Neisseria gonorrhoeae Resistant to Ciprofloxacin and Ofloxacin

ALTHOUGH THE NUMBER of cases of gonorrhea has decreased significantly in many geographic areas during the last decade, antimicrobial resistance in Neisseria gonorrhoeae remains an important factor that affects adversely efforts to control this disease. As a result of the emergence of penicillin-, tetracycline-, and spectinomycin-resistant strains of N. gonorrhoeae, the Centers for Disease Control and Prevention has recommended that broad-spectrum cephalosporins and fluoroquinolones be used to treat persons with uncomplicated gonorrhea.1 Fluoroquinolones have been used to treat gonorrhea in many countries. Although gonococcal isolates have not developed resistance to broad-spectrum cephalosporins, clinically significant resistance to ciprofloxacin and ofloxacin has emerged.2–7 Discussions of gonococcal resistance to fluoroquinolones is complicated by the fact that different regimens, including either 250 mg or 500 mg ciprofloxacin, or 400 mg or 600 mg ofloxacin given as a single dose, are used to treat gonorrhea.1,3,7,8 The criteria for the interpretation of resistance to fluoroquinolones must be tailored for the dose administered and for the method used to determine in vitro susceptibilities.9 In the United States, the National Committee for Clinical Laboratory Standards has defined strains of N. gonorrhoeae as resistant if they have minimal inhibitory concentrations(MICs) of ≥1.0 μg/ml ciprofloxacin or ≥2.0 μg/ml ofloxacin.10 These criteria have been adopted for use in the United States and Australia, and are used throughout this editorial. It is also important to note that the discussion in this editorial is limited to fluoroquinolones with activity equivalent to ciprofloxacin and ofloxacin. Comments should not be extrapolated to fluoroquinolones that have lesser or greater activity against N. gonorrhoeae. The emergence of ciprofloxacin and ofloxacin resistance can be traced back to the late 1980s and early 1990s when resistance was detected sporadically among gonococcal strains isolated from persons in the Far East.11–13 By 1994, fluoroquinolone-resistant N. gonorrhoeae strains accounted for as many as 10% of isolates in Hong Kong, the Republic of the Philippines, and Japan, but had not been isolated frequently in Thailand.14–17 Recent studies15,18 in the Republic of the Philippines have shown that ciprofloxacin-resistant strains have increased from approximately 12% of isolates in 1994 to 72.6% of isolates in 1996 to 1997, and that 45.4% of women infected with strains with ciprofloxacin MICs of ≥4.0 μg/ml failed to respond to therapy with 500 mg of ciprofloxacin compared with 8% of women infected with strains with MICs of 1.0 to 2.0 μg/ml. Ciprofloxacin-resistant strains have been introduced sporadically into other countries. In assessing the immediate and long-term threat of resistant gonococcal strains to the effectiveness of disease control methods, it is helpful to understand the “dynamics” of an outbreak, including the numbers of patients and the epidemiology of infections with resistant strains, as well as the molecular epidemiology of infections with strains characterized by typing techniques now used widely to describe gonococcal strains. The article by Tapsall et al. describes the course of the “epidemic” in Sydney, Australia, which has progressed from the introduction of strains with intermediate resistance to ciprofloxacin in 1984 to the introduction of strains exhibiting clinically significant resistance to ciprofloxacin (MICs, 1.0 μg/ml) beginning in 1990 and then, in 1994, the introduction of ciprofloxacin-resistant strains exhibiting MICs as high as 16.0 μg/ml.19–21 Ciprofloxacin-resistant strains have increased from 3.1% in 1995 to 12.4% in 1997. The epidemic has been characterized by the isolation of a large number of gonococcal auxotype/serovar (A/S) classes between 1984 and 1995 followed by the repeated isolation of fewer A/S classes, indicating that individual ciprofloxacin-resistant strains have become endemic in Sydney.19–21 The dynamics of the epidemic in Sydney follow closely the dynamics of the emergence of ciprofloxacin resistance in N. gonorrhoeae in the Far East. Epidemiologic data showed that although heterosexual men in Sydney have acquired infections caused by ciprofloxacin-resistant N. gonorrhoeae from commercial sex workers(CSWs), few homosexual men have acquired such infections. Outbreaks or epidemics associated with CSWs have been documented in the spread of antimicrobial-resistant strains of N. gonorrhoeae. However, the epidemic in Sydney has been associated with a rare phenomenon of “international” CSWs, who entered Australia legally but remained in the country illegally after their visas expired.21 In contrast to domestic CSWs, these sex workers have high rates of sexually transmitted diseases and were not examined and treated through routine healthcare facilities. The report by Tapsall et al.21 provides an excellent primer for public health scientists working to prevent or control the development of epidemics caused by ciprofloxacin-resistant strains. The experience with ciprofloxacin-resistant N. gonorrhoeae in the United States mimics the Sydney experience in that multiple importations of phenotypically diverse strains with intermediate and clinically significant resistance to ciprofloxacin have been detected.22–24 Although an epidemic caused by a limited number of strains with intermediate ciprofloxacin resistance has been documented in Ohio, strains with clinically significant ciprofloxacin resistance have not become endemic to our knowledge.22 The report by Tapsall et al.21 demonstrates not only the importance of surveillance for antibiotic-resistant N. gonorrhoeae but also the usefulness of phenotyping to understand the dynamics of outbreaks. As clinical laboratories increasingly use nonculture methods to diagnose gonorrhea, public health laboratories must maintain the capability to culture N. gonorrhoeae and to measure antimicrobial susceptibilities.