To the Editor:
A recent article in Sexually Transmitted Diseases by Echols et al1 deserves some comment. Their summary of the clinical data supporting the use of a single 250-mg dose of ciprofloxacin as a treatment for uncomplicated gonorrhea and the Food and Drug Administration's (FDA) recent approval of that regimen may leave some readers questioning why the Centers for Disease Control and Prevention (CDC)2 recommends a higher dose.
It should not be surprising that the CDC might recommend a regimen different from that approved by the FDA when one considers that:
- the FDA evaluates only regimens submitted for its approval; the CDC evaluates all well studied and available regimens3; and
- the FDA's primary concern is whether a specific regimen is or is not safe and effective; the CDC's concern is which of the available regimens offer the best balance of safety, effectiveness, tolerability, price, and public health benefit.
Echols et al,1 in their article, focused on proven clinical efficacy, which is necessarily past clinical efficacy, making the point that “quinolone resistance has not been a problem in the United States and current data support the use of the 250-mg single dose.” The CDC's treatment guidelines panel acknowledged that both 250-mg and 500-mg doses have been shown to be safe and effective, but the panel tried to anticipate the future efficacy of fluoroquinolone regimens, which may not be as great as it has been in the past. The CDC panel2 observed that “No resistance [to the quinolones] has been reported in the United States, but strains with decreased susceptibility to some quinolones are becoming common in Asia and have been reported in North America (p. 58).”
Echols et al, acknowledging concerns about the spread of decreased susceptibility to the fluoroquinolones among gonococci, cautioned that “continued surveillance of antimicrobial susceptibility is warranted.” The CDC panel chose to assume that quinolone resistance will become a problem in the United States, explaining that “The 500 mg dose is recommended, rather than the 250 mg dose, because of the trend toward decreasing susceptibility to quinolones and because of rare reports of treatment failures.”
Since the Echols article and the CDC Guidelines were written, concerns about the future of the fluoroquinolones in the treatment of gonorrhea have multiplied:
From Africa, a report from Kigali, Rwanda, is of particular concern.4 In Kigali, fluoroquinolones were used for the routine treatment of gonorrhea only at a single clinic from 1985 to 1989, and only 200 g of norfloxacin is believed to have been dispensed elsewhere in Kigali during the same time. For gonorrhea, 800 mg of norfloxacin was used from 1985 to 1988 and 400 mg of ofloxacin in 1989. Antimicrobial susceptibility monitoring showed increases in the proportions of strains less susceptible to fluoroquinolones. Among nonpenicillinase-producing Neisseria gonorrhoeae (PPNG) strains, the percentage with norfloxacin minimum inhibitory concentrations (MICs) ≥0.125 μg/ml increased from 2.4 in 1985, to 4.6 in 1986 to 1987, to 38.8 in 1989. Among PPNG strains, the percentage with norfloxacin MICs ≥0.125 μg/ml increased from 0 in 1985, to 5.8 in 1986 to 1987, to 20.7 in 1989. There were few documented treatment failures, but among those documented for which pretreatment susceptibility data were obtained, treatment failure was positively correlated with decreased susceptibility.
In Asia, the situation seems to be most worrisome in the Philippines, where fluoroquinolones have long been used for the treatment of gonorrhea. Among 135 N. gonorrhoeae isolates collected as long ago as 1989, ciprofloxacin MICs ranged from <0.001 to >2 μg/ml, with an MIC50 of 0.004 and an MIC90 of 0.250.5 In Japan, where fluoroquinolones have been used for several years as a first-line therapy for gonorrhea, decreased susceptibility to fluoroquinolones has been observed. Among 69 N. gonorrhoeae strains isolated in 1992, the ciprofloxacin MICs ranged from ≤0.001 to 0.5 μg/ml, with an MIC50 of 0.063, and an MIC90 of 0.5.6
In Europe, treatment failures and the isolation of strains with decreased susceptibility to the fluoroquinolones have been reported occasionally during the past several years. Turner et al,7 reporting on an N. gonorrhoeae isolate with a ciprofloxacin MIC of 0.1 μg/ml in 1990 raised “a note of caution in the use of single dose [i.e., 250 mg] ciprofloxacin in the treatment of uncomplicated genital gonorrhoea.” More recently, N. gonorrhoeae with a ciprofloxacin MIC of 16 μg/ml was cultured in the United Kingdom from a seaman presumed to have been infected in Spain. The infection had not responded to ciprofloxacin given 250 mg twice daily for 5 days.8
In the United States, ciprofloxacin treatment failure has not been reported, but N. gonorrhoeae strains with decreased susceptibility to ciprofloxacin (MICs of 0.125 μg/ml to 0.25 μg/ml) have been reported sporadically.9 More recently, strains with an MIC of 2.0 μg/ml were imported into Hawaii, and strains with MICs of 0.125 μg/ml to 0.25 μg/ml were found to be circulating in Ohio.10
In summary, there is agreement that the 250-mg dose of ciprofloxacin has been proven to be safe and effective for the treatment of uncomplicated gonococcal infections. The CDC recommends that when ciprofloxacin is used for the treatment of gonorrhea, it be given as a 500-mg dose because this dose is safe and effective and likely to be more effective than the 250-mg dose for gonococcal strains with decreased sensitivity to the fluoroquinolones. N. gonorrhoeae strains with decreased susceptibility to the fluoroquinolones are becoming common in Asia and may well be encountered more and more frequently in the United States and the rest of the world in the future.
Note: Since this letter was submitted, a case of Neisseria gonorrhoeae infection unresponsive to fluoroquinolone therapy has been reported in the United States. The patient apparently was infected in March 1995 in the Philippines and was treated with 400 mg of ofloxacin in Denver, Colorado on May 24. He returned to the clinic with persistent symptoms on June 7, at which time he was found to be infected with a strain of N. gonorrhoeae with an ofloxacin MIC of 8 μg/ml and a ciprofloxacin MIC of 4 μg/ml. (Centers for Disease Control and Prevention [CDC]. Fluoroquinolone resistance in Neisseria gonorrhoeae—Colorado and Washington, 1995. MMWR 1995; 44:761–764.)
1. Echols RM, Heyd A, O'Keefe BJ, Schacht P. Single-dose ciprofloxacin for the treatment of uncomplicated gonorrhea: a worldwide summary. Sex Transm Dis 1994; 21: 345–352.
2. Centers for Disease Control and Prevention. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993; 42(No. RR-14):56–60.
3. Moran JS, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis 1995; 20(Suppl I):S47–S65.
4. Bogaerts J, Tello WM, Akingeneye J, Mukantabana V, Van Dyck E, Piot P. Effectiveness of norfloxacin and ofloxacin for treatment of gonorrhoea and decrease of in vitro susceptibility to quinolones over time in Rwanda. Genitourin Med 1993; 69:196–200.
5. Clendennen TE III, Hames CS, Kees ES, et al. In vitro antibiotic susceptibilities of Neisseria gonorrhoeae
isolates in the Philippines. Antimicrob Agents Chemother 1992; 36:277–282.
6. Tanaka M, Kumazawa J, Matsumoto T, Kobayashi I. High prevalence of Neisseria gonorrhoeae
strains with reduced susceptibility to fluoroquinolones in Japan. Genitourin Med 1994; 70:90–93.
7. Turner A, Jephcott AE, Haji TC, Gupta PC. Ciprofloxacin resistant Neisseria gonorrhoeae
in the UK. Genitourin Med 1990; 6:43.
8. Birley H, McDonald P, Carey P. High level ciprofloxacin resistance in Neisseria gonorrhoeae.
Genitourin Med 1994; 70:292–293.
9. Gorwitz RJ, Nakashima AK, Moran JS, Knapp JS. Sentinel surveillance for antimicrobial resistance in Neisseria gonorrhoeae:
United States, 1988–1991. MMWR
1993; 42(No. SS-3):29–39.
10. Centers for Disease Control and Prevention (CDC). Decreased susceptibility of Neisseria gonorrhoeae
to flouroquinolones: Ohio and Hawaii, 1992–1994. MMWR 1994; 43:325–327.