The use of metronidazole in adult dogs with acute onset, uncomplicated, diarrhoea

a Knowledge Summary by

Emma Rogers-Smith BSc(Hons) BA VetMB MRCVS ^1*

¹Davies Veterinary Specialists, Manor Farm Business Park, Higham Gobion, Hitchin SG5 3HR
^*Corresponding Author (Emma.Rogers-Smith@cantab.net)

Clinical scenario

You are presented with an 18 month old female neutered Labrador Retriever with a 3 day history of mixed bowel diarrhoea which includes a small amount of fresh blood following an episode of dietary indiscretion. The patient is up-to-date with routine vaccination and anthelmintic treatment. The dog is bright and your physical examination is completely unremarkable. You wish to provide treatment for this patient and the client is requesting metronidazole treatment as this helped ‘to clear things up quickly’ the last time the patient raided the bins.

The evidence

Until as recently as 2019 the evidence basis for the use of metronidazole in the face of uncomplicated acute canine diarrhoea (UACD) and its superiority to supportive treatment alone (dietary modification, probiotics and more recently faecal matter transplant) has been anecdotal. Four papers were found to be fully or partially relevant to the PICO question; two randomised, double blinded placebo-controlled trials (Shmalberg et al., 2019; and Langlois et al., 2020), one prospective controlled treatment trial (Chaitman et al., 2020) and one retrospective observational study (Singleton et al., 2019). All four studies measured time to resolution of diarrhoea. Other factors considered included faecal microbiome and metabolome diversity (Chaitman et al, 2020). The evidence for the PICO question was found to be weak and at this time there is insufficient evidence to suggest metronidazole is superior in reducing the duration of clinical signs of UACD when compared to supportive measures alone.

Summary of the evidence

Appraisal, application and reflection

The available evidence is split between two randomised prospective double blinded clinical trials (Shmalberg et al., 2019; and Langlois et al., 2020), a prospective treatment trial without blinding or randomisation (Chaitman et al., 2020) and a retrospective study (Singleton et al., 2019). The retrospective study ranks low on the hierarchy of evidence and so meaningful clinical conclusions are challenging. However, the remaining studies (Shmalberg et al., 2019; Langloise et al., 2020; and Chaitman et al., 2020) are prospective, with two being randomised, double blinded, controlled trials, therefore ranking them at the highest possible level in terms of hierarchy of evidence for individual clinical studies (excluding metanalysis or systematic review). However, both of these studies are limited by small sample sizes albeit with one basing sample size on pre-study power calculation. Whilst direct comparisons between the studies cannot be made given the different treatment variables there is approximate consistency in the outcome variable assessed (time to resolution of normal faecal consistency) in all papers bar the Singleton et al. (2019) paper which assumed resolution of clinical signs if the patient does not represent to the clinic for GI signs within 30 days. However, there is no standardisation in the assessment of this outcome which, given its subjective nature, does lend towards observer and assessment bias. Especially given that in the three studies that utilised a faecal consistency chart (Langlois et al., 2020; Shmalberg et al., 2019; and Chaitman et al., 2020), each used a different tool, which whilst similar in nature does mean that direct study end-point (normalisation of faecal consistency) comparisons must be made with caution. Furthermore, despite the availability of veterinary faecal consistency charts, the Langlois et al. (2020) paper elected to use the Bristol Stool Chart which has been validated for humans rather than animals.

The inclusion/exclusion criteria across the three prospective studies (Shmalberg et al., 2019; Langloise et al., 2020; and Chaitman et al., 2020) allow for comparable population of dogs with what can be described as uncomplicated acute canine diarrhoea (UACD), the population that the PICO question addresses. The definition of acute diarrhoea was variable amongst paper including <2 day duration (Singleton et al., 2019), <7 days duration (Langlois et al., 2020; and Shmalberg et al., 2019) and <14 days duration (Chaitman et al., 2020). The Singleton et al. (2019) paper did not outline whether cases with severe clinical signs, confounding co-morbidities or chronic gastrointestinal histories were excluded/included and so the population evaluated may not be directly comparable to the population outlined in the PICO question. Three of the studies consider tertiary veterinary centres, two university based practices (Langlois et al., 2020; and Shmalberg et al., 2019) and one specialist centre (Chaitman et al., 2020) which may lead to a referral filter bias whilst the retrospective study is more likely to representative of a general practice population (Singleton et al., 2019).

The Singleton et al. (2019) study assessed the prescribing habits of UK first opinion practitioners when faced with a case of UACD in general practice and of the 2,429 cases that were including in the analysis 52.5% of those were prescribed antibiotics within 10 days of initial presentation. Of those cases metronidazole was the most commonly prescribed (47% of antibiotic prescribing cases). Furthermore, the study identified 1,050 cases (35.7%) where a patient was normothermic, with mild non-haemorrhagic diarrhoea and still prescribed antibiotics. However, the multivariable analysis of the records in this paper found no positive correlation between the prescribing of pharmaceutical agents (including antibiotics) and resolution of clinical signs. Whilst the limitations of this paper, given its retrospective nature, large loss to follow-up and inconsistency in record keeping, are significant, the large population size adds strength to the clinical utility of this information.  This lack of positive correlation between antibiotic use and resolution of clinical signs was mirrored in both the Shmalberg et al. (2019) and Chaitman et al. (2020) studies, neither of which found a statistically significant superior effect of metronidazole use on the resolution of diarrhoea in when compared to a probiotic and placebo or to faecal matter transplant respectively. Both the Shmalberg et al. (2019) and Chaitman et al. (2020) studies suffer from small treatment groups and the Chatiman et al. (2020) paper did not have a placebo-control for comparison, although a healthy control population was present. Whilst a significant positive association was found between metronidazole use and duration of clinical signs in the Langlois et al. (2020) paper this study is the only one available within the literature and the small treatment group size means that caution should be taken in the clinical conclusions drawn from the data.

Chaitman et al. (2020) considered both the utility of faecal matter transplant (FMT) when compared to metronidazole on time to resolution of clinical signs as well as the impact of both FMT and metronidazole on diversity of both the microbiome and metabolome of the test subjects. The study is particularly impactful given dogs treated with metronidazole still had altered microbial and metabolic profiles 4 weeks from the start of treatment when compared to those treated with FMT or healthy controls. This study would however have benefited from a placebo control group as, although a healthy control population was assessed at a single time point, the inclusion of a placebo treatment trial would have strengthened the validity of the results of this study. The clinical significance, indeed our understanding of the implications of the findings of this study are uncertain given research into the impact of the gut microbiome is still in its infancy. However, in human medicine the intestinal bile acid pathway has been identified as important in the pathophysiology of diarrhoea (Duboc et al., 2013). The Chaitman et al. (2020) study found an increase proportion of primary bile acids in the faeces of dogs with acute diarrhoea at day 0 when compared with healthy controls. Similarly, the metronidazole treated group had higher levels of primary bile acids (and lower levels of bacteria involved in the conversion of primary bile acids to secondary bile acids) when compared to healthy controls suggestive of ongoing alteration of intestinal function, despite normalisation of faecal consistency.

Standardisation of treatment protocols was lacking across the three prospective treatment trial papers as well as the retrospective longitudinal study. When considering the Shmalberg et al. (2019) paper there was no standardisation in regards to the administration of crystalloid fluids, fenbendazole or maropitant and no standardisation of diet – owners do not appear to have been requested to continue to feed a normal diet and so there is potential for variation from normal diet which may have a confounding effect on duration of clinical signs. The Langlois et al. (2020) paper has similar potential for confounding effects with the administration of crystalloid fluids and maropitant although additional oral medications were not prescribed to these patients. There was a lack of standardisation of treatment in the Chaitman et al. (2020) paper in regards to both maropitant use and dietary advice. Maropitant, a NK1 antagonist is a generally very well tolerated medication but diarrhoea has been described as a rare side effect in dogs (Zoetis, 2019). However, a study assessing the use of maropitant in the face of doxorubicin associated delayed vomiting found a reduction in frequency of patients developing diarrhoea, hypothesising that there may be a role of substance P in the development of diarrhoea – or at least diarrhoea associated with chemotherapy (Rau et al., 2010) although no further studies have evaluated this link. So, whilst it is unlikely to have a significant impact on the outcome of these studies, its potential as a confounding variable cannot be discounted. However, clinically the use of maropitant is unlikely to be detrimental in a case of acute diarrhoea and given its potent anti-emetic effects its use should not be discounted when faced of a concurrently nauseous patient. There is also considerable variation in the prescribed dose of metronidazole across the studies (Shmalberg et al., [2019] 17.8 ± 4.6 mg/kg PO BID; Langlois et al., [2020] 10–15 mg/kg PO BID and Chaitman et al., [2020] 15 mg/kg PO BID; with no details provided of dosages in the Singleton et al. [2019] study) again limiting direct comparison of results across the studies.

Finally, although out of the scope of this Knowledge Summary, it feels prudent to touch upon the results pertaining to probiotics in these studies. The utility of probiotics was not found to be superior when compared to either placebo or metronidazole treatment in the Shmalberg et al. (2019) study however a positive correlation was found between the utility of nutraceutical products and resolution of clinical signs in the Singelton et al. (2019) paper. Within the Singelton et al. (2019) study multiple different products were included within this one variable, compared with a single formulation within the Shmalberg et al. (2019) paper which limits the direct comparison between these two studies. However, this variability in outcome appears consistent with the latest systematic review of the available literature which concludes uncertain clinical benefit to the utility of probiotics in acute gastrointestinal disease (Jensen & Bjornvad, 2019).

Whilst the available literature is limited, at this time there is insufficient evidence to conclude a benefit to the prescribing of metronidazole in UACD in favour of supportive measures alone. There is also evidence to suggest that the use of metronidazole can have long-term detrimental implications for the gut microbiome and metabolome. Therefore, based on this current review of the available evidence, metronidazole would not be recommended as a first-line treatment in a case of UACD. There would be benefit for further studies of a higher power (prospective, randomised, blinded placebo-controlled treatment trial) with closer standardisation of protocol and larger treatment groups. Furthermore, the utility of both subjective, but validated, faecal consistency scoring and quantitative microbiome/metabolome analysis should be considered as well as multivariant analysis in an attempt to control for confounding variables to better ascertain appropriate, evidence-based treatment protocols for the management of UACD.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts via the Ovid platform covering 1972-2021. PubMed 1980–2021 Web of Science 1992–2021
Search strategy:	CAB Abstracts: (dog or dogs or canine) AND (metronidazole) AND (diarrhoea or diarrhea)   PubMed: (dog or dogs or canine) AND (metronidazole) and (diarrhoea OR diarrhea)   Web of Science: (“acute diarrhoea”) AND (dog)
Dates searches performed:	15 Jun 2021

Exclusion / Inclusion Criteria
Exclusion:	Single case reports. Duplicate papers. Book chapters. Conference proceedings. Articles not published in English. Articles not relevant to the PICO question.
Inclusion:	Any relevant primary research paper.

Search Outcome
Database	Number of results	Excluded – Not relevant to PICO	Excluded – Single case/report/book chapter/conference proceeding/duplicate	Excluded – Not available in English	Total relevant papers
CAB Abstracts	90	85	2	0	3
PubMed	47	44	0	0	3
Web of Science	18	17	0	0	1
Total relevant papers when duplicates removed					4

The author declares no conflicts of interest.

1. Chaitman, J., Ziese, A., Pilla, R., Minamoto, Y., Blake, A.B., Guard, B.C., Isaiah, A., Lidbury, J.A., Steiner, J.M., Unterer, S. & Suchodolski, J.S. (2020). Faecal Microbial and Metabolic Profiles in Dogs With Acute Diarrhoea Receiving Either Faecal Microbiota Transplantation or Oral Metronidazole. Frontiers in Veterinary Science. 7(192). DOI: https://doi.org/10.3389/fvets.2020.00192
2. Duboc, H., Rajca, S., Rainteau, D., Benarous, D., Maubert, M-A., Quervain, E., Thomas, G., Barbu, V., Humbert, L., Despras, G., Bridonneau, C., Dumetz, F., Grill, J-P., Masliah, J., Beaugerie, L., Cosnes, J., Chazouillères, O., Poupon, R., Wolf, C., Mallet, J-M., Langella, P., Trugnan, G., Sokol, H. & Seksik, P. (2013). Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut. 62(4), 531–539. DOI: https://doi.org/10.1136/gutjnl-2012-302578
3. Jensen, A.P. & Bjørnvad, C.R. (2019). Clinical effect of probiotics in prevention or treatment of gastrointestinal disease in dogs: A systematic review. Journal of Veterinary Internal Medicine. 33(5), 1849–1864. DOI: https://doi.org/10.1111/jvim.15554
4. Langlois, D., Koenigshof, A.M. & Mani, R. (2020). Metronidazole treatment of acute diarrhoea in dogs: A randomized doubled blinded placebo-controlled clinical trial. Journal of Veterinary Internal Medicine. 34(1), 98–104. DOI: https://doi.org/10.1111/jvim.15664
5. Rau, S.E., Barber, L.G. & Burgess, K.E. (2010). Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs. Journal of Veterinary Internal Medicine. 24(6), 1452–1457. DOI: https://doi.org/10.1111/j.1939-1676.2010.0611.x
6. Shmalberg, J., Montalbano, C., Morelli, G. & Buckley, G.J. (2019). A Randomized Double Blinded Placebo-Controlled Clinical Trial of a Probiotic or Metronidazole for Acute Canine Diarrhea. Frontiers in Veterinary Science. 6(163). DOI: https://doi.org/10.3389/fvets.2019.00163
7. Singleton, D.A., Noble, P.J.M., Sánchez-Vizcaíno, F., Dawson, S., Pinchbeck, G.L., Williams, N.J., Radford, A.D. & Jones, P.H. (2019). Pharmaceutical Prescription in Canine Acute Diarrhoea: A Longitudinal Electronic Health Record Analysis of First Opinion Veterinary Practices. Frontiers in Veterinary Science. 6(218). DOI: https://doi.org/10.3389/fvets.2019.00218