life correlates well with creatinine clearance: 1, 7

• CrCl >50 mL/min: Standard dose every 8 hours
• CrCl 26-50 mL/min: Standard dose every 12 hours
• CrCl 10-25 mL/min: Half dose every 12 hours
• CrCl <10 mL/min: Half dose every 24 hours

Pediatric Dosing (≥3 Months, Normal Renal Function)

• cSSSI: 10 mg/kg (max 500 mg) every 8 hours; 20 mg/kg for P. aeruginosa 1
• cIAI: 20 mg/kg (max 1 gram) every 8 hours 1
• Meningitis: 40 mg/kg (max 2 grams) every 8 hours 1

Role in Carbapenem-Resistant Infections

Combination Therapy

• For carbapenem-resistant Enterobacterales (CRE), high-dose extended-infusion meropenem (6 g/day, 3-hour infusion) combined with polymyxin may be effective when meropenem MIC is ≤8-16 mg/L. 6
• The AIDA and OVERCOME trials showed no statistically significant mortality difference between colistin monotherapy versus colistin-meropenem combination for CRE infections, though trends favored combination therapy. 6

Meropenem-Vaborbactam

• For severe CRE infections (particularly KPC-producing organisms), meropenem-vaborbactam is recommended as it combines meropenem with a β-lactamase inhibitor active against class A (KPC) and class C β-lactamases. 6, 4
• The TANGO-II trial demonstrated superior clinical cure and reduced 28-day mortality (15.6% vs 33.3%) compared to best available therapy. 6

Safety Profile

Central Nervous System

• Meropenem has a low propensity for inducing seizures compared to imipenem, making it suitable for treating bacterial meningitis and the only carbapenem approved for this indication. 8, 2, 9
• Seizures and other adverse CNS experiences have been reported but are infrequent. 1

Other Adverse Effects

• Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. 1
• Severe cutaneous adverse reactions have been reported. 1
• The incidence of drug-related nausea and vomiting is low and does not increase with dose or speed of administration (unlike imipenem/cilastatin). 9

Clinical Efficacy

Meropenem monotherapy has demonstrated efficacy comparable to comparator regimens in multiple clinical trials: 8

• Similar efficacy to imipenem/cilastatin in cIAI, cSSSI, febrile neutropenia, and complicated UTI
• Superior efficacy to ceftazidime or piperacillin/tazobactam in febrile neutropenia 8
• Greater efficacy than ceftazidime plus aminoglycosides in nosocomial pneumonia 8, 9
• Similar efficacy to cefotaxime in bacterial meningitis 8

Carbapenem-Sparing Considerations

In settings with high carbapenem resistance rates, carbapenem-sparing strategies using beta-lactam/beta-lactamase inhibitor combinations (BL-BLICs) are desirable to reduce selection pressure for carbapenemase-producing strains. 6 However, meropenem remains essential for ESBL-producing organisms and severe infections where alternative agents are inadequate. 4