Pelvic inflammatory disease

Continued use of oral doxycycline and metronidazole is hard to justify

Standing at the therapeutic crossroads trying to choose a path for outpatients with pelvic inflammatory disease, a clinician may find his or her evidence based map lacking in detail. Not only is pelvic inflammatory disease hard to diagnose; once it has been diagnosed it is not clear what the best outpatient treatment is.

Pelvic inflammatory disease remains a condition with imprecise diagnostic criteria where the clinical features are neither sensitive nor specific[1] and where the "gold standard" of laparoscopy lacks standardisation and is not routinely available in clinical practice. Non-invasive diagnosis using magnetic resonance imaging has potential and may be comparable with laparoscopy and superior to transvaginal ultrasound,[2] but data and access are both limited.

Once the diagnosis of pelvic inflammatory disease has been made what outcomes are realistic after treatment? Rapid resolution of symptoms, preservation of fertility, and low rates of ectopic pregnancy are all desirable outcomes, but only the first, short term control of symptoms, has been assessed in most randomised controlled trials. In the pre-antibiotic era many women seem to have had resolution of their symptoms but then gone on to develop long term sequelae, and even those women who do receive antibiotics have a significantly increased risk of subsequent complications.[3]

Not only is choosing the best therapeutic road difficult but it remains uncertain whether the best route has, as yet, been found. The available clinical evidence leans heavily on parenteral therapy of inpatients with pelvic inflammatory disease.[4] To extrapolate these findings to outpatients receiving oral antibiotics may result in inconvenience and overtreatment, while direct conversion to oral regimens might be associated with reduced efficacy. The use of a two week treatment period in trials reflects common clinical practice, but it is not known whether outcomes would be similar for shorter treatment periods or improved with longer courses. The choice of therapy is only partially aided by microbiological studies that show a wide variety of bacteria in the fallopian tubes of women with pelvic inflammatory disease but which cannot determine whether some or all of these are primary pathogens.

Despite these limitations, signposts, in the form of national guidelines, which generally point in the same direction, have been erected at the crossroads. Outpatient therapy with a parenteral cephalosporin followed by doxycycline and metronidazole, or a combination of oral ofloxacin with metronidazole, is recommended by the American, Dutch, and British

guidelines.[5-7] The presence of guidelines in themselves may not change clinical practice, and in some countries, including the UK, the use of doxycycline (for two weeks) with metronidazole (for one to two weeks) remains common. This provides cover for Chlamydia trachomatis, the commonest recognised causal pathogen, and anaerobes, associated with tubo-ovarian abscess formation. The three available trials comparing this combination with alternative antibiotic regimens treated a total of only 56 patients and report clinical cure rates of 70-85%[4] despite most patients receiving their treatment parenterally. One further small study with longer term follow up reported infertility in 43% (6/14) of patients treated with doxycycline plus metronidazole.[8]

The evidence for ofloxacin is derived primarily from two randomised controlled trials enrolling a total of 165 patients and reporting clinical cure rates of 95% and 96%.[4] In both trials outpatient management was assessed, with oral therapy used throughout. The quoted cure rates were obtained with ofloxacin alone, but concerns about inadequate coverage of anaerobes have led to the recommendation that metronidazole should be added the regimen.[9] Longer term outcomes were assessed in an additional small study: at repeat laparoscopy none of the patients with mild tubal disease at the initial examination had progressed to tubal occlusion (n=14), while 6 of 9 patients with severe disease at an initial laparoscopy developed bilateral tubal occlusion.[10]

No Cochrane review is available but a meta-analysis published in 1993[4] and updated in 1999[9] assessed a variety of different antibiotic regimens. Microbiological and clinical cure rates of 91% to 100% were reported, except for the combination of doxycycline plus metronidazole, which had a pooled clinical cure rate of 75% and microbiological cure rate of 71%. There is biological plausibility for this lower success rate related to the limited bacteriological cover provided by doxycycline plus metronidazole: resistance may occur to Neisseria gonorrhoeae[11] and other facultative bacteria, such as coliforms, Garnerella vaginalis, and virdans streptococci,[12] which are commonly found in the fallopian tubes of women with pelvic inflammatory disease.

There are many questions about the treatment of pelvic inflammatory disease that remain unanswered, and much work remains to be done. From the available published evidence the use of oral doxycycline and metronidazole appears to have a lower cure rate than alternative therapies. Until, and unless, new evidence becomes available it is difficult to justify their continuing use in isolation.

[1] Morcos R, Frost N, Hnat M, Petrunak A, Caldito G. Laparoscopic versus clinical diagnosis of acute pelvic inflammatory disease. J Reproduct Med 1993;38:53-6.

[2] Tukeva TA, Aronen HJ, Karjalainen PT Molander P, Paavonen T, Paavonen J. MR imaging in pelvic inflammatory disease: comparison with laparoscopy and US. Radiology 1999;210:209-16.

[3] Buchan H, Vessey M, Goldacre M, Fairweather J. Morbidity following pelvic inflammatory disease. Br J Obstet Gynaecol 1993;100:558-62.

[4] Walker CK, Kahn JG, Washington AE, Peterson HB, Sweet RL. Pelvic inflammatory disease: metaanalysis of antimicrobial regimen efficacy. J Infect Dis 1993;168:969-78.

[5] CDC Guidelines on Sexually Transmitted Diseases. MMWR Morb Mortal Wkly Rep 1998;47:RR02

[6] Netherlands Association for Dermatology and Venereology. STD Diagnosis and Therapy Guidelines. 2nd ed. Amsterdam: Netherlands Association for Obstetrics and Gynaecology, 1997.

[7] Ross JDC. UK national guidelines for the management of pelvic inflammatory disease. Sex Transm Infect 1999;75:S54-6.

[8] Brunham RC, Binns B, Guijon F, Danforth D, Kosseim ML, Rand F, et al. Etiology and outcome of acute pelvic inflammatory disease. J Infect Dis 1988;158:510-7.

[9] Walker CK, Workowski KA, Washington AE, Soper DE, Sweet RL. Anaerobes in pelvic inflammatory disease: implications for the Centers for Disease Control and Prevention's guidelines for treatment of sexually transmitted diseases. Clin Infect Dis 1999;98:S29-36.

[10] Soper DE, Brockwell NJ, Dalton HP. Microbial etiology of urban emergency department acute salpingitis: treatment with ofloxacin. Am J Obstet Gynecol 1992;167:653-60.

[11] Lewis DA, Bond M, Butt KD, Smith CP, Shafi MS, Murphy SM. A one-year survey of gonococcal infection seen in the genitourinary medicine department of a London district general hospital. Int J STD AIDS 1999;10:588-94.

[12] Hasselquist MB, Hillier S. Susceptibility of upper-genital tract isolates from women with pelvic inflammatory disease to ampicillin, cefpodoxime, metronidazole, and doxycycline. Sex Transm Dis 1991;18:146-9.

Jonathan D C Ross consultant physician in genitourinary medicine

Whittall Street Clinic, Birmingham B4 6DH (jonathan.ross@bscht.wmids.nhs.uk)

BMJ 2001:322:251-2

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COPYRIGHT 2001 Gale Group