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Treatment of Acute Epididymitis: A Systematic Review and Discussion of the Implications for Treatment Based on Etiology

Louette, Aaron*; Krahn, Jessica*; Caine, Vera PhD*; Ha, Shalane MSc; Lau, Tim T. Y. PharmD; Singh, Ameeta E. BMBS, MSc§

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doi: 10.1097/OLQ.0000000000000901
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Epididymitis refers to inflammation of the epididymis, whereas epididymo-orchitis refers to inflammation of both the epididymis and testes.1 Acute epididymitis is a clinical syndrome of pain, swelling, and inflammation of the epididymis that lasts less than 6 weeks.2 The prevalence of epididymitis is unknown because it is not a reportable condition in most jurisdictions. A 2002 study reported approximately 600,000 new cases of epididymitis per year in the United States, most of which occurred in men between 18 and 35 years of age.3 A 2005 Canadian study found that 1% of men presenting to a Canadian outpatient urology clinic had epididymitis.4

Epididymitis may be caused by infectious and non-infectious processes.1 The etiology of bacterial epididymitis is dependent on age, sexual practices, and the presence of urinary tract abnormalities or history of instrumentation.1,5,6 Several earlier studies linking sexually transmitted pathogens to acute epididymitis were conducted in sexually transmitted infection (STI) centers and in army hospitals.5,7,8 This has led to the consensus that in men younger than 35 years, epididymo-orchitis is often associated with sexually transmitted organisms such as Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (NG) while in men over 35 years of age, it is often caused by non-sexually transmitted enteric organisms, such as Escherichia coli and Proteus sp. In this group, the epididymis usually becomes infected in the setting of bacteruria secondary to bladder outlet obstruction (eg, benign prostatic hyperplasia), prostate biopsy, urinary tract instrumentation or surgery, systemic disease, and/or immunosuppression.6 In addition, men who are the insertive partner during unprotected anal intercourse may also develop acute epididymitis from enteric organisms (eg, Escherichia coli).5

Treatment recommendations for epididymitis are largely based on etiologic studies conducted in the 1980s and 1990s9–11 and the last prospective treatment trial of epididymitis published in 1999.12 Selection of presumptive therapy is therefore based on risk for chlamydia and gonorrhea and/or enteric organisms with the goals of treatment of acute epididymitis to achieve: (1) microbiologic cure, (2) improvement of signs and symptoms, (3) prevention of transmission of CT and NG to others, and (4) a decrease in potential complications of CT/NG epididymitis (eg, infertility and chronic pain).13

Current guidelines for presumed sexually transmitted epididymitis recommend ceftriaxone 250 to 500 mg by intramuscular injection in a single dose in combination with doxycycline 100 mg orally twice daily for 10 to 14 days.13–17 For epididymitis, most likely caused by enteric organisms, alternate treatment options include ofloxacin 200 to 300 mg orally twice daily for 14 days, levofloxacin 500 mg orally once daily for 10 days, or ciprofloxacin 500 mg orally daily for 10 days.13–15 The Centers for Disease Control and Prevention guidelines also include a separate recommendation for the treatment of acute epididymitis caused by sexually transmitted and enteric organisms (eg, men who practice insertive anal sex) to include a combination of ceftriaxone plus levofloxacin or ofloxacin.13 For patients reporting allergies or sensitivities to cephalosporin (ceftriaxone) and/or tetracycline (doxycycline) antibiotics, the only cited alternate options are quinolone antibiotics, ofloxacin, and levofloxacin; ofloxacin was recently withdrawn from the Canadian market and is not available in the United States.3,18 The impact of resistance to antibiotics used to treat STIs, especially gonorrhea, is also unknown.

In light of the limited therapeutic options available for the treatment of epididymitis, we sought to conduct a systematic review to guide the optimal treatment of acute epididymitis.

METHODS

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.19

Protocol and Registration

Details of the protocol for this systematic review were registered on PROSPERO (CRD42017073095).

Inclusion and Exclusion Criteria

All primary experimental (randomized and non-randomized controlled trials) and observational studies (cohort, case-control,) reporting antibiotic treatment(s) in adolescent (13–19 years) and adult (>19 years) males with acute epididymitis due to sexually transmitted or enteric pathogens were included. Interventions comprised of any antibiotic used in the treatment of epididymitis as compared with other antibiotics, placebo, no therapy or other dosing regimens of the same antibiotic. Only English and French language studies were included. We included published peer-reviewed studies; reference lists of relevant articles were hand-searched. Cross-sectional studies, case reports, case series, modeling studies, letters, comments, opinion pieces, narrative reviews, and audits evaluating adherence to treatment guidelines were excluded.

Search Strategy

The following databases were searched: Ovid MEDLINE/PubMed, Ovid EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL Plus with Full-text, Web of Science Core Collection, Scopus, ProQuest Dissertations & Theses Global, Clinicaltrials.gov, and Health Canada Trials Database from January 1, 2006, to August 6, 2017. The search period was dated back to 2006, because this was when the Canadian Guidelines on Sexually Transmitted Infections were last updated. Table 1 provides an overview of the study protocol.

TABLE 1
TABLE 1:
Study Protocol

Study selection process

All retrieved abstracts were uploaded to Covidence (https://www.covidence.org/), and duplicates were removed. Two reviewers (J.K. and A.L.) screened all identified titles and abstracts according to inclusion criteria. A third reviewer (A.S. or V.C.) resolved discrepancies. After title and abstract screening, full texts of articles were independently reviewed by 2 authors (J.K. and A.L.), and conflicts between the 2 were resolved by a third reviewer (A.S. or V.C.).

Data Extraction Process

The following data were extracted from the included studies: author, year of publication, study design, location, population, methods, intervention, test used to diagnose, study duration, sample size, and outcomes (including cure, treatment failure (TF), symptom resolution, and adverse events).

Outcomes

Outcomes of included studies were clinical cure (complete/partial), microbiological cure (nucleic acid amplification test [NAAT] and culture or immunofluorescence, or enzyme immunoassay negative), symptom resolution, clinical and microbiologic cure rate, pain, infertility, and TF. Unintended effects included adverse events during treatment and the development of antimicrobial resistance.

Assessment of Methodological Quality (or Risk of Bias)

Two independent reviewers (J.K. and A.L.) assessed the risk of bias of included randomized controlled trials using study the Revised Cochrane Risk of Bias 2.0 tool for randomized trials20 and the Newcastle Ottawa Quality Assessment Scale21 for nonrandomized studies.

Analysis

A meta-analysis was not possible because only a single study was identified.

RESULTS

Study Selection

Figure 1 (Prisma Diagram) summarizes the review process. Of the 1534 records identified through the database search, 1246 remained after removal of duplicates. Of 1246 records screened at title and abstract level, 1217 were excluded as irrelevant, leaving 29 records that were assessed for eligibility at full-text level. Of these, only 1 study was deemed eligible for inclusion.

Figure 1
Figure 1:
Epididymitis systematic review.

Study characteristics

The included study was a retrospective review of patients with gonococcal and chlamydial epididymitis at 2 STI clinics in Alberta, Canada.22 Of 68 eligible patients, 57 records were available for review (42 with chlamydia, 9 with gonorrhea, and 6 coinfected with chlamydia and gonorrhea), and 35 (61.4%) returned for follow-up. The time frame for the follow-up tests for TF was variable (days 2, 9, 17, 28, 31, 42). All tests were conducted using the Gen-probe APTIMA Combo-2 Assay (Hologic Inc, San Diego, CA) (personal communication, A. Singh).

Treatment efficacy and adverse events

The majority of patients (n = 41; 71.9%) were treated with a preferred or alternate regimen as per the Canadian Guidelines on Sexually Transmitted Infections. Of 6 TF, 3 did not receive therapy according to guideline. Of the 2 TF cases infected with NG, both had isolates which were susceptible to the prescribed antibiotics. No adverse events were reported.

Risk of Bias Assessment

This study scored 6 of 10 on the Newcastle-Ottawa Scale, which indicates moderate risk of bias.

DISCUSSION

The results of our systematic review of published literature since 2006 identified only 1 small observational retrospective study evaluating the treatment of epididymitis.22 The findings provide some reassurance that currently recommended regimens are effective for the treatment of epididymitis in populations at high risk for STIs in 1 Canadian region. However, our review also highlights the paucity of published data on treatment for epididymitis.

Most international guidelines for the treatment of epididymitis have been based on etiologic studies which are more than ten years old.13–15,17 More recent studies have highlighted a shift in the age distribution, causative organism, and the importance of sexual activity on the etiology. For example, a 2010 study in Japan reported that among 56 patients with acute epididymitis younger than 40 years, C. trachomatis was identified in 50%, Mycoplasma genitalium in 8.9%, N. gonorrhoeae in 5.4% and Ureaplasma urealyticum in 8.9%.23 A more recent study of patients seen in outpatient urology clinics in Germany and using sensitive molecular diagnostic tests identified STIs in 14% of cases, of which 74% were caused by CT, 18% were due to NG and 24% due to Mycoplasma sp.24 Of particular note in this article, STI pathogens as a cause of epididymitis were not limited to men younger than 35 years. More importantly, half of all STI pathogens were detected in sexually active patients who did not report such risks. This highlights the need to screen all sexually active men with epididymitis for STI pathogens.

Although the link between M. genitalium and urethritis is clearly established, the clinical evidence that it causes epididymitis appears biologically plausible but weak.25 Hamasuna described a patient with epididymitis where M. genitalium was the sole pathogen identified, who had no clinical response to minocycline and cephalosporin antibiotics but responded to levofloxacin.26 This case, together with the studies cited above, provides limited data supporting the emerging importance of M. genitalium as a causative organism in epididymitis.23,24 Because M. genitalium is a bacterial STI second only to C. trachomatis in prevalence,27 it has the potential to be implicated in a significant proportion of the causative organisms of sexually transmitted epididymitis. In addition, over the last 20 years M. genitalium has developed increasing resistance to a number of antibiotics, including the quinolone antibiotics (ofloxacin and levofloxacin), which are commonly recommended in treatment regimens for epididymitis.28 The importance of this organism has led to the recent revision of the European guideline on the management of epididymo-orchitis to include recommendations for the treatment of M. genitalium epididymitis with a 14-day course of moxifloxacin.16

The lack of recent clinical trials for the treatment of epididymitis is also concerning in light of emerging resistance in antibiotics used to treat gonorrhea, especially because most current etiologic studies either use molecular diagnostic tests or do not perform antimicrobial susceptibility testing.22,23 Although gonorrhea appears to be a less common cause of sexually transmitted epididymitis, the increasing resistance of antibiotics currently used to treat gonorrhea poses a significant threat to successful treatment of gonococcal epididymitis.29 In the study by Chen et al., of the 6 TFs, 3 did not receive treatment according to guidelines. Reasons for nonadherence to the clinical guidelines may be multifactorial, but may include lack of awareness of the guideline, lack of agreement with the guideline, lack of confidence utilizing the guideline, disbelief that application of the guideline will result in the desired outcome, inertia of previous practices, and other drug regimen-related barriers (eg, treatment regimen is cumbersome and inability to administer injectable medications).30 In the Chen study, the other 3 patients who experienced TF received multi-day courses of antibiotics, raising the possibility that drug adherence was a factor, as reported in other studies.31

In summary, our review highlights the near absence of data evaluating the treatment outcomes of patients treated for epididymitis. The findings of 1 small retrospective study and additional data reporting antimicrobial etiologies of epididymitis provide some reassurance that current regimens for the treatment of gonococcal and chlamydial epididymitis are appropriate. Taking a sexual history is of paramount importance; the historical recommendation to only attribute epididymitis caused by STIs in patients younger than or older than 35 years needs to be revisited. Finally, prospective, multi-center comparative trials evaluating treatment regimens, especially for gonococcal epididymitis and using NAAT only tests for STIs, are urgently needed in the context of rising resistance in gonorrhea and the increasing recognition of M. genitalium as a potential pathogen.

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