Carbapenems

1. Introduction

• Carbapenems are β-lactam antibiotics with the broadest antibacterial spectrum among β-lactams

• Structurally related to penicillins but with a carbon atom substituted for sulfur in the thiazolidine ring

• Highly resistant to most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC enzymes

• Often reserved for serious or multidrug-resistant (MDR) bacterial infections

• Examples include imipenem, meropenem, ertapenem, doripenem

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2. Mechanism of Action

• Inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs)

• Blocks the final transpeptidation step in peptidoglycan cross-linking → cell wall weakening → bacterial lysis and death

• Exhibits time-dependent bactericidal activity

• Stable against hydrolysis by most β-lactamases but can be inactivated by carbapenemases

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3. Antibacterial Spectrum

Gram-positive

• Streptococcus species

• Methicillin-susceptible Staphylococcus aureus (MSSA)

• Enterococcus faecalis (variable activity, strongest with imipenem)

Gram-negative

• Enterobacterales (including ESBL producers)

• Pseudomonas aeruginosa (except ertapenem)

• Acinetobacter baumannii (variable activity; ertapenem generally ineffective)

Anaerobes

• Excellent activity against most clinically significant anaerobes, including Bacteroides fragilis

Ineffective against

• Methicillin-resistant Staphylococcus aureus (MRSA)

• Enterococcus faecium

• Stenotrophomonas maltophilia

• Most carbapenemase-producing organisms

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4. Common Agents and Features

• Imipenem

  • Co-administered with cilastatin (inhibits renal dehydropeptidase-I to prevent inactivation)

  • Broadest Gram-positive activity among carbapenems

  • Higher risk of seizures compared to others

• Meropenem

  • Lower seizure risk than imipenem

  • Preferred in CNS infections due to better CSF penetration

  • Strong Gram-negative and anaerobic coverage

• Ertapenem

  • Once-daily dosing (longer half-life)

  • Lacks activity against Pseudomonas and Acinetobacter

  • Often used in community-acquired complicated infections

• Doripenem

  • Similar to meropenem but with potent Pseudomonas activity

  • Restricted in some regions due to concerns about safety in pneumonia trials

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5. Pharmacokinetics

• Administration: Intravenous; ertapenem also has intramuscular option

• Distribution: Widely distributed into most body tissues and fluids; good CSF penetration (meropenem, imipenem)

• Metabolism:

  • Imipenem hydrolyzed by renal dehydropeptidase-I (cilastatin co-administration needed)

  • Others not significantly metabolized

• Excretion: Primarily renal; dose adjustment required in renal impairment

• Half-life: Short (1–2 hours) except ertapenem (~4 hours)

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6. Clinical Indications

FDA/EMA-approved

• Complicated intra-abdominal infections (cIAI)

• Complicated urinary tract infections (cUTI), including pyelonephritis

• Community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP)

• Complicated skin and skin structure infections (cSSSI)

• Bacterial meningitis (meropenem)

• Sepsis due to susceptible organisms

Off-label

• Febrile neutropenia in immunocompromised patients

• Empirical therapy for suspected MDR Gram-negative infections in critically ill patients

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7. Contraindications

• Hypersensitivity to carbapenems, other β-lactams (possible cross-reactivity)

• History of severe anaphylaxis to penicillins or cephalosporins

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8. Adverse Effects

Common

• Nausea, vomiting, diarrhea

• Rash, pruritus

• Injection-site reactions

Serious

• Hypersensitivity reactions (anaphylaxis, angioedema)

• Seizures (more frequent with imipenem in high doses or renal impairment)

• Clostridioides difficile-associated diarrhea

• Hepatic enzyme elevations

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9. Drug Interactions

• Valproic acid: carbapenems can reduce serum levels significantly, leading to loss of seizure control

• Probenecid: may increase carbapenem concentrations by reducing renal clearance

• Ganciclovir: co-administration with imipenem increases seizure risk

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10. Resistance Mechanisms

• Carbapenemase production (e.g., KPC, NDM, VIM, OXA-type enzymes)

• Alterations in PBPs

• Efflux pump overexpression

• Porin loss combined with β-lactamase production

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11. Special Precautions

• Use reserved for confirmed or strongly suspected infections due to MDR pathogens to reduce resistance development

• Monitor renal function during therapy

• Adjust dose in elderly patients with impaired kidney function

• Avoid unnecessary prolonged therapy

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12. Advantages and Limitations

Advantages

• Broadest β-lactam spectrum

• Potent activity against ESBL-producing Enterobacterales

• Reliable anaerobic coverage

• Generally well tolerated

Limitations

• Ineffective against MRSA and most carbapenemase producers

• Risk of seizures (especially imipenem)

• Intravenous administration limits outpatient convenience

• Potential for rapid resistance development if overused