• Second Generation Cephalosporins:  Cefoxitin

  • Cefoxitin Resistance Mechanism⁷

    • β-lactamase hydrolysis

    • Changed PBPs (for example,mecA/PBP2a) in MRSA

    • Reduced outer membrane permeability

      • AmpC β-lactamase–producing Enterobacterales (e.g., Enterobacter cloacae complex, Citrobacter freundii, Serratia marcescens) may show initial in-vitro susceptibility but can induce AmpC expression under cefoxitin exposure, leading to clinical failure.

        • EUCAST expert rules and IDSA AMR guidance emphasize the importance of recognizing AmpC phenotypes.^9,10

  • Cefoxitin Pharmacokinetics

    • Basic Pharmacokinetic parameters^11,12

      • Route of Administration:  IV only (no oral bioavailability)^11,14,15 

        • Cefoxitin is available only for parenteral use (intravenous or intramuscular), and after IM administration its bioavailability is high, with ≥70–90% of the dose absorbed into the systemic circulation within several hours.

          • Following a typical IV dose, the serum concentration–time course is well described by a linear, two‑compartment open model, with a distribution phase followed by an elimination half‑life of approximately 45–80 minutes in adults with normal renal function.

      • Protein Binding

        • Protein binding is moderate (about 50–75%), and the apparent volume of distribution is low to moderate (around 0.3 L/kg), consistent with confinement largely to the extracellular fluid compartment.

          • Cefoxitin distributes widely into many tissues and fluids, achieving therapeutic concentrations in peritoneal fluid, pleural fluid, joint fluid, bile, and female genital tract secretions, but penetration into cerebrospinal fluid is poor in the absence of meningeal inflammation and is generally insufficient for treatment of meningitis.^14,15,16,17
            

      • Volume of distribution ≈ 10–15 L¹³

      • Serum half-life ~41–59 minutes in subjects with normal renal function

        • Total body clearance averages about 3–5 ml/min/kg in adults, and the elimination half‑life is significantly prolonged in renal impairment and by concomitant administration of probenecid, which competitively inhibits tubular secretion.11,17 

        • In pregnancy, cefoxitin crosses the placenta with fetal:maternal ratios around 0.6 within less than an hour of maternal dosing, and it appears at low levels in breast milk, but available (though limited) human and animal data have not shown teratogenicity at therapeutic doses.^16,18 

      • Primarily renal clearance; accumulation with renal impairment^{11, 14}

        • Metabolism of cefoxitin is minimal, with roughly 2% or less of an administered dose undergoing biotransformation, so the parent compound accounts for nearly all antimicrobial activity.

        • Approximately 80–85% of the dose is excreted unchanged in the urine within 6 hours, by a combination of glomerular filtration and active tubular secretion; consequently, urinary concentrations are very high and the drug is efficiently cleared by the kidney.

  • Cefoxitin: Therapeutic Uses

    • Overview

      • Cefoxitin is used primarily for infections where mixed aerobic–anaerobic flora from the gastrointestinal or genital tract are implicated, taking advantage of its anaerobic and Enterobacterales coverage in a single drug.¹⁹ 

      • With the availability of of third‑generation cephalosporins and β‑lactam/β‑lactamase inhibitor combinations, Cefoxitin use has narrowed but remains a rational choice in specific settings where cost, spectrum, and local resistance patterns so indicate.

    • Surgical Prophylaxis

      • Cefoxitin is a preferred agent for colorectal and abdominal surgery prophylaxis because it covers both aerobic Gram-negative rods and anaerobic flora.¹⁹ 

        • A classic use of cefoxitin is in complicated intra‑abdominal infections such as perforated appendicitis, diverticulitis with perforation or abscess, and postoperative peritonitis, where cefoxitin can cover typical Enterobacterales and anaerobes in community‑acquired disease of mild to moderate severity.^16,21  

        • Cefoxitin is also widely employed for obstetric and gynecologic infections, including:

          • Pelvic inflammatory disease (PID)

          • Postpartum endometritis, and

          • Septic abortion

        • U.S. CDC‑linked guidance has historically listed cefoxitin plus doxycycline as a first‑line regimen for in‑hospital management or single‑dose parenteral therapy of PID.

        • Cefoxitin is frequently used for surgical prophylaxis in procedures at high risk for contamination with colonic or vaginal flora, including colorectal surgery, some gynecologic operations (e.g., hysterectomy), and appendectomy.

          • Cefoxitin is usually administered as a single pre‑incision dose (often with redosing in prolonged operations), and prophylaxis is generally discontinued within 24 hours to minimize selection of resistant organisms and Clostridioides difficile infection.²²
             

    • Complicated Urinary Tract Infections and Pyelonephritis

      • Because of its high urinary excretion and potent activity against many Enterobacterales, cefoxitin can be used as an alternative agent for complicated urinary tract infections and pyelonephritis when local susceptibility patterns are favorable.

        • In orthopedic and soft‑tissue infections arising from bowel or perineal sources, such as sacral decubitus ulcers with osteomyelitis, cefoxitin can provide convenient single‑agent coverage for polymicrobial flora that include anaerobes and susceptible Gram‑negative bacilli.^12,23

    • Pelvic Inflammatory Disease (PID)²⁰

      • Cefoxitin is used in combination with doxycycline for inpatient treatment to cover N. gonorrhoeae and anaerobic vaginal pathogens.

  • Cefoxitin: Adverse Reactions^22,24,25,26

     

    • Overview

      • Adverse‑effect profile of cefoxitin is similar to that of other parenteral cephalosporins, with most reactions being mild and reversible but some serious toxicities requiring vigilance in clinical practice.

        • Common, generally self‑limited effects include local pain or inflammation at the injection site, mild gastrointestinal upset such as nausea and diarrhea, and transient laboratory abnormalities like eosinophilia or mild elevations in liver transaminases.

    • Hypersensitivity reactions

      • Simple morbilliform rash and pruritus

      • Urticaria

      • Angioedema

      • Serum sickness–like syndromes, and

      • Anaphylaxis (rarely) especially in patients with prior immediate‑type reactions to penicillins or other β‑lactams.

        • As with other broad‑spectrum antibiotics, cefoxitin can precipitate Clostridioides difficile–associated diarrhea and colitis, which may present during therapy or weeks to months after discontinuation, manifesting as severe, often bloody diarrhea, crampy abdominal pain, and systemic toxicity.^21,25,27

    • Cefoxitin administration, like several second‑ and third‑generation cephalosporins, has been associated with positive Coombs tests and, rarely, immune hemolytic anemia, as well as thrombocytopenia, leukopenia, and eosinophilia, particularly with prolonged courses.

      • Nephrotoxicity is uncommon when cefoxitin is used alone but may occur, especially when combined with other nephrotoxic agents (aminoglycosides, high‑dose diuretics), and accumulation with neurotoxic manifestations (seizures, encephalopathy) can occur in severe renal impairment if dosage is not adjusted.^21,25,27

    • Prolonged or repeated therapy may promote overgrowth of non‑susceptible organisms, including Candida (leading to oral thrush or vaginal candidiasis) and resistant Gram‑negative bacilli, necessitating clinical and microbiologic reassessment if there is failure to respond.

      • As with other cephalosporins, rare severe cutaneous adverse reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported, warranting immediate discontinuation if blistering rash, mucosal erosions, or systemic symptoms develop.^25,26,27
         

January 2016