Why Cefixime Is Not Commonly Used
Cefixime is not commonly used primarily because it has been removed as a first-line treatment for gonorrhea due to rising antimicrobial resistance, demonstrates inferior pharmacokinetic properties compared to ceftriaxone (particularly poor pharyngeal penetration), and offers no significant advantage over other oral cephalosporins for most common infections.
Primary Reason: Removal from Gonorrhea Treatment Guidelines
The most significant factor limiting cefixime use is its removal from recommended gonorrhea treatment protocols:
The CDC no longer recommends routine use of cefixime as a first-line regimen for gonorrhea treatment in the United States due to rising minimum inhibitory concentrations (MICs) among Neisseria gonorrhoeae isolates 1.
Between 2006 and 2011, isolates with elevated cefixime MICs increased from 0.2% to 1.4% nationally, with the West region showing an increase from 0.2% to 3.2% 1.
Among men who have sex with men (MSM), the percentage of isolates with elevated cefixime MICs increased from 0.2% in 2006 to 3.8% in 2011 1.
This pattern mirrors the emergence of fluoroquinolone resistance in the 1990s, which also began in the West and among MSM before spreading nationwide 1.
Inferior Pharmacokinetic Profile
Cefixime has significant pharmacokinetic limitations compared to alternative cephalosporins:
A 400-mg oral dose of cefixime does not provide bactericidal levels as high or as sustained as an intramuscular 250-mg dose of ceftriaxone 1.
Cefixime demonstrates limited efficacy for treatment of pharyngeal gonorrhea, a critical limitation given that pharyngeal infections serve as reservoirs for resistant strains 1.
The oral bioavailability of cefixime is only 40-50%, regardless of food intake 2.
While cefixime has a 3-hour elimination half-life permitting twice-daily dosing 3, this offers no advantage over once-daily ceftriaxone for serious infections.
Risk of Accelerating Ceftriaxone Resistance
A critical concern is that continued cefixime use could compromise the last effective single-dose gonorrhea treatment:
Continued use of cefixime might hasten the development of resistance to ceftriaxone, which remains the last antimicrobial known to be highly effective in a single dose for gonorrhea treatment at all anatomic sites 1.
Maintaining effectiveness of ceftriaxone for as long as possible is critical, making preservation of this agent a public health priority 1.
Limited Spectrum Compared to Other Third-Generation Cephalosporins
Cefixime has notable gaps in antimicrobial coverage:
Cefixime has little activity against Staphylococcus aureus and is inactive against Pseudomonas aeruginosa, limiting its utility in many clinical scenarios 3.
For respiratory infections, cefixime offers no clear advantage over cefdinir, cefpodoxime, or amoxicillin-clavulanate, which are more established options 4, 5.
In pneumonia treatment, cefotaxime and ceftriaxone are preferred third-generation cephalosporins with better-established efficacy 1.
Lack of Inclusion in Modern Treatment Algorithms
Contemporary guidelines consistently omit cefixime from recommended regimens:
WHO's 2024 essential medicines recommendations do not include cefixime for any infection category, instead prioritizing cefotaxime, ceftriaxone, and other agents 1.
For intra-abdominal infections, the WHO recommends cefotaxime or ceftriaxone with metronidazole, not cefixime 1.
Cefepime remains acceptable for febrile neutropenia despite controversy, but cefixime is not mentioned as an alternative 1.
Clinical Niche: Limited to Specific Urinary Tract Infections
Cefixime retains FDA approval for specific indications but these represent narrow clinical niches:
FDA-approved indications include uncomplicated urinary tract infections, otitis media, pharyngitis/tonsillitis, acute exacerbations of chronic bronchitis, and uncomplicated gonorrhea 2.
For uncomplicated UTIs in women, cefixime 400 mg once daily can be effective, particularly when first-line agents are contraindicated or resistance is documented 6, 7.
In UTI treatment, cefixime showed comparable efficacy to co-trimoxazole and amoxicillin in controlled trials 3, 7.
However, for complicated UTIs, treatment should not be initiated without sensitivity testing due to potential resistance among gram-positive and non-fermenting pathogens 7.
Adverse Effect Profile
While generally well-tolerated, cefixime has notable gastrointestinal effects:
Diarrhea and stool changes occur in up to 20% of patients, representing the most common adverse effects 2, 8.
Once-daily dosing (400 mg) shows higher incidence of gastrointestinal adverse effects than twice-daily dosing (200 mg), leading to recommendations for divided doses 7.
Other reported adverse effects include pseudomembranous colitis, hypersensitivity reactions, transient hepatic enzyme elevations, and CNS effects including seizures in patients with renal impairment 2.
Common Pitfalls to Avoid
When considering cefixime use:
Never use cefixime for gonorrhea treatment given current CDC recommendations against its routine use 1.
Do not use cefixime empirically for complicated UTIs or serious infections without culture and sensitivity data 7.
Avoid cefixime for suspected Pseudomonas or Staphylococcus aureus infections due to poor activity 3.
Do not use cefixime for pharyngeal infections when gonorrhea is a consideration, given its poor efficacy at this site 1.
Adjust dosing in renal impairment and monitor patients on dialysis carefully 2.