Sexually Transmitted Diseases:
Single-Dose Gatifloxacin Compared With Ofloxacin for the Treatment of Uncomplicated Gonorrhea: A Randomized, Double-Blind, Multicenter Trial
STONER, BRADLEY P. MD, PhD*; DOUGLAS, JR, JOHN M. MD†; MARTIN, DAVID H. MD‡; HOOK, EDWARD W. III MD§; LEONE, PETER MD//; McCORMACK, WILLIAM M. MD¶; MROCZKOWSKI, TOMASZ F. MD#; JONES, ROBERT MD**; YANG, JOANNA PhD†† AND; BAUMGARTNER, TODD MD, MPH††
From the *Washington University School of Medicine,St. Louis, Missouri; †Denver Department of Public Health, Denver, Colorado; ‡Louisiana State University Health Sciences Center and the Delgado STD Clinic, New Orleans, Louisana; §University of Alabama–Birmingham, Birmingham, Alabama; //University of North Carolina/Wake County Department of Health, Raleigh, North Carolina; ¶State University of New York Health Sciences Center, Brooklyn, New York; #Tulane Medical School, New Orleans, Louisana; **Indiana University Medical Center, Indianapolis, Indiana; and ††Bristol-Myers Squibb, Wallingford, Connecticut
Reprint requests: Bradley P. Stoner, MD, PhD, Washington University School of Medicine, Campus Box 8051, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: firstname.lastname@example.org
Received for publication March 21, 2000,
revised July 10, 2000, and accepted July 14, 2000.
Background: Treatment of gonorrhea is complicated by widespread resistance of Neisseria gonorrhoeae to antimicrobial agents of choice, including decreased susceptibility to ciprofloxacin.
Goal: To demonstrate the efficacy and safety of gatifloxacin, a novel 8-methoxy fluoroquinolone antibiotic, compared with ofloxacin in treating patients with uncomplicated gonococcal infection.
Study Design: In a double-blind, randomized (2:2:1), controlled trial, 340 men and 388 women with uncomplicated gonorrhea who were 16 years or older received a single oral dose of gatifloxacin (400 mg or 600 mg) or ofloxacin (400 mg). Primary analysis of efficacy was based on bacteriologic eradication from sites of infection. Secondary analyses examined clinical response and adverse event profiles.
Results: Bacteriologic eradication rates for gatifloxacin in evaluable men with urethral gonorrhea were 99% (400 mg) and 100% (600 mg) versus 100% for ofloxacin (n = 117, 122, and 55, respectively;P = ns). Eradication rates in evaluable women with endocervical gonorrhea were 99% for both 400 mg and 600 mg gatifloxacin versus 100% for ofloxacin (n = 101, 104, and 55, respectively;P = ns). Eradication rates were 100% for both rectal (n = 43) and pharyngeal (n = 31) infection across all treatment groups. All three drug regimens were well tolerated and exhibited similar clinical response profiles.
Conclusion: Gatifloxacin is safe and effective as a single 400-mg or 600-mg dose for the treatment of uncomplicated gonorrhea. Similar efficacy rates were observed with the 400-mg and 600-mg doses. A single 400-mg dose can be recommended for treatment of uncomplicated gonorrhea.
THE TREATMENT OF GONORRHEA is currently complicated by widespread increasing resistance of Neisseria gonorrhoeae to antimicrobial agents of choice. 1,2 Although the incidence of gonorrhea in the United States has decreased during the past two decades, the proportion of gonococcal isolates showing drug resistance has increased. In 1994, 30.5% of isolates had chromosomally or plasmid-mediated resistance to penicillin or tetracycline, and 1.3% of isolates showed decreased susceptibility to ciprofloxacin. 3 Recovery of gonococcal isolates with decreased susceptibility to ciprofloxacin (MIC, 0.125–0.5 μg/ml) is increasing in the United States and abroad. 4–9 Frank resistance to ciprofloxacin (MIC ≥ 1.0 μg/ml), though still rare in the United States, has been identified in up to 10% of isolates in Hong Kong, the Republic of the Philippines, and Bangladesh. 10,11 Treatment failures with ciprofloxacin have also been reported. 12,13 Therefore, selection of appropriate antimicrobial agents for gonorrhea necessitates knowledge of local community resistance patterns, and consideration of clinical features such as anatomical site of infection and possible coinfection with Chlamydia trachomatis. Current treatment recommendations by the Centers for Disease Control and Prevention (CDC) called for the use of an expanded-spectrum cephalosporin (intramuscular ceftriaxone or oral cefixime) or a quinolone antibiotic (oral ciprofloxacin or oral ofloxacin) administered as a single dose, in most cases to be given with presumptive treatment for C trachomatis. 14
Gatifloxacin, a novel 8-methoxy fluoroquinolone antibiotic, is highly active against N gonorrhoeae, C trachomatis, and a broad array of gram-positive and gram-negative organisms. In vitro studies show that gatifloxacin activity is equal to ciprofloxacin for fully susceptible N gonorrhoeae strains (MIC50, 0.008 μg/ml), but is fourfold more active against strains with par C or gyr A mutations and resistance to ciprofloxacin (MIC90, 0.064–0.094 μg/ml). 15 The drug has dose-proportional pharmacokinetics in vivo, with a peak concentration (CMAX) of 3.4 μg/ml to 3.8 μg/ml, time to CMAX of 1.4 hours to 1.7 hours, area under the curve (AUC0–∞) of 51 μg.h/ml, and urine recovery of 83% to 84% after a single 400-mg oral dose. 16 These pharmacokinetic properties suggest that single doses of gatifloxacin should be efficacious for treatment of uncomplicated gonorrhea. We now report the results of a multicenter study comparing the clinical efficacy and safety of two oral, single-dose regimens of gatifloxacin (400 mg and 600 mg) with single-dose ofloxacin (400 mg) for treating uncomplicated gonococcal infection in men and women.
Patients and Methods
The study was conducted at 13 clinical sites across the United States. Patients 16 years or older were eligible to participate, local statute permitting (in some sites, minimum age of consent was 18 years). Male and female patients were enrolled if they had gram-stained or gentian violet-stained urethral or endocervical smears showing gram-negative diplococci, or diplococci within polymorphonuclear leukocytes. Women were also eligible to participate if they had a history of a positive culture or nonculture test for gonorrhea within the previous 14 days and had not yet been treated, or if they had a history of sexual exposure within the previous 14 days to a male with gonorrhea. Women of childbearing potential were required to have a negative serum or urine pregnancy test within 48 hours of receiving study medication and to use an effective method of contraception for the duration of the study. Patients were excluded for any of the following conditions: signs or symptoms of complicated gonococcal infection, confirmed or suspected primary syphilis, receipt of systemic antibiotics within 72 hours of enrollment, pregnancy or lactation, history of hypersensitivity to quinolone antibiotics, malabsorption syndromes, likelihood of noncompliance with study requirements, or known renal, gastrointestinal, or hepatic disease. Each center’s Institutional Review Board approved the study and all participants gave written informed consent.
Procedures and Diagnostic Tests
Pretreatment assessment occurred within 48 hours of initiating study medication and included medical history, physical examination, measurement of vital signs, standard blood and urine panels, and pregnancy test for women. Clinical evaluation was performed, including assessment of potential signs and symptoms of gonococcal infection. (Assessed signs and symptoms of potential gonococcal infection in males included urethral discharge, dysuria, urethritis, lymphadenopathy, and penile or urethral pain, edema, or itching. Assessed signs and symptoms of potential gonococcal infection in females included vaginal discharge or increased vaginal discharge, mucopurulent cervical exudate, cervicitis, dysuria, metrorrhagia, vaginal itching, intermenstrual bleeding, abdominal pain, vaginal erythema, friable cervix, lymphadenopathy, or pharyngitis.) Swab specimens were obtained from the urethra and pharynx in males, and from the endocervix, pharynx, and rectum in females. Rectal swabs were obtained for males with a history of anorectal sexual exposure, and urethral swabs were obtained for females with absent or surgically removed cervix. Among participants at two study sites (Birmingham and Indianapolis), swab specimens for C trachomatis culture were also obtained from the urethra (males) or endocervix (females).
Study Design and Treatment
Patients were randomized to the study by means of a centralized telephone call-in system. The randomization program used a dynamic balancing algorithm to adjust assignment probabilities to minimize imbalance of treatment arms by gender and study site. Patients were allocated to receive a single-dose regimen of gatifloxacin 400 mg (one tablet), gatifloxacin 600 mg (one 400-mg tablet and one 200-mg tablet), or ofloxacin 400 mg (one tablet) in a 2:2:1 ratio. Study drugs were packaged in double-blind, double-dummy blister cards to mask differences in dosage regimens, with each patient receiving the same number and combination of capsules and tablets. Medication was administered orally to each patient under direct observation at the clinical site, and neither the investigator nor the patient knew the identity of the regimen used. Because some quinolone antibiotics have been associated with phototoxicity, patients were instructed to avoid excessive sunlight or artificial ultraviolet light. Patients were also instructed to avoid taking iron tablets, antacids, or other medications that may inhibit quinolone absorption from the gastrointestinal tract.
Patients were instructed to return for follow-up examination 4 days to 10 days after treatment. At this visit, physical examination was performed and vital signs were measured; cultures for N gonorrhoeae were repeated, as were those for C trachomatis at all sites where tested at study enrollment; and routine blood and urine laboratory tests were repeated. Adverse events reported by the patient or observed by the investigator were recorded. Additional treatment was provided for concurrent C trachomatis or other sexually transmitted infection only after the patient had completed his or her participation in the study (i.e., after posttreatment cultures were obtained at the day 4 to day 10 follow-up visit). Pretreatment signs or symptoms of gonorrhea were reassessed, and clinical response was recorded as symptoms resolved, symptoms persisted, or unable to determine. (This last category was used to classify persons who were incompletely assessed at follow-up examination or who received another antigonococcal antibiotic before follow up.) Bacteriologic efficacy was based on posttreatment culture results for N gonorrhoeae and recorded as eradicated, persisted, or unable to determine. Assessment was also made of potential sexual reexposure since treatment. Four males and 10 females received antigonococcal medication at follow up because of persistent signs or symptoms or potential reexposure.
All specimens for isolation of N gonorrhoeae were inoculated onto modified Thayer-Martin media and incubated at 35 °C in a carbon dioxide-rich atmosphere. Presumptive gonococcal isolates were confirmed by standard carbohydrate use or immunochemical methods. Positive cultures were tested for susceptibility to gatifloxacin, ofloxacin, and ciprofloxacin using agar dilution methodology. Isolates were also tested for β-lactamase production using the chromogenic cephalosporin method. Hematology, blood chemistry, and urinalysis tests were performed by a central reference laboratory according to standard methods. Specimens from participants in Birmingham and Indianapolis were also processed using standard cell-culture systems to isolate and identify C trachomatis.
Standard descriptive statistics were used to characterize the study population. Chi-square or two-tailed Fisher exact tests were used to determine relative response to therapy and frequency of adverse events. Exact 95% confidence intervals of overall eradication rates were computed for each treatment arm.
Demographic characteristics of the study sample are provided in Table 1. A total of 728 patients were enrolled in the study and received study medication. Ten additional patients were enrolled but did not receive treatment because of study ineligibility or withdrawal of consent. There were no significant differences across treatment regimens by gender, race, or age of study participants. A total of 554 persons (75%) were evaluable for bacteriologic efficacy analysis. Primary reasons for unevaluability of enrolled patients were negative pretreatment culture for N gonorrhoeae (122 patients) and lack of posttreatment follow-up assessment (44 patients).
Bacteriologic Response: Eradication of N gonorrhoeae
All three treatment regimens showed high levels of bacteriologic efficacy against N gonorrhoeae in evaluable patients (Table 2). There were no significant differences in eradication rates across the three treatment arms. Among men, urethral infection was eradicated in 293 of 294 persons treated (> 99%) and pharyngeal infection was eradicated in all nine persons treated. The lone patient with a positive urethral culture at follow up acknowledged unprotected sexual contact with an infected partner between the day of treatment and the follow-up visit. The pretreatment isolate was fully susceptible to gatifloxacin (MIC, 0.008 μg/ml). Among women, uncomplicated endocervical infection was eradicated in 258 of 260 patients treated (99%), and cure was achieved for 100% of rectal and pharyngeal infections treated (43 patients and 22 patients, respectively). One patient with a positive endocervical culture at follow up acknowledged having unprotected sexual contact with an untreated partner, and the gonococcal isolate identified at the follow-up visit differed in antibiotic susceptibility from the pretreatment isolate, suggesting reinfection (pretreatment MIC, 0.008 μg/ml). The other patient with a positive follow-up culture denied sexual contact since treatment, and pretreatment and posttreatment isolates showed the same antibiotic susceptibility profile, with a gatifloxacin MIC of 0.004 μg/ml.
Clinical Response: Resolution of Symptoms
Assessment of clinical response was based on resolution or improvement of signs and symptoms of gonococcal infection present at enrollment in 554 evaluable patients (Table 3). Four male and 49 female patients were asymptomatic at enrollment and were excluded from the analysis of clinical response. Symptomatic improvement was noted in 96% of male patients (278 of 290 patients) and in 73% of female patients (155 of 211 patients) at follow up on day 4 to day 10. All three treatment regimens were equally efficacious in achieving clinical response. Persistent signs and symptoms were generally nonspecific for gonococcal infection. None of the symptomatic female patients and only one of the symptomatic male patients (described previously) had a positive culture for N gonorrhoeae at the follow-up examination. As noted previously, 14 patients were treated with antigonococcal medication at follow up because of persistent signs or symptoms or possible reexposure.
Safety and Tolerability
Adverse clinical events occurred in 226 (31%) of patients who were treated. Approximately 74% of all reported adverse events were judged by investigators to be certainly, probably, or possibly drug related. There were no significant differences in the incidence or distribution of adverse events across the three treatment groups (Table 4). The most commonly reported adverse events were gastrointestinal intolerance (nausea, diarrhea, vomiting, or abdominal pain), though these events were no more likely to occur in the gatifloxacin-treated patients than in those receiving ofloxacin. Other commonly reported adverse events included headache, dizziness, and nonmonilial vaginitis (among women). Vaginal yeast infections were uncommon (1–3% of treated women) and did not differ by treatment group. The majority of drug-related adverse events were determined to be mild (74%) or moderate (24%) in severity. The only serious adverse event (hospitalization for elective tonsillectomy 3 weeks after receiving 400 mg gatifloxacin) was determined to be unrelated to the study medication. Slightly fewer drug-related adverse events were seen among patients taking 400 mg gatifloxacin relative to those receiving 600 mg gatifloxacin (22% versus 26%), though this difference was not statistically significant (P = 0.29).
Antimicrobial Susceptibility of N gonorrhoeae
Pretreatment isolates of N gonorrhoeae from 298 male urethral specimens and 252 female endocervical specimens were tested for antibiotic susceptibility against gatifloxacin, ofloxacin, and ciprofloxacin (except for one endocervical specimen, which was not tested against ciprofloxacin) (Fig. 1). Minimum inhibitory concentrations to gatifloxacin ranged from 0.001 μg/ml to 0.25 μg/ml, whereas MICs to ofloxacin and ciprofloxacin ranged from 0.001 μg/ml to 2.0 μg/ml and from 0.001 μg/ml to 0.5 μg/ml, respectively. More than 99% of male urethral isolates had gatifloxacin and ciprofloxacin MICs ≤ 0.016 μg/ml, and all male isolates demonstrated MICs ≤ 0.063 μg/ml for all three fluoroquinolones. Among female endocervical specimens, 99% of isolates demonstrated gatifloxacin and ofloxacin MICs ≤ 0.03 μg/ml and ciprofloxacin MICs ≤ 0.016 μg/ml. Two endocervical isolates had reduced fluoroquinolone susceptibility, with a ciprofloxacin MIC of 0.5 μg/ml and ofloxacin MICs of 1 μg/ml and 2 μg/ml; the gatifloxacin MICs for these isolates were 0.125 μg/ml and 0.25 μg/ml. No treatment failures due to reduced fluoroquinolone susceptibility were documented.
A total of 310 male urethral isolates and 264 female endocervical isolates were tested for β-lactamase production. Of these, 28 urethral specimens (9%) and 12 endocervical specimens (5%) were positive for β-lactamase. There were no differences in β-lactamase producing strains across treatment groups, and no treatment failures were identified in persons with β-lactamase–positive strains.
Response in Patients With Chlamydial Infection
Ninety-eight participants from two study sites were evaluated for chlamydial infection before receiving treatment with gatifloxacin or ofloxacin. C trachomatis was isolated in eight of 41 men (20%) and in 25 of 57 women (44%) tested before treatment. Among the 26 subjects who returned for test-of-cure cultures after treatment, C trachomatis was isolated in zero of six males and in 9 of 20 females (45%). All six evaluable males had been treated with gatifloxacin (three with a 400-mg dose and three with a 600-mg dose). Among evaluable females, persistence of C trachomatis was seen in four of seven persons treated with 400 mg of gatifloxacin (57%), in two of eight persons treated with 600 mg of gatifloxacin (25%), and in three of five persons treated with ofloxacin (60%) (P = 0.39).
This multicenter, randomized, double-blind trial is the largest oral antigonococcal treatment study reported to date. The trial showed that treatment with a single oral dose of gatifloxacin (400 mg or 600 mg) is equally efficacious to treatment with a single 400-mg oral dose of ofloxacin for the treatment of uncomplicated gonococcal infections. Cure rates for all three regimens were 99% or greater, and no statistical differences in bacteriologic or clinical efficacy were noted across the three treatment regimens studied. All regimens cured 100% of pharyngeal and rectal infections, albeit with small numbers of participants in each treatment group. Among all patients treated with gatifloxacin, slightly fewer side effects (and equivalent bacteriologic and clinical efficacy) occurred in those receiving the lower dose, supporting the use of the 400-mg single-dose regimen for routine therapy.
These findings suggest that single-dose gatifloxacin is a useful first-line agent for the treatment of uncomplicated genitourinary, pharyngeal, or anorectal infection with N gonorrhoeae. Clinical outcomes in this trial were comparable to those achieved with regimens currently recommended by the CDC. 14 Handsfield et al 17 outline the necessary characteristics of regimens for routine treatment of gonorrhea, including activity against all gonococci circulating in the community, cure rates approaching 100% for genital and rectal infections, high levels of antibiotic in blood or infected tissues, and few serious adverse events. Despite increasing prevalence of N gonorrhoeae with relative resistance to some fluoroquinolones, these agents remain useful for treatment of gonococcal infections owing to a favorable safety profile, high cure rates, and oral rather than parenteral administration. 18,19 In this study, MICs for gatifloxacin were substantially lower than those for ciprofloxacin and ofloxacin, even among strains with decreased fluoroquinolone susceptibility. Therefore, gatifloxacin may prove valuable for treating gonococcal infections in areas with an increasing prevalence of ciprofloxacin-resistant N gonorrhoeae, 8–12 and in settings with high levels of plasmid-mediated and chromosomally-mediated resistance to penicillin and tetracycline. Although still relatively uncommon, gonococcal isolates with reduced fluoroquinolone susceptibility are increasingly identified in the United States. 3–7 In 1998, the CDC noted that 44 of 4,712 isolates (0.9%) submitted to the national Gonococcal Isolate Surveillance Project exhibited intermediate resistance to ciprofloxacin (MICs, 0.125–0.5 μg/ml), and four isolates were resistant to ciprofloxacin (MICs ≥ 1.0 μg/ml). 20 The efficacy of gatifloxacin for the treatment of uncomplicated gonorrhea caused by such strains remains to be determined in clinical trials with larger numbers of ciprofloxacin-resistant and ofloxacin-resistant isolates.
Relatively high levels of coinfection with C trachomatis were documented among the 98 persons tested (20% of males, 44% of females), a finding that is consistent with previous studies. 14,21 As expected, single-dose treatment with gatifloxacin or ofloxacin did not reliably eradicate genital tract infection with C trachomatis. Among 20 female patients at two study sites who were tested for endocervical C trachomatis before and after treatment, persistence of chlamydial infection was documented in 45%, and response to therapy did not vary according to treatment regimen. Although urethral chlamydial infection was eradicated in all six evaluable male patients, there were no patients in the ofloxacin-comparator treatment regimen, and no conclusions may be drawn as to the efficacy of gatifloxacin with such a small evaluable sample size. Fluoroquinolones show in vitro activity against C trachomatis, but extended treatment regimens are generally needed to eradicate clinical infection. Therefore, patients treated with gatifloxacin for uncomplicated gonococcal infection should also be treated empirically with an antichlamydial regimen of documented efficacy if chlamydial infection is suspected or documented. Further studies are required to determine the clinical efficacy of gatifloxacin for the treatment of chlamydial urethritis and cervicitis.
Gatifloxacin, given as a 400-mg or 600-mg single oral dose, is safe and effective for the treatment of uncomplicated gonococcal infection in men and women. Eradication rates of N gonorrhoeae are comparable with other approved treatment regimens, with favorable safety profiles. Both gatifloxacin doses were equally efficacious in this trial, though activity against quinolone-resistant isolates could not be evaluated. Among smaller subgroups, there were no treatment failures for rectal and pharyngeal infection, suggesting an efficacy for treating these sites of infection, as well as urethral and endocervical sites. A single 400-mg dose of gatifloxacin can be recommended for treatment of uncomplicated gonococcal infection.
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