A nurse is preparing to administer clindamycin 450 mg PO to a client who has endometriosis

Cochrane Database Syst Rev. 2017 Apr; 2017(4): CD010285.

Abstract

Background

Pelvic inflammatory disease (PID) is an infection that affects 4% to 12% of young women, and is one of the most common causes of morbidity in this age group. The main intervention for acute PID is the use of broad‐spectrum antibiotics which cover Chlamydia trachomatis, Neisseria gonorrhoeae, and anaerobic bacteria, administered intravenously, intramuscularly, or orally. In this review, we assessed the optimal treatment regimen for PID.

Objectives

To assess the effectiveness and safety of antibiotic regimens used to treat pelvic inflammatory disease.

Search methods

We searched the Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which included randomized controlled trials (RCTs) from 1944 to 2016, located through electronic searching and handsearching; the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to July 2016); MEDLINE (1946 to July 2016); Embase (1947 to July 2016); LILACS, iAHx interface (1982 to July 2016); World Health Organization International Clinical Trials Registry Platform (July 2016); Web of Science (2001 to July 2016); OpenGrey (1990, 1992, 1995, 1996, and 1997); and abstracts in selected publications.

Selection criteria

We included RCTs comparing the use of antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. We limited our review to comparison of drugs in current use that are recommended for consideration by the 2015 US Centers for Disease Control and Prevention (CDC) guidelines for treatment of PID.

Data collection and analysis

At least two review authors independently selected trials for inclusion, extracted data, and assessed risk of bias. We contacted investigators to obtain missing information. We resolved disagreements by consensus or by consulting a fourth review author if necessary. We assessed the quality of the evidence using GRADE criteria, classifying it as high, moderate, low, or very low. We calculated Mantel‐Haenszel risk ratios (RR), using either random‐effects or fixed‐effect models and number needed to treat for an additional beneficial outcome or for an additional harmful outcome, with their 95% confidence interval (CI), to measure the effect of the treatments. We conducted sensitivity analyses limited to studies at low risk of bias, for comparisons where such studies were available.

Main results

We included 37 RCTs (6348 women). The quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision.

Azithromycin versus doxycycline

There was no clear evidence of a difference between the two drugs in rates of cure for mild‐moderate PID (RR 1.18, 95% CI 0.89 to 1.55, I2 = 72%, 2 RCTs, 243 women, very low‐quality evidence), severe PID (RR 1.00, 95% CI 0.96 to 1.05, 1 RCT, 309 women, low‐quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.71, 95% CI 0.38 to 1.34, 3 RCTs, 552 women, I2 = 0%, low‐quality evidence). In a sensitivity analysis limited to a single study at low risk of bias, azithromycin was superior to doxycycline in achieving cure in mild‐moderate PID (RR 1.35, 95% CI 1.10 to 1.67, 133 women, moderate‐quality evidence).

Quinolone versus cephalosporin

There was no clear evidence of a difference between the two drugs in rates of cure for mild‐moderate PID (RR 1.04, 95% CI 0.98 to 1.10, 3 RCTs, 459 women, I2 = 5%, low‐quality evidence), severe PID (RR 1.06, 95% CI 0.91 to 1.23, 2 RCTs, 313 women, I2 = 7%, low‐quality evidence), or adverse effects leading to discontinuation of treatment (RR 2.24, 95% CI 0.52 to 9.72, 5 RCTs, 772 women, I2 = 0%, very low‐quality evidence).

Nitroimidazole versus no use of nitroimidazole

There was no conclusive evidence of a difference between the nitroimidazoles (metronidazole) group and the group receiving other drugs with activity over anaerobes (e.g. amoxicillin‐clavulanate) in rates of cure for mild‐moderate PID (RR 1.01, 95% CI 0.93 to 1.10, 5 RCTs, 2427 women, I2 = 60%, moderate‐quality evidence), severe PID (RR 0.96, 95% CI 0.92 to 1.01, 11 RCTs, 1383 women, I2 = 0%, moderate‐quality evidence), or adverse effects leading to discontinuation of treatment (RR 1.00, 95% CI 0.63 to 1.59; participants = 3788; studies = 16; I2 = 0% , low‐quality evidence). In a sensitivity analysis limited to studies at low risk of bias, findings did not differ substantially from the main analysis (RR 1.06, 95% CI 0.98 to 1.15, 2 RCTs, 1201 women, I2 = 32%, high‐quality evidence).

Clindamycin plus aminoglycoside versus quinolone

There was no evidence of a difference between the two groups in rates of cure for mild‐moderate PID (RR 0.88, 95% CI 0.69 to 1.13, 1 RCT, 25 women, very low‐quality evidence), severe PID (RR 1.02, 95% CI 0.87 to 1.19, 2 studies, 151 women, I2 = 0%, low‐quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.21, 95% CI 0.02 to 1.72, 3 RCTs, 163 women, very low‐quality evidence).

Clindamycin plus aminoglycoside versus cephalosporin

There was no clear evidence of a difference between the two groups in rates of cure for mild‐moderate PID (RR 1.02, 95% CI 0.95 to 1.09, 2 RCTs, 150 women, I2 = 0%, low‐quality evidence), severe PID (RR 1.00, 95% CI 0.95 to 1.06, 10 RCTs, 959 women, I2 = 21%, moderate‐quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.78, 95% CI 0.18 to 3.42, 10 RCTs, 1172 women, I2 = 0%, very low‐quality evidence).

Authors' conclusions

We found no conclusive evidence that one regimen of antibiotics was safer or more effective than any other for the cure of PID, and there was no clear evidence for the use of nitroimidazoles (metronidazole) compared to use of other drugs with activity over anaerobes. Moderate‐quality evidence from a single study at low risk of bias suggested that a macrolide (azithromycin) may be more effective than a tetracycline (doxycycline) for curing mild‐moderate PID. Our review considered only the drugs that are currently used and mentioned by the CDC.

Treatment for pelvic inflammatory disease

Review question

We assessed the effectiveness and safety of different treatments for pelvic inflammatory disease (PID) that are recommended for consideration by current clinical guidelines for treatment of PID (the 2015 US Centers for Disease Control and Prevention guidelines for treatment of PID).

Background

PID is an infection of the upper part of the woman's reproductive system (womb, fallopian tubes (tube connecting the womb and ovary that the egg travels along), ovaries (which make eggs), and inside of the pelvis). It is a common condition affecting women of childbearing age. Symptoms of PID vary, ranging from no symptoms to severe symptoms. If effective treatment is not started promptly, the consequences of the condition can be infertility (unable to have children), pregnancies outside of the womb, and chronic pelvic pain (pain in the lower tummy). There is a wide range of treatment options, the choice of which is based on severity of symptoms, experience of the doctor, national/international guidelines, and rate of side effects. We wanted to learn if there is a better antibiotic (used to treat bacterial infections) therapy with higher rates of cure and lower side effects to treat PID.

Trial characteristics

We searched the available literature up to 11 July 2016 and included 37 studies with 6348 women with an average of 14 days of treatment and follow‐up (monitoring after treatment). These trials included women of childbearing age with mild to severe PID. Trials mostly used a combination of antibiotics with different administration routes: intravenous (into a blood vessel), intramuscular (into the muscle), and oral (as a tablet). In mild‐moderate cases, intramuscular and oral treatments were prescribed, and in moderate‐severe cases, treatments were usually started in hospital and were completed at home.

Key results

We found no conclusive evidence that one treatment was safer or more effective than any other for the cure of PID, and there was no clear evidence for the use of nitroimidazoles (a type of antibiotic; metronidazole) compared to use of other antibiotics. Moderate‐quality evidence from a single study at low risk of bias suggested that a macrolide (a type of antibiotic; azithromycin) may be more effective than a tetracycline (a type of antibiotic; doxycycline) for curing mild‐moderate PID.

Quality of evidence

The quality of the evidence ranged from very low to high, the main problems being serious risk of bias (poor reporting of study methods; doctors and women may have known which medicine was given), and results differed across studies.

Summary of findings

Summary of findings for the main comparison

Macrolides (azithromycin) compared to tetracycline (doxycycline) for pelvic inflammatory disease (PID)

Table 2

Summary of findings 2

Quinolone compared to cephalosporins for pelvic inflammatory disease

Table 3

Summary of findings 3

Nitroimidazole compared to no nitroimidazole for pelvic inflammatory disease

Table 4

Summary of findings 4

Clindamycin plus aminoglycoside compared to quinolone for pelvic inflammatory disease

Table 5

Summary of findings 5

Clindamycin plus aminoglycoside compared to cephalosporin for pelvic inflammatory disease

Background

Description of the condition

Pelvic inflammatory disease (PID) in women describes inflammation of the upper genital tract and surrounding structures as a result of ascending infection from the lower genital tract ‐ bacteria spread directly from the cervix to the endometrium and on to the upper genital tract (Soper 2010). The signs and symptoms of PID are not specific and may range from asymptomatic to serious illness. PID can produce endometritis, parametritis (infection of the structures near the uterus), salpingitis (infection of the fallopian tubes), oophoritis (infection of the ovary), and tubo‐ovarian abscess (Workowski 2015). Peritonitis (infection inside the peritoneum, the thin layer of tissue lining the abdomen) and perihepatitis (infection around the liver) can also occur. Peritonitis, tubo‐ovarian abscess, and severe systemic illness (e.g. fever and malaise) are considered severe forms of PID; the other forms of presentation are considered mild or moderate according to the subjective opinion of the examining doctor or nurse (Soper 2010).

The most common complaint of PID is lower abdominal pain, with or without vaginal discharge. Specific grading of the clinical presentation using symptom scores has been described (e.g. McCormack 1977; Hager 1989), but has not been validated, and use of these scores is inconsistent. PID does not have a diagnostic gold standard. The most commonly used diagnostic criteria are based on those from the Centers for Disease Control and Prevention (CDC) (Workowski 2015), namely sexually active young women and other women at risk for sexually transmitted disease (STD) who are experiencing recent pelvic or lower abdominal pain where no cause other than PID can be identified, and one or more of the following minimum criteria are present on pelvic examination: cervical motion tenderness, uterine tenderness, or adnexal tenderness. The requirement for all three minimum criteria to be present increases the specificity of the diagnosis but reduces sensitivity.

Two sexually transmitted infections (Chlamydia trachomatis and Neisseria gonorrhoeae) have been strongly implicated in the aetiology of PID; however, based on the pattern of organisms isolated from the upper genital tract, the infection may often be polymicrobial (caused by more than one type of bacteria) (Eschenbach 1975; Arredondo 1997; Baveja 2001; Haggerty 2006). This suggests that initial damage produced by C trachomatis or N gonorrhoeae may permit the opportunistic entry of other bacteria, including anaerobes (bacteria that do not need oxygen to grow) (Ross 2014b).

The public health importance of PID can be estimated from the frequency of chlamydial and gonococcal infections. In 2012, among women aged 15 to 49 years, the estimated global prevalence of chlamydia was 4.2% (95% confidence interval (CI) 3.7% to 4.7%), gonorrhoea (0.8%, 95% CI 0.6% to 1.0%), and trichomoniasis (5.0%, 95% CI 4.0% to 6.4%) (Newman 2015). In a prospective study of 1170 women with elevated risk for having chlamydial cervicitis, 8.6% developed PID within three years; among women with chlamydia, the risk ratio (RR) for developing PID was 2.5 (95% CI 1.5 to 4.0) (Ness 2006). In the UK, the prevalence of PID is around 2% among women between 16 and 46 years old (Simms 1999; Datta 2012; Ross 2014b). However, in some other countries, the rates of chlamydia infection are lower, for example, in Jordan it is 0.6 and 0.5% in symptomatic and asymptomatic women, respectively (Mahafzah 2008). Among women with PID, 10% to 20% may become infertile, 40% will develop chronic pelvic pain, and 10% of those who conceive will have an ectopic pregnancy (Blanchard 1998; Ness 2002; Ness 2005; Mahafzah 2008).

The morbidity associated with PID relates to the acute inflammatory process, which can cause abdominal pain, vaginal discharge, dyspareunia (pain during sexual intercourse), and abnormal menstrual bleeding. In addition, long‐term complications secondary to tubal damage occur and include chronic pelvic pain, ectopic pregnancy, and infertility (Workowski 2015). PID has a prevalence of between 2% and 12%, and it cannot be diagnosed reliably from clinical symptoms and signs, which have a positive predictive value for salpingitis of only 65% to 90% compared with laparoscopy (Workowski 2015). Direct visualization of the fallopian tubes via laparoscopy has a higher sensitivity, but there is considerable inter‐ and intra‐observer reproducibility (Molander 2003). Endometrial biopsy may have some utility (Ross 2004), but is not performed routinely and is of uncertain diagnostic and prognostic value, since endometritis (infection of the inner mucosal lining of the uterus) can persist despite the resolution of clinical symptoms (Ness 2002; Savaris 2007).

The financial cost of pelvic infection has been estimated to exceed USD 2.4 billion in the USA, and the mean total cost per episode is around USD 5000 (Trent 2011). In the UK, the mean cost of a non‐complicated episode of PID is GBP 163 (Aghaizu 2011).

Description of the intervention

The main intervention for acute PID is the use of broad‐spectrum antibiotics which cover C trachomatis, N gonorrhoeae, and anaerobic bacteria. There are three routes of administration (intravenous, intramuscular, or oral). These routes of administration (oral and intramuscular versus intravenous) have been considered effective (Ness 2002; Walker 2007). In refractory cases, surgery to drain an abscess or hydrosalpinx may be necessary. When parenteral treatment is used, it is usually discontinued 24 hours after a woman improves clinically (Workowski 2015).

The optimal treatment strategy is unclear. A variety of antibiotic regimens have been used, with marked geographical variation. Current practice generally involves the use of multiple agents to cover C trachomatis,N gonorrhoeae, and anaerobic bacteria, but the best combination of agents is unknown. The background prevalence and antimicrobial resistance patterns of bacterial pathogens in different regions may influence the choice of empirical therapy.

Guidelines have been produced in the USA (Workowski 2015), and in Europe (Judlin 2010b; Ross 2014a), to guide therapy, but these have not been based on a formal systematic review. In addition, to choose an antibiotic for PID treatment, it is necessary to consider its spectrum, cost, adverse effects, and posology (i.e. dosage, interval) to achieve the best balance between compliance and efficacy. There are no current systematic reviews on this topic.

The different antibiotic regimens proposed to treat PID vary in cost, reported efficacy, and adverse effects. Potential adverse effects of therapy for PID include allergic reactions and gastrointestinal symptoms, which can lead to discontinuation of therapy. Lack of evidence is revealed in the current CDC and British Association for Sexual Health and HIV (BASHH) guidelines, where the authors state that there is limited evidence for the need to eradicate anaerobes and for the use of alternative regimens, such as azithromycin (Workowski 2015), and the comparison between clindamycin plus aminoglycoside and fluoroquinolones (Ross 2014a). Likewise, if the prevalence of N gonorrhoeae is low, the use of fluoroquinolones can be considered if allergy to cephalosporin is an issue (Workowski 2015).

How the intervention might work

It is likely that the intervention works by eradicating bacterial pathogens and reducing the associated inflammation which leads to scarring. Necrotic tissue and pus present in an abscess may prevent antibiotics reaching the infected area. Mechanical drainage of the abscess through open surgery, laparoscopy, or aspiration through a large bore needle is likely to work by removing infected material which antibiotics are unable to treat (Workowski 2015). Clinical cure without surgery in women with a tubo‐ovarian abscess is around 75% (DeWitt 2010). The rationale for using broad‐spectrum antibiotics is to cover the wide variety of pathogens found in PID, which include Gram‐positive (e.g. Streptococcus), Gram‐negative (e.g. Chlamydia, Klebsiella, Escherichia coli, Neisseria), and anaerobic bacteria (Gram positive or negative: Peptostreptococcus, Bacteroides).

Why it is important to do this review

PID is a common disease (4.4%) that is accompanied by high rates of morbidity in young women (Ness 2002; Morris 2014). It requires effective treatment to reduce the incidence of chronic pelvic pain, infertility, and transmitted STDs. A variety of different antibiotic regimens have been proposed to treat PID, which vary in cost, reported efficacy, and adverse effects, but the optimal treatment strategy is unclear.

Currently there are no systematic reviews of this subject and the optimal treatment strategy is unclear. This review will address clinical questions raised by current guidelines on the treatment of PID (Ross 2014a; Workowski 2015), regarding the effectiveness and safety of nitroimidazole, the relative benefits of azithromycin versus doxycycline, the use of quinolones, and the relative benefits of cephalosporins compared to the most‐used regimen of clindamycin plus aminoglycoside, to inform future guideline development and clinical practice.

Objectives

To assess the effectiveness and safety of antibiotic regimens used to treat pelvic inflammatory disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs), including those which did not describe their method of randomization (i.e. where the authors stated that treatment was randomized without providing further details). We chose randomized trials as providing the strongest evidence for evaluating the efficacy of therapy (Higgins 2011). We included studies irrespective of publication status or language.

We excluded quasi‐randomized trials because they produce effects estimates indicating more extreme benefits when compared with RCTs (Higgins 2011). We also excluded cross‐over and cluster trials.

Types of participants

Women of reproductive age (14 years of age or older) diagnosed as having acute PID (symptoms for less than six weeks) based on clinical findings, laparoscopy, endometrial biopsy, or detectable gonorrhoea or chlamydia in the upper genital tract.

We divided women into two groups: mild‐moderate (e.g. absence of tubo‐ovarian abscess) and severe (e.g. systemically unwell, presence of tubo‐ovarian abscess).

Types of interventions

We limited our review to comparison of drugs in current use that are recommended for consideration by the 2015 US CDC guidelines for treatment of PID (Workowski 2015).

We included trials comparing the following treatments for PID:

• azithromycin versus doxycycline;

• quinolone versus cephalosporin;

• nitroimidazole versus no nitroimidazole;

• clindamycin plus aminoglycoside versus quinolone;

• clindamycin plus aminoglycoside versus cephalosporin.

Types of outcome measures

Primary outcomes

• Effectiveness: clinical cure according to the criteria defined by the treating physician (e.g. resolution or improvement of signs and symptoms related to PID).

• Adverse events: any antibiotic‐related adverse event leading to discontinuation of therapy.

Secondary outcomes

• Microbiological clearance of chlamydia from either the upper or lower genital tract, according to the method provided by the authors.

• Microbiological clearance of gonorrhoea from either the upper or lower genital tract, according to the method provided by the authors.

• Laparoscopic evidence of resolution of PID based on physician opinion.

• Length of stay (for inpatient care).

• Rate of fertility based on at least one participant‐reported live birth following PID treatment in women not using effective contraception.

Where studies included women with various types of pelvic infection, we considered only women with endometritis, salpingitis, parametritis, or oophoritis (not related to labour, delivery, cancer, or surgery).

Where studies reported multiple time points, we considered the period between 14 and 28 days after initiation of treatment.

Search methods for identification of studies

We identified relevant RCTs of 'antibiotic therapy' for 'PID', irrespective of their language of publication, publication date, and publication status (published, unpublished, in press, and in progress). We used both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Electronic searches

We contacted the Information Specialist of the Cochrane Sexually Transmitted Infections Review Group to implement a comprehensive search strategy capturing as many relevant RCTs as possible in electronic databases. We used a combination of controlled vocabulary (MeSH, Emtree, DeCS, including exploded terms) and free‐text terms (considering spelling variants, synonyms, acronyms, and truncation) for 'pelvic inflammatory disease (PID)' and 'antibiotic therapy', with field labels, proximity operators, and Boolean operators. We have presented the search strategies in Appendix 1. Specifically, we searched the following electronic databases.

• The Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which includes RCTs from 1944 to 2016 located through electronic searching and handsearching. The electronic databases searched for the register are CENTRAL, MEDLINE, and Embase.

• The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to 11 July 2016).

• MEDLINE, Ovid platform (1946 to 11 July 2016).

• MEDLINE In‐Process & Other Non‐Indexed Citations, Ovid platform (1946 to 11 July 2016).

• MEDLINE Daily Update, Ovid platform (1946 to 11 July 2016).

• Embase (1947 to 11 July 2016).

• LILACS, iAHx interface (1982 to 11 July 2016).

• Web of Science (2001 to July 2016).

In MEDLINE, we used the Cochrane Highly Sensitive Search Strategy for identifying RCTs: sensitivity and precision maximizing version (2008 revision), Ovid format (Higgins 2011). The LILACS search strategy combined RCTs filter of iAHx interface.

Searches were updated to within 12 months of publication of the review.

Searching other resources

We attempted to identify other relevant RCTs using the methods below.

We searched the following trials registers:

• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/);

• ClinicalTrials.gov (ClinicalTrials.gov/).

We searched for grey literature in OpenGrey (www.opengrey.eu/) (1990, 1992, 1995, 1996, and 1997). We contacted authors of all RCTs identified by other methods as well as pharmaceutical companies producing 'antibiotic therapy' for 'pelvic inflammatory disease (PID).'

We handsearched conference proceeding abstracts in the following publications: Indian Journal of Sexually Transmitted Diseases (2007 to July 2016), Sexually Transmitted Diseases (1974 to July 2016), Sexually Transmitted Infections (1996 to July 2016), Journal of Sexual Medicine (2004 to July 2016), Sexual and Relationship Therapy (2000 to July 2016), and the Society for the Scientific Study of Sexuality's Sexual Science Newsletter (2000 to July 2016).

We handsearched previous systematic reviews on similar topics identified from:

• the Cochrane Library (www.thecochranelibrary.com/);

• Epistemonikos (www.epistemonikos.org/).

We handsearched the reference lists of all identified RCTs.

Data collection and analysis

Selection of studies

Two review authors (DGF and RVD) performed an initial screen of titles and abstracts retrieved by the search, and we retrieved the full text of all potentially eligible studies. Two review authors (DGF and RVD) independently examined these studies for compliance with the inclusion criteria and selected studies that met these criteria. We resolved disagreements regarding eligibility by discussion or by consulting a third review author (JR). We documented the selection process in a PRISMA flow chart (Figure 1). We excluded pelvic infection related to obstetric or surgical procedures. Where a study contained both 'eligible' and 'ineligible' participants, we included a subset of data relating to the 'eligible' participants if sufficient details were provided for analysis.

Data extraction and management

Three review authors (SF, DGF, RVD) independently extracted data from each study using a data extraction form that the review authors designed and pilot tested. We collected data from the included studies in sufficient detail to complete the Characteristics of included studies table. We also extracted detailed numerical outcome data in duplicate to allow calculation of Mantel‐Haenszel RRs for each comparison. We examined data for errata, retraction, fraud, and inconsistencies. We resolved disagreements by consensus or by consulting a fourth review author (JR or RFS).

If a study had more than two intervention arms, we included or combined only those that met the predefined inclusion criteria. For instance, if the study compared azithromycin (group A) versus azithromycin plus metronidazole (group B) versus metronidazole plus cefoxitin or doxycycline (group C), and the analysis was between the use or not of metronidazole, we combined groups B and C versus group A. The treatment effect was expressed as rate of cure (%) and its magnitude and direction checked in forest plots to ensure consistency with the original study. Where studies had multiple publications, we used the main trial report as the reference and derived additional details from secondary papers. We corresponded with study investigators for further data as required.

Data collected with the data extraction form were piloted‐tested and included:

• Study factors:

  • author, date of publication, journal;

  • date of study;

  • study design;

  • location;

  • setting;

  • quality of randomization, treatment allocation, and blinding;

  • method of PID diagnosis;

  • sample size.

• Participant factors:

  • age, ethnicity;

  • pregnancy;

  • presence of intrauterine device (IUD);

  • duration of symptoms;

  • presence of abscess (pyosalpinx, tubo‐ovarian abscess).

• Outcome measured:

  • method of assessment of pelvic pain and score;

  • timing of assessment;

  • adverse events;

  • additional assessments of outcome: laparoscopy, microbiology, fertility.

• Intervention factors:

  • antibiotic given: dose, route, length of therapy;

  • comparator regimen: dose, route, length of therapy;

  • additional treatment given.

• Additional data:

  • whether contact tracing was performed.

Assessment of risk of bias in included studies

Three review authors (SF, DGF, RVD) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved disagreements between two review authors by consensus or by involving a third review author (JR or RFS). We assessed risk of bias using the Cochrane 'Risk of bias' tool provided in Review Manager 5 (RevMan 2014). We provided justification for risk of bias (high, low, unclear) in the 'Risk of bias' table by direct reference to the relevant report. We requested missing information from the study investigators using open‐ended questions.

1. Random sequence generation (checking for possible selection bias)

For each included study, we verified the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• unclear risk of bias (e.g. authors stated that women were randomized to one of the treatments, without further explanation).  

2. Allocation concealment (checking for possible selection bias)

For each included study, we verified the method used to conceal allocation to interventions prior to assignment, and we assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

• low risk of bias (e.g. telephone or central randomization; consecutively numbered, sealed, opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes; alternation; date of birth); or

• unclear risk of bias (allocation was mentioned without further details).   

3.1. Blinding of participants and personnel (checking for possible performance bias)

For each included study, we verified the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered studies to be at:

• low risk of bias if participants and personnel were blinded, or if we judged that the lack of blinding would be unlikely to affect results (e.g. culture for N gonorrhoeae);

• high risk if participants and personnel were not blinded;

• unclear risk of bias if no further details were provided.

3.2. Blinding of outcome assessment (checking for possible detection bias)

For each included study, we verified the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received.  We assessed blinding separately for different outcomes or classes of outcomes. We assessed methods used to blind outcome assessment as:

• low risk of bias if assessors were blinded, or if we judged that the lack of blinding would be unlikely to affect results (e.g. culture for N gonorrhoeae);

• high risk if assessors were not blinded;

• unclear risk of bias if no further details were provided.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data)

For each included study, and for each outcome or class of outcomes, we verified the completeness of data, including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re‐included missing data in the analyses we undertook.

We assessed methods as:

• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

• high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomization); or

• unclear risk of bias: no further details were provided.

We used a cutoff point of 20% missing data in determining if a study was at low or high risk of bias (Fewtrell 2008).

5. Selective reporting (checking for reporting bias)

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

• low risk of bias (where it was clear that all the study's prespecified outcomes and all expected outcomes of interest to the review were reported);

• high risk of bias (where not all the study's prespecified outcomes were reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; study did not include results of a key outcome that would have been expected to have been reported); or

• unclear risk of bias: no further details were provided.

6. Other bias (checking for bias due to problems not covered by 1. to 5. above)

For each included study, we described any important concerns we had about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

• low risk of bias;

• high risk of bias; or

• unclear whether there is risk of bias.

7. Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to 1. to 6. above, we assessed the likely magnitude and direction of the bias and whether we considered that it was likely to impact on the findings.  We explored the impact of the level of bias by undertaking sensitivity analyses (see Sensitivity analysis).

Measures of treatment effect

For dichotomous data, we used number of events in the control and intervention groups to calculate Mantel‐Haenszel risk ratios (RR). We presented 95% confidence intervals (CI) for all outcomes. For number need to treat for an additional beneficial (NNTB) or harmful (NNTH) outcome, we followed the recommendation given by Altman (Altman 1998). When we observed a treatment effect we reported the NNTH or NNTB were given with their 95% CIs.

When possible, we performed analysis based on intention to treat (ITT). When information for an ITT analysis was not available, we used the results provided by the authors.

We performed meta‐analysis separately for mild‐moderate PID and severe PID. We defined severe PID as the presence of tubo‐ovarian abscess, being systemically unwell, or the presence of peritonitis, and mild‐moderate PID as no presence of tubo‐ovarian abscess. We further analyzed cases in these two groups across different classes of antibiotics.

Unit of analysis issues

The primary unit of analysis was an event per woman randomized, which was used to calculate the percentage response rate (e.g. clinical cure).

Dealing with missing data

We analyzed the data on an ITT basis to the greatest degree possible and made attempts to obtain missing data from the original trials. Where we were unable to obtain these data, we considered cases that were lost to follow‐up as treatment failure (worst‐case scenario) in the primary analysis. For other outcomes, we analyzed the available data. We did not analyze data from other reported outcomes (e.g. pooled rates of cure of different diseases, including PID).

Assessment of heterogeneity

We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity by measure of the I2 statistic as follows: low (l2 value below 40%), moderate (l2 value of 40% to 75%), or high (l2 value above 75%) (Sutton 2008; Higgins 2011). We also assessed statistical heterogeneity in each meta‐analysis using the t2 and Chi2 statistics.

We regarded heterogeneity as substantial if I2 was greater than 40% and either t2 was greater than zero, or there was a low P value (less than 0.10) in the Chi2 test for heterogeneity. If we detected substantial heterogeneity, we explored possible explanations for it in subgroup analyses (see Subgroup analysis and investigation of heterogeneity). We took statistical heterogeneity into account when interpreting the results, especially if there was any variation in the direction of effect. If so, we used random‐effects analysis, instead of fixed‐effect analysis.

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. Some types of reporting bias (e.g. publication bias, multiple publication bias, language bias, etc.) reduce the likelihood that all studies eligible for a review are retrieved (Higgins 2011). If all eligible studies are not retrieved, the review would be biased. In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimize their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, we used a funnel plot to explore the possibility of small‐study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

We performed statistical analyses using Review Manager 5 (RevMan 2014). We used a fixed‐effect meta‐analysis for combining data where it was reasonable to assume that trials were estimating the same underlying treatment effect (i.e. where trials were examining the same intervention, and the trials' populations and methods were sufficiently similar). We conducted separate analyses for mild‐moderate and severe PID.

If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if we detected substantial statistical heterogeneity (I2 40% or greater), we used a random‐effects meta‐analysis to produce an overall summary if a mean treatment effect across trials was considered clinically meaningful. We treated the random‐effects summary as the mean range of possible treatment effects, and discussed the clinical implications of treatment effects differing between trials.

If the mean treatment effect was not clinically meaningful, we did not combine trials. Where we used random‐effects analyses, we presented the results as the mean treatment effect with 95% CIs, and the estimates of the t2 and I2 statistics.

Subgroup analysis and investigation of heterogeneity

Where data were available, we performed the following prespecified subgroup analyses:

• route of antibiotic administration (oral, intramuscular, or intravenous);

• length of therapy (less or more than seven continuous days receiving antibiotics);

• detection of chlamydia;

• detection of gonorrhoea;

• site of initiation of treatment (inpatient or outpatient).

We avoided selective reporting of a particular subgroup by not performing multiple subgroup analysis. If we identified substantial heterogeneity (I2 40% or greater), we used a random‐effects analysis as the primary statistical analysis.

Where there was substantial heterogeneity, we explored possible reasons for this finding by stratifying results according to the characteristics of the study population (e.g. method of PID diagnosis), the intervention (e.g. class of antibiotics used, dose of antibiotic, route of administration), or methodological characteristics (e.g. length of time to outcome measurement).

Sensitivity analysis

We undertook the following sensitivity analysis to investigate whether our conclusions were robust to methodological decisions made by review authors:

• risk of bias (restricting analysis to blinded studies at low risk of selection bias).

Grading the quality of evidence

We used GRADEpro software (GRADEpro GDT 2014) to produce 'Summary of findings' tables. The GRADE approach considers the following criteria: risk of bias, inconsistency, indirectness of evidence, imprecision, and publication bias, and specifies four levels of quality: high, moderate, low, and very low, starting from high for RCTs. If there was a flaw in the RCT, we downgraded the quality of the evidence by one or two levels.

Two review authors independently applied a consistent grading for GRADE in the 'Summary of findings' tables. We resolved any disagreements by consensus. We downgraded for risk of bias due to crucial risk of bias for two or more criteria (as it was graded in Figure 2). The evidence was downgraded further if there was inconsistency. Inconsistency was based on statistical test for heterogeneity and how much variation there was in the findings of the studies that contributed to the outcome. We also considered imprecision, and downgraded if the CIs were compatible with benefit in one or both groups, or with no difference between the groups. In each domain, we downgraded one level for serious risk of bias and two levels for very serious risk of bias.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Results

Description of studies

Results of the search

We retrieved 2133 references and screened 2094 records after removing duplicated references. We discarded 1955 records as clearly irrelevant and considered 139 full‐text articles. After full‐text review, 37 studies met our inclusion criteria and we excluded 102 studies (Figure 1). The reasons for exclusion of the 102 full‐text studies are explained in the Characteristics of excluded studies table. We extracted data from the full‐text article for each study.

Included studies

The 37 included trials had 6348 women, with a sample size ranging from 25 (Apuzzio 1989), to 1156 (Aşicioğlu 2013). Retrieved studies came from a wide range of inpatient and outpatient settings from different continents (Americas, Europe, Asia, Oceania, and Africa) and were written in English, German, French, Japanese, and Italian.

Population

The included trials recruited women aged 14 years and over with diagnosis of PID according to CDC criteria (pelvic or lower abdominal pain and one or more of the following clinical criteria: cervical motion tenderness, uterine tenderness, or adnexal tenderness) (Workowski 2015). Studies varied in degree of disease severity of participants, treatment location (i.e. inpatient or outpatient), and countries and continents. PID was considered severe in the presence of systemically unwell women, peritonitis, or pelvic abscess.

Interventions

The 37 RCTs yielded 6348 women and made the following comparisons.

For mild‐moderate PID:

• clindamycin plus aminoglycoside versus quinolone (Apuzzio 1989);

• clindamycin plus aminoglycoside versus cephalosporin (Walters 1990).

For severe PID:

• azithromycin versus doxycycline (Bevan 2003);

Outcomes

The main outcome was clinical cure, and 5147 women were reported as clinically cured. We defined clinical cure according to the authors' definitions, which ranged from absence of symptoms for 24 hours (Apuzzio 1989), to a 60% or greater reduction in total pain score at day 21 combined with an absence of pelvic discomfort/tenderness, temperature less than 37.8 °C, and white blood cell level less than 10,000/mm3 on day 21 (Aşicioğlu 2013). Most of the trials used clinical parameters for cure, that is, defervesce, reduction, or absence of pain at different time points after treatment. We identified adverse effects leading to discontinuation of treatment as those related to suspension of therapeutic regimen.

Excluded studies

We excluded 102 studies. The most common reason for exclusion was that the study did not report a comparison of interest to this review (47 studies). Other common reasons for exclusion were that PID cases were not distinguished from other pelvic infectious conditions (21 studies) or the studies was not randomized (14 studies) (see Characteristics of excluded studies table).

Risk of bias in included studies

We performed a full risk of bias assessment on all included studies. We classified those studies where authors stated that women were randomized to one of two treatments, without further details, as at unclear risk of selection bias. Many of these studies were performed before the year 2000, and predated the introduction of CONSORT guideline.

We have summarized the risk of bias in Figure 2 and Figure 3. Additional details of the included trials are provided in the Characteristics of included studies table.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Selective reporting

For most of the included studies, the trial protocol was not available, and it was unclear whether the published reports included all the expected outcomes, including those that were prespecified. The reports had insufficient information to permit judgement of 'yes' or 'no', and were therefore rated as at unclear risk of bias. For three trials, the trial protocol was available, and it was clear that the published reports included all the expected outcomes, including those that were prespecified, making reporting bias unlikely (Ross 2006; Savaris 2007; Aşicioğlu 2013).

Other potential sources of bias

One study had imbalances in baseline characteristics and was at high risk of potential bias (Soper 1988). Out of 37 trials, 13 had some form of funding by pharmaceutical companies (Arredondo 1997;Crombleholme 1989; Hemsell 1994; Heystek 2009; Judlin 2010a; Landers 1991; Martens 1993; Ross 2006; ;Roy 1990; Savaris 2007; Thadepalli 1991; Walters 1990; Wendel 1991); however, there is no clear evidence that trial methods are more likely to be flawed if a trial is industry funded (Sterne 2013), therefore these trials were rated as at unclear risk. The remaining trials provided insufficient information to permit a judgement of 'yes' or 'no' and were therefore rated as at unclear risk of bias.

Assessment of reporting bias

We explored publication bias through visual assessment of funnel plot asymmetry when there were data from 10 or more trials in the same analysis. We constructed a funnel plot for Analysis 3.3 (Figure 4) and noted some asymmetry in the plot, suggestive of potential publication bias. There are five possible causes for the asymmetric funnel plot: reporting bias, poor methodological quality, true heterogeneity, artefactual, and chance (Egger 1997). Only through formal statistical analysis or using 'contour‐enhanced' funnel plot is an explication for these asymmetrical funnel plots possible. Although it is usually impossible to know the precise mechanism for funnel plot asymmetry, publication bias could explain the presence of an asymmetrical funnel plot.

Funnel plot of comparison: 3.2 Effectiveness of cure in severe PID in regimens containing nitroimidazoles versus without nitroimidazoles.

Comparison 3 Regimens containing nitroimidazoles versus no nitroimidazoles, Outcome 3 Effectiveness of cure in severe PID.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5

We analyzed effectiveness of clinical cure and adverse effects leading to discontinuation of treatment in five scenarios based on drug class comparison:

• regimens containing macrolides (azithromycin) versus tetracycline (doxycycline);

• regimens containing quinolones versus cephalosporin;

• regimens containing nitroimidazoles versus without nitroimidazoles;

• regimens containing clindamycin plus aminoglycoside versus quinolone;

• regimens containing clindamycin plus aminoglycoside versus cephalosporin.

We analyzed the efficacy of therapy in these five comparisons in women with mild‐moderate PID and women with severe PID. We also compared adverse events leading to discontinuation of the therapy. Lack of further analysis is discussed in the Differences between protocol and review section.

1. Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline)

Three studies compared azithromycin versus doxycycline in mild‐moderate (Malhotra 2003; Savaris 2007) or severe (Bevan 2003) PID.

Primary outcomes

1.1. Effectiveness

1.1a. Clinical cure in mild‐moderate pelvic inflammatory disease

We included two trials in the analysis of clinical cure in mild‐moderate PID (Malhotra 2003; Savaris 2007). There was no clear evidence of a difference between azithromycin and doxycycline regimens (RR 1.18, 95% CI 0.89 to 1.55; 243 women; 2 studies; I2 = 72%; very low‐quality evidence) (Analysis 1.1; Figure 5).

1.1 Effectiveness of cure in mild‐moderate PID on regimens containing macrolides (azithromycin) versus tetracycline (doxycycline) using ITT.

Comparison 1 Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline), Outcome 1 Effectiveness of cure in mild‐moderate PID.

In a sensitivity analysis limited to the study at low risk of bias, azithromycin was superior to doxycycline in achieving cure in mild‐moderate PID (RR 1.35, 95% CI 1.10 to 1.67, 133 women, moderate‐quality evidence) (Analysis 1.2)

Comparison 1 Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline), Outcome 2 Sensitivity analysis by risk of bias: effectiveness of cure in mild‐moderate PID.

1.1b. Clinical cure in severe pelvic inflammatory disease

One trial reported clinical cure in severe PID (Bevan 2003). There was no clear evidence of a difference in rates of cure between regimens using azithromycin or doxycycline to treat severe PID (RR 1.00, 95% CI 0.96 to 1.05; 309 women; 1 study; low‐quality evidence) (Analysis 1.3; Figure 6.

1.2 Effectiveness of cure in severe PID in regimens containing macrolides (azithromycin) versus tetracycline (doxycycline).

Comparison 1 Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline), Outcome 3 Effectiveness of cure in severe PID.

1.2. Adverse events

1.2.1. Antibiotic‐related adverse effects leading to discontinuation of therapy

We included three trials in the analysis of antibiotic‐related adverse effects leading to discontinuation of therapy (Bevan 2003; Malhotra 2003; Savaris 2007). There was no clear evidence of a difference between the groups (RR 0.71, 95% CI 0.38 to 1.34; 552 women; 3 studies; I2 = 0%, low‐quality evidence) (Analysis 1.4).

Comparison 1 Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline), Outcome 4 Any antibiotic‐related adverse effect leading to discontinuation use of macrolide versus tetracycline.

Data are depicted in Table 1.

Secondary outcomes

1.3. Microbiological clearance of chlamydia

Two studies reported chlamydia clearance (Bevan 2003; Savaris 2007) and cure was obtained in 49/50 women in the azithromycin group (cure 98%, 95% CI 89% to 100%) and 33/33 women in the doxycycline group (cure 100%, 95% CI 90% to 100%).

1.4. Microbiological clearance of gonorrhoea

Two studies reported gonorrhoea clearance (Bevan 2003; Savaris 2007), but only one found evidence of N gonorrhoeae (Bevan 2003). In the azithromycin group, there was cure in 11/11 cases (100%, 95% CI 74% to 100%). Cure was also 100% in the doxycycline group (5/5 cases; 100%, 95% CI 57% to 100%).

1.5. Laparoscopic evidence of resolution of pelvic inflammatory disease based on physician opinion

We found no data for laparoscopic evidence of resolution of PID.

1.6. Length of stay (for inpatient care)

One study reported length of hospital stay (Bevan 2003). Women were kept in the hospital, per protocol, for 13 to 18 days.

1.7. Rate of fertility

We found no data for rate of fertility.

2. Regimens containing quinolones versus cephalosporins

Six studies compared quinolones versus cephalosporins in mild‐moderate PID (Wendel 1991; Martens 1993; Arredondo 1997) or severe PID (Okada 1988; Martens 1993; Fischbach 1994).

Primary outcomes

2.1. Effectiveness

2.1a. Clinical cure in mild‐moderate pelvic inflammatory disease

We included three trials in the analysis of clinical cure in mild‐moderate PID (Wendel 1991; Martens 1993; Arredondo 1997). There was no clear evidence of a difference between the groups (RR 1.04, 95% CI 0.98 to 1.10; 459 women; 3 studies; I2 = 5%; low‐quality evidence) (Analysis 2.1).

Comparison 2 Regimens containing quinolones versus cephalosporins, Outcome 1 Effectiveness of cure in mild‐moderate PID.

2.1b. Clinical cure in severe pelvic inflammatory disease

We included two trials in the analysis of clinical cure in severe PID (Okada 1988; Fischbach 1994). There was no clear evidence of a difference in rates of cure between regimens using quinolones or cephalosporins to treat severe PID (RR 1.06, 95% CI 0.91 to 1.23; 313 women; 2 studies; I2 = 7%; low‐quality evidence) (Analysis 2.2).

Comparison 2 Regimens containing quinolones versus cephalosporins, Outcome 2 Effectiveness of cure in severe PID.

2.2. Adverse events

2.2.1. Antibiotic‐related adverse effect leading to discontinuation of therapy

The five trials reported few adverse effects leading to discontinuation of treatment (quinolones: 1.2%, 95% CI 0.5 to 2.9 versus cephalosporin: 0.5%, 95% CI 0.1 to 1.9%), with no clear evidence of a difference in rates of discontinuation (RR 2.24, 95% CI 0.52 to 9.72; 772 women; 5 studies; I2 = 0%, very low‐quality evidence) (Okada 1988; Wendel 1991; Martens 1993; Fischbach 1994; Arredondo 1997) (Analysis 2.3).

Comparison 2 Regimens containing quinolones versus cephalosporins, Outcome 3 Any antibiotic‐related adverse effect leading to discontinuation cephalosporin versus quinolone.

Data are depicted in Table 2.

Secondary outcomes

2.5. Laparoscopic evidence of resolution of pelvic inflammatory disease based on physician opinion

We found no data for laparoscopic evidence of resolution of PID.

2.6. Length of stay (for inpatient care)

We found no data suitable for analysis for length of hospital stay. Fischbach and colleagues admitted women for intravenous treatment for two to five days, followed by seven to 12 days of oral therapy, without further details (Fischbach 1994).

2.7. Rate of fertility

We found no data for rate of fertility.

3. Regimens containing nitroimidazoles versus no nitroimidazoles

Sixteen studies compared nitroimidazoles versus without nitroimidazoles in mild‐moderate PID (Burchell 1987; Tison 1988; Ross 2006; Judlin 2010a; Aşicioğlu 2013) or severe PID (Ciraru‐Vigneron 1986; Crombleholme 1986; Crombleholme 1987; Leboeuf 1987; Buisson 1989; Ciraru‐Vigneron 1989; Giraud 1989; Heinonen 1989; Fischbach 1994; Sirayapiwat 2002; Heystek 2009).

Primary outcomes

3.1. Effectiveness

3.1a. Clinical cure in mild‐moderate pelvic inflammatory disease

We included five studies in the analysis of clinical cure in mild‐moderate PID (Burchell 1987; Tison 1988; Ross 2006; Judlin 2010a; Aşicioğlu 2013). In all the studies the nitroimidazole used was metronidazole. There was no conclusive evidence of a difference in effectiveness between metronidazole versus no use of metronidazole in mild‐moderate PID (RR 1.01, 95% CI 0.93 to 1.10; 2427 women; 5 studies; I2 = 60%; moderate‐quality evidence) (Analysis 3.1; Figure 7).

3.1 Effectiveness of cure in mild‐moderate PID in regimens containing nitroimidazoles versus without nitroimidazoles.

Comparison 3 Regimens containing nitroimidazoles versus no nitroimidazoles, Outcome 1 Effectiveness of cure in mild‐moderate PID.

Sensitivity analysis restricted to the two studies at low risk of bias did not substantially change the main findings (RR 1.06, 95% CI 0.98 to 1.15; 1201 women; 2 studies; I2 = 32%; high‐quality evidence) (Ross 2006; Judlin 2010a) (Analysis 3.2).

Comparison 3 Regimens containing nitroimidazoles versus no nitroimidazoles, Outcome 2 Sensitivity analysis by risk of bias: effectiveness of cure in mild‐moderate PID.

3.2. Adverse events

Secondary outcomes

3.3. Microbiological clearance of chlamydia

This is not applicable, since nitroimidazoles do not have activity against chlamydia.

3.4. Microbiological clearance of gonorrhoea

This is not applicable, since nitroimidazoles do not have activity against gonorrhoea.

3.5. Laparoscopic evidence of resolution of pelvic inflammatory disease based on physician opinion

We found no data for laparoscopic evidence of resolution of PID.

3.6. Length of stay (for inpatient care)

Burchell and colleagues did not give details of the length of hospital stay: the authors mentioned that "ampicillin plus metronidazole in group II began with four 1 g intravenous doses given at 6‐hourly intervals and then 400 mg 8‐hourly orally for 14 days" and in Table III stated "patient response after 4 days treatment" (Burchell 1987).

Ciraru‐Vigneron and colleagues reported that women treated with amoxicillin plus clavulanate had a stay of 3.6 days and with ampicillin plus gentamicin plus metronidazole had a stay of 3.7 days (Ciraru‐Vigneron 1986).

Buisson and colleagues reported that the mean treatment for the amoxicillin plus clavulanate group was four days followed by a mean of 17 days of oral therapy, and for the triple treatment (ampicillin plus gentamicin plus metronidazole) it was seven days per protocol, due to the use of gentamicin, followed by ampicillin plus metronidazole until clinical improvement (Buisson 1989).

Ciraru‐Vigneron and colleagues reported that the mean duration of intravenous therapy was 7.6 ± 2.1 days in amoxicillin plus clavulanate and 7.7 ± 2.2 days in the ampicillin plus gentamicin plus metronidazole group. They did not specify if the oral treatment, followed intravenous treatment, was performed in hospital, but both were similar (11.2 ± 4.8 days with amoxicillin plus clavulanate and 11.1 ± 6.6 days with ampicillin plus gentamicin plus metronidazole) (Ciraru‐Vigneron 1989).

Crombleholme and colleagues report that treatment was for 14 days, starting with intravenous infusion and switched to oral, but they did not provide details if oral therapy was in hospital (Crombleholme 1989). In their previous study, intravenous treatment length was mentioned as at least five days, without further details (Crombleholme 1986).

Fischbach and colleagues admitted women for intravenous treatment for two to five days, followed by seven to 12 days of oral therapy, without further details (Fischbach 1994).

3.7. Rate of fertility

We found no data for rate of fertility.

4. Regimens containing clindamycin plus aminoglycoside versus quinolone

Three studies compared clindamycin plus aminoglycoside versus quinolone in mild‐moderate PID (Apuzzio 1989) or severe PID (Crombleholme 1989; Thadepalli 1991).

Primary outcomes

4.1. Effectiveness

4.1a. Clinical cure in mild‐moderate pelvic inflammatory disease

Only one study compared clindamycin with an aminoglycoside (gentamicin) versus a quinolone (ciprofloxacin) (Apuzzio 1989). It was unclear whether there was any difference between the regimens (RR 0.88, 95% CI 0.69 to 1.13; 25 women; 1 study; I2 = 0%; very low‐quality evidence) (Analysis 4.1).

Comparison 4 Regimens containing clindamycin plus aminoglycoside versus quinolone, Outcome 1 Effectiveness of cure in mild‐moderate PID.

4.1b. Clinical cure in severe pelvic inflammatory disease

We included two studies in the analysis of clinical cure in severe PID (Crombleholme 1989; Thadepalli 1991). There was no clear evidence of a difference between these regimens in rates of cure for severe PID (RR 1.02, 95% CI 0.87 to 1.19; 151 women; 2 studies; I2 = 0%; low‐quality evidence) (Analysis 4.2).

Comparison 4 Regimens containing clindamycin plus aminoglycoside versus quinolone, Outcome 2 Effectiveness of cure in severe PID.

4.2. Adverse events

4.2.1. Antibiotic‐related adverse effects leading to discontinuation of therapy

The incidence of antibiotic‐related adverse effects leading to discontinuation of therapy with clindamycin with aminoglycoside was 0% (95% CI 0% to 4.4%) and with quinolone was 5% (95% CI 1.9% to 12%). There was no clear evidence of a difference between regimens (RR 0.21, 95% CI 0.02 to 1.72; 163 women; 3 studies; I2 = 0%; very low‐quality evidence) (Analysis 4.3).

Comparison 4 Regimens containing clindamycin plus aminoglycoside versus quinolone, Outcome 3 Any antibiotic‐related adverse effect leading to discontinuation.

Data are depicted in Table 4.

Secondary outcomes

4.3. Microbiological clearance of chlamydia

Three studies reported chlamydia clearance (Apuzzio 1989; Crombleholme 1989; Thadepalli 1991), and cure occurred in 10/10 women in the clindamycin plus aminoglycoside group (100%, 95% CI 72% to 100%) and in 11/12 women in the quinolone group (92%, 95% CI 65% to 99%).

4.4. Microbiological clearance of gonorrhoea

Three studies reported gonorrhoea clearance (Apuzzio 1989; Crombleholme 1989; Thadepalli 1991), and cure occurred in 44/44 women in the clindamycin plus aminoglycoside group (100%, 95% CI 92% to 100%) and in 41/41 women in the quinolone group (100%, 95% CI 91% to 100%).

4.5. Laparoscopic evidence of resolution of pelvic inflammatory disease based on physician opinion

We found no data for laparoscopic evidence of resolution of PID.

4.6. Length of stay (for inpatient care)

We found no data suitable for analysis for length of hospital stay. Crombleholme and colleagues reported that treatment was for 14 days, starting with intravenous infusion and then switched to oral, but they did not provide details if oral therapy was in hospital (Crombleholme 1989). Appuzio and colleagues did not give many details of the length of stay. They mentioned that women received intravenous antibiotics for three to five days until they were asymptomatic for 24 hours (Apuzzio 1989). Likewise, Thadepalli reported that women received intravenous ciprofloxacin for three or more days, followed by oral ciprofloxacin for about one week (Thadepalli 1991).

4.7. Rate of fertility

We found no data for rate of fertility.

5. Regimens containing clindamycin plus aminoglycoside versus cephalosporin

Ten studies compared clindamycin plus aminoglycoside versus cephalosporin in mild‐moderate PID (Sweet 1985; Walters 1990) or severe PID (Roy 1985; Sweet 1985; Soper 1988; Martens 1990; Roy 1990; Walters 1990; Landers 1991; Maria 1992; Hemsell 1994; Balbi 1996). Studies from Sweet 1985 and Walters 1990 had both populations with mild‐moderate and severe PID, thus they were used in both analyses.

Primary outcomes

5.1. Effectiveness

5.1a. Clinical cure in mild‐moderate pelvic inflammatory disease

We analyzed two studies for clinical cure in mild‐moderate PID (Sweet 1985; Walters 1990). There was no clear evidence of a difference between these regimens in rates of cure for mild‐moderate PID (RR 1.02, 95% CI 0.95 to 1.09; 150 women; 2 studies; I2 = 0%, low‐quality evidence) (Analysis 5.1; Figure 9).

Forest plot of comparison: 5 Regimens containing clindamycin plus aminoglycoside versus cephalosporin, outcome: 5.1 Effectiveness of cure in mild‐moderate PID.

Comparison 5 Regimens containing clindamycin plus aminoglycoside versus cephalosporin, Outcome 1 Effectiveness of cure in mild‐moderate PID.

5.1b. Clinical cure in severe pelvic inflammatory disease

We included 10 studies in the analysis of clinical cure in severe PID (Roy 1985; Sweet 1985; Soper 1988; Martens 1990; Roy 1990; Walters 1990; Landers 1991; Maria 1992; Hemsell 1994; Balbi 1996). There was no clear evidence of a difference between these regimens in rates of cure of severe PID (RR 1.00, 95% CI 0.95 to 1.06; 959 women; 10 studies; I2 = 21%; moderate‐quality evidence) (Analysis 5.2; Figure 10).

5.2 Effectiveness of cure in severe PID in regimens containing clindamycin plus aminoglycoside versus cephalosporin.

Comparison 5 Regimens containing clindamycin plus aminoglycoside versus cephalosporin, Outcome 2 Effectiveness of cure in severe PID.

5.2. Adverse events

5.2.1. Antibiotic‐related adverse effects leading to discontinuation of therapy

We included 10 studies in the analysis of antibiotic‐related adverse effects leading to discontinuation of therapy (Roy 1985; Sweet 1985; Soper 1988; Martens 1990; Roy 1990; Walters 1990; Landers 1991; Maria 1992; Hemsell 1994; Balbi 1996). There was no clear evidence of a difference between groups in adverse effects leading to discontinuation of treatment (RR 0.78, 95% CI 0.18 to 3.42; 1172 women; 10 studies; I2 = 0%; very low‐quality evidence) (Analysis 5.3).

Comparison 5 Regimens containing clindamycin plus aminoglycoside versus cephalosporin, Outcome 3 Any antibiotic‐related adverse effect leading to discontinuation.

Data are depicted in Table 5.

Secondary outcomes

5.3. Microbiological clearance of chlamydia

Five studies reported chlamydia clearance (Sweet 1985; Roy 1990; Walters 1990; Maria 1992; Balbi 1996). Cure occurred in 53/56 women in the cephalosporin group (94.6%, 95% CI 85% to 98%) and in 75/78 women in the clindamycin plus aminoglycoside group (96%, 95% CI 89% to 99%).

5.4. Microbiological clearance of gonorrhoea

Five studies reported gonorrhoea clearance (Sweet 1985; Roy 1990; Walters 1990; Maria 1992; Balbi 1996). Cure occurred in 96/96 women in the clindamycin plus aminoglycoside group (100%, 95% CI 96% to 100%) and 115/117 women in the cephalosporin group (98%, 95% CI 94% to 99%).

5.5. Laparoscopic evidence of resolution of pelvic inflammatory disease based on physician opinion

We found no data for laparoscopic evidence of resolution of PID.

5.6. Length of stay (for inpatient care).

Seven studies did not provide enough data for analysis of length of hospital stay (Roy 1985; Sweet 1985; Roy 1990; Walters 1990; Landers 1991; Maria 1992; Balbi 1996). Three studies provided the mean and standard deviations of hospital stay, or range of days (Soper 1988; Martens 1990; Hemsell 1994). The mean length of stay for the cephalosporin group varied from 5.8 days to 9.6 days (range 3 days to 18 days) in the clindamycin plus aminoglycoside group and the mean days of in hospital days varied from 5.8 days to 9.8 days (range from 2 days to 25 days).

5.7. Rate of fertility

We found no data for rate of fertility.

Other analyses

We were unable to conduct our planned subgroup analyses due to insufficient data in the included studies.

Discussion

Summary of main results

We included 37 trials with 6348 women in the review. We found no clear evidence of a difference between any of the regimens studied in terms of effectiveness or safety.

The only comparison that clearly suggested a difference between the interventions was the sensitivity analysis of cases of mild‐moderate PID for the comparison macrolide (azithromycin) versus tetracycline (doxycycline). When we limited analysis to the single study at low risk of bias, moderate‐quality evidence suggested that azithromycin was superior to doxycycline in achieving clinical cure (Table 1).

Some guidelines have recommended the use of nitroimidazoles for treating PID (Ross 2007; Workowski 2015). We found no conclusive evidence of a difference between the use or not of nitroimidazoles (metronidazole) in rates of cure in either mild‐moderate or severe PID. There was also no clear evidence of a difference in rates of adverse effects.

Overall completeness and applicability of evidence

Although we conducted comprehensive searches to identify all published and unpublished RCTs, this systematic review included trials at high risk of bias and consequently with low confidence in the estimate of effect (see Table 1; Table 2; Table 3; Table 4; Table 5). When we used ITT analysis, there was substantial heterogeneity in the azithromycin trial results, which may limit our conclusions.

Data were lacking for several of our secondary outcomes. None of the included studies reported data on fertility or laparoscopic evidence of PID resolution, and data were very scant on length of stay.

The applicability of the evidence to the target population (women of reproductive age diagnosed with PID) was broad because the included trials were conducted in different clinical settings and implemented varying diagnostic approaches. Additionally, the interventions analyzed in the review are available in various clinical settings and represent the most frequently used therapeutic schemes in current clinical practice. Given these factors, we consider that the evidence identified applies to a wide range of women with PID varying in disease severity, age, geographical location, and diagnostic criteria, which provides external validity.

PID can be life or fertility threatening, and treatment is routinely started before laboratory cultures or laparoscopic confirmation. In some cases, women were subsequently diagnosed with another condition; however, we included all women in our ITT analysis, in accordance with our review protocol.

Quality of the evidence

Most of the 37 included studies had unclear or high risk of bias in most domains, and only three were at low risk of bias in most domains (Ross 2006; Savaris 2007; Judlin 2010a). The remaining studies had a number of limitations, for instance, 25 trials did not clearly define randomization, and there was potential performance and detection bias in 20 studies (Figure 3).

The overall quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision. There was substantial heterogeneity in the comparison between azithromycin and doxycycline (I2 = 72%; Figure 5) and in the comparison of nitroimidazole versus no nitroimidazole (I2 = 60%; Figure 7). Imprecision was related to suboptimal sample sizes and the low number of studies for some comparisons.

The quality of evidence for the outcomes analyzed is provided in the 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4; Table 5). The only high‐quality evidence was for the sensitivity analysis regarding the use (or not) of nitroimidazole. There was moderate‐quality evidence in the sensitivity analysis regarding the use of azithromycin in mild‐moderate cases of PID, in comparisons between the use or not of nitroimidazole for curing mild‐moderate or severe PID, and in comparisons between clindamycin plus aminoglycoside versus cephalosporins for curing severe PID.

For all other comparisons, the evidence was low or very low quality.

Potential biases in the review process

An important limitation of this systematic review was the potential for measurement bias introduced by using the investigators' definitions of cure. This approach was necessary because of the wide variation in methods used and lack of a widely accepted objective outcome measure. The short‐term follow‐up of most of the studies prevented the identification of long‐term sequelae. In addition, the inaccuracy of clinical diagnosis for PID and the wide variety of assessment criteria used for clinical cure may have reduced the power of the analysis to detect a significant effect.

Some studies identified PID and endometritis separately but these were pooled for our analysis.

Agreements and disagreements with other studies or reviews

One previous meta‐analysis, published in 1993, formed the basis for the CDC guidelines (Walker 1993). The authors reported pooled clinical cure rates ranging from 75% to 94%, which is similar to our updated review with overall rate of cure of 81%. Therefore, our results support the updated 2015 CDC guidelines (Workowski 2015) and the International Union against Sexually Transmitted Infections (IUSTI)/BASHH (Judlin 2010b; Ross 2014a), but not the inclusion of nitroimidazoles in treatment regimens.

Authors' conclusions

We found no conclusive evidence that one regimen is safer or more effective than any other for the cure of PID, and there is no clear evidence for the use of nitroimidazoles (metronidazole) compared to use of other drugs with activity over anaerobes. Moderate‐quality evidence from a single study at low risk of bias suggests that a macrolide (azithromycin) may be more effective than a tetracycline (doxycycline) for curing mild‐moderate PID. Our review considers only the drugs that are currently used and mentioned by the US Centers for Disease Control and Prevention (CDC).

There is a need for high‐quality randomized controlled trials following CONSORT guidance to assess treatments for women with PID, particularly further trials comparing oral azithromycin versus oral doxycycline and the use of nitroimidazoles. The lack of a consistent outcome measure to assess response to therapy is a major limitation and there is a clear need for core outcome measures to be developed.

Acknowledgements

We acknowledge the support of Helen Nagels, Motokazu Yanagi, Kensuke Takaoka, and Chen Hengxi with the non‐English language studies.

Appendices

Appendix 1. Electronic search strategies

CENTRAL (Ovid platform)

1 exp Pelvic Inflammatory Disease/ (418)

2 (pelvic adj5 inflammatory adj5 disease$).tw. (282)

3 pid.tw. (273)

4 pelvic inflammat$.tw. (310)

5 pelvic peritonitis.tw. (0)

6 adnexitis.tw. (10)

7 exp Pelvic Infection/ (196)

8 (pelvic adj5 infection$).tw. (208)

9 (ovar$ adj5 inflammation).tw. (16)

10 exp Oophoritis/ (7)

11 oophoriti$.tw. (7)

12 exp Endometritis/ (216)

13 endometritis.tw. (356)

14 endomyometritis.tw. (56)

15 exp Salpingitis/ (42)

16 salpingiti$.tw. (56)

17 exp Parametritis/ (9)

18 parametriti$.tw. (2)

19 (celluliti$ adj5 pelvic).tw. (26)

20 exp Fallopian Tube Diseases/ (134)

21 (fallopian adj5 tube adj5 disease$).tw. (5)

22 (tubal adj5 obstruction$).tw. (19)

23 (uterine adj5 tube adj5 disease$).tw. (0)

24 (tuboovarian adj5 abscess).tw. (5)

25 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 (1286)

26 exp Anti‐Bacterial Agents/ (20463)

27 (anti adj5 bacterial$).tw. (90)

28 antibacterial$.tw. (1562)

29 antibiotic$.tw. (13603)

30 bacteriocid$.tw. (13)

31 bactericide$.tw. (5)

32 exp Anti‐Infective Agents/ (48142)

33 (anti adj5 infective$).tw. (127)

34 antiinfective$.tw. (21)

35 microbicid$.tw. (257)

36 antimicrobial$.tw. (3551)

37 (anti adj5 microbial$).tw. (93)

38 exp Aminoglycosides/ (6672)

39 aminoglycosides.tw. (211)

40 exp Amoxicillin‐Potassium Clavulanate Combination/ (461)

41 amoxicillin.tw. (2645)

42 exp Azithromycin/ (702)

43 azithromycin.tw. (1283)

44 exp Cefotaxime/ (1574)

45 cefotaxime.tw. (598)

46 exp Cefotetan/ (105)

47 cefotetan.tw. (155)

48 exp Cefoxitin/ (274)

49 cefoxitin.tw. (410)

50 exp Ceftizoxime/ (164)

51 ceftizoxime.tw. (125)

52 exp Ceftriaxone/ (565)

53 ceftriaxone.tw. (940)

54 exp Ciprofloxacin/ (941)

55 ciprofloxacin.tw. (1597)

56 exp Clindamycin/ (664)

57 clindamycin.tw. (1082)

58 exp Doxycycline/ (731)

59 doxycycline.tw. (1120)

60 exp Gentamicins/ (1044)

61 gentamicin.tw. (1284)

62 exp Metronidazole/ (1688)

63 metronidazole.tw. (2693)

64 moxifloxacin.tw. (667)

65 exp Ofloxacin/ (752)

66 ofloxacin.tw. (824)

67 levofloxacin.tw. (730)

68 sultamicillin.tw. (44)

69 (ampicillin adj5 sulbactam).tw. (229)

70 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 (63988)

71 25 and 70 (611)

MEDLINE (Ovid platform)

1 exp Pelvic Inflammatory Disease/ (10207)

2 (pelvic adj5 inflammatory adj5 disease$).tw. (4083)

3 pid.tw. (3492)

4 pelvic inflammat$.tw. (4283)

5 pelvic peritonitis.tw. (105)

6 adnexitis.tw. (496)

7 exp Pelvic Infection/ (5135)

8 (pelvic adj5 infection$).tw. (1833)

9 (ovar$ adj5 inflammation).tw. (279)

10 exp Oophoritis/ (499)

11 oophoriti$.tw. (407)

12 exp Endometritis/ (3599)

13 endometritis.tw. (3169)

14 endomyometritis.tw. (200)

15 exp Salpingitis/ (1994)

16 salpingiti$.tw. (1513)

17 exp Parametritis/ (198)

18 parametriti$.tw. (112)

19 (celluliti$ adj5 pelvic).tw. (97)

20 exp Fallopian Tube Diseases/ (7297)

21 (fallopian adj5 tube adj5 disease$).tw. (84)

22 (tubal adj5 obstruction$).tw. (423)

23 (uterine adj5 tube adj5 disease$).tw. (3)

24 (tuboovarian adj5 abscess).tw. (143)

25 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 (23104)

26 exp Anti‐Bacterial Agents/ (613243)

27 (anti adj5 bacterial$).tw. (2879)

28 antibacterial$.tw. (52343)

29 antibiotic$.tw. (261141)

30 bacteriocid$.tw. (544)

31 bactericide$.tw. (658)

32 exp Anti‐Infective Agents/ (1415302)

33 (anti adj5 infective$).tw. (3071)

34 antiinfective$.tw. (417)

35 microbicid$.tw. (5363)

36 antimicrobial$.tw. (111599)

37 (anti adj5 microbial$).tw. (2944)

38 exp Aminoglycosides/ (140356)

39 aminoglycosides.tw. (8449)

40 exp Amoxicillin‐Potassium Clavulanate Combination/ (2250)

41 amoxicillin.tw. (11786)

42 exp Azithromycin/ (4124)

43 azithromycin.tw. (6083)

44 exp Cefotaxime/ (12415)

45 cefotaxime.tw. (7263)

46 exp Cefotetan/ (485)

47 cefotetan.tw. (734)

48 exp Cefoxitin/ (1763)

49 cefoxitin.tw. (3821)

50 exp Ceftizoxime/ (1101)

51 ceftizoxime.tw. (887)

52 exp Ceftriaxone/ (5094)

53 ceftriaxone.tw. (8422)

54 exp Ciprofloxacin/ (11440)

55 ciprofloxacin.tw. (20547)

56 exp Clindamycin/ (5195)

57 clindamycin.tw. (8787)

58 exp Doxycycline/ (8330)

59 doxycycline.tw. (10686)

60 exp Gentamicins/ (17804)

61 gentamicin.tw. (21225)

62 exp Metronidazole/ (11543)

63 metronidazole.tw. (13091)

64 moxifloxacin.tw. (3450)

65 exp Ofloxacin/ (6176)

66 ofloxacin.tw. (5988)

67 levofloxacin.tw. (5700)

68 sultamicillin.tw. (141)

69 (ampicillin adj5 sulbactam).tw. (1564)

70 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 (1632933)

71 randomized controlled trial.pt. (425167)

72 controlled clinical trial.pt. (91285)

73 randomized.ab. (355829)

74 placebo.ab. (174189)

75 clinical trials as topic.sh. (178323)

76 randomly.ab. (254885)

77 trial.ti. (155344)

78 71 or 72 or 73 or 74 or 75 or 76 or 77 (1039211)

79 exp animals/ not humans.sh. (4280378)

80 78 not 79 (957018)

81 25 and 70 and 80 (684)

Embase

#1 'pelvic inflammatory disease'/exp (13,726)

#2 'pelvic inflammatory disease':ti,ab (4326)

#3 p.i.d.:ti,ab (55)

#4 pid:ti,ab (5,216)

#5 'pelvic infection':ti,ab (731)

#6 (pelvi? NEAR/5 inflammat*):ti,ab (5,453)

#7 'pelvic peritonitis':ti,ab (137)

#8 'ovary inflammation'/exp (695)

#9 (ovar* NEAR/5 inflammatio*):ti,ab (377)

#10 oophoriti*:ti,ab (471)

#11 ovaritis:ti,ab (48)

#12 'endometritis'/exp (5,280)

#13 endometritis:ti,ab (3,647)

#14 'salpingitis'/exp (2,633)

#15 salpingitis:ti,ab (1,657)

#16 'uterine tube disease'/exp (9,070)

#17 'uterine tube disease':ti,ab (1)

#18 'uterine tube inflammation':ti,ab (1)

#19 'fallopian tube diseases':ti,ab (3)

#20 'fallopian tube inflammation':ti,ab (2)

#21 'adnexitis'/exp (1,019)

#22 adnexitis:ti,ab (552)

#23 'adnex inflammation uterine':ti,ab (0)

#24 'adnexa infection':ti,ab (0)

#25 'adnexa inflammation':ti,ab (0)

#26 parametriti*:ti,ab (112)

#27 (para NEAR/5 metriosis):ti,ab (0)

#28 'tuboovarian abscess':ti,ab (190)

#29 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16

OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 (31,956)

#30 'antiinfective agent'/exp (2,566,913)

#31 'antiinfective agent':ti,ab (25)

#32 antibacterial*:ti,ab (70,680)

#33 'anti bacterial':ti,ab (3,425)

#34 'anti infective':ti,ab (3,462)

#35 antimicrobial*:ti,ab (147,222)

#36 bacteriocid*:ti,ab (660)

#37 bactericide*:ti,ab (1,159)

#38 microbicid*:ti,ab (6,092)

#39 'antibiotic agent'/exp (1,121,485)

#40 antibiotic*:ti,ab (338,040)

#41 'aminoglycoside'/exp (13,112)

#42 aminoglycoside:ti,ab (12,338)

#43 'amoxicillin plus clavulanic acid'/exp (29,766)

#44 'amoxicillin':ti,ab (16,673)

#45 'azithromycin'/exp (26,174)

#46 azithromycin:ti,ab (8,812)

#47 'cefotaxime'/exp (35,191)

#48 cefotaxime:ti,ab (9,344)

#49 'cefotetan'/exp (3,075)

#50 cefotetan:ti,ab (977)

#51 'cefoxitin'/exp (15,495)

#52 cefoxitin:ti,ab (4,658)

#53 'ceftizoxime'/exp (3,860)

#54 ceftizoxime:ti,ab (1,234)

#55 'ceftriaxone'/exp (45,306)

#56 ceftriaxone:ti,ab (12,087)

#57 'ciprofloxacin'/exp (77,874)

#58 ciprofloxacin:ti,ab (27,319)

#59 'clindamycin'/exp (42,275)

#60 clindamycin:ti,ab (11,122)

#61 'doxycycline'/exp (41,407)

#62 doxycycline:ti,ab (14,273)

#63 'gentamicin'/exp (90,658)

#64 gentamicin:ti,ab (26,194)

#65 'metronidazole'/exp (56,425)

#66 metronidazole:ti,ab (17,513)

#67 'moxifloxacin'/exp (13,514)

#68 moxifloxacin:ti,ab (4,833)

#69 'ofloxacin'/exp (22,915)

#70 ofloxacin:ti,ab (7,905)

#71 'levofloxacin'/exp (25,916)

#72 levofloxacin:ti,ab (8,786)

#73 'sultamicillin'/exp (8,641)

#74 sultamicillin:ti,ab (277)

#75 'ampicillin sulbactam':ti,ab (1,567)

#76 #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 (2,684,527)

#77 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp OR random*:ab,ti OR placebo*:ab,ti OR allocat*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti NOT ('animal'/de OR 'animal experiment'/de OR 'nonhuman'/de NOT ('animal'/de OR 'animal experiment'/de OR 'nonhuman'/de AND 'human'/de)) (1,286,106)

#78 #29 AND #76 AND #77 (812)

LILACS (IAHx interface)

((mh:"Enfermedad Inflamatoria Pélvica" OR tw:"enfermedad inflamatoria pélvica" OR tw:"pelvic inflammatory disease" OR tw:"doença inflamatória pélvica" OR tw:"doença pélvica inflamatória" OR tw:"doença inflamatória da pelve" OR tw:anexit$ OR tw:adnexitis OR tw:epi OR tw:eip OR tw:"inflamación pélvica" OR tw:"inflamación del ovario" OR tw:"peritonitis pélvica" OR tw:"absceso tubo ovárico" OR mh:Endometritis OR tw:endometrit$ OR tw:endomiometrit$ OR tw:endomyometritis OR mh:Ooforitis OR tw:ooforit$ OR tw:oophoritis OR mh:Parametritis OR tw:parametrit$ OR tw:"celulitis pélvica" OR tw:"cellulitis pelvic" OR tw:"celulite pélvica" OR mh:Salpingitis OR tw:salpingit$ OR mh:"Infección Pélvica" OR tw:"infección pélvica" OR tw:"pelvic infection" OR tw:"infecção pélvica" OR mh:"Enfermedades de las Trompas Uterinas" OR tw:"enfermedades de las trompas uterinas" OR tw:"fallopian tube diseases" OR tw:"doenças das tubas uterinas" OR tw:"enfermedades de las trompas de falopio" OR tw:"doenças das trompas de falópio") AND (mh:Antibacterianos OR tw:antibacterian$ OR tw:"anti bacterial" OR tw:antibacterial$ OR tw:antibiótic$ OR tw:antibiotic$ OR tw:bactericid$ OR mh:Antiinfecciosos OR tw:antiinfeccioso$ OR tw:"anti infective" OR tw:microbicid$ OR tw:antimicrobian$ OR mh:Aminoglicósidos OR tw:aminoglicósidos OR tw:aminoglycosides OR tw:aminoglicosídeos OR mh:"Combinación Amoxicilina‐Clavulanato de Potasio" OR tw:"combinación amoxicilina clavulanato de potasio" OR tw:"amoxicillin potassium clavulanate combination" OR tw:"combinação amoxicilina clavulanato de potássio" OR mh:Azitromicina OR tw:azitromicina OR tw:azithromycin OR mh:Cefotaxima OR tw:cefotaxim$ OR mh:Cefotetán OR tw:cefotetán OR tw:cefotetan OR mh:Cefoxitina OR tw:cefoxitin$ OR mh:Ceftizoxima OR tw:ceftizoxim$ OR mh:Ceftriaxona OR tw:ceftriaxon$ OR mh:Ciprofloxacino OR tw:ciprofloxacin$ OR mh:Clindamicina OR tw:clindamicina OR tw:clindamycin OR mh:Doxiciclina OR tw:doxiciclina OR tw:doxycycline OR mh:Gentamicinas OR tw:gentamicin$ OR mh:Metronidazol OR tw:metronidazol$ OR tw:moxifloxacina OR mh:Ofloxacino OR tw:ofloxacin$ OR tw:levofloxacino OR tw:"ampicilina sulbactam"))

RCTs filter:

((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado" OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudios multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego" OR MH:"metodo simple‐ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos OR PT:"in vitro")

Data and analyses

Comparison 1

Regimens containing macrolides (azithromycin) versus tetracycline (doxycycline)

Comparison 2

Regimens containing quinolones versus cephalosporins

Comparison 3

Regimens containing nitroimidazoles versus no nitroimidazoles

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Effectiveness of cure in mild‐moderate PID	5	2427	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.93, 1.10]
2 Sensitivity analysis by risk of bias: effectiveness of cure in mild‐moderate PID	2	1201	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.15]
3 Effectiveness of cure in severe PID	11	1383	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.92, 1.01]
4 Any antibiotic‐related adverse effect leading to discontinuation Open in a separate window Analysis 3.4 Comparison 3 Regimens containing nitroimidazoles versus no nitroimidazoles, Outcome 4 Any antibiotic‐related adverse effect leading to discontinuation.	16	3788	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.63, 1.59]

Comparison 4

Regimens containing clindamycin plus aminoglycoside versus quinolone

Comparison 5

Regimens containing clindamycin plus aminoglycoside versus cephalosporin

Differences between protocol and review

We made the following changes to the protocol dated from 5 September 2013.

Criteria for considering studies

Types of interventions

In our protocol, we stated: "Trials comparing any antibiotics regimen compared to an alternative regimen or placebo will be eligible for inclusion."

After a long debate involving discussion with editorial board and reviewers, we decided to focus on the most clinically relevant interventions and comparisons; as identified in current clinical guidelines for treatment of PID.

Types of outcomes

The protocol listed a secondary outcome of "If the percentage of pain is available, a treatment will be considered effective when the reduction is 50% or more." However, from the clinical point of view, a reduction of pain over 50% is not relevant. For instance, if a woman with PID has an initial pain level of 10 and after treatment, the pain level was 4, this woman had a 60% reduction. However, in another case, a women with PID had an initial pain level of 5, and after treatment, her pain level was 3. In these two cases, if the 50% reduction in pain score criteria was used, the first woman would have obtained clinical cure while the second woman would not, despite the second woman having a lower pain level. Therefore, we did not perform this analysis, and used the clinical cure according to the criteria defined by the treating physician (e.g. resolution or improvement of signs and symptoms related to PID).

We amended the wording under secondary outcomes to clarify that where studies reported multiple time points, we considered the period between 14 and 28 days after initiation of treatment.

Search

In our protocol, we planned that searches would be updated within six months of publication in the review. Due to a lengthy publication process, we have extended this to 12 months

Data collection and analysis

Data extraction and management

In our protocol, we did not plan to conduct separate analyses for differing severity of disease. However, while preparing our review, we determined that severe PID (i.e. with tubo‐ovarian abscess) is a distinct condition from mild‐moderate PID (i.e. without tubo‐ovarian abscess). Therefore, we decided to present separate analyses for these two groups.

Statistical model

The protocol planned fixed‐effect models. However, we decided to use a random‐effects model where analyses had substantial heterogeneity (I2 40% or greater), to present a more conservative effect estimate.

Effect measure

We stated in the protocol that we would calculate Peto odds ratios for dichotomous outcomes. However, we noted that the Cochrane Handbook for Systematic Reviews of Interventions suggests avoiding using the Peto method as a default method of analysis because it may cause bias unless events are not particularly common and there are similar numbers in the intervention and control groups (Higgins 2011). As these criteria were not fulfilled in the review, we therefore, used Mantel‐Haenszel risk ratios for all dichotomous outcomes,

Subgroup analysis

In our protocol, we planned to undertake a subgroup analysis by PID severity, but in view of our decision to present separate analyses for mild‐moderate and severe PID, the subgroup analysis was no longer appropriate.

Sensitivity analyses

In our protocol, we planned to undertake sensitivity analyses for the following factors: risk of bias, heterogeneity (I2 40% or greater), length of time to measurement of outcomes, and method of PID diagnosis.

In the review, we listed variables that would be used to explore heterogeneity under the heading "Investigation of heterogeneity", and we included length of time to outcome measurement and method of PID diagnosis as two of these variables.

For the sensitivity analysis by risk of bias, we added a definition of low risk of bias (which we defined as blinded, and at low risk of selection bias).

Quality assessment

We added the reporting of quality of evidence following MECIR guidelines.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Contributions of authors

RFS: co‐ordination, study design, statistical analysis and review, writing the manuscript, grading the evidence in GRADE, and final approval of the manuscript.

DGF: data collection, extraction, grading risk of bias, and final approval of the manuscript.

RVD: data collection, extraction, grading risk of bias, and final approval of the manuscript.

SF: data collection, extraction, grading risk of bias, and final approval of the manuscript.

JR: study design, writing the manuscript, grading the evidence in GRADE, and final approval of the manuscript.

Sources of support

Internal sources

• No sources of support supplied

External sources

• NIHR’s 2012 Cochrane Review Incentive Scheme Award, UK.

Declarations of interest

All authors certify that they do not have any affiliations with, or involvement in, any organization or entity with a direct financial interest in the subject matter of this review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony). They disclose that two of the authors (RFS and JR) had two publications used in the analysis. RFS and JR did not participate in the process for considering these studies for inclusion, data extraction, and grading for risk of bias.

Notes

References

References to studies included in this review

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