Women with mild or moderate PID can be treated in primary care

• There is evidence from a large randomized trial that women with mild-to-moderate PID can be safely treated at home. Outpatient and inpatient treatments are equally effective for women with clinically mild-to-moderate PID, and there is evidence that long-term reproductive outcomes are also similar.

Importance of excluding pregnancy

• National guidance from the Royal College of Obstetrics and Gynaecology stresses the importance of excluding an ectopic pregnancy in all women suspected of having PID [RCOG, 2009].

Referral for contact tracing and screening

• These recommendations are based on guidance from the Royal College of Obstetricians and Gynaecologists [RCOG, 2009] and the British Association for Sexual Health and HIV [BASHH, 2005].

Analgesia

• This recommendation is based on expert advice in the European guideline for the management of pelvic inflammatory disease [Ross et al, 2008] and the British Association for Sexual Health and HIV [BASHH, 2005].

Importance of prompt treatment

• It is likely that delaying treatment increases the risk of the PID becoming worse, and increases the risk of complications such as ectopic pregnancy, subfertility, or chronic pelvic pain occurring in the future [BASHH, 2005; CDC, 2006; Ross, 2008; RCOG, 2009].
• A low threshold for commencing an empirical antibiotic (that is, before the results of tests are available) is recommended because of the risk of serious complications if treatment is delayed. This is particularly important in women younger than 25 years of age because there is a higher incidence of PID in this age group.
• Negative swabs do not exclude PID and should not necessarily influence the decision to treat.
• There is limited evidence from a case-controlled study that fertility may be impaired and ectopic pregnancy may be more likely if treatment for acute pelvic inflammatory disease is delayed for 3 days or more after the onset of symptoms.

Recommended antibiotic regimens

• The antibiotic regimens included are those which are practical for use in primary care (that is, they do not require intravenous antibiotics) and are recommended in guidelines produced by the Royal College of Obstetricians and Gynaecologists and the British Association for Sexual Health and HIV [BASHH, 2005; RCOG, 2009].
• These guidelines recognize that there is uncertainty about the optimum treatment regimen [RCOG, 2009] due to limited evidence from clinical trials. However, the recommended regimens are likely to be effective against the most likely pathogens involved (Chlamydia trachomatis, Neisseria gonorrhoeae, anaerobes).
• There is a better evidence base for the use of cefoxitin than ceftriaxone but, as it is not easily available in the UK, intramuscular ceftriaxone is recommended in its place [RCOG, 2009].
• Metronidazole is included in the intramuscular ceftriaxone plus oral doxycycline regimen to improve coverage for anaerobic bacteria.
• Ofloxacin and azithromycin should be avoided in women at high risk of gonorrhoea because of increasing resistance in the UK [BASHH, 2005; BASHH, 2005].
• Although PID presenting in primary care may be less severe than in other settings, there is no published evidence to support the use of less intensive regimens.
• Recent guidance from the Royal College of Obstetricians and Gynaecologists recommends the combination of intramuscular ceftriaxone and oral azithromycin but states that clinical trial evidence for this regimen is less strong [RCOG, 2009]. There is limited evidence from two randomized controlled trials that azithromycin used alone or in combination with ceftriaxone is effective in the treatment of PID.
• Oral cefixime as a single dose (off-label use) is recommended as an alternative to the intramuscular ceftriaxone component of the regimens by the Health Protection Agency, for practical issues of administration in primary care [HPA and Association of Medical Microbiologists, 2010].
• Ceftriaxone is included in the regimen primarily to cover gonorrhoea. A single dose of oral cefixime 400 mg is an alternative treatment option recommended for gonorrhoea by British Association for Sexual Health and HIV (BASHH) [BASHH, 2005], a primary care guideline [RCGP and BASHH, 2006], and a European guideline [Bignell, 2009].

Antibiotic regimens not recommended

• A combination of metronidazole and doxycyline (without intramuscular ceftriaxone). Although this regimen has been recommended in the past and is still used in primary care it is not recommended in the guidelines produced by the British Association for Sexual Health and HIV or the Royal College of Obstetricians and Gynaecologists [BASHH, 2005; RCOG, 2009]. Guidelines from the Royal College of Obstetricians and Gynaecologists state that there are no clinical trials adequately assessing the effectiveness of this regimen, and its use in isolation (that is, without intramuscular ceftriaxone) is not recommended [RCOG, 2009]. There is evidence from a retrospective study and a systematic review that metronidazole combined with doxycycline is not suitable for the treatment of acute PID in the UK. The addition of intramuscular ceftriaxone as an initial dose significantly improved the clinical cure rate in the one retrospective study [Piyadigamage and Wilson, 2005].
• Azithromycin used alone (that is, without intramuscular ceftriaxone). Data supporting its use alone are limited and it is not recommended [RCOG, 2009].
• Moxifloxacin alone. There is evidence from one high quality randomized controlled trial that moxifloxacin has similar efficacy to a combination of ofloxacin and metronidazole. CKS does not recommend its use as it is a black triangle drug (under intensive surveillance by the Medicines and Healthcare products Regulatory Agency [MHRA]), and there are concerns that it may have similar issues with gonococcal resistance to ofloxacin. In addition, although moxifloxacin is now licensed for the treatment of PID, the Medicines and Healthcare products Regulatory Agency (MHRA) has restricted its indications to second-line use to when other medicines cannot be prescribed or have failed. This is because of an increased risk of life-threatening liver reactions and other serious risks associated with its use [MHRA, 2008; MHRA, 2011 ].

Drug choice during very early pregnancy (before a positive pregnancy test)

• Experience suggests that paracetamol can be used at any time during pregnancy or breastfeeding [NTIS, 2004; Schaefer et al, 2007].
• The UK Teratology Information Service (UKTIS, formerly the National Teratology Information Service [NTIS]), reviewed safety data of NSAIDs from published research and postmarketing surveillance systems. They concluded that 'the available data do not indicate that exposure to ibuprofen before 30 weeks of pregnancy is associated with an increased risk of congenital defects or spontaneous abortions' [NTIS, 2004].
• The Royal College of Obstetricians and Gynaecologists recommends that the risk of giving any of their recommended antibiotic regimens in very early pregnancy (before a positive pregnancy test) is low, since significant drug toxicity results in failed implantation [RCOG, 2009].
• Ceftriaxone has not specifically been studied during pregnancy. However, the risk associated with use of cephalosporins during pregnancy is thought to be low and, although data are limited for individual agents such as ceftriaxone, the cephalosporins as a class are considered to be an appropriate choice during pregnancy [NTIS, 2008]. Although ceftriaxone crosses the placental barrier, it has not been associated with adverse events on fetal development in laboratory animals [ABPI Medicines Compendium, 2009].
• Doxycycline is contraindicated beyond the 15th week of gestation because, from the 16th week of pregnancy it causes tooth and bone discolouration and inhibits bone growth. However, it can be used in the first trimester. Inadvertent first-trimester use of tetracyclines occurs frequently and has not been associated with an increased risk of congenital malformations [Schaefer et al, 2007].
• Metronidazole has been in clinical use for a long time, and experience suggests that it is not teratogenic in humans [Schaefer et al, 2007]. A recent prospective controlled study in 228 women exposed to metronidazole in pregnancy, 86% of whom had first trimester exposure, confirms these findings [Schaefer et al, 2007].
• Ofloxacin has only limited pregnancy-exposure data. Quinolones have caused arthropathy in animal studies. However, a recent study (most of the data are on ciprofloxacin and norfloxacin, but some are on ofloxacin) did not find that quinolone use in the first trimester of pregnancy was associated with an increased risk of malformations or other adverse effects on pregnancy outcome [Schaefer et al, 2007].
• There are fewer published data on the use of azithromycin rather than erythromycin during pregnancy and breastfeeding. The limited published data and follow-up data collected by the UK Teratology Information Service (UKTIS, formerly the National Teratology Information Service [NTIS]), do not demonstrate an increased risk of congenital malformations following exposure to azithromycin in human pregnancy [NTIS, 2008].

Management of women with HIV

• Women with HIV may experience more severe symptoms of PID, but will usually respond to the standard antibiotic regimens. No change in treatment from that recommended for women without HIV infection is required [BASHH, 2005]. There is no evidence to suggest that HIV-positive women benefit from hospitalization or parenteral treatment [Sweet, 2009].