110 1992; 166 (October)
Concise Communications
serovar-specific and common antigenic determinants of the major outer membrane protein of Chlamydia trachomatis. J Exp Med 1988; 167:817-31. 10. Schachter J, Dawson CR. Human chlamydial infections. Littleton, MA: PSG Publishing. 1978. II. Dean D. Patton M, Stephens RS. Direct sequence evaluation of the major outer membrane protein gene variant regions of Chlamydia trachomatis subtypes D'. 1', and L2'. Infect Immun 1991;59: 157982. 12. Fazekas de St Groth S. Webster RG. Disquisitions on original antigenic sin. II. Proof in lower creatures. J Exp Med 1966; 124:347-6 I.
919
13. Su H. Zhang YX. Barrera O. Watkins NO. Caldwell HD. Differential effect of trypsin on infectivity of Chlamydia trachomatis:loss of'infectivity requires cleavage of major outer membrane protein variable domains II and IV. Infect Immun 1988;56:2094-100. 14. Treharne JD. Dwyer RSC, Darougar S. Jones BR. Daghfous T. Antichlamydial antibody in tears and sera and serotypes of Chlamydia trachomatis isolated from school children in southern Tunisia. Br J Ophthalmol 1978;62:509-15. 15. Taylor HR, Siler JA, Mkocha HA, et at. Longitudinal study of the microbiology of endemic trachoma. J Clin Microbiol 1991;29: 1593-5.
Pierre J. Plourde, Mark Tyndall, Elizabeth Agoki, John Ombette, Leslie A. Slaney, Lourdes J. D'Costa, Jackoniah O. Ndinya-Achola, and Francis A. Plummer
World Health Organization Centre for Research and Training on Sexually Transmitted Diseases, Department of Medical Microbiology. University of Nairobi, and Special Treatment Clinic, Nairobi City Commission, Kenya; Departments ofInternal Medicine and Medical Microbiology, University ofManitoba, Canada
Sexually transmitted diseases (STDs) have had a significant adverse effect on reproductive and child health worldwide. The control of STDs such as gonorrhea is therefore an absolute priority. Cefixime, an oral third-generation cephalosporin with in vitro activity similar to that of ceftriaxone, may be an effective candidate for the treatment of gonorrhea. The efficacy of a single oral 400-mg dose of cefixime was compared with that of a single intramuscular 250-mg dose of ceftriaxone for the treatment of Neisseria gonorrhoeae urethritis in 190 men and cervicitis in 46 women in Nairobi, Kenya. A bacteriologic cure was recorded in 100% of63 evaluatable patients treated with ceftriaxone and 118 (98%) of 121 evaluatable patients treated with cefixime. Cefixime, as a single oral dose, is an effective alternative for the treatment of uncomplicated gonococcal urethritis in men and cervicitis in women.
Sexually transmitted diseases (STDs), including gonorrhea, have had a significant adverse effect on reproductive and child health worldwide. Slowing the spread ofgonorrhea is a major public health priority at this time. Treatment of Neisseria gonorrhoeae infection has been complicated by the
Received 3 February 1992; revised 4 May 1992. Presented in part: Ninth meeting of the International Society for Sexually Transmitted Diseases Research. Banff, Canada, October 1991. This study received institutional review board approval from the University of Manitoba and the University of Nairobi. Verbal informed consent was obtained prior to enrollment into the study. Financial support: American Cyanamid Company, Lederle Laboratories; Medical Research Council ofCanada (fellowships to PJ.P. and M.T., Scientist award to EA.P.). Reprints or correspondence: Dr. Pierre J. Plourde, Department of Medical Microbiology. Basic Sciences Building. Room 544. 730 William Ave., Winnipeg. Manitoba. Canada. R3E OW3. The Journal of Infectious Diseases 1992;166:919-22 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0037$01.00
emergence of chromosomally and plasmid-mediated antimicrobial-resistant strains [1]. Plasmid-mediated resistance, first reported in 1976. resulted in the emergence of penicillinase-producing N. gonorrhoeae [2]. Third-generation cephalosporins offer an excellent therapeutic choice because of their intrinsic .B-lactamase resistance. Intramuscular ceftriaxone has been established as an ideal treatment for N. gonorrhoeae [3] and is currently the recommended first-line therapy of choice [4]. However, wherever possible, it would be preferable to avoid parenteral therapy when an efficacious oral antibiotic exists. Cefixime, an orally administered third-generation cephalosporin, has favorable phamacokinetics for single-dose treatment of uncomplicated gonorrhea [5] and has high in vitro activity against antimicrobial-resistant isolates of N. gonorrhoeae [6,7]. This study was designed to determine the safety and efficacy of a single 400-mg oral dose of cefixime compared with a single 250-mg intramuscular (im) dose of ceftriaxone for
Downloaded from http://jid.oxfordjournals.org/ at University of Birmingham on June 15, 2015
Single-Dose Cefixime versus Single-Dose Ceftriaxone in the Treatment of Antimicrobial-Resistant Neisseria gonorrhoeae Infection
920
Concise Communications
the treatment of uncomplicated gonorrhea in men and women attending an STD clinic in Nairobi, Kenya.
Materials and Methods
dourethral and endocervical swabs were obtained using calcium alginate or dacron swabs and placed in a sucrose-buffered-phosphate transport medium. Specimens were then inoculated onto monolayers of McCoy cells by centrifugation and incubated for 72 h at 37°C. After fixing, cells were stained with monoclonal antibodies (Microtrak; Syva, Kanata, Canada) and read with a fluorescent microscope. Alternatively, swabs were processed using an EIA diagnostic kit (Chlamydiazyme; Abbott, Abbott Park,IL). Data analysis. Univariate analysis was done on selected variables using x 2 for parametric and Student's t test for nonparametric data.
Results Of the 236 patients enrolled, 159 received cefixime and 77 received ceftriaxone. There were no significant differences between study groups with respect to age, marital status, number of sex partners, prostitute exposures, condom use, or duration of symptoms (data not shown). All patients were heterosexual and none reported sexual practices other than vaginal intercourse. Microbiologic response is shown in table 1. A total of 46 patients (19.5%) were lost to follow-up. One patient in the ceftriaxone group was excluded from further analysis because she had been inadvertently enrolled with no positive cultures. Five patients with cultures positive for C. trachomatis and negative for N. gonorrhoeae (2 in the ceftriaxone group and 3 who received cefixime) were excluded. Six men (10%) in the ceftriaxone group and 16 men (13%) in the cefixime group who had intracellular gram-negative diplococci on Gram's stain of their urethral discharge but who were culture negative were also included in the analysis. There were 63 and 121 evaluatable patients in the ceftriaxone and cefixime treatment groups, respectively. Eradication, defined by a culture negative for N. gonorrhoeae at the follow-up visit, was seen in 118 (98%) of 121 patients receiving cefixime and in all 63 patients treated with ceftriaxone. Eradication rates for cefixime were 98% for men and 96% for women (table 1). Treatment failed for 3 subjects, 2 single men who presumably had persistent infections (1 complicated by epididymitis) and 1 woman who reported unprotected sexual intercourse with her untreated boyfriend during the study period (considered to have a probable reinfection). A positive pharyngeal culture was seen in one woman who was cured after receiving ceftriaxone. No men had positive pharyngeal cultures and no women had positive rectal cultures. Eight patients had chlamydial infection at enrollment. C. trachomatis cultures were done at follow-up for 173 patients (73%). Six cultures (3%) were positive, three in each treatment group. In each of the treatment groups, I patient had positive cultures at both baseline and follow-up visits, and 2 patients had negative baseline chlamydial cultures and positive follow-up cultures.
Downloaded from http://jid.oxfordjournals.org/ at University of Birmingham on June 15, 2015
Study population. Patients 18-65 years old attending the Nairobi City Commission Special Treatment Clinic from October 1989 to August 1990 were recruited. Men were enrolled if a Gram's stain of their urethral discharge showed intracellular gram-negative diplococci. Women were enrolled if a culture of their cervical discharge was positive for N. gonorrhoeae. At enrollment, demographic information and a medical history including sexually transmitted diseases and sexual practices were obtained from each patient in an interview using a standard questionnaire. General physical and genital examinations were done; swab specimens in men (urethral) and women (cervical) were cultured for N. gonorrhoeae and Chlamydia trachomatis. In addition, pharyngeal swabs from all patients and rectal swabs from women were cultured only for N. gonorrhoeae. Therapy was assigned using consecutive randomization envelopes with a predetermined 2: I cefixime-to-ceftriaxone ratio. Patients randomized to receive cefixime were given a single 400mg oral dose in the presence of the clinical investigator. Those who received ceftriaxone were given a 250-mg im injection. Counseling concerning STDs, high-risk sexual practices, and condom use was offered. Patients were instructed to abstain from sexual intercourse or genital contact during the study period and were encouraged to refer sex partners for examination and treatment. A follow-up appointment was scheduled for 4-7 days after enrollment. At the follow-up, a medical and sexual history was obtained, a physical examination was done, and swabs were obtained from affected areas for culture. Patients were questioned about adverse experiences that had occurred since the initial visit. To be evaluatable, a patient had to have a baseline culture positive for N. gonorrhoeae (or a positive Gram's stain in men), a follow-up visit in 4-7 days, and no other antimicrobials taken within 72 h prior to or during the study. Patients with complicated gonococcal infection such as pelvic inflammatory disease, hypersensitivity to penicillins or cephalosporins, any other STDs, or pregnancy were excluded. Laboratory methods. N. gonorrhoeae and C. trachomatis were cultured using standard media and techniques. Culture swabs were inoculated directly onto modified Thayer-Martin agar [8] and incubated in humidified candle-extinction jars (3%5%CO2) for 48 h. N. gonorrhoeae was identified by colony morphology, Gram's stain, and oxidase reactivity. ,B-lactamase production was assayed by a rapid chromogenic cephalosporin method (Becton Dickinson, Cockeysville, MD). Isolates of N. gonorrhoeaewere tested by agar-dilution methods for susceptibility to cefixime, ceftriaxone, penicillin G, tetracycline, and spectinomycin. Plasmid-mediated tetracycline resistance was defined by a tetracycline MIC of ~ 16 JLg/mL [9]. An isolate was considered to have chromosomally mediated resistance to tetracycline if the MIC was 2.0-8.0 JLg/mL or to penicillin if the MIC was ~2.0 JLg/mL in the absence of ,B-Iactamase production [9]. C. trachomatis was identified using one of two methods. En-
1ID 1992; 166 (October)
lID 1992; 166 (October)
Concise Communications
921
Table 1. Microbiologic response to cefixime or ceftriaxone in 236 patients with Neisseria gonorrhoeae infection. No. (%)of patients Antibiotic. group (n) Cefixime Men (127) Women (32) Ceftriaxone Men (63) Women (14)
Lost to follow-up
Excluded*
Evaluatable
With eradication of infection t
95% CI eradication rate
31 (24) 4 (13)
3 (2) 0
93 (73) 28 (88)
91 (98) 27 (96)
95.6-100 89.2-100
10(16) I (7)
2 (3) I (7)
51 (81) 12 (86)
51 (100) 12(100)
99.1-100 98.2-100
A total of 164 N. gonorrhoeae isolates obtained at enrollment and surviving storage and transportation from Nairobi to Winnipeg were assayed for MICs against several antibiotics (table 2). The high MICs of penicillin G and tetracycline confirmed a high level of resistance to these antibiotics in this population. Penicillinase production was found in 108 strains (66%) and plasmid-mediated tetracycline resistance was present in 47 (29%). Chromosomally mediated resistance to tetracycline and penicillin was seen in 113 (69%) and 43 (26%) strains, respectively. Only I strain showed no resistance. The MICs of both ceftriaxone and cefixime were favorable for single-dose therapy. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or ciprofloxacin. The 3 N. gonorrhoeae isolates that were not eradicated demonstrated chromosomally mediated resistance to both tetracycline and penicillin. The MICs of cefixime for these 3 isolates were 0.06 JLg/mL for 2 and 0.008 JLg/mL for the other. An association was seen between penicillin and cefixime MICs. Of 148 isolates with penicillin MICs ~2 JLg/mL, 60 (41 %)demonstrated cefixime MICs ~0.03 JLg/mL while only I (6%) of 16 isolates with penicillin MICs
Concise Communications
serovar-specific and common antigenic determinants of the major outer membrane protein of Chlamydia trachomatis. J Exp Med 1988; 167:817-31. 10. Schachter J, Dawson CR. Human chlamydial infections. Littleton, MA: PSG Publishing. 1978. II. Dean D. Patton M, Stephens RS. Direct sequence evaluation of the major outer membrane protein gene variant regions of Chlamydia trachomatis subtypes D'. 1', and L2'. Infect Immun 1991;59: 157982. 12. Fazekas de St Groth S. Webster RG. Disquisitions on original antigenic sin. II. Proof in lower creatures. J Exp Med 1966; 124:347-6 I.
919
13. Su H. Zhang YX. Barrera O. Watkins NO. Caldwell HD. Differential effect of trypsin on infectivity of Chlamydia trachomatis:loss of'infectivity requires cleavage of major outer membrane protein variable domains II and IV. Infect Immun 1988;56:2094-100. 14. Treharne JD. Dwyer RSC, Darougar S. Jones BR. Daghfous T. Antichlamydial antibody in tears and sera and serotypes of Chlamydia trachomatis isolated from school children in southern Tunisia. Br J Ophthalmol 1978;62:509-15. 15. Taylor HR, Siler JA, Mkocha HA, et at. Longitudinal study of the microbiology of endemic trachoma. J Clin Microbiol 1991;29: 1593-5.
Pierre J. Plourde, Mark Tyndall, Elizabeth Agoki, John Ombette, Leslie A. Slaney, Lourdes J. D'Costa, Jackoniah O. Ndinya-Achola, and Francis A. Plummer
World Health Organization Centre for Research and Training on Sexually Transmitted Diseases, Department of Medical Microbiology. University of Nairobi, and Special Treatment Clinic, Nairobi City Commission, Kenya; Departments ofInternal Medicine and Medical Microbiology, University ofManitoba, Canada
Sexually transmitted diseases (STDs) have had a significant adverse effect on reproductive and child health worldwide. The control of STDs such as gonorrhea is therefore an absolute priority. Cefixime, an oral third-generation cephalosporin with in vitro activity similar to that of ceftriaxone, may be an effective candidate for the treatment of gonorrhea. The efficacy of a single oral 400-mg dose of cefixime was compared with that of a single intramuscular 250-mg dose of ceftriaxone for the treatment of Neisseria gonorrhoeae urethritis in 190 men and cervicitis in 46 women in Nairobi, Kenya. A bacteriologic cure was recorded in 100% of63 evaluatable patients treated with ceftriaxone and 118 (98%) of 121 evaluatable patients treated with cefixime. Cefixime, as a single oral dose, is an effective alternative for the treatment of uncomplicated gonococcal urethritis in men and cervicitis in women.
Sexually transmitted diseases (STDs), including gonorrhea, have had a significant adverse effect on reproductive and child health worldwide. Slowing the spread ofgonorrhea is a major public health priority at this time. Treatment of Neisseria gonorrhoeae infection has been complicated by the
Received 3 February 1992; revised 4 May 1992. Presented in part: Ninth meeting of the International Society for Sexually Transmitted Diseases Research. Banff, Canada, October 1991. This study received institutional review board approval from the University of Manitoba and the University of Nairobi. Verbal informed consent was obtained prior to enrollment into the study. Financial support: American Cyanamid Company, Lederle Laboratories; Medical Research Council ofCanada (fellowships to PJ.P. and M.T., Scientist award to EA.P.). Reprints or correspondence: Dr. Pierre J. Plourde, Department of Medical Microbiology. Basic Sciences Building. Room 544. 730 William Ave., Winnipeg. Manitoba. Canada. R3E OW3. The Journal of Infectious Diseases 1992;166:919-22 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0037$01.00
emergence of chromosomally and plasmid-mediated antimicrobial-resistant strains [1]. Plasmid-mediated resistance, first reported in 1976. resulted in the emergence of penicillinase-producing N. gonorrhoeae [2]. Third-generation cephalosporins offer an excellent therapeutic choice because of their intrinsic .B-lactamase resistance. Intramuscular ceftriaxone has been established as an ideal treatment for N. gonorrhoeae [3] and is currently the recommended first-line therapy of choice [4]. However, wherever possible, it would be preferable to avoid parenteral therapy when an efficacious oral antibiotic exists. Cefixime, an orally administered third-generation cephalosporin, has favorable phamacokinetics for single-dose treatment of uncomplicated gonorrhea [5] and has high in vitro activity against antimicrobial-resistant isolates of N. gonorrhoeae [6,7]. This study was designed to determine the safety and efficacy of a single 400-mg oral dose of cefixime compared with a single 250-mg intramuscular (im) dose of ceftriaxone for
Downloaded from http://jid.oxfordjournals.org/ at University of Birmingham on June 15, 2015
Single-Dose Cefixime versus Single-Dose Ceftriaxone in the Treatment of Antimicrobial-Resistant Neisseria gonorrhoeae Infection
920
Concise Communications
the treatment of uncomplicated gonorrhea in men and women attending an STD clinic in Nairobi, Kenya.
Materials and Methods
dourethral and endocervical swabs were obtained using calcium alginate or dacron swabs and placed in a sucrose-buffered-phosphate transport medium. Specimens were then inoculated onto monolayers of McCoy cells by centrifugation and incubated for 72 h at 37°C. After fixing, cells were stained with monoclonal antibodies (Microtrak; Syva, Kanata, Canada) and read with a fluorescent microscope. Alternatively, swabs were processed using an EIA diagnostic kit (Chlamydiazyme; Abbott, Abbott Park,IL). Data analysis. Univariate analysis was done on selected variables using x 2 for parametric and Student's t test for nonparametric data.
Results Of the 236 patients enrolled, 159 received cefixime and 77 received ceftriaxone. There were no significant differences between study groups with respect to age, marital status, number of sex partners, prostitute exposures, condom use, or duration of symptoms (data not shown). All patients were heterosexual and none reported sexual practices other than vaginal intercourse. Microbiologic response is shown in table 1. A total of 46 patients (19.5%) were lost to follow-up. One patient in the ceftriaxone group was excluded from further analysis because she had been inadvertently enrolled with no positive cultures. Five patients with cultures positive for C. trachomatis and negative for N. gonorrhoeae (2 in the ceftriaxone group and 3 who received cefixime) were excluded. Six men (10%) in the ceftriaxone group and 16 men (13%) in the cefixime group who had intracellular gram-negative diplococci on Gram's stain of their urethral discharge but who were culture negative were also included in the analysis. There were 63 and 121 evaluatable patients in the ceftriaxone and cefixime treatment groups, respectively. Eradication, defined by a culture negative for N. gonorrhoeae at the follow-up visit, was seen in 118 (98%) of 121 patients receiving cefixime and in all 63 patients treated with ceftriaxone. Eradication rates for cefixime were 98% for men and 96% for women (table 1). Treatment failed for 3 subjects, 2 single men who presumably had persistent infections (1 complicated by epididymitis) and 1 woman who reported unprotected sexual intercourse with her untreated boyfriend during the study period (considered to have a probable reinfection). A positive pharyngeal culture was seen in one woman who was cured after receiving ceftriaxone. No men had positive pharyngeal cultures and no women had positive rectal cultures. Eight patients had chlamydial infection at enrollment. C. trachomatis cultures were done at follow-up for 173 patients (73%). Six cultures (3%) were positive, three in each treatment group. In each of the treatment groups, I patient had positive cultures at both baseline and follow-up visits, and 2 patients had negative baseline chlamydial cultures and positive follow-up cultures.
Downloaded from http://jid.oxfordjournals.org/ at University of Birmingham on June 15, 2015
Study population. Patients 18-65 years old attending the Nairobi City Commission Special Treatment Clinic from October 1989 to August 1990 were recruited. Men were enrolled if a Gram's stain of their urethral discharge showed intracellular gram-negative diplococci. Women were enrolled if a culture of their cervical discharge was positive for N. gonorrhoeae. At enrollment, demographic information and a medical history including sexually transmitted diseases and sexual practices were obtained from each patient in an interview using a standard questionnaire. General physical and genital examinations were done; swab specimens in men (urethral) and women (cervical) were cultured for N. gonorrhoeae and Chlamydia trachomatis. In addition, pharyngeal swabs from all patients and rectal swabs from women were cultured only for N. gonorrhoeae. Therapy was assigned using consecutive randomization envelopes with a predetermined 2: I cefixime-to-ceftriaxone ratio. Patients randomized to receive cefixime were given a single 400mg oral dose in the presence of the clinical investigator. Those who received ceftriaxone were given a 250-mg im injection. Counseling concerning STDs, high-risk sexual practices, and condom use was offered. Patients were instructed to abstain from sexual intercourse or genital contact during the study period and were encouraged to refer sex partners for examination and treatment. A follow-up appointment was scheduled for 4-7 days after enrollment. At the follow-up, a medical and sexual history was obtained, a physical examination was done, and swabs were obtained from affected areas for culture. Patients were questioned about adverse experiences that had occurred since the initial visit. To be evaluatable, a patient had to have a baseline culture positive for N. gonorrhoeae (or a positive Gram's stain in men), a follow-up visit in 4-7 days, and no other antimicrobials taken within 72 h prior to or during the study. Patients with complicated gonococcal infection such as pelvic inflammatory disease, hypersensitivity to penicillins or cephalosporins, any other STDs, or pregnancy were excluded. Laboratory methods. N. gonorrhoeae and C. trachomatis were cultured using standard media and techniques. Culture swabs were inoculated directly onto modified Thayer-Martin agar [8] and incubated in humidified candle-extinction jars (3%5%CO2) for 48 h. N. gonorrhoeae was identified by colony morphology, Gram's stain, and oxidase reactivity. ,B-lactamase production was assayed by a rapid chromogenic cephalosporin method (Becton Dickinson, Cockeysville, MD). Isolates of N. gonorrhoeaewere tested by agar-dilution methods for susceptibility to cefixime, ceftriaxone, penicillin G, tetracycline, and spectinomycin. Plasmid-mediated tetracycline resistance was defined by a tetracycline MIC of ~ 16 JLg/mL [9]. An isolate was considered to have chromosomally mediated resistance to tetracycline if the MIC was 2.0-8.0 JLg/mL or to penicillin if the MIC was ~2.0 JLg/mL in the absence of ,B-Iactamase production [9]. C. trachomatis was identified using one of two methods. En-
1ID 1992; 166 (October)
lID 1992; 166 (October)
Concise Communications
921
Table 1. Microbiologic response to cefixime or ceftriaxone in 236 patients with Neisseria gonorrhoeae infection. No. (%)of patients Antibiotic. group (n) Cefixime Men (127) Women (32) Ceftriaxone Men (63) Women (14)
Lost to follow-up
Excluded*
Evaluatable
With eradication of infection t
95% CI eradication rate
31 (24) 4 (13)
3 (2) 0
93 (73) 28 (88)
91 (98) 27 (96)
95.6-100 89.2-100
10(16) I (7)
2 (3) I (7)
51 (81) 12 (86)
51 (100) 12(100)
99.1-100 98.2-100
A total of 164 N. gonorrhoeae isolates obtained at enrollment and surviving storage and transportation from Nairobi to Winnipeg were assayed for MICs against several antibiotics (table 2). The high MICs of penicillin G and tetracycline confirmed a high level of resistance to these antibiotics in this population. Penicillinase production was found in 108 strains (66%) and plasmid-mediated tetracycline resistance was present in 47 (29%). Chromosomally mediated resistance to tetracycline and penicillin was seen in 113 (69%) and 43 (26%) strains, respectively. Only I strain showed no resistance. The MICs of both ceftriaxone and cefixime were favorable for single-dose therapy. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or ciprofloxacin. The 3 N. gonorrhoeae isolates that were not eradicated demonstrated chromosomally mediated resistance to both tetracycline and penicillin. The MICs of cefixime for these 3 isolates were 0.06 JLg/mL for 2 and 0.008 JLg/mL for the other. An association was seen between penicillin and cefixime MICs. Of 148 isolates with penicillin MICs ~2 JLg/mL, 60 (41 %)demonstrated cefixime MICs ~0.03 JLg/mL while only I (6%) of 16 isolates with penicillin MICs
