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Abstract
Introduction The antimicrobial treatment options for patients with intestinal spirochaetosis (caused by Brachyspira pilosicoli and Brachyspira aalborgi) are not well defined. We aimed to systematically review the literature to explore antimicrobial treatment options to inform future clinical guidelines.
Method We systematically searched three bibliographical databases (MEDLINE, EMBASE, SCOPUS and Web of Science) for manuscripts written in English up to January 2024. The primary author conducted an initial abstract screen and two authors conducted independent full-text reviews. We included manuscripts which included primary data for patients with intestinal spirochaetosis who had received antimicrobial treatment and had an outcome measured. Quality and risk of bias was assessed independently by two authors using the Joanna Briggs Institute critical appraisal tools. We used the nine-point synthesis method to synthesise narrative data.
Results There were 58 manuscripts included in this review published between 1977 and 2023 (42 case reports, 12 case series, 3 cross-sectional studies, and 1 prospective cohort). In total, there were 270 individuals with intestinal spirochaetosis: 225 patients received oral metronidazole monotherapy, 1 intravenous metronidazole, 2 rectal metronidazole, 5 metronidazole as part of a dual/triple regimen, 17 doxycycline monotherapy, 5 doxycycline (or tetracycline) dual therapy with either a beta-lactam, or neomycin, 4 benzathine penicillin, 1 procaine penicillin/steroids and 3 other antimicrobials including clarithromycin and vancomycin. 230 (85%) of patients in this review had an adequate clinical and or histological response to treatment with a median follow-up period of 30 days (IQR 14–90). The combined treatment response to all metronidazole-based treatment was 195/233 (84%).
Conclusion Metronidazole, doxycycline and parenteral penicillin are the most frequently used antimicrobials for the treatment of human intestinal spirochaetosis and treatment response is generally good. More work is needed to understand the pathophysiology and treatment outcomes in patients with symptomatic intestinal spirochaetosis including the development of non-invasive diagnostic tools.
- INTESTINAL BACTERIA
- ANTIBIOTICS
- COLORECTAL PATHOLOGY
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Intestinal spirochaetosis can cause significant morbidity and clinical guidleines are limited by a paucity of treatment studies.
WHAT THIS STUDY ADDS
We have highlighted the available data on antimicrobial treatment options and outcomes.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The treatment options and outcoms in this review can be used to guide future clincal guildelines and research.
Introduction
Pathogenic human spirochetes (Spirochaetaceae) are gram-negative bacteria, which have been classified into three phylogenetic groups: Borrelia (Spirochaeta, Spironema, and Treponema), that is, Lyme disease, relapsing fever and syphilis; Leptospiraceae (Leptonema and Leptospira), that is, leptospirosis; and Brachyspiraceae (Brachyspira aalborgi and Brachyspira pilosicoli), that is, intestinal spirochaetosis.1 2 Spirochaetes are distinguished from other bacteria by the location of their flagella which facilitates movement. Intestinal spirochetes were first reported in 1719 by van Leeuwenhoek who detected lively moving spiral “animalcules” in his own faeces.3 B. aalborgi and B. pilosicoli form a thick blue ‘brush border’ on the epithelial surface which attach to the apical cell membrane of colorectal epithelium. The pathophysiology of intestinal spirochaetosis is poorly understood and is often asymptomatic.1–3 In culture medium, B. aalborgi and B. pilosicoli grow very slowly and are classified as opportunistic anaerobes; they exhibit a cytopathic effect whereby microvilli at the brush border of the mucosal surface are flattened and destroyed.4–6 The presence of intestinal spirochaetosis can produce gastrointestinal symptoms characterised by diarrhoea, abdominal pain, bloating and proctitis (rectal bleeding, rectal mucous, rectal discharge, flatulence, tenesmus and rectal pain).7 Some patients describe constitutional symptoms including fever, rash and in rare cases, sepsis and multiple organ failure.8
The true prevalence of intestinal spirochaetosis is unknown; small studies suggest that the prevalence varies globally and is higher in people living in low income and rural regions, and in men who have sex with men (MSM).2 9 10 Intestinal spirochaetosis in MSM is associated with biological factors, including living with HIV, coinfection with sexually transmitted infections and enteric infections (eg, Giardia duodenalis) and antimicrobial use, and behavioural factors including oro-anal sexual contact, receptive anal sex and multiple sexual partners.7 Diagnosis is confirmed using histological examination from colonoscopy biopsy samples and has a classic appearance of a diffuse blue fringe (using a H&E stain) along the brush border of the colon and/or rectal mucosa, also described as a false brush border, which is a dense layer of spirochaetes.4 11 Spontaneous clearance of intestinal spirochaetosis has been described.8 12 13
Antimicrobial treatment may be required in patients with symptoms, however, there is no consensus on the optimal treatment reflected in any clinical guidelines. In vitro studies suggest that isolates of B. pilosicoli are susceptible to metronidazole, ceftriaxone, meropenem, tetracycline, moxifloxacin and chloramphenicol.14 Erythromycin, ciprofloxacin, amoxycillin and clindamycin have poorer activity against these organisms.14 However, a mixed response to antibiotic therapy has been observed in clinical studies, possibly related to the intensity of mucosal invasion.15
We aimed to review the literature to explore antimicrobial treatment used for patients with intestinal spirochaetosis to inform and provide insight for future treatment guidelines.
Method
Search strategy and selection
A systematic review of the literature was conducted in January 2024 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to explore the optimal antimicrobial treatment for patients with intestinal spirochaetosis. We searched four bibliographic databases (MEDLINE, EMBASE, SCOPUS and Web of Science) to identify eligible manuscripts. We used the flowing search terms: (“brachyspira pilosicoli” OR “brachyspira aalborgi " OR “serpulina pilosicoli” OR “serpulina aalborgi” OR spirochetosis OR spirochaetosis) AND (antibiotic OR antimicrobial OR treatment OR therapy OR management OR penicillin OR metronidazole OR amoxicillin) AND NOT (swine OR pig OR porcine OR chicken OR dog OR canine OR avian OR rabbit OR bovine). Manuscripts meeting the following criteria were included in our review: participants were diagnosed with intestinal spirochaetosis using histology and received antimicrobial treatment. We only included manuscripts written in English language, containing primary data where antimicrobial treatment was given and an outcome was described (either clinical and/or histological), and publication date was not restricted. Conference abstracts, editorials, review articles, opinion articles and grey literature were excluded. A staged process was used for screening and selection of manuscripts for the final review. Each record from the initial search of citations was imported into the Mendeley software and duplicate citations were removed. Manuscripts abstracts were screened by the primary researcher (JKSL) and then full-text manuscripts were then assessed for eligibility independently by the primary researcher (JKSL) and an associate researcher (LR). Any discrepancies were discussed (JKSL, LR, DR) for a final eligibility decision.
Quality assessment, risk of bias assessment and data synthesis
Quality assessment and risk of bias was assessed for each manuscript independently by the primary researcher (JKSL) and the associate researchers (LR and DR) using the Joanna Briggs Institute critical appraisal checklists.16 Any discrepancies were discussed collectively (by JKSL, LR, and DR) for a final decision. We extracted data into a table and performed a narrative synthesis. In manuscripts containing both eligible and ineligible participants including where follow-up data were not available or no antimicrobial treatment received, we only extracted data on the eligible participants. Data were synthesised into a table exploring antimicrobial treatment and treatment response. The review protocol was registered on PROSPERO (CRD42023455014).
Results
The initial search identified 755 citations, 396 duplicates were removed, 359 abstracts were screened and 199 were excluded. 160 full-text manuscripts were assessed for eligibility and 102 were excluded including 67 conference abstracts (figure 1). 58 manuscripts were included in the final review (table 1). The manuscripts were published between 1977 and 2023 and were from the USA (n=18), the UK (n=7), Japan (n=10), Spain (n=5), Brazil (n=3), Pakistan (n=3), Sweden (n=2), Italy (n=2), Ireland (n=1), Germany (n=1), Switzerland (n=1), Canada (n=1), Saudi Arabia (n=1), India (n=1), South Africa (n=1) and Portugal (n=1).5 6 17–72 We assessed the risk of bias as being medium in 2 manuscripts and high in 56 manuscripts (online supplemental table 1). The manuscripts consisted of 42 case reports, 12 case series, 3 cross-sectional studies and 1 prospective cohort. In total, there were 270 individuals included in this review, 8 female patients, 64 male patients and 198 where the gender was not reported. 225 patients received oral metronidazole monotherapy, 1 intravenous metronidazole, 2 rectal metronidazole, and 3 received metronidazole dual therapy with either ciprofloxacin or ceftriaxone, and 2 patients received metronidazole triple therapy with either co-trimoxazole/azithromycin or ciprofloxacin/azithromycin (table 2).5 6 15 18–27 29 32 33 35 37–72 17 patients received doxycycline monotherapy and 5 patients received doxycycline (or tetracycline) dual therapy with either a beta-lactam, or neomycin.6 17 56 70 Four patients received benzathine penicillin G, one procaine penicillin and steroids and three patients received other antimicrobials (clarithromycin, vancomycin).5 6 28 30 31 36 Four patents received a non-specified macrolide and three unknown antimicrobials.6 70 230 (85%) patients in this review had an adequate clinical and or histological response to treatment.5 15 17–30 32 33 36–55 57–72 Where a follow-up time was documented (in 25 manuscripts), the median follow-up period was 30 days (IQR 14–90 days).18 21–23 25 27 30 31 33 35 40 41 43 45–51 54 57 59–62 68 69 71 72 The combined treatment response to all metronidazole-based treatment was 195/233 (84%).5 6 15 18–27 29 32 33 35 37–72
Supplemental material
Flow chart of study selection for inclusion in the systematic review. HIS, human intestinal spirochaetosis.
Antimicrobial treatment used in intestinal spirochaetosis
Antimicrobials and treatment outcomes for intestinal spirochaetosis5 6 17–72
Discussion
In the absence of any controlled trials to provide guidance for the optimal antimicrobial treatment for people with symptomatic intestinal spirochaetosis, this systematic review has highlighted the antimicrobial treatment and treatment response used in published clinical reports over the past 47 years. Metronidazole-based treatment was the most frequent antimicrobial strategy used and we have highlighted that 84% of people using metronidazole-based treatment experience a clinical response. Doxycycline and parenteral penicillin were also used with a good reported clinical response. The lack of non-invasive testing for intestinal spirochaetosis and poor understanding of the pathophysiology and impact of asymptomatic disease provides significant barriers for designing and conducting controlled drug treatment trials.
Metronidazole, a nitroimidazole, is frequently used for the treatment of vaginitis, oral cavity infections and gastrointestinal infections and is generally affordable and well tolerated, and antimicrobial resistance is currently rare.73 The oral doses of metronidazole in the mono-oral, dual-oral and triple-oral therapy schedules used in this review were highly variable ranging from 100 mg per day to 800 mg three times per day and there did not appear to be a dose-related response pattern. Many of the manuscripts did not provide any detail of the dose or length of treatment used in their patients. The majority of patients in this review had symptomatic intestinal spirochaetosis: in clinical practice, only symptomatic patients would be tested. It is unclear how asymptomatic patients impact the transmission and epidemiology of intestinal spirochaetosis and what the role of treatment has for asymptomatic individuals. The mechanism for treatment failure is not well understood, and this review has not been able to provide any further insights into treatment response or failure.73 It has been suggested that the extent of the mucosal invasion of B. aalborgi and B. pilosicoli could correlate with the clinical signs and symptoms, and the response to antimicrobial therapy.4 One study has suggested that in some cases, paradoxically, metronidazole can promote Brachyspira relocation into goblet secretory granules.60
There are several important limitations to this review including the large number of heterogeneous case reports and case series and the high risk of bias in most of the manuscripts. There was significant reporting bias due to the barriers that exist with the diagnosis of intestinal spirochaetosis. Case reports and case series have inherent bias and an inability to control for confounding factors. Most of the manuscripts are from high-income or middle-income settings and there is poor representation from low-income settings. There also appears to be poor representation from women and children. Due to the broad heterogenicity of the manuscripts in this review, we were unable to determine accurate treatment responses to any of the treatment modalities used. There were no controlled or comparator trials in this review to establish any benefit of one treatment over another. Many of the manuscripts did not accurately describe or measure treatment thresholds, eligibility, adherence to treatment or treatment response accurately or systematically.
We have highlighted that metronidazole, doxycycline and parenteral penicillin are the most frequently used antimicrobials for the treatment of intestinal spirochaetosis and that the treatment response is generally good. More work is needed to understand the pathophysiology and treatment outcomes in patients with symptomatic intestinal spirochaetosis including the development of non-invasive diagnostic tools.
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Patient consent for publication
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors DR came up with the study concept, JKSL and DR designed the study protocol, JKSL conducted the data search, JKSL, LR independently reviewed the manuscript's eligibility, JKSL and LR independently conducted the risk of bias assessment, JKSL and DR conducted the data synthesis and JKJL, LR, CF, DW and DR all contributed to the final manuscript. DR is the study guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.