• Third Generation Cephalosporins in More Detail

  Third Generation Cephalosporins: A Comprehensive Audio Overview

  • Introduction

    • Third‑generation cephalosporins—cefotaxime, ceftriaxone, and cefixime—are broad‑spectrum β‑lactam antibiotics central to modern management of serious Gram‑negative and many community‑acquired infections, especially in CNS, respiratory, abdominal, genitourinary, and systemic disease.

    • These drugs share a common mechanism but differ markedly in pharmacokinetics, formulation, and safety, which drives their distinct roles in clinical infectious‑diseases practice.^2,3,6,7

  • Mechanism of action and resistance^3,4,5

    • Cephalosporins inhibit bacterial cell wall synthesis by binding to penicillin‑binding proteins (PBPs) and blocking the transpeptidation and cross‑linking of peptidoglycan, producing structurally weak cell walls and osmotic lysis of susceptible bacteria.

    • Bactericidal activity is time‑dependent

      • Clinical efficacy correlates with the fraction of the dosing interval for which free drug concentrations exceed the MIC (fT>MIC), which underlies the frequent dosing of cefotaxime and high single doses of ceftriaxone.

    • Third‑generation cephalosporins are relatively stable to many plasmid‑encoded β‑lactamases and have enhanced activity versus Enterobacterales, Neisseria, and Haemophilus spp., but they are hydrolyzed by Extended-Spectrum Beta-Lactamases (ESBLs) (e.g., CTX‑M family) and many AmpC enzymes.

      • Resistance develops as result of:^2,3,8  

        • ESBLs and AmpC β‑lactamases that efficiently hydrolyze cefotaxime, ceftriaxone, and cefixime, often leaving carbapenems or newer β‑lactam/β‑lactamase‑inhibitor combinations as preferred options.^2,3,8

        • Changes in Penicillin-Binding Proteins (PBPs) in Streptococcus pneumoniae and Neisseria gonorrhoeae, which increase MICs and have contributed to cefixime clinical failures in gonorrhea.^9,10,11,12

        • Decreased outer‑membrane permeability and upregulated efflux pumps in Gram‑negative bacilli that act synergistically with β‑lactamase production.^2,3

          • These mechanisms have resulted in major guideline changes, including removal of cefixime from first‑line gonorrhea treatment in favor of higher‑dose IM ceftriaxone.^10,13,14 

       

    • Cefotaxime

      Cefotaxime

    • Mechanism and pharmacological profile

      • Cefotaxime is a parenteral third‑generation cephalosporin active against Enterobacterales (E. coli, Klebsiella, Proteus, some Enterobacter), Neisseria, H. influenzae, and many streptococci including S. pneumoniae;

      • Cefotaxime exhibits weaker antistaphylococcal activity compared to first‑generation cephalosporins and lacks significant anaerobic and Pseudomonas coverage.

        • Cefotaxime, similar to other β‑lactams,  binds multiple PBPs, with high affinity for those essential to cell wall cross‑linking in Gram‑negative bacilli.^2,4,15,16

       

      Cefotaxime Antibacterial Spectrum of Activity

  • Cefotaxime Pharmacokinetics

    • Principal pharmacokinetic characteristics^{2, 5,17}

      • Administration and distribution: Given IV or IM (no oral formulation), cefotaxime distributes rapidly into extracellular fluids; adult volumes of distribution are approximately 20–27 L, indicating extensive tissue penetration.

      • Cefotaxime penetrates well into lung, pleural, peritoneal, bone, synovial fluid, and inflamed meninges.^2,5,16,17

        • Meninges

          Attribution Meninges of the Central Nervous System SVG by Mysid, original by SEER Development Team [1], Jmarchn, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Meninges-en.svg

       

      • CSF penetration

        • In infants receiving 50 mg/kg every 6 h, mean serum concentrations 15 minutes after infusion were around 120 μg/mL, with CSF concentrations around 6 μg/mL and mean CSF:serum ratios near 0.29 in inflamed meninges.

          • This drug concentration is deemed sufficient to exceed MICs for N. meningitidis, H. influenzae, and most S. pneumoniae strains.^5,18 

      • Metabolism and  Elimination^15,17

        • Cefotaxime is partly metabolized to desacetylcefotaxime, an active metabolite with a longer half‑life (~2 h) and complementary antibacterial activity.

          • Parent drug and metabolite are primarily renally eliminated;.

          • Total half‑life in adults with normal renal function is ~0.8–1 h for cefotaxime and ~2 h for desacetylcefotaxime,.

            • Given these half-lives, dosing is likely required every 6–8 h in serious infections.

      • Dose adjustments

        • Significant renal impairment requires dose reduction or prolonged dosing intervals to avoid accumulation and neurotoxicity.^15,17

  • Cefotaxime: Therapeutic Uses (detailed)

    • Cefotaxime is a mainstay for hospitalized patients with serious infections when Pseudomonas and ESBLs are not major concerns.^15,16,19

    • Community‑acquired and hospital‑acquired pneumonia^20,21,22  

      • In Community Acquired Pneumonia (CAP) requiring hospitalization, cefotaxime (1–2 g IV q8h) is recommended by ATS/IDSA as one of the β‑lactam options combined with a macrolide or doxycycline agent.  The β-lactam targets S. pneumoniae, H. influenzae, and Enterobacterales while the other drug covers atypicals.

        • In early Hospital Acquired Pneumonia (HAP) without high Multi-Drug Resistance (MDR) risk, Cefotaxime can be part of empiric therapy, but in later‑onset or high‑risk HAP, broader anti‑pseudomonal β‑lactams are preferred.

         

      • Pneumonia:  Community-Acquired vs. Hospital Acquired

        References Metlay J Waterer G Long A Anzueto A Brozek J Crothers K Cooley L Dean N Fine M Flanders S Griffin M Metersky M Musher D Restrepo M Whitney C On behalf of the American Thoracic Society and Infectious Diseases Society of America. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. American Thoracic Society Documents. May/August 2019. https://www.idsociety.org/globalassets/idsa/practice-guidelines/community-acquired-pneumonia-in-adults/executive_summary.pdf   Kalil A Metersky M Klompas M Muscedere J Sweeney D Palmer L Napolitano L O'Grady N Bartlett J Carratala J El Solh A Ewig S Fey P File JR T Restrepo M Robers J Waterer G Cruse P Knight S Brozek J Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clinical Infectious Diseases, Volume 63, Issue 5, 1 September 2016, Pages e61–e111 https://academic.oup.com/cid/article/63/5/e61/2237650   Torres A Niederman M Chastre J Ewig S Fernandez-Baldellos P Hanberger H Kollef M Bassi G Luna C Martin-Loeches I Paiva J Read R Rigau D Timsit J Welte T Wunderink R International ERS/ESICM/ESCMID/ALAT Guidelines for the Management of Hospital-Acquired Peumonia and Ventilator-associated Pneumonia. European Respiratory Journal 2017 50(3). https://publications.ersnet.org/content/erj/50/3/1700582

     

    • Complicated Urinary Tract Infections and Pyelonephritis^16,19

      • For hospitalized pyelonephritis or complicated UTIs due to susceptible Enterobacterales, cefotaxime achieves high serum and urinary concentrations and is effective where fluoroquinolone resistance is problematic.

        • Cefotaxime is often used as initial IV therapy in the Emergency Department or inpatient settings, followed by oral step‑down once the patient is stable and susceptibilities permit.

      • References Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women. Clinical Infectious Diseases. 2011;52(5):e103–e120. https://academic.oup.com/cid/article/52/5/e103/388285 Grigoryan L, Trautner BW, Gupta K. Diagnosis and management of urinary tract infections in the outpatient setting. JAMA. 2014;312(16):1677–1684. https://jamanetwork.com/journals/jama/article-abstract/1917443 Hooton TM. Uncomplicated urinary tract infection. New England Journal of Medicine. 2012;366(11):1028–1037. https://www.nejm.org/doi/full/10.1056/NEJMcp1104429 Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2019;68(10):e83–e110. https://pubmed.ncbi.nlm.nih.gov/30895288/ Johnson JR, Russo TA. Acute pyelonephritis in adults. New England Journal of Medicine. 2018;378(1):48–59. https://www.nejm.org/doi/full/10.1056/NEJMcp1702758 Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infectious Disease Clinics of North America. 2014;28(1):1–13. https://pubmed.ncbi.nlm.nih.gov/24484571/ European Association of Urology (EAU). EAU Guidelines on Urological Infections. 2023 Edition. Arnhem, The Netherlands: EAU Guidelines Office. https://uroweb.org/guidelines/urological-infections/summary-of-changes/2023 Centers for Disease Control and Prevention (CDC). Catheter-associated Urinary Tract Infections (CAUTI). https://www.cdc.gov/infection-control/hcp/cauti/index.html

February, 2026