Original Article
A Comparison of Single-Dose Cefixime with Ceftriaxone as Treatment for Uncomplicated Gonorrhea
N Engl J Med 1991; 325:1337-1341November 7, 1991
- Abstract
- Abstract
Background.
Because of the widespread existence of Neisseria gonorrhoeae resistant to penicillin or tetracycline, ceftriaxone is now recommended for the treatment of gonorrhea. There is, however, a need for effective antibiotics that can be administered orally as an alternative to ceftriaxone, which requires intramuscular administration. Cefixime is an orally absorbed cephalosporin that is active against resistant gonococci and has pharmacokinetic activity suitable for single-dose administration.
Methods and Results.
In a randomized, unblinded multicenter study of 209 men and 124 women with uncomplicated gonorrhea, we compared three single-dose treatment regimens: 400 mg or 800 mg of cefixime, administered orally, and 250 mg of ceftriaxone administered intramuscularly. The overall cure rates were 96 percent for the 400-mg dose of cefixime (89 of 93 patients) (95 percent confidence interval, 93.5 to 97.8 percent); 98 percent for the 800-mg dose of cefixime (86 of 88 patients) (95 percent confidence interval, 94.6 to 100 percent); and 98 percent for ceftriaxone (92 of 94 patients) (95 percent confidence interval, 94.9 to 100 percent). The cure rates were similar in men and women, and pharyngeal infection was eradicated in 20 of 22 patients (91 percent). Thirty-nine percent of 303 pretreatment gonococcal isolates had one or more types of antimicrobial resistance; the efficacy of all three regimens was independent of the resistance pattern. Chlamydia trachomatis infection persisted in at least half the patients infected in each treatment group. All three regimens were well tolerated.
Conclusions.
In the treatment of uncomplicated gonorrhea, a single dose of cefixime (400 or 800 mg) given orally appears to be as effective as the currently recommended regimen of ceftriaxone (250 mg given intramuscularly). (N Engl J Med 1991;325:1337–41.)
Media in This Article
Table 1
Demographic Characteristics of 333 Patients Treated with Cefixime or Ceftriaxone for Uncomplicated Gonorrhea.Table 2
Eradication of N. gonorrhoeae, According to Sex and Site of Infection.Article Activity
- Article
THE proportion of isolates of Neisseria gonorrhoeae in the United States that had absolute or relative resistance to the penicillins or tetracyclines rose greatly in the 1980s, especially in the second half of the decade.1 By 1989, ≥5 percent of cases of gonorrhea were caused by strains that produced plasmid-mediated β-lactamase (penicillinase),2 and ≥17 percent of isolates had chromosomally mediated resistance to the penicillins or tetracyclines1; almost all areas of the country have been affected. Accordingly, the U.S. Public Health Service now recommends the administration of 250 mg of ceftriaxone intramuscularly as the single-dose regimen of choice for all cases of uncomplicated gonorrhea.3 However, intramuscular administration is inconvenient, and many clinicians may prefer to reduce the frequency with which needles are used in populations at risk for infection with human immunodeficiency virus. Cefixime is a new, orally administered cephalosporin with excellent activity against N. gonorrhoeae with and without chromosomally mediated or plasmid-mediated antimicrobial resistance.4 , 5 Its pharmacokinetic properties4 , 6 , 7 suggest that single doses of cefixime should be effective for treatment of uncomplicated gonorrhea, and preliminary clinical studies have shown promising results.8 , 9 In a multicenter study of men and women with uncomplicated gonorrhea, we compared the efficacy and tolerance of cefixime in a dose of either 400 mg or 800 mg administered orally with those of ceftriaxone in a dose of 250 mg administered intramuscularly.
Methods
Patients
The patients studied were recruited at public clinics for sexually transmitted diseases in Seattle, Brooklyn, Baltimore, and Denver. The lower age limit was 16 years at the Seattle center and 18 years at the other study centers. Patients were enrolled if they had Gramstained urethral or endocervical smears showing gram-negative diplococci within polymorphonuclear leukocytes or, in women, a history of sexual exposure to a man with urethral gonorrhea. Isolation of N. gonorrhoeae at enrollment was required in order to evaluate the efficacy of treatment. Patients were excluded if they had signs or symptoms of complicated gonorrhea; were pregnant or nursing; were known to have gastrointestinal, hepatic, or renal disease; or had a history of an immediate hypersensitivity reaction to β-lactam drugs.
The study was approved by each study center's institutional review board, and all participants gave written informed consent.
Diagnostic Tests
Specimens for the isolation of N. gonorrhoeae were obtained from the urethra and pharynx in men and from the rectum if there was a history of exposure. Endocervical, rectal, and pharyngeal specimens were obtained from women. Specimens for Chlamydia trachomatis culture were obtained from the urethra in men and the cervix in women. A serologic test for syphilis, a complete blood count, a blood chemistry profile, and urinalysis were performed.
Treatment and Study Design
The patients were treated in an unblinded fashion with 400 mg or 800 mg of cefixime orally or with 250 mg of ceftriaxone (in 1 percent lidocaine) intramuscularly. The first 294 patients were assigned to one of the three regimens in a 1:1:1 distribution according to a computer-generated random-number program. Initially, more women treated with 800 mg of cefixime could be evaluated than women treated with the other two regimens. Therefore, an additional 39 women were enrolled in Brooklyn and Seattle and assigned to treatment with 400 mg of cefixime or ceftriaxone in a 2:1 ratio.
Efficacy was evaluated only in the patients who returned for examination and culture for N. gonorrhoeae 3 to 10 days after treatment. At the follow-up visit, specimens for culture of N. gonorrhoeae and C. trachomatis were obtained from all anatomical sites from which specimens had been obtained at enrollment, except that chlamydia cultures were not repeated in Denver. Efficacy was assessed on the basis of the post-treatment culture results, without regard to symptoms, signs, or history of sexual reexposure. Patients from whom C. trachomatis was isolated at enrollment were treated at their follow-up visit; in Brooklyn, all patients were given antichlamydial treatment at follow-up.
Laboratory Procedures
Specimens for the isolation of N. gonorrhoeae were inoculated directly onto selective mediums containing antibiotics and were promptly incubated at 35°C in a carbon dioxide-rich environment. All presumptive gonococcal isolates were confirmed by carbohydrate-utilization tests or immunochemical methods. β-Lactamase production was determined by the chromogenic cephalosporin method.10 The minimal inhibitory concentrations (MICs) of cefixime, ceftriaxone, penicillin G, tetracycline hydrochloride, and spectinomycin were determined by agar dilution; all four laboratories used the same recently described method.1 Plasmid-mediated tetracycline resistance was defined phenotypically by a tetracycline MIC of ≥16 mg per liter.1 An isolate was considered to have chromosomally mediated resistance if the MIC of tetracycline was 2.0 to 8.0 mg per liter or if the isolate did not produce β-lactamase and the MIC of penicillin G was ≥2.0 mg per liter.1 Each laboratory used its standard cell-culture system to isolate and identify C. trachomatis. The hematologic and biochemical tests, urinalysis, and serologic tests for syphilis were performed according to standard methods in each center's clinical laboratory.
Statistical Analysis
Chi-square analysis or Fisher's exact test (two-tailed) was used to compare the responses to therapy and the frequency of side effects.
Results
Study Population
The demographic characteristics of the patients are summarized in Table 1Table 1
Demographic Characteristics of 333 Patients Treated with Cefixime or Ceftriaxone for Uncomplicated Gonorrhea.. There were no significant differences among the four study centers in the distribution of patients according to age, sex, or race (data not shown). All patients described themselves as heterosexual except two men and two women who described themselves as bisexual. Treatment efficacy against gonorrhea could be determined in 275 of the 333 patients enrolled (83 percent), and safety and tolerance in 302 (91 percent). Among the 58 patients in whom efficacy or tolerance could not be determined, there were 26 in whom N. gonorrhoeae was not isolated before treatment, 30 who failed to return for follow-up within 10 days, and 2 who received additional antimicrobial therapy before follow-up.Eradication of N. gonorrhoeae
The overall cure rates in men and women combined were 96 to 98 percent for the three regimens (Table 2Table 2
Eradication of N. gonorrhoeae, According to Sex and Site of Infection.). Two women treated with 400 mg of cefixime had rectal but not cervical infection; therefore, a complete cure of genital and rectal infection was achieved in 33 of 35 women treated with 400 mg of cefixime (94 percent), 24 of 25 treated with 800 mg of cefixime (96 percent), and 28 of 29 treated with ceftriaxone (97 percent). There were no significant differences in efficacy between the four study centers (data not shown). All six subjects with persistent genital or rectal gonorrhea denied sexual reexposure. The pretreatment and post-treatment isolates from four of these six patients were available for auxotyping11 and serotyping12; the post-treatment isolates of all four showed no change (data not shown).Tolerance and Safety
Table 3Table 3
Side Effects in 302 Patients Followed to Assess the Safety of and Tolerance to Treatment.* shows the side effects judged to be definitely, probably, or possibly due to treatment. All regimens were well tolerated. Of the 44 patients with side effects, 38 (86 percent) had reactions judged to be mild and 6(14 percent) had reactions considered moderate; none had severe reactions.All reactions resolved rapidly (usually within 24 hours) without treatment. The incidence of all gastrointestinal side effects in the patients given 800 mg of cefixime (16 of 91 patients [18 percent]) was higher than in those given 400 mg (9 of 107 [8 percent], P = 0.06) or the patients given ceftriaxone (4 of 104 [4 percent], P = 0.004); the difference between the latter two groups in the incidence of reactions was not significant. No patient vomited. Seven patients given ceftriaxone had post-injection pain; the pain was mild in all seven. One patient treated with ceftriaxone described having a generalized, nonpruritic skin rash the day of treatment, but no abnormality was observed at follow-up four days later.
Antimicrobial Susceptibility of N. gonorrhoeae
The pretreatment isolates of N. gonorrhoeae from 303 patients survived storage and were available for antimicrobial-susceptibility testing. At least one type of resistance was present in 118 isolates (39 percent). Seventy-nine isolates (26 percent) produced β-lactamase, 36 (12 percent) had plasmid-mediated tetracycline resistance, and 35 (12 percent) had chromosomally mediated resistance to penicillin or tetracycline. Gonorrhea was cured in 164 of 167 patients (98 percent) with fully susceptible strains, 23 of 24 (96 percent) infected with strains with chromosomally mediated resistance, 70 of 73 (96 percent) with strains producing β-lactamase, and 28 of 29 (97 percent) infected with plasmid-mediated tetracycline-resistant gonococci; there were no significant differences between the treatment groups in the cure rates.
The MICs of the five antibiotics tested were in the expected range (Table 4Table 4
Antimicrobial Susceptibility of 303 Pretreatment Isolates of N. gonorrhoeae*). Among the six subjects with persistent infection after cefixime therapy, the MICs of cefixime for the pretreatment gonococcal isolates were 0.004 mg per liter in three patients and 0.015 mg per liter in three. The pretreatment isolates from the two patients who had persistent infection after treatment with ceftriaxone had MICs of ceftriaxone of 0.001 and 0.004 mg per liter.Chlamydial Infection
C. trachomatis was isolated before treatment in 48 of 311 subjects (15 percent) who had technically satisfactory pretreatment cultures. Among the 31 subjects who returned and had post-treatment cultures, the organism was isolated again from 26 (84 percent), including all 12 treated with 400 mg of cefixime, 5 of 10 treated with 800 mg of cefixime, and all 9 treated with ceftriaxone (chi-square = 12.52 with 2 df, P<0.01). In addition, C. trachomatis was first isolated at follow-up in seven patients who were not tested or who had negative cultures before treatment, including one given 400 mg of cefixime, three given 800 mg of cefixime, and three given 250 mg of ceftriaxone.
Discussion
In this randomized study, single doses of 400 mg or 800 mg of cefixime given orally and 250 mg of ceftriaxone given intramuscularly had similar efficacy in the treatment of uncomplicated gonorrhea, with cure rates of 96 to 98 percent. Cefixime appeared to be effective against pharyngeal as well as genital and rectal infection, although the number of patients with pharyngeal infection was small. Thirty-nine percent of the gonococcal isolates had one or more types of antimicrobial resistance, and the efficacy of all three regimens was independent of the type of resistance. Megran et al.9 reported that 800 mg of cefixime cured 96 of 97 men with gonococcal urethritis (99 percent), and Kuhlwein and Nies8 found that 400 mg cured all of 30 men with urethral infections. To date, in studies supported by the manufacturer of cefixime in four countries (including the present study), the overall cure rate for uncomplicated gonorrhea in men treated with 400 mg was 97 percent (192 of 197 patients; 95 percent confidence interval, 95.2 to 99.7 percent), and the rate in men treated with 800 mg was 98 percent (174 of 177 patients; 95 percent confidence interval, 96.4 to 100 percent). The corresponding rates in women were 97 percent (104 of 107 patients; 95 percent confidence interval, 94.1 to 100 percent) and 96 percent (43 of 45 patients; 95 percent confidence interval, 89.5 to 100 percent) (Marinaccio A, Lederle Laboratories: personal communication, February 26, 1991).
As anticipated, none of the three regimens reliably eradicated C. trachomatis. Although the 800-mg dose of cefixime apparently cured 5 of 10 infections, we believe this was a chance event, despite the apparent statistical significance of the difference in cure rate between this regimen and the other two. In addition, C. trachomatis was first detected after treatment in three other patients given this dose. Megran et al. reported that C. trachomatis infection persisted in 11 of 13 men after treatment with 800 mg of cefixime.9
All three regimens were well tolerated. The most common side effects of cefixime were gastrointestinal, usually consisting of mild diarrhea, loose stools, or flatulence that began several hours to two days after treatment. Mild nausea or epigastric pain occurred in one patient given 400 mg of cefixime and in four treated with 800 mg. We doubt that the few reported episodes of mild fatigue, dizziness, or somnolence were due to treatment.
A regimen for routine treatment of gonorrhea should have several characteristics. The drug used must have excellent activity against all gonococci circulating in the community. Single-dose treatment should result in cure rates that approach 100 percent for genital and rectal infections; we consider 95 percent to be the lowest acceptable rate. To reduce the potential for selection of increasingly resistant strains of N. gonorrhoeae, levels of antibiotic in the blood or infected tissues should substantially exceed the concentrations required to inhibit the most resistant strains for several hours.13 Finally, the regimen should have few serious adverse effects. These criteria are met by many available antibiotics.14 , 15 Accordingly, routine therapy can be chosen on the basis of several secondary desirable properties. These include efficacy against pharyngeal gonorrhea; efficacy in aborting early syphilis; a low potential for rapid selection of high-level antibiotic resistance; safety in women who are nursing, pregnant, or possibly pregnant; minor side effects; convenience (e.g., oral versus intramuscular administration); and low cost.14 , 15 Efficacy against C. trachomatis is also desirable, but no approved single-dose regimen is effective against both gonorrhea and chlamydial infection.
Single-dose treatment with cefixime has many of these secondary attributes. Its efficacy against incubating syphilis has not been studied, but cefixime is active against syphilis in rabbits (Lukehart SA: personal communication). Although studies of cefixime treatment in pregnant and nursing women are lacking, the drug is not teratogenic in animals (Lederle Laboratories, Pearl River, N.Y.: unpublished data), and the cephalosporins as a class are considered safe for pregnant women and young children. By contrast, the currently available quinolones — the most suitable alternatives for single-dose oral treatment14— are inactive against Treponema pallidum 16 and are widely considered to be contraindicated in pregnant or nursing women and young children.17 In addition, the quinolones can readily induce single-step resistance in gonococci and other bacteria,18 , 19 and quinolone-resistant strains of N. gonorrhoeae have appeared in several areas after these drugs were introduced to treat gonorrhea.20 21 22 On the other hand, both the eradication of incubating syphilis and the prevention of resistance may be achieved with a quinolone plus a second agent for chlamydial infection.1 , 3 , 14
Both the 400-mg and 800-mg doses of cefixime produce plasma drug levels that exceed the highest MIC of cefixime yet reported for N. gonorrhoeae (0.125 mg per liter) for more than 24 hours,4 , 6 , 7 suggesting that stepwise selection of resistance is unlikely to be a problem. In gonococci that do not produce β-lactamase, the highest MICs of β-lactam drugs are due to the additive effects of at least three genes, pen A, pen B, and mtr. 23 The maximal MIC of penicillin due to these and other chromosomal genes (2 to 4 mg per liter) has not changed appreciably in four decades,1 and the maximal MIC of the cephalosporins is closely linked to that of penicillin.23 , 24 Unlike the maximal MIC of penicillin, however, that of cefixime is well within the range of concentrations achieved in plasma with single-dose treatments. Therefore, unless unknown genetic mechanisms are discovered or evolve, N. gonorrhoeae seems unlikely to develop clinically important chromosomally mediated resistance to cefixime. The absence of clinically relevant resistance to ceftriaxone after five years of widespread use,1 often in a dose of only 125 mg,25 lends credence to this conclusion. However, TEM-type β-lactamases that are active against third-generation cephalosporins have evolved in many gram-negative species,26 and it will be important to monitor closely the efficacy of cefixime and the susceptibility of N. gonorrhoeae to the cephalosporins.
The average wholesale cost of a 400-mg dose of cefixime is $4.69, as compared with $7.46 for a 250-mg dose of ceftriaxone (when dispensed from 1-g vials).27 The recommended single-dose regimens of ciprofloxacin (500 mg), norfloxacin (800 mg), and ofloxacin (400 mg) have average wholesale costs of $2.55, $4.06, and $3.20, respectively.27 Cefuroxime axetil (1.0 g orally) is effective against genital and rectal gonorrhea14 , 28 but is unreliable against pharyngeal infection28 and has an average wholesale cost of $10.87, including the cost of probenecid (1.0 g).27 These prices vary greatly, however, and public clinics and large institutions can often buy these antibiotics at substantially lower costs.
In summary, single-dose cefixime may now be the preferred choice for initial treatment of uncomplicated gonorrhea, unless the lower cost of the quinolones is of particular importance. We favor the 400-mg dose of cefixime because it costs less and has better gastrointestinal tolerance than the 800-mg dose. However, our sample was too small for a definitive conclusion that these doses are equally effective, and additional data are needed. We are planning studies of a 200-mg dose of cefixime; if this dose is effective, confidence in the 400-mg dose will be enhanced. Regardless of the dose used, cefixime treatment should be followed by a regimen effective against C. trachomatis. Studies are planned to assess the efficacy and tolerance of cefixime when it is given with azithromycin, a new antibiotic that is effective in single doses against genital chlamydial infection.29 , 30
Supported by grants from Lederle Laboratories.
Presented in part at the Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 22, 1990.
We are indebted to Anna Marinaccio (Lederle Laboratories), Judith Hale, B.S., Carol Root, R.N., Kenneth Draft, M.D., Solomon Benes, M.D., Walter Stamm, M.D., and the staffs of the sexually transmitted—disease clinics of the Seattle–King County Department of Public Health, the City of New York Department of Health, the Baltimore City Health Department, and the Denver Department of Public Health.
Note added in proof: The Seattle center has initiated a study of cefixime in a dose of 200 mg for gonorrhea. Of the first 23 men with gonococcal urethritis, 22 (96 percent) were cured.
Source Information
* Other members of the Gonorrhea Treatment Study Group were Nancy A. Siegal, P.A.-C, Seattle; Barry Smith, P.A.-C, and Marinella C. Cummings, M.S., Brooklyn, N.Y.; Catherine Hutchinson, M.D., and Mindy Goldberg, P.A.-C., Baltimore; and Ann M. Schempf, R.N., Denver.
From the Seattle–King County Department of Public Health and the University of Washington, Seattle (H. H. H., M. S. V.); the City of New York Department of Health and the State University of New York Health Sciences Center, Brooklyn (W.M.M., J.M.C.); the Baltimore City Health Department and Johns Hopkins University, Baltimore (E.W.H., C.A.R.); and the Denver Disease Control Service and University of Colorado Health Sciences Center, Denver (J.M.D., J.M.E.). Address reprint requests to Dr. Handsfield at Harborview Medical Center ZA-89, 325 Ninth Ave., Seattle, WA 98104.
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- Citing Articles (16)
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L. M. Newman, J. S. Moran, K. A. Workowski. (2007) Update on the Management of Gonorrhea in Adults in the United States. Clinical Infectious Diseases 44:Supplement 3, S84-S101
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Richard G White, Kate K Orroth, Eline L Korenromp, Roel Bakker, Mwita Wambura, Nelson K Sewankambo, Ron H Gray, Anatoli Kamali, James A. G Whitworth, Heiner Grosskurth, J Dik F Habbema, Richard J Hayes. (2004) Can Population Differences Explain the Contrasting Results of the Mwanza, Rakai, and Masaka HIV/Sexually Transmitted Disease Intervention Trials?. JAIDS Journal of Acquired Immune Deficiency Syndromes 37:4, 1500-1513
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William M Geisler. (2004) Approaches to the management of uncomplicated genital Chlamydia trachomatis infections. Expert Review of Anti-infective Therapy 2:5, 771-785
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THOMAS L. GIFT, CATHLEEN WALSH, ANNE HADDIX, KATHLEEN L. IRWIN. (2002) A Cost-Effectiveness Evaluation of Testing and Treatment of Chlamydia trachomatis Infection Among Asymptomatic Women Infected With Neisseria gonorrhoeae. Sexually Transmitted Diseases 29:9, 542-551
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BRADLEY P. STONER, JOHN M. DOUGLAS, JR, DAVID H. MARTIN, EDWARD W. HOOK, PETER LEONE, WILLIAM M. McCORMACK, TOMASZ F. MROCZKOWSKI, ROBERT JONES, JOANNA YANG, TODD BAUMGARTNER. (2001) Single-Dose Gatifloxacin Compared With Ofloxacin for the Treatment of Uncomplicated Gonorrhea. Sex Transm Dis 28:3, 136-142
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Dennis J. Fortenberry, Edward J. Brizendine, Barry P. Katz, Kara K. Wools, Margaret J. Blythe, Donald P. Orr. (1999) Subsequent Sexually Transmitted Infections Among Adolescent Women With Genital Infection Due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis. Sexually Transmitted Diseases 26:1, 26-32
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LAI YIN CHONG, WAI MAN CHEUNG, CHUN SING LEUNG, CHI WAH YU, LOI YUEN CHAN. (1998) Clinical Evaluation of Ceftibuten in Gonorrhea. Sexually Transmitted Diseases 25:9, 464-467
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Maria J. Wawer, Ronald H. Gray, Nelson K. Sewankambo, David Serwadda, Lynn Paxton, Seth Berkley, Denise McNairn, Fred Wabwire-Mangen, Chuanjun Li, Fred Nalugoda, Noah Kiwanuka, Thomas Lutalo, Ronald Brookmeyer, Robert Kelly, Thomas C. Quinn. (1998) A randomized, community trial of intensive sexually transmitted disease control for AIDS prevention, Rakai, Uganda. AIDS 12:10, 1211-1225
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ANTTI NISSINEN, HELINÄ JÄRVINEN, OILI LIIMATAINEN, MATTI JAHKOLA, PENTTI HUOVINEN. (1997) Antimicrobial Resistance in Neisseria gonorrhoeae in Finland, 1976 to 1995. Sexually Transmitted Diseases 24:10, 576-581
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Peter K. Kohl, Yating Tu, Ulrike Hostalek, Detlef Petzoldt. (1995) Activity of cefixime against Neisseria gonorrhoeae. Journal of the European Academy of Dermatology and Venereology 4:2, 155-159
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