Indian Journal of Medical Sciences, Volume 57, Number 12, December 2003, pp. 549-555
CIPROFLOXACIN-TINIDAZOLE COMBINATION, FLUCONAZOLE- AZITHROMICIN-SECNIDAZOLE-KIT AND DOXYCYCLINE- METRONIDAZOLE COMBINATION THERAPY IN SYNDROMIC MANAGEMENT OF PELVIC INFLAMMATORY DISEASE: A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL
M MALHOTRA, J B SHARMA,* S BATRA,** R ARORA,*** S SHARMA****
MD Senior Research Associate; *MD, MRCOG, Associate Professor; **MD, FICOG, Director, Professor & Head; ***MD, Professor; ****MSc, Statistician*
Accepted Date 26-12-2003
Code Number: ms03046
Background: Pelvic inflammatory disease is a common problem faced by the gynecologists in out patient department.
KEY WORDS: Pelvic Inflammatory disease, Reproductive tract infections, Sexually transmitted disease, Syndromic approach, Genital discharge.
The general term pelvic inflammatory disease has been used to describe infection of the uterus and fallopian tubes usually occurring following ascent of bacteria present in the cervix and presents with history of abnormal vaginal discharge, fever and adnexal tenderness requiring microbiological studies on cervical smear or diagnostic laparoscopy for the diagnosis.1-3 In 2002, the Center for Disease Control (CDC) published recommendations for the treatment of pelvic inflammatory disease based on current knowledge of the etiology of pelvic inflammatory disease and of the antimicrobial activity of available antibiotic.3 The World Health Organisation (WHO) has also promulgated new treatment guidelines.4 Out-patient treatment of pelvic inflammatory disease with cefoxitin and doxycycline or clindamycin with amikacin or gentamicin has been used with equally good results after microbiological testing.5,7 Symptomatic management has been advocated in the developing countries for the management of STDs and PID using clinical algorithms based on symptoms and signs to select patients who should receive antimicrobial therapy.8 Syndromic management is not only more feasible in many resource poor settings than laboratory based management, but has the advantage of immediate treatment, avoidance of the costs associated with laboratory tests and assurance of treatment for those who are actually infected. ST syndrome packets have been developed to improve syndromic management of STDs in developing countries.9-11 Gynecologists often prescribe combination of antibiotics of their choice from their clinical experience, which may not cover the microbiological flora adequately. There is a real need of performing prospective randomized controlled studies to see whether syndromic approach using various antibiotic combinations in general use is effective and safe in clinical setting. We conducted a prospective study to compare the safety and efficacy of the commonly used antibiotic regimens in the clinical Syndromic management of PID in our out-patient setting.
MATERIAL AND METHODS
A total of 165 patients over one year period from July 2001 to July 2002 presenting to gynecological outpatient department of our hospital with symptoms of lower abdominal pain and vaginal discharge underwent speculum and bimanual vaginal examination. Verbal informed consent was taken from all the patients and the departmental ethical committee approved the study. Only women with first episode of PID were included. Women with recurrent PID or with previous antibiotic therapy were excluded. The sample size for the study was estimated assuming the cure rate 95% for the best treatment and 85% for the other two treatments. Thus, to estimate a significant difference of 10% in the treatment efficiency between the treatments with the power of the study of 80% and chance factor to be 5%, the estimated sample size worked out to be 53 patients in each of the treatment groups. Thus it was proposed to enroll 55 patients in each arm.
A clinical diagnosis of pelvic inflammatory disease was made if there were signs of vaginal discharge, cervicitis and associated tenderness in the uterus and/or induration and tenderness in the fornices (adnexal tenderness) with or without cervical excitation pain. Using a computer generated number, all women were randomized to one of the three-treatment groups initially, and later it was a block randomization to equalize the group. Depending upon the randomization, prescription was given for the regimens. Unfortunately we could not get similar looking packs from the market so the assignment was not concealed from the investigator.
1. Group 1: 55 women were given Ciprofloxacin (500 mg) with Tinidazole (600mg) (Table Brakke, Franko India Pharma, Mumbai, India) for seven days. The treatment costs about 128 rupees (Rs. 9 per tablet).
2. Group 2: Another 55 women were given a kit containing one tablet of fluconazole (150 mg) one tablet of azithromycin (1 gm) and two tablets of secnidazole (2 gms) (Fas-3 kit Lyka, Mumbai, India). They were advised to take azithromycin on empty stomach in the morning, secnidazole with or after food and fluconazole in the evening. One kit cost about Rs. 130.
3. Group 3: 55 women were started on doxycyline 100 mg twice daily and metronidazole 200 mg thrice daily for one week. These two drugs were available in the hospital pharmacy free of cost. They cost about Rs 60 for the total cost in market.
Women were assessed at the first visit for a severity score (Modified Severity Score of Soper and Despres, 1988).6 The findings at the first examination and severity score were noted in the proforma filled for every patient. The patients were asked to report after one week and four weeks. Repeat gynecological examination and severity score were performed and recorded in the proforma. All women were advised to report within 3 days if there was no improvement in symptoms, any deterioration in their condition, or inability to carry on with the oral therapy when they were hospitalized.
All patients were asked to keep a record of any side effects of the drugs during the treatment. They were informed to record any side effects like acidity, epigastric discomfort and pain, nausea, vomiting, any skin rash, pruritis, metallic taste or any other deviation from normal life. Clinical cure was defined as at least 70% reduction in the severity score, no more than mild abdominal pain and no recurrence of symptoms or signs of pelvic inflammatory disease within 4 weeks of the therapy. Treatment failure was defined as less than 20% decrease in tenderness score (Wolner Hanssen et al).5
Sexual partners of all patients were advised to take the same regimen as the patient and were asked to abstain from intercourse during the treatment.
Out of 165 patients (55 in each group), 7 patients were lost to follow up. They were excluded from the analysis.
In group 1: one patient was lost on follow up, one patient underwent laparotomy after 5 days of starting therapy for worsening abdominal pain and was found to have a chronic ectopic pregnancy. One patient had a tubercular tuboovarian mass and had a prior history of pulmonary tuberculosis and was excluded from evaluation. Thus 52 women were left in the group.
In group 2: Four patients were lost to follow up; one patient had urinary symptoms, which were aggravated after 2 days. The patient was found to have a urinary tract infection on subsequent culture and was treated accordingly. Two patients did not take the kit due to the high cost, and were put in group 3. Thus 48 women completed the trial in group 2.
In group 3: Two patients were lost to follow up. One patient had intolerable nausea and vomiting and the medicines had to be discontinued (Patient put on Ciprofloxacin-tinidazole combination). Another patient had to be admitted in surgery emergency after 3 days of the start of therapy for appendicitis. Thus 53 women were left in-group 3.
The patients who were lost to follow up or who were found to have different pathology were not included in analysis. The characteristics of the patients are shown in Table 1. There were no significant differences in the mean age, parity, contraceptive history, number of women with inflammatory mass and the mean size of inflammatory mass in the three groups.
There was a significant reduction in the severity score after 1 week in all the three groups, which was further reduced after 4 weeks. The mean and S.D for the severity scores were 8.38 + 1.6, 3.4 + 2.5 and 1.05 + 1.1, 8.35 + 1.5, 2.06 + 2.7 and 0.8 + 1.4, 8.71 + 1.9, 3.3 + 2.55 and 1.49 + 2.5 respectively in the three groups at 1st visit after one week and 4 weeks (P=0.001). The maximum reduction in score was seen in group 2 after the first week but it was not statistically different.
The cure rate was 96% (47/49) in-group 1,93.5% (43/46) in group 2 and 91.3% (42/46) in group 3. The difference was not statistically significant (P=0.65). Hence the three groups were equally effective.
The resolution of inflammatory masses in the three groups is shown in Table 1. The resolution of inflammatory masses was highest in-group 1 where 7 out of 9 (77.7%) masses resolved with the treatment. Given that the number of patients with inflammatory masses in each group was different and the cure rate for patients with mass varied, a stratified analysis of the three regimens was conducted without inflammatory masses but there was no imbalance in the randomization of this variable in the three groups.
Although all partners were advised to take the treatment only 35/52 (67.3%), 38/48(79.2%) and 25/53(47.1%) took it. There was no significant difference in groups 1 and 2 (P=0.27), but there was a borderline significant difference in group 1 versus 3 (P=0.05) and significant difference in group 2 versus 3 (P=0.002). Minor side effects were seen in 10/52 (19.2%), 6/48 (12.5%), and 16/53 (30.18%) cases respectively in the three groups and were giddiness, vertigo, bad taste, nausea, vomiting, epigastric pain and diarrhea. Rash was uncommon. The difference was not statistically significant (P=0.09).
The compliance rate was 94.2% (49/52) in group 1, 92% (46/48) in group 2 and 86.7% (46/53) in group 3.The compliance was lowest in the doxycycline and metronidazole combination due to side effects like metabolic taste but the difference was not statistically different (P=0.19).
The results of present study depict a cure rate of 96%, 93.5% and 91.3% respectively for the three different antibiotic combinations, which were statistically same. The side effects were also similar in the three groups.
The traditional approach to the diagnosis and management of a presumed pelvic inflammatory disease is through laboratory diagnosis to determine the etiological agent.5 Although scientific, this approach is expensive in terms of diagnostics and laboratory infrastructure maintenance, and it delays the diagnosis and treatment. Unfortunately the majority of victims of STDs live in developing countries, especially Africa and Asia, where laboratory facilities for diagnosis are not available at a health center or dispensary level. Even where laboratories do exist, quality controls to validate them are often lacking . To address these limitations, WHO developed and recommended appropriate patient management strategies based on the syndromic approach which is especially suitable for developing countries like India.12
The syndromic approach to STD case management is based on the identification of a relatively constant combination of symptoms and signs (Syndrome) and on knowledge of the most common causative organisms of these syndromes and their antimicrobial susceptibility. The syndromic approach not only finds application in the developing countries, but has also been widely used in the industrialized countries for the management of pelvic inflammatory disease. The advantages of such management are expedited care, treatment at the first visit, cost saving by avoiding expensive laboratory tests, increased client satisfaction and no risk of losing the patient to follow up before starting treatment. The main disadvantage is the cost of over diagnosis and over treatment when multiple antimicrobials are given to the patient with no infection and also there is a potential for developing antibiotic resistance.
Various studies have confirmed the cost effectiveness of the syndromic approach in pelvic inflammatory disease.13-15 Combination antimicrobial therapies like cefoxitin and doxycycline or gentamycin _ clindamycin have been used and found to be effective in the management of PID5-7 Ciprofloxacin with metronidazole or tinidazole has been found to be effective and well tolerated and treatment was successful in 97% cases.16 Oral clindamycin and ciprofloxacin versus intramuscular cefotriaxone and oral doxycycline have been used very safely and effectively in out patient treatment of mild to moderate pelvic inflammatory disease.16 Our results confirm the cost effectiveness of a Syndromic approach for suspected pelvic inflammatory disease. The ciprofloxacin and tinidazole combination was found to be more effective in resolution of inflammatory masses than the other two regimens. The incidence of side effects was higher and compliance was lower in the doxycycline and metronidazole group, but was not statistically significant. The lowest compliance rate among partners was in the doxycycline and metronidazole group, where it was statistically significant.
To conclude, Syndromic management of genital infection appears to be a cost-effective proposition in Indian communities. All three treatments were equally effective in control of pelvic inflammatory disease with statistically similar side effects in the three regimens.
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