Disappearing Antibiotics
Abstracts & Commentary
Synopsis: The discontinuation of manufacture of cefixime has implications for the treatment of gonorrhea and for the future of antibiotic therapy in general.
Sources: CDC. Notice to Readers: Discontinuation of Cefixime Tablets—United States. MMWR Morb Mortal Wkly Rep. 2002;51:1052; CDC. Oral alternatives to cefixime for the treatment of uncomplicated Neisseria gonorrhoeae urogenital infections. http://www.cdc.gov/std/treatment/Cefixime.htm.
In anticipation of the expiration of its patent on November 10, 2002, Wyeth Pharmaceuticals discontinued the manufacture of cefixime. Since no company has elected to manufacture cefixime as a generic, the drug is no longer available. Should we care?
The answer is YES!
Uncomplicated N gonorrhoeae infections may be treated with single-dose regimens of cefixime 400 mg orally, ceftriaxone 125 mg intramuscularly, or an oral fluoroquinolone (ciprofloxacin 500 mg, levofloxacin 250 mg, or ofloxacin 400 mg).
Cefixime was the only CDC-recommended oral antimicrobial agent to which Neisseria gonorrhoeae has not developed significant resistance. The only recommended remaining orally administered agents for now are fluoroquinolones. However, resistance to fluoroquinolones is increasing, and this class of antibiotics should not be used for treatment of gonorrhea if the infection was acquired in Asia, the Pacific Islands (including Hawaii), or California because the prevalence of fluoroquinolone-resistant N gonorrhoeae is high in those areas.
In the absence of cefixime, the primary recommended treatment option for gonorrhea in Hawaii and California, as well as in young children and pregnant women, is ceftriaxone. Fluoroquinolones can continue to be used for treating gonorrhea in areas of the United States with low prevalence of fluoroquinolone-resistant N gonorrhoeae, but antimicrobial susceptibility monitoring should routinely be performed.
The CDC states that to be considered as a recommended treatment for uncomplicated gonorrhea, an antimicrobial regimen should cure > 95% of urogenital infections. Studies documenting efficacy should have sufficient sample size so that the lower limit of the confidence interval (CI) of the cure rate is also > 95%. The available data do not demonstrate that any single-dose oral antimicrobial regimen, other than cefixime or the fluoroquinolones, meet these efficacy criteria for gonococcal urogenital infection; published data on efficacy of alternative oral regimens in treating pharyngeal gonococcal infection are even more limited.
Azithromycin 2 g, as a single oral dose, has demonstrated an efficacy of 99.2% (95% CI, 97.2-99.9%) for urogenital infections and treatment efficacy of 100% for pharyngeal infection (95% CI, 82.3-100%) but has not been recommended because of expense and frequency of gastrointestinal intolerance. Nonetheless, this regimen may be considered (although not CDC-recommended) when IM ceftriaxone is not available or acceptable in circumstances in which fluoroquinolones cannot be used. Unfortunately, resistance to azithromycin has already been described.1
Comment by Stan Deresinski, MD, FACP
Why the "YES!" answer above? While the unavailability of cefixime is an annoyance, its disappearance has broader implications in a world of increasing microbial resistance to antibiotics. We are already faced with reduced efficacy and repeated shortages of existing antibiotics, as well as limited new development of new agents.2-4 Now we have an example of the unwillingness of a pharmaceutical company to continue the manufacture of an existing approved antibiotic for which there is an important need. Perhaps we are sliding into the "post-antibiotic era" much faster than we thought.
Dr. Deresinski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center
References
1. Arreaza L, et al. Emergence of gonococcal strains with resistance to azithromycin in Spain. J Antimicrob Chemother. 2003;51:190-191.
2. http://www.fda.gov/cder/drug/shortages/default.htm.
3. http://www.ashp.org/shortage/index.cfm.
4. Deresinski S. Deflecting the Post-Antibiotic Era. Infectious Disease Alert. In press.
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