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Monday, August 11, 2025

Carbapenems / beta-lactamase inhibitors


1. Introduction

  • Carbapenems are a subgroup of β-lactam antibiotics with the broadest spectrum among β-lactams.

  • They inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs).

  • Highly resistant to most β-lactamases, but certain bacteria produce carbapenemases that can inactivate them.

  • Beta-lactamase inhibitors (BLIs) are co-administered with carbapenems to inhibit β-lactamase enzymes, restoring or enhancing activity against resistant pathogens.

  • The carbapenem/BLI combinations are specifically developed to address multidrug-resistant Gram-negative infections.

2. Mechanism of Action

Carbapenem component

  • Binds irreversibly to PBPs → inhibits final transpeptidation step in peptidoglycan synthesis → weakens bacterial cell wall → lysis and death.

  • Stable against most serine β-lactamases (class A and C) and metallo-β-lactamases (some exceptions).

BLI component

  • Inhibits serine β-lactamases (including extended-spectrum β-lactamases [ESBLs] and some carbapenemases).

  • Common BLIs used with carbapenems:

    • Vaborbactam – boronic acid-based, potent against class A carbapenemases (KPC).

    • Relebactam – diazabicyclooctane (DBO) inhibitor active against class A and C β-lactamases.

    • Avibactam – DBO inhibitor active against class A, C, and some class D β-lactamases.

3. Common Carbapenem / Beta-Lactamase Inhibitor Combinations

  • Meropenem / Vaborbactam

    • Indication: Complicated urinary tract infections (cUTI), including pyelonephritis, caused by KPC-producing Enterobacterales.

    • Vaborbactam restores activity against KPC carbapenemase producers.

  • Imipenem / Cilastatin / Relebactam

    • Indication: cUTI, complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP).

    • Cilastatin prevents renal metabolism of imipenem; relebactam inhibits β-lactamases.

  • Meropenem / Avibactam

    • Not yet as widely approved as the above two; activity profile similar to ceftazidime/avibactam but with carbapenem spectrum.

    • Investigational or region-specific approvals.

4. Spectrum of Activity

Broad Gram-negative coverage

  • Enterobacterales, including ESBL and AmpC producers.

  • Pseudomonas aeruginosa (including some resistant strains).

  • Resistant strains producing KPC carbapenemases (depending on BLI used).

Gram-positive coverage

  • Streptococci, methicillin-susceptible Staphylococcus aureus (MSSA), Enterococcus faecalis (variable activity).

Anaerobic coverage

  • Excellent, including Bacteroides fragilis group.

Not effective against

  • Most metallo-β-lactamase (MBL) producers (e.g., NDM, VIM, IMP).

  • Some non-fermenters (e.g., Stenotrophomonas maltophilia).

5. Pharmacokinetics (General Trends)

  • Administration: Intravenous only (due to poor oral absorption).

  • Distribution: Widely distributed in body tissues and fluids, including CSF (especially meropenem).

  • Metabolism:

    • Imipenem hydrolyzed by renal dehydropeptidase-I → co-administered with cilastatin.

    • Meropenem and ertapenem not significantly metabolized.

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

6. Clinical Indications

FDA- or EMA-approved indications (vary by combination):

  • Complicated urinary tract infections (cUTI), including pyelonephritis.

  • Complicated intra-abdominal infections (cIAI).

  • Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).

  • Certain multidrug-resistant Gram-negative infections with limited treatment options.

Off-label uses

  • Treatment of severe infections caused by KPC-producing Enterobacterales when other options fail.

  • Empirical therapy in critically ill patients with high risk of multidrug resistance (MDR), pending cultures.

7. Contraindications

  • Hypersensitivity to carbapenems, β-lactamase inhibitors, or other β-lactams (cross-reactivity possible with penicillins and cephalosporins).

  • Severe anaphylaxis history to β-lactams.

8. Adverse Effects

Common

  • Diarrhea, nausea, vomiting.

  • Headache.

  • Rash, pruritus.

  • Infusion-site reactions.

Serious

  • Hypersensitivity reactions (anaphylaxis, angioedema).

  • Seizures (higher risk with imipenem, especially in CNS disease or renal impairment).

  • Clostridioides difficile–associated diarrhea.

  • Hepatic enzyme elevations.

9. Drug Interactions

  • Valproic acid: carbapenems may significantly lower serum levels, reducing seizure control.

  • Probenecid: can increase carbapenem levels by reducing renal clearance.

  • Other β-lactams: potential for additive toxicity but rarely clinically relevant.

10. Resistance Considerations

  • BLIs restore activity against many serine β-lactamases, but not all.

  • Resistance may occur via:

    • Production of metallo-β-lactamases (e.g., NDM).

    • Altered PBPs.

    • Efflux pump overexpression.

    • Porin loss combined with enzyme production.

11. Monitoring

  • Renal function (especially for dosing adjustments).

  • Signs of hypersensitivity.

  • Liver function tests during prolonged therapy.

  • Neurological status in high-risk patients (to detect seizure risk early).

12. Advantages and Limitations

Advantages

  • Expanded activity against multidrug-resistant Gram-negative pathogens.

  • Life-saving role in carbapenemase-producing infections.

  • High stability against ESBL and AmpC producers.

Limitations

  • No activity against most MBLs.

  • Reserved for severe, resistant infections to preserve efficacy.

  • IV-only administration limits outpatient use.



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