Which of the following best justifies the use of tube 2 as a control treatment?

BMJ. 2001 Feb 3; 322(7281): 251–252.

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 specific1 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 19934 and updated in 19999 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 gonorrhoeae11 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.

References

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