“If this blog helped you out, don’t keep it to yourself—share the link on your socials!” 👍 “Like what you read? Spread the love and share this blog on your social media.” 👍 “Found this useful? Hit share and let your friends know too!” 👍 “If you enjoyed this post, please share the URL with your friends online.” 👍 “Sharing is caring—drop this link on your social media if it helped you.”

Sunday, August 10, 2025

Cephalosporins / beta-lactamase inhibitors


1. Introduction

  • Cephalosporins combined with beta-lactamase inhibitors form a crucial category of antibacterial agents.

  • The combination addresses two major challenges in infectious disease management:

    • The need for broad-spectrum coverage against diverse pathogens.

    • The rising prevalence of beta-lactamase-mediated resistance in both Gram-negative and Gram-positive bacteria.

  • This approach merges a cephalosporin antibiotic, which inhibits bacterial cell wall synthesis, with a beta-lactamase inhibitor that protects the antibiotic from enzymatic degradation.

  • These combinations are particularly important in hospital settings where multidrug-resistant organisms are common, but they also play a role in community-acquired infections caused by resistant bacteria.

2. Cephalosporins: General Characteristics

History

  • Discovered in the 1940s from the fungus Acremonium (formerly Cephalosporium).

  • First compound identified was cephalosporin C, notable for its resistance to penicillinase.

  • Development of the 7-aminocephalosporanic acid (7-ACA) nucleus allowed chemical modifications leading to multiple generations of cephalosporins.

Chemical Structure

  • All cephalosporins have:

    • A beta-lactam ring fused to a six-membered dihydrothiazine ring.

    • Modifications at the 7-position on the beta-lactam ring alter antimicrobial activity and beta-lactamase resistance.

    • Changes at the 3-position of the dihydrothiazine ring influence pharmacokinetics and administration route.

Mechanism of Action

  • Bind to penicillin-binding proteins (PBPs) in bacterial cell membranes.

  • Inhibit the final step of peptidoglycan cross-linking during cell wall synthesis.

  • Disruption of cell wall integrity leads to osmotic instability and bacterial lysis.

  • Activity is bactericidal and time-dependent.

3. Classification of Cephalosporins by Generation

First Generation

  • Examples: cefazolin, cephalexin, cefadroxil.

  • Spectrum: strong activity against Gram-positive cocci, moderate activity against a few Gram-negative species.

  • Clinical uses: skin and soft tissue infections, surgical prophylaxis, some urinary tract infections.

Second Generation

  • Examples: cefuroxime, cefaclor, cefprozil, cefotetan, cefoxitin.

  • Broader Gram-negative coverage compared to first generation.

  • Some agents have anaerobic activity (e.g., cefoxitin, cefotetan).

  • Clinical uses: respiratory tract infections, intra-abdominal infections (with anaerobic coverage), gynecological infections.

Third Generation

  • Examples: ceftriaxone, cefotaxime, ceftazidime, cefixime.

  • Enhanced Gram-negative activity, stability against many beta-lactamases.

  • Good cerebrospinal fluid penetration (ceftriaxone, cefotaxime, ceftazidime).

  • Clinical uses: sepsis, meningitis, complicated urinary tract infections, pneumonia.

  • Ceftazidime: notable for Pseudomonas aeruginosa coverage.

Fourth Generation

  • Example: cefepime.

  • Combines Gram-positive potency with extended Gram-negative spectrum.

  • Greater stability against chromosomal beta-lactamases (AmpC).

  • Clinical uses: febrile neutropenia, hospital-acquired pneumonia, complicated intra-abdominal infections.

Fifth Generation

  • Example: ceftaroline.

  • Retains Gram-negative coverage of earlier generations.

  • Unique activity against methicillin-resistant Staphylococcus aureus (MRSA).

  • Clinical uses: community-acquired bacterial pneumonia, acute bacterial skin infections.

4. Limitations of Cephalosporins

  • Susceptible to hydrolysis by beta-lactamase enzymes in resistant bacteria.

  • Extended-spectrum beta-lactamases (ESBLs) can hydrolyze third-generation agents.

  • AmpC beta-lactamases confer resistance to many cephalosporins.

  • Carbapenemases can also inactivate most cephalosporins.

  • Overuse and misuse have contributed to rising resistance.

5. Beta-lactamase Inhibitors: Overview

Purpose

  • Designed to inactivate beta-lactamase enzymes produced by bacteria.

  • Protect the partner antibiotic from enzymatic degradation.

  • Extend the activity of the antibiotic to cover resistant organisms.

Mechanism of Action

  • Bind to beta-lactamases and form a stable, irreversible complex.

  • Prevent hydrolysis of the beta-lactam ring in the companion antibiotic.

  • While structurally similar to beta-lactams, some modern inhibitors are non-beta-lactam molecules.

Types

  • Older inhibitors: clavulanic acid, sulbactam, tazobactam.

  • Novel inhibitors: avibactam, relebactam, vaborbactam, enmetazobactam.

  • Spectrum varies:

    • Traditional inhibitors target mainly class A beta-lactamases.

    • Newer inhibitors have activity against class C and some class D enzymes.

6. Cephalosporin / Beta-lactamase Inhibitor Combinations

Rationale

  • Cephalosporin provides the antibacterial killing mechanism.

  • Beta-lactamase inhibitor neutralizes bacterial enzymes that would inactivate the cephalosporin.

  • Combination expands spectrum to include resistant Gram-negative organisms.

Common Combinations and Features

  • Ceftazidime / Avibactam

    • Ceftazidime: third-generation cephalosporin with strong Gram-negative coverage, including Pseudomonas aeruginosa.

    • Avibactam: non-beta-lactam inhibitor targeting class A, class C, and some class D enzymes.

    • Uses: complicated intra-abdominal infections (with metronidazole), complicated urinary tract infections, hospital-acquired pneumonia, infections due to carbapenem-resistant Enterobacterales (CRE).

  • Ceftolozane / Tazobactam

    • Ceftolozane: novel cephalosporin optimized for anti-pseudomonal activity.

    • Tazobactam: inhibitor of many class A beta-lactamases and some class C enzymes.

    • Uses: complicated intra-abdominal infections (with metronidazole), complicated urinary tract infections, hospital-acquired and ventilator-associated pneumonia.

  • Cefepime / Enmetazobactam

    • Cefepime: fourth-generation cephalosporin with broad Gram-negative and Gram-positive coverage.

    • Enmetazobactam: newer inhibitor with extended beta-lactamase inhibition profile.

    • Uses: infections caused by ESBL-producing Enterobacteriaceae, severe nosocomial infections.

  • Cefepime / Tazobactam

    • Combines the extended spectrum of cefepime with beta-lactamase protection from tazobactam.

    • Uses: complicated intra-abdominal infections, hospital-acquired pneumonia, resistant urinary tract infections.

  • Ceftriaxone / Sulbactam

    • Ceftriaxone: third-generation cephalosporin with good tissue penetration and long half-life.

    • Sulbactam: older inhibitor with some intrinsic activity against Acinetobacter baumannii.

    • Uses: respiratory tract infections, intra-abdominal infections, gynecological infections.

7. Spectrum of Activity

  • Gram-positive bacteria

    • Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae.

    • Methicillin-susceptible Staphylococcus aureus (MSSA).

    • MRSA (only ceftaroline among cephalosporins).

  • Gram-negative bacteria

    • Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis.

    • Enterobacter cloacae, Serratia marcescens.

    • Pseudomonas aeruginosa (with ceftazidime, cefepime, ceftolozane).

    • Acinetobacter baumannii (coverage variable, better with sulbactam-containing combinations).

  • Anaerobes

    • Variable activity; combinations may be used with metronidazole when anaerobic coverage is needed.

8. Pharmacokinetics and Pharmacodynamics

  • Administration

    • Primarily intravenous; some intramuscular options.

    • Reserved for moderate to severe infections requiring systemic therapy.

  • Distribution

    • Good penetration into most tissues and fluids, including lung, urine, peritoneal fluid, bone, and soft tissue.

    • Some agents achieve therapeutic cerebrospinal fluid concentrations.

  • Elimination

    • Mostly renal excretion; dose adjustment needed in renal impairment.

    • Minimal hepatic metabolism for most agents.

  • Pharmacodynamics

    • Time-dependent killing: efficacy linked to the duration that drug concentrations remain above the MIC (minimum inhibitory concentration) of the pathogen.

9. Clinical Indications

  • Complicated urinary tract infections and pyelonephritis.

  • Complicated intra-abdominal infections (often combined with anaerobic coverage).

  • Hospital-acquired pneumonia, including ventilator-associated pneumonia.

  • Bloodstream infections, including sepsis caused by resistant Gram-negative bacteria.

  • Infections due to ESBL-producing Enterobacteriaceae.

  • Select cases of central nervous system infections.

  • Severe skin and soft tissue infections caused by resistant organisms.

10. Adverse Effects

  • Common

    • Diarrhea, nausea, vomiting.

    • Headache, rash.

    • Injection-site pain or inflammation.

  • Less common but serious

    • Hypersensitivity reactions (urticaria, anaphylaxis).

    • Clostridioides difficile–associated diarrhea.

    • Hematologic effects: neutropenia, thrombocytopenia.

    • Hepatic enzyme elevations.

    • Seizures in high doses or renal impairment.

11. Contraindications and Precautions

  • History of severe hypersensitivity to cephalosporins, penicillins, or other beta-lactams.

  • Use with caution in patients with renal impairment; adjust dosing.

  • Monitor for superinfection with prolonged use.

  • Evaluate risk–benefit ratio in pregnancy; many agents are generally considered safe but require case-by-case assessment.

  • Exercise caution in patients with seizure disorders.

12. Drug Interactions

  • Probenecid: may increase cephalosporin levels by inhibiting renal excretion.

  • Aminoglycosides: potential increased nephrotoxicity when combined.

  • Loop diuretics: increased risk of renal effects.

  • Anticoagulants: possible increased bleeding tendency.

  • Live vaccines: potential reduced effectiveness due to antibiotic suppression of bacterial growth needed for immune response.

13. Antimicrobial Stewardship Considerations

  • Use guided by culture and susceptibility results whenever possible.

  • Avoid empirical use in low-risk patients to prevent resistance development.

  • Reserve for documented or strongly suspected multidrug-resistant Gram-negative infections.

  • De-escalate to narrower spectrum agents when appropriate.

  • Monitor local resistance trends to inform prescribing practices.




on

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)