Evaluation of 3-Day Course of Doxycycline for the Treatment of Uncomplicated Chlamydia trachomatis Cervicitis

Objective: The purpose of this study was to compare the efficacy of a 3-day course of doxycycline to a standard 7-day course for treating uncomplicated chlamydia cervicitis. Methods: During an 18-month period, 77 women with uncomplicated chlamydia cervicitis were randomized to receive either a 3-day or a 7-day course of doxycycline (100 mg twice daily). Tests of cure were performed 3 weeks after completion of therapy with the Amplicor polymerase chain reaction (PCR) assay (Roche Molecular Systems, Branchburg, NJ). Demographics, therapeutic results, and side effects for the two groups were compared. Results: Seventy-three patients completed the study: 35 in the 3-day group and 38 in the 7-day group. There were no significant differences in age, gravidity, or parity between the groups. There was a 94% (33/35) cure rate in the 3-day group and a 95% (36/38) cure rate in the 7-day group (P = 1.0). Thirty-four percent and 32% of the patients in the 3- and 7-day groups reported side effects, respectively; there was no significant differences between the 3- and 7-day groups in regard to population demographics, patient compliance, therapeutic outcome, or side effects. Conclusions: A 3-day course of doxycycline appears to be as effective as a 7-day course of doxycycline for the treatment of uncomplicated chlamydia cervicitis.

A total of 77 nonpregnant women with uncom-plicated Chlamydia trachomatis cervicitis were randomized into 2 treatment arms. Group 1 received the standard CDC-recommended treatment consisting of 100 mg doxycycline twice daily for 7 days. Group 2 received 100 mg doxycycline twice daily for 3 days. A central office allocated patients by computer-generated randomization schedule.
Patients were treated free of charge. Sexual partners were also offered the standard 7-day course of doxycycline free of charge. Patients were asked to refrain from intercourse with their partner until they had completed their medication. If the patient missed a menstrual cycle or was not practicing a reliable form of contraception (i.e., oral contraceptives, tubal ligation, Norplant(R), Depo-Provera(R)), a serum pregnancy test was performed. If a coexisting cervical infection with Neisseria gonorrhoeae was present, patients were treated with 250 mg of intramuscular ceftriaxone.
Each patient returned approximately 3 weeks after completion of their medication. At the followup appointment, a cervical swab was obtained for chlamydia PCR assay, and each patient was asked questions from a post-treatment questionnaire. Patients received a $30.00 stipend when they returned for the follow-up visit. The post-treatment questionnaire consisted of the following questions: 1) How many pills did you take? 2) Did you have any side effects, i.e., vomiting, headache, diarrhea, stomachache, and did you take the medicine with food? 3) Did your partner take all of his medicine? If not, how many pills did he take? 4) Did you have intercourse with your partner or anyone else since your enrollment into the study? All data forms and questionnaires were forwarded to a central site to be inventoried and entered into an established data management system. Data collection forms were checked for inconsistencies and missing values by a computerized editchecking system. Any inconsistencies were reported to the investigator for correction or verification. Summary and descriptive statistics for all baseline variables were performed using SAS software package (Cary, NC). Comparisons between study groups were done using the Student's t-test or chi-square analysis on the appropriate demographic variables. Adherence to the prescribed treatment within each group was assessed by performing pill counts. Incidence of side effects was

RESULTS
During an 18-month interval, 77 women were randomized to receive either a 3or 7-day course of doxycycline. Three patients were lost to follow-up (1 patient in the 7-day group and 2 patients in the 3-day group). Another patient was dropped from the study after randomization when a repeated pregnancy test was positive. Seventy-three patients completed the study. Thirty-five patients were randomized to the 3-day group and 38 patients to the 7-day group. The mean age of the 3-day group was 21.8 (___5.5 years), compared with 21.3 (___4.5 years) in the 7-day group. There was no significant differences among groups in age (P 0.65), gravidity (P 0.16), or parity (P 0.09). Follow-up PCR assays were obtained approximately 3 weeks after completion of therapy. There was no significant difference (P 0.27) in follow-up intervals between the 3-day (3.7 weeks) and the 7-day (4.2 weeks) groups. Of the 35 patients in the 3-day group, there were 2 treatment failures (efficacy, 94%). The 7-day group had 2 treatment failures out of 38 patients (efficacy, 95%). There was no significant difference in efficacy between the two groups (Fisher's exact test P 1.0). Table 2 provides descriptions of the 4 treatment failures.
Patients in the 7-day group took all their medication appropriately. Two patients in the 3-day group did not complete their medication. One patient took only 5 pills over a 3-week period instead of 3 days in a row. This patient's test of cure was positive. The second patient took 4 pills over 2 days and did not take the 3rd day of pills due to nausea. This patient's test of cure was negative. Thirty-four percent of patients in the 3-day group and 32% in the 7-day group reported side effects (P 1.0). The most common side effect was nausea (Table 3).

DISCUSSION
Chlamydia trachomatis has a complex and long life cycle. The elementary body (infectious particle) attaches to and enters the endocervical cells. The elementary body remains as a cytoplasmic inclusion throughout its life cycle within the cell. Within the inclusion body, noninfectious but metabolically active reticulate bodies are formed. The reticulate bodies condense to form elementary bodies. The typical life cycle takes between 48 and 72 h to complete. For an antimicrobial agent to be effective against chlamydia, it must be present over a period of 2-3 days. 6 Azithromycin is a new macrolide antibiotic which has been shown to be as effective as a 7-day course of doxycycline in the treatment of uncomplicated chlamydia infections of the uterine cervix. Azithromycin is effective in treating chlamydia with a single dose due to its long half-life (68 h) and adequate tissue penetration. 6 Doxycycline is one of the current drugs of choice for the treatment of chlamydia cervicitis. It is the drug to which all other therapeutic regimens are compared. It is well absorbed by the gastroin- A few reports have shown that shorter dosing regimens of antibiotics are as effective in treating chlamydia as the standard 7-day course of doxycycline or erythromycin. Stature et al. 1 compared a 3-day course of trimethoprin-sulfamethoxazole (TMP-SMZ) with a 5-day course of tetracycline and found 30 of 32 (94%) women cured in the TMP-SMZ group and 27 of 29 (93%) cured in the tetracycline group. Bowie et al. 11 compared the efficacy of several treatment regimens for lower genital tract chlamydia infections in women. They made an interesting observation that of the 3 women who took only 3 days of ampicillin, all had negative cultures. Also of interest is a study by Levallois and Rioux lz in which they performed a randomized, double-blind, placebo-controlled trial of doxycycline for suction curettage abortion prophylaxis. Seventy-five women who preoperatively screened positive for chlamydia were randomized into a prophylaxis and placebo group. Prophylaxis consisted of 100 mg of doxycycline preoperatively and a 200 mg dose postoperatively. In the prophylaxis group, only of 33 (3.0%) had signs or symptoms of post-abortal pelvic infection vs. 11 of 42 (26.2%) of women in the placebo group. Though this study's endpoint was post-abortal pelvic infection, a 1-day course of doxycycline significantly reduced the risk of infection in women with chlamydia infection.
We elected to perform a test of cure 3 weeks following the completion of therapy. We chose 3 weeks instead of a longer time interval for the fol-lowing reasons. First, we were concerned that the longer the interval from completion of therapy to test of cure, the greater the risk of reinfection and losing the patient for follow-up, z,4,6 Second, after reviewing the literature, we found that many studies, including the recommendations from the CDC, use between 2 and 4 weeks for repeat testing, z, [3][4][5][6] Workowski et al. 6 studied the duration of detecting chlamydia by PCR and tissue culture following a 7-day course of doxycycline. They found that chlamydia is eradicated immediately after treatment as detected by tissue culture, but can be detected up to week following therapy by PCR.
The major side effects of doxycycline in patients are related to gastrointestinal effects. We anticipated that shortening the course of therapy would reduce the side effects. However, there was no significant reduction in side effects when compared to the 7-day course of therapy. We believe this demonstrates that side effects from doxycyclinc occur early in the course of therapy. Though there was no difference in patient compliance in this study, we believe patients off study protocols are more likely to complete a 3-day course of therapy than 7 days. This study was designed as a preliminary study to see if a 3-day course of doxycycline was a feasible treatment option for chlamydia cervicitis. Therefore, we chose a study design which could identify a 25% difference between groups at a power of 0.8 and a P-value of 0.05. For comparison, it would take 280 patients (140 per treatment arm) to perform a study which could identify a 10% difference between groups with a power of 0.8 and a P-value of 0.05. Our institution does not have a sexually transmitted disease population large enough to perform a study of this magnitude in a reasonable amount of time. We believed that if no statistical difference was found between a 3-and a 7-day course of therapy, further study would be warranted.
There were no statistically significant differences between groups in population demographics, patient compliance, efficacy, or side effects when comparing the 3-day and the 7-day study groups. A 3-day course of doxycycline appears to be as effective as a 7-day course of therapy for uncomplicated chlamydia cervicitis. This report provides strong preliminary data to support further investigation with this treatment regimen.