ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1992, p. 1144-1146
Vol. 36, No. 5
0066-4804/92/051144-03$02.00/0 Copyright © 1992, American Society for Microbiology
Ofloxacin versus Doxycycline for Treatment of Cervical Infection with Chlamydia trachomatis THOMAS M. HOOTON,1t* BYRON E. BATTEIGER,2 FRANKLYN N. JUDSON,3 SPOTSWOOD L. SPRUANCE,4 AND WALTER E. STAMM'
Department of Medicine, Division of Infectious Diseases, University of Washington School of Medicine, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 981041; Division of Infectious Diseases, Indiana University Medical Center, Indianapolis, Indiana 462232; Department ofMedicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, and Disease Control Service, Denver, Colorado 80204'; and Department of Medicine, Division of Infectious Diseases, University of Utah School of Medicine, and the Salt Lake City-County Health Department, Salt Lake City, Utah 841324 Received 4 November 1991/Accepted 13 February 1992
Women with culture-proven Chlamydia trachomatis cervical infection were randomized to receive either ofloxacin (300 mg) or doxycycline (100 mg), orally twice daily for 7 days. All 56 had negative cultures 5 to 9 days after treatment. Four weeks after treatment, 26 (93%) of 28 ofloxacin-treated patients and all 22 doxycycline-treated patients were cured. We conclude that 300 mg of ofloxacin given twice daily for 7 days provides effective therapy for chlamydial infection of the cervix. Institutional Review Board, and all patients gave written, informed consent. Women were eligible for enrollment if they were between 18 and 65 years old, were not pregnant and using contraception, had received no systemic antimicrobial therapy within 30 days and no intravaginal antibacterial agent within 14 days prior to enrollment, had no allergy to carboxyquinolones or doxycycline, had no other significant medical illnesses, and had one or more of the following: 10 or more polymorphonuclear cells per high-power field (1,000 x) on a cervical gram stain, mucopurulent endocervical discharge, or a positive cervical culture for C. trachomatis. At enrollment, subjects underwent a medical history, physical examination, cervical gram stain, and culture for N. gonorrhoeae and C. trachomatis. Patients were then randomized to receive either ofloxacin (300 mg) or doxycycline hyclate (100 mg), orally twice daily for 7 days. Medications were dispensed according to a computer-generated randomization schedule prepared by Ortho Pharmaceutical Corporation, Raritan, N.J. Patients were asked to return between days 5 and 9 and again at days 21 to 28 after therapy. Patients were asked to keep daily diaries and to record all symptoms noted while on the study drugs. At each return visit, patients underwent a history and physical examination and collection of cervical cultures. Standard microbiologic procedures were used in transporting, isolating, and identifying C. trachomatis at each center. Only those women with chlamydial infection of the cervix are included in this report. Data on all patients who took their assigned antibiotic regimen and who returned for at least one follow-up visit were included in analyses of microbiologic outcome. Because methods for recording detailed descriptions of the cervix on speculum examination and leukocytes on cervical smear were not standardized for all centers, we could not evaluate the clinical response to treatment. The Fisher's exact test was used to test for differences between the
Mucopurulent cervicitis is among the most common sexually transmitted disease syndromes in women and can eventually lead to pelvic inflammatory disease, infertility, and obstetrical complications. It has not been as well studied as urethritis in men, but it is thought to have both similar prevalence and causes (3). As in male nongonococcal urethritis, Chlamydia trachomatis is the most common etiologic pathogen, causing as many as 50% of cases, whereas Neisseria gonorrhoeae is less common (3). Although tetracycline congeners and erythromycin are effective in eradicating C. trachomatis, they cause frequent side effects, must be taken two to four times daily, and are not reliably effective against N. gonorrhoeae. A single agent effective against both of these pathogens in women with mucopurulent cervicitis would be desirable for reasons of patient convenience and cost. The new fluoroquinolone antibiotics have excellent in vitro activity against both N. gonorrhoeae and C. trachomatis, and some have the potential for once-daily therapy (6). In particular, ofloxacin has been very effective in eradicating gonococcal infections and has been demonstrated in studies of men with urethritis and in small numbers of women with cervicitis to be as active against chlamydia as doxycycline (6). However, only small numbers of women were studied and posttreatment follow-up was no longer than 2 weeks in these studies. We report findings from a multicenter study comparing ofloxacin and doxycycline for treatment of chlamydial infection of the cervix with a follow-up visit 4 weeks after treatment. Data from four centers which took part in a multicenter study by using identical protocols were combined for this report. The centers are the University of Washington, Seattle, Wash.; Indiana University Medical Center, Indianapolis, Ind.; the University of Colorado and Disease Control Service, Denver, Colo.; and the University of Utah, Salt Lake City, Utah. The study was approved by each center's
treatment groups. *
Among 142 women enrolled at the four centers, there were 29 patients in the ofloxacin group whose cervical cultures were positive for chlamydia at enrollment and who returned
Corresponding author.
t Present address: Harborview Medical Center Madison Clinic, 1001 Broadway, Suite 206, Seattle, WA 98122. 1144
NOTES
VOL. 36, 1992
1145
TABLE 1. Review of cervical chlamydia treatment studies with ofloxacina No. of failures or recurrences/no. evaluable (%)
Chlamydia detection method
Posttreatment follow-up interval
Comparative Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
3 to 4 weeks 3 to 4 weeks
0/5 (0) 0/4 (0)
1c
Ofloxacin, 200 (BID, 9 days) Doxycycline, 200 (QD, 10 days)
Culture Culture
5 days 4 days
1/10 (10) 0/7 (0)
5 5
Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
4 to 5 weeks 4 to 5 weeks
5/26 (19) 2/22 (9)
8c 8
Ofloxacin, 400 (QD, 7 days) Doxycycline, 100 (BID, 7 days)
Antigen Antigen
2 weeks 2 weeks
0/28 (0) 0/24 (0)
9 9
Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
3 to 4 weeks 3 to 4 weeks
0/13 (0) 0/7 (0)
10 10
Open Ofloxacin, Ofloxacin, Ofloxacin, Ofloxacin,
Antigen Antigen Antigen
3 days 1 week 1 week 2 weeks
2/5 (40) 1/18 (6) 1/12 (8) 0/17 (0)
2 4 4 11
Regimenb (mg)
200 100 200 200
(BID, (BID, (BID, (BID,
5 days) 10 days) 7 days) 7 days)
Culture
Reference
1
a Includes only studies that clearly methods and follow-up. b BID, twice daily; QD, once daily. distinguish study c Some of the patients in these two preliminary reports are included in the current report.
for at least one follow-up visit and 27 in the doxycycline group. The mean age of evaluable women in the ofloxacin group was 23 years compared with 22 years in the doxycycline group; 72 and 59%, respectively, were Caucasian. Likewise, there were no significant differences between the two groups in the number of sexual partners in the previous month or history of previous sexually transmitted diseases. Self-reported compliance with taking the medications was excellent in both groups. All 56 women had negative cervical cultures for chlamydia at the first follow-up visit (day 5 to 9). Among those who returned for the last follow-up visit (day 21 to 28), 26 (93%) of 28 ofloxacin-treated patients and all 22 doxycyclinetreated patients were cured. One of the 2 ofloxacin-treated patients with recurrent chlamydia at the last visit reported sexual intercourse without condom use prior to this visit compared with 14 (54%) of the 26 culture-negative women. Nine (41%) of the 22 doxycycline-treated patients who were culture-negative at the last visit reported prior unprotected intercourse. N. gonorrhoeae was eradicated from five of six coinfected patients in the ofloxacin group compared with all six coinfected patients in the doxycycline group. The one treatment failure reported unprotected intercourse prior to the visit. Adverse effects were equally common but generally mild in the two groups. Our results demonstrate that both doxycycline and ofloxacin are highly effective in initially eradicating C. trachomatis from the cervix. Doxycycline was slightly more effective than ofloxacin in maintaining eradication of C. trachomatis from the cervix at the 4-week visit, but this difference was not statistically significant. However, of the few published studies of ofloxacin for the treatment of chlamydial cervical infection, all of which are small, some of the others have also shown a similar trend (Table 1). Ciprofloxacin, which has a somewhat higher MIC against 90% of the C. trachomatis strains tested than ofloxacin (1.6 versus 0.8 ,ug/ml, respectively [12]) and is less well absorbed, proved ineffective in
the treatment of chlamydial urethritis in men because of relapses occurring 2 to 4 weeks posttreatment (7). Thus, although it appears that ofloxacin is more effective than ciprofloxacin in eradicating chlamydia, larger treatment studies with ofloxacin and a 4- to 6-week follow-up are indicated to better evaluate the possibility of late chlamydial
relapses. REFERENCES 1. Batteiger, B. E., R. B. Jones, and A. White. 1989. Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease. Am. J. Med. 87(Suppl. 6C):75-77. 2. Bischoff, W. 1986. Ofloxacin: therapeutic results in Chlamydia
trachomatis urethritis. Infection 14(Suppl. 4):316-317.
3. Brunham, R. C., J. Paavonen, C. E. Stevens, N. Kiviat, C.-C. Kuo, C. W. Critchlow, and K. K. Holmes. 1984. Mucopurulent cervicitis-the ignored counterpart in women of urethritis in men. N. Engl. J. Med. 311:1-6. 4. Chandeying, V., S. Sutthiumroon, and S. Tungphaisal. 1989. Evaluation of ofloxacin in the treatment of mucopurulent cervicitis: response of chlamydia-positive and chlamydia-negative forms. J. Med. Assoc. Thai. 72:331-337. 5. Fransen, L., D. Avonts, and P. Piot. 1986. Treatment of genital chlamydial infection with ofloxacin. Infection 14(Suppl. 4):318320. 6. Hooper, D. C., and J. S. Wolfson. 1989. Treatment of genitourinary tract infections with fluoroquinolones: clinical efficacy in genital infections and adverse effects. Antimicrob. Agents Chemother. 33:1662-1667. 7. Hooton, T. M., M. E. Rogers, T. G. Medina, L. E. Kuwamura, C. Ewers, P. L. Roberts, and W. E. Stamm. 1990. Ciprofloxacin compared with doxycycline for nongonococcal urethritis: ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA 264:1418-1421. 8. Judson, F. N., B. S. Beals, and K. J. Tack. 1986. Clinical experience with ofloxacin in sexually transmitted disease. Infection 14(Suppl. 4):309-310. 9. Kitchen, V. S., C. Donegan, H. Ward, B. Thomas, J. R. W. Harris, and D. Taylor-Robinson. 1990. Comparison of ofloxacin with doxycycline in the treatment of non-gonococcal urethritis
1146
NOTES
and cervical chlamydial infection. J. Antimicrob. Chemother. 26(Suppl. D):99-105. 10. Mogabgab, W. J., B. Holmes, M. Murray, R. Beville, F. B. Lutz, and K. J. Tack. 1990. Randomized comparison of ofloxacin and doxycycline for chlamydia and ureaplasma urethritis and cervicitis. Chemotherapy 36:70-76. 11. Nayagam, A. T., G. L. Ridgway, and J. D. Oriel. 1988. Efficacy
ANTIMICROB. AGENTS CHEMOTHER.
of ofloxacin in the treatment of non-gonococcal urethritis in men and genital infections caused by Chlamydia trachomatis in men and women. J. Antimicrob. Chemother. 22(Suppl. C):155-158. 12. Wolfson, J. S., and D. C. Hooper. 1989. Treatment of genitourinary tract infections with fluoroquinolones: activity in vitro, pharmacokinetics, and clinical efficacy in urinary tract infections and prostatitis. Antimicrob. Agents Chemother. 33:1655-1661.
Vol. 36, No. 5
0066-4804/92/051144-03$02.00/0 Copyright © 1992, American Society for Microbiology
Ofloxacin versus Doxycycline for Treatment of Cervical Infection with Chlamydia trachomatis THOMAS M. HOOTON,1t* BYRON E. BATTEIGER,2 FRANKLYN N. JUDSON,3 SPOTSWOOD L. SPRUANCE,4 AND WALTER E. STAMM'
Department of Medicine, Division of Infectious Diseases, University of Washington School of Medicine, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 981041; Division of Infectious Diseases, Indiana University Medical Center, Indianapolis, Indiana 462232; Department ofMedicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, and Disease Control Service, Denver, Colorado 80204'; and Department of Medicine, Division of Infectious Diseases, University of Utah School of Medicine, and the Salt Lake City-County Health Department, Salt Lake City, Utah 841324 Received 4 November 1991/Accepted 13 February 1992
Women with culture-proven Chlamydia trachomatis cervical infection were randomized to receive either ofloxacin (300 mg) or doxycycline (100 mg), orally twice daily for 7 days. All 56 had negative cultures 5 to 9 days after treatment. Four weeks after treatment, 26 (93%) of 28 ofloxacin-treated patients and all 22 doxycycline-treated patients were cured. We conclude that 300 mg of ofloxacin given twice daily for 7 days provides effective therapy for chlamydial infection of the cervix. Institutional Review Board, and all patients gave written, informed consent. Women were eligible for enrollment if they were between 18 and 65 years old, were not pregnant and using contraception, had received no systemic antimicrobial therapy within 30 days and no intravaginal antibacterial agent within 14 days prior to enrollment, had no allergy to carboxyquinolones or doxycycline, had no other significant medical illnesses, and had one or more of the following: 10 or more polymorphonuclear cells per high-power field (1,000 x) on a cervical gram stain, mucopurulent endocervical discharge, or a positive cervical culture for C. trachomatis. At enrollment, subjects underwent a medical history, physical examination, cervical gram stain, and culture for N. gonorrhoeae and C. trachomatis. Patients were then randomized to receive either ofloxacin (300 mg) or doxycycline hyclate (100 mg), orally twice daily for 7 days. Medications were dispensed according to a computer-generated randomization schedule prepared by Ortho Pharmaceutical Corporation, Raritan, N.J. Patients were asked to return between days 5 and 9 and again at days 21 to 28 after therapy. Patients were asked to keep daily diaries and to record all symptoms noted while on the study drugs. At each return visit, patients underwent a history and physical examination and collection of cervical cultures. Standard microbiologic procedures were used in transporting, isolating, and identifying C. trachomatis at each center. Only those women with chlamydial infection of the cervix are included in this report. Data on all patients who took their assigned antibiotic regimen and who returned for at least one follow-up visit were included in analyses of microbiologic outcome. Because methods for recording detailed descriptions of the cervix on speculum examination and leukocytes on cervical smear were not standardized for all centers, we could not evaluate the clinical response to treatment. The Fisher's exact test was used to test for differences between the
Mucopurulent cervicitis is among the most common sexually transmitted disease syndromes in women and can eventually lead to pelvic inflammatory disease, infertility, and obstetrical complications. It has not been as well studied as urethritis in men, but it is thought to have both similar prevalence and causes (3). As in male nongonococcal urethritis, Chlamydia trachomatis is the most common etiologic pathogen, causing as many as 50% of cases, whereas Neisseria gonorrhoeae is less common (3). Although tetracycline congeners and erythromycin are effective in eradicating C. trachomatis, they cause frequent side effects, must be taken two to four times daily, and are not reliably effective against N. gonorrhoeae. A single agent effective against both of these pathogens in women with mucopurulent cervicitis would be desirable for reasons of patient convenience and cost. The new fluoroquinolone antibiotics have excellent in vitro activity against both N. gonorrhoeae and C. trachomatis, and some have the potential for once-daily therapy (6). In particular, ofloxacin has been very effective in eradicating gonococcal infections and has been demonstrated in studies of men with urethritis and in small numbers of women with cervicitis to be as active against chlamydia as doxycycline (6). However, only small numbers of women were studied and posttreatment follow-up was no longer than 2 weeks in these studies. We report findings from a multicenter study comparing ofloxacin and doxycycline for treatment of chlamydial infection of the cervix with a follow-up visit 4 weeks after treatment. Data from four centers which took part in a multicenter study by using identical protocols were combined for this report. The centers are the University of Washington, Seattle, Wash.; Indiana University Medical Center, Indianapolis, Ind.; the University of Colorado and Disease Control Service, Denver, Colo.; and the University of Utah, Salt Lake City, Utah. The study was approved by each center's
treatment groups. *
Among 142 women enrolled at the four centers, there were 29 patients in the ofloxacin group whose cervical cultures were positive for chlamydia at enrollment and who returned
Corresponding author.
t Present address: Harborview Medical Center Madison Clinic, 1001 Broadway, Suite 206, Seattle, WA 98122. 1144
NOTES
VOL. 36, 1992
1145
TABLE 1. Review of cervical chlamydia treatment studies with ofloxacina No. of failures or recurrences/no. evaluable (%)
Chlamydia detection method
Posttreatment follow-up interval
Comparative Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
3 to 4 weeks 3 to 4 weeks
0/5 (0) 0/4 (0)
1c
Ofloxacin, 200 (BID, 9 days) Doxycycline, 200 (QD, 10 days)
Culture Culture
5 days 4 days
1/10 (10) 0/7 (0)
5 5
Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
4 to 5 weeks 4 to 5 weeks
5/26 (19) 2/22 (9)
8c 8
Ofloxacin, 400 (QD, 7 days) Doxycycline, 100 (BID, 7 days)
Antigen Antigen
2 weeks 2 weeks
0/28 (0) 0/24 (0)
9 9
Ofloxacin, 300 (BID, 7 days) Doxycycline, 100 (BID, 7 days)
Culture Culture
3 to 4 weeks 3 to 4 weeks
0/13 (0) 0/7 (0)
10 10
Open Ofloxacin, Ofloxacin, Ofloxacin, Ofloxacin,
Antigen Antigen Antigen
3 days 1 week 1 week 2 weeks
2/5 (40) 1/18 (6) 1/12 (8) 0/17 (0)
2 4 4 11
Regimenb (mg)
200 100 200 200
(BID, (BID, (BID, (BID,
5 days) 10 days) 7 days) 7 days)
Culture
Reference
1
a Includes only studies that clearly methods and follow-up. b BID, twice daily; QD, once daily. distinguish study c Some of the patients in these two preliminary reports are included in the current report.
for at least one follow-up visit and 27 in the doxycycline group. The mean age of evaluable women in the ofloxacin group was 23 years compared with 22 years in the doxycycline group; 72 and 59%, respectively, were Caucasian. Likewise, there were no significant differences between the two groups in the number of sexual partners in the previous month or history of previous sexually transmitted diseases. Self-reported compliance with taking the medications was excellent in both groups. All 56 women had negative cervical cultures for chlamydia at the first follow-up visit (day 5 to 9). Among those who returned for the last follow-up visit (day 21 to 28), 26 (93%) of 28 ofloxacin-treated patients and all 22 doxycyclinetreated patients were cured. One of the 2 ofloxacin-treated patients with recurrent chlamydia at the last visit reported sexual intercourse without condom use prior to this visit compared with 14 (54%) of the 26 culture-negative women. Nine (41%) of the 22 doxycycline-treated patients who were culture-negative at the last visit reported prior unprotected intercourse. N. gonorrhoeae was eradicated from five of six coinfected patients in the ofloxacin group compared with all six coinfected patients in the doxycycline group. The one treatment failure reported unprotected intercourse prior to the visit. Adverse effects were equally common but generally mild in the two groups. Our results demonstrate that both doxycycline and ofloxacin are highly effective in initially eradicating C. trachomatis from the cervix. Doxycycline was slightly more effective than ofloxacin in maintaining eradication of C. trachomatis from the cervix at the 4-week visit, but this difference was not statistically significant. However, of the few published studies of ofloxacin for the treatment of chlamydial cervical infection, all of which are small, some of the others have also shown a similar trend (Table 1). Ciprofloxacin, which has a somewhat higher MIC against 90% of the C. trachomatis strains tested than ofloxacin (1.6 versus 0.8 ,ug/ml, respectively [12]) and is less well absorbed, proved ineffective in
the treatment of chlamydial urethritis in men because of relapses occurring 2 to 4 weeks posttreatment (7). Thus, although it appears that ofloxacin is more effective than ciprofloxacin in eradicating chlamydia, larger treatment studies with ofloxacin and a 4- to 6-week follow-up are indicated to better evaluate the possibility of late chlamydial
relapses. REFERENCES 1. Batteiger, B. E., R. B. Jones, and A. White. 1989. Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease. Am. J. Med. 87(Suppl. 6C):75-77. 2. Bischoff, W. 1986. Ofloxacin: therapeutic results in Chlamydia
trachomatis urethritis. Infection 14(Suppl. 4):316-317.
3. Brunham, R. C., J. Paavonen, C. E. Stevens, N. Kiviat, C.-C. Kuo, C. W. Critchlow, and K. K. Holmes. 1984. Mucopurulent cervicitis-the ignored counterpart in women of urethritis in men. N. Engl. J. Med. 311:1-6. 4. Chandeying, V., S. Sutthiumroon, and S. Tungphaisal. 1989. Evaluation of ofloxacin in the treatment of mucopurulent cervicitis: response of chlamydia-positive and chlamydia-negative forms. J. Med. Assoc. Thai. 72:331-337. 5. Fransen, L., D. Avonts, and P. Piot. 1986. Treatment of genital chlamydial infection with ofloxacin. Infection 14(Suppl. 4):318320. 6. Hooper, D. C., and J. S. Wolfson. 1989. Treatment of genitourinary tract infections with fluoroquinolones: clinical efficacy in genital infections and adverse effects. Antimicrob. Agents Chemother. 33:1662-1667. 7. Hooton, T. M., M. E. Rogers, T. G. Medina, L. E. Kuwamura, C. Ewers, P. L. Roberts, and W. E. Stamm. 1990. Ciprofloxacin compared with doxycycline for nongonococcal urethritis: ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA 264:1418-1421. 8. Judson, F. N., B. S. Beals, and K. J. Tack. 1986. Clinical experience with ofloxacin in sexually transmitted disease. Infection 14(Suppl. 4):309-310. 9. Kitchen, V. S., C. Donegan, H. Ward, B. Thomas, J. R. W. Harris, and D. Taylor-Robinson. 1990. Comparison of ofloxacin with doxycycline in the treatment of non-gonococcal urethritis
1146
NOTES
and cervical chlamydial infection. J. Antimicrob. Chemother. 26(Suppl. D):99-105. 10. Mogabgab, W. J., B. Holmes, M. Murray, R. Beville, F. B. Lutz, and K. J. Tack. 1990. Randomized comparison of ofloxacin and doxycycline for chlamydia and ureaplasma urethritis and cervicitis. Chemotherapy 36:70-76. 11. Nayagam, A. T., G. L. Ridgway, and J. D. Oriel. 1988. Efficacy
ANTIMICROB. AGENTS CHEMOTHER.
of ofloxacin in the treatment of non-gonococcal urethritis in men and genital infections caused by Chlamydia trachomatis in men and women. J. Antimicrob. Chemother. 22(Suppl. C):155-158. 12. Wolfson, J. S., and D. C. Hooper. 1989. Treatment of genitourinary tract infections with fluoroquinolones: activity in vitro, pharmacokinetics, and clinical efficacy in urinary tract infections and prostatitis. Antimicrob. Agents Chemother. 33:1655-1661.
