An evaluation of the use of ronidazole for the treatment of Tritrichomonas foetus in cats
a Knowledge Summary by
Genever Morgan BSc (Hons) BVetMed (Hons) MRCVS 1*
1Royal Veterinary College, 4 Royal College Street, London, NW1 0TU
*Corresponding Author (genevermorgan1987@gmail.com)
Vol 4, Issue 4 (2019)
Published: 04 Dec 2019
Reviewed by: Katherine Briscoe (BVSc (Hons I), MVetStud, FANZCVS) and Nicolette Joosting (BSc (Hons), MANZCVS, BVSc)
Next review date: 03 Mar 2021
DOI: 10.18849/VE.V4I4.263
In cats infected with Tritrichomonas foetus, does treatment with oral ronidazole compared to an alternative antiprotozoal treatment or placebo result in successful resolution of clinical signs and eradication of disease?
Clinical bottom lineRonidazole use appears to be efficacious in eradicating infection with Tritrichomonas foetus and resolving diarrhoea associated with infection. A dose range of 30–50 mg/kg 12–24 hourly has been suggested, with evidence suggesting that a dose of 30 mg/kg 24 hourly for 14 days may be effective. However, some cats may require higher doses and some may not respond to treatment, and relapse may occur during a protracted period following completion of the treatment course. Neurological side effects appear to be uncommon but may occur with doses of 30 mg/kg and above.
A total of six studies are reviewed: Three randomised, controlled studies, one cohort study and two case series (one retrospective). Findings indicate efficacy of ronidazole treatment in eradicating infection and resolving diarrhoea, however many studies involved small sample sizes and limited follow-up. Therefore, evidence to support the use of ronidazole in Tritrichomonas foetus infected cats remains relatively limited.
Clinical scenario
Tritrichomonas foetus is one of the most common causes of infectious colitis in cats. Remission from the diarrhoea associated with T. foetus infection may occur with time, however persistence of infection is common. This is particularly pertinent in cattery and shelter populations in which T. foetus infection is widespread.
Ronidazole is currently the only drug with demonstrated efficacy against T. foetus, however it has a narrow safety margin and its use is currently off-license in the UK (Gookin et al. 2017).
The evidence
There is a small body of in vivo evidence for the treatment of cats infected with Tritrichomonas foetus using ronidazole, and of that evidence only half of the relevant papers are randomised, controlled, blinded studies. Therefore, the strength of the evidence is relatively low. A significant proportion of the evidence is from case series or cohort studies, where bias may be inherently introduced from case selection, the lack of blinding, no presence of a control/comparator and loss of patients to follow-up.
Most studies identified had a small sample size, with a limited follow up period in many.
There are three randomised, controlled studies examining the efficacy of ronidazole for treatment of T. foetus infection compared to placebo, all utilising different doses (10–50 mg/kg) and different dosing schedules (12–24 hourly).
Summary of the evidence
Population: | Cats naturally infected with T. foetus in French catteries |
Sample size: | 47 cats |
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Study design: | Randomised, controlled, double-blinded study |
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Limitations: |
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Population: | An adult cat with naturally occurring T. foetus infection and 10 week old, specific-pathogen free kittens |
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Study design: | Randomised, controlled study (specific-pathogen free kittens) |
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Population: | Abyssinian cats in a cattery |
Sample size: | 11 cats |
Intervention details: |
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Study design: | Case series |
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Population: | Medical records of domestic cats presented to two veterinary clinics in Hong Kong over a 5 year period. Only cases with complete medical record and confirmed T. foetus diagnosis (history, clinical examination and details of diagnostic testing) included. |
Sample size: | 29 cats |
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Study design: | Case series, retrospective |
Outcome Studied: |
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Population: | 5–7 month old Korean Domestic Short Hair kittens |
Sample size: | Six kittens |
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Study design: | Randomised controlled, non-blinded study |
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Population: | Abyssinian cats. Two male, five female cats with intermittent large bowel diarrhoea despite treatment with fenbendazole. |
Sample size: | Seven cats |
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Study design: | Cohort study |
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Appraisal, application and reflection
There are few papers examining the in vivo efficacy of oral ronidazole treatment in cats infected with Tritrichomonas foetus. Of these papers, half were randomised, controlled, blinded studies comparing the use of oral ronidazole with placebo, however the remaining half were case series or cohort studies. Therefore, there is a significant amount of lower quality evidence present.
One major problem present in most of the papers is that a small sample size was utilised. Although many results were significant, this may mean that the results are not representative of a wider population and conclusions may not be robust.
Infection with T. foetus was induced experimentally via orogastric intubation in two of the randomised, controlled studies (Gookin et al. 2006 and Lim et al. 2012), therefore the results of these studies may not be truly reflective of naturally occurring infection.
There is significant variation in the treatment protocols described in the studies. All three randomised, controlled, blinded studies utilised different doses and dosing schedules of ronidazole. Grellet et al. (2017) used 30 mg/kg once daily for 14 days, Gookin et al. (2006) initially used 10 mg/kg twice daily for 14 days, then 30–50 mg/kg twice daily for 14 days and Lim et al. (2012) used 50 mg/kg twice daily for 14 days.
Both Grellet et al. (2017) and Lim et al. (2012) observed eradication of T. foetus in treated cats at the end of treatment after 14 days of treatment (determined via PCR on rectal swab), however clinical signs of diarrhoea were not examined and there was limited monitoring for recurrence following cessation of treatment. Gookin et al. (2006) observed that lower dose (10 mg/kg) ronidazole did initially resolve infection during the treatment period, however all kittens relapsed within 2–20 weeks and required further treatment with 30–50 mg/kg ronidazole twice daily, after which no relapse was observed in the following 21–30 weeks and diarrhoea resolved.
The use of 35–45 mg/kg ronidazole twice daily for 14 days was also demonstrated to eradicate T. foetus on faecal culture and resolve diarrhoea in six cats, with repeated negative culture on follow–up in a small case series by Gookin et al. (2010).
Koster et al. (2015) presented a retrospective case series also describing the use of 30 mg/kg ronidazole q 24 hours for 14 days in cats presented to a hospital environment with T. foetus confirmed via faecal smear microscopy and PCR. This dosing schedule was found to successfully resolve diarrhoea in 24/29 cats, however confirmation of resolution of infection via faecal PCR was not undertaken and there was no follow-up to determine whether relapse occurred.
The use of 30 mg/kg ronidazole q 24 hours for 14 days was also documented by Reinert et al. (2016) in a small cohort study and found to be successful in eradicating infection (demonstrated via faecal PCR) and preventing relapse up to 800 days following treatment completion. Presence of diarrhoea was not described. However, this was a small cohort study of five treated cats with no control or comparator group to substantiate the result.
A confounding factor for both the Koster et al. (2015) case series and Grellet et al. (2017) randomised, controlled study is that treated cats which continued to live in a multi-cat household environment were included. In both studies, a proportion of cats did not respond to treatment/remained infected, however it is impossible to know why treatment failure occurred as this could be a demonstration of resistance of T. foetus to ronidazole therapy, or simply reinfection.
Therefore, the use of 30 mg/kg ronidazole q 24 hours for 14 days may be a useful initial treatment regimen in eradicating infection with T. foetus and resolution of diarrhoea, with a successful result documented in the randomised, controlled study by Grellet et al. (2017) and supported by the cohort study by Reinert et al. (2016) and case series by Koster et al. (2015). However further case controlled, analytical studies should be undertaken to substantiate this. The case series and cohort studies are subject to bias and the result of the randomised, controlled study is complicated by the test and placebo cats not being housed separately during treatment, leading to possible reinfection.
Ronidazole appeared to be superior in efficacy against T. foetus compared to metronidazole and tinidazole (Gookin et al. 2006 and Gookin et al. 2010) and was effective in eradicating infection in cats previously treated unsuccessfully with fenbendazole in the small cohort study by Reinert et al. (2016). However, two cats did not respond to repeated ronidazole administration in the case series by Gookin et al. (2010). Resistance in vivo was suggested, and in vitro resistance was demonstrated in aerobic conditions in one cat, although further studies on larger numbers of cats are required to validate this finding.
Ronidazole is suggested to have a narrow therapeutic range and neurological side effects are documented to occur with treatment (Gookin et al., 2017), however these were infrequently evidenced in this knowledge summary, with only Reinert et al. (2016) observing effects in 2 cats which resolved on pausing treatment. Lim et al. (2012) specifically described the use of high dose 50 mg/kg ronidazole 12 hourly for 14 days. This was found to be successful in eradicating infection on faecal analysis, however the presence of any neurological side effects was unfortunately not discussed. Gookin et al. (2006) also administered doses up to 50 mg/kg twice daily and no adverse effects were seen.
Conclusions
There is a small amount of good quality evidence for the use of ronidazole to treat cats with diarrhoea as a result of Tritrichomonas foetus infection, and a range of therapeutic protocols have been described. A dose of 30–50 mg/kg administered once to twice daily for 14 days appears to be successful in eradicating infection and may successfully prevent relapse of infection for up to 800 days, although the evidence for this is limited. Neurological side effects may be observed in cats treated with doses of 30 mg/kg and above. Resistance of T. foetus to ronidazole has been suggested (Gookin et al., 2010), however additional work is needed to substantiate this further.
The small body of evidence currently available would suggest that the use of ronidazole is efficacious in treating T. foetus in cats and does resolve the associated diarrhoea, supporting the use of ronidazole in clinical practice in cats with diarrhoea and T. foetus confirmed via PCR/faecal culture. Based on this, the use of ronidazole as an off-license medication is therefore justified in the absence of a licensed alternative. The studies by Grellet et al. (2017), Koster et al. (2015) and Reinert et al. (2016) all suggest that a dosing schedule of 30 mg/kg once daily for 14 days is successful in treating infection, therefore may be a useful initial regimen. Based on the evidence generated by the search strategy for this knowledge summary, twice daily dosing and doses of up to 50 mg/kg may be required to eradicate infection and appeared to be safely tolerated. However, the studies detailing twice daily dosing are relatively old. A study by LeVine et al. (2011) investigating the pharmacokinetics of both intravenous and oral administration of ronidazole to cats observed a prolonged half-life of 10.5 hours for ronidazole.
Therefore, due to concerns about ronidazole accumulation and increased risk of neurological side effects occurring, twice daily dosing is no longer recommended (LeVine et al., 2011 and LeVine et al., 2014).
Importantly it appears that some cats may not respond to treatment and relapse may occur in a protracted period post-treatment, therefore patients should be monitored for this occurring.
Methodology Section
Search Strategy | |
Databases searched and dates covered: | CAB Abstracts via CAB Direct (1973–Week 8 2019)
PubMed via NCBI website (1946–Week 8 2019) Scopus via Elsevier (1823–Week 8 2019) |
Search strategy: | (cat OR cats OR feline OR felis) AND Tritrichomonas(foetus OR fetus) AND ronidazole AND (efficacy OR susceptibility) |
Dates searches performed: | 24/02/2019–3/3/2019 |
Exclusion / Inclusion Criteria | |
Exclusion: | Completely in vitro studies, review articles, studies not relevant to the PICO question, conference proceedings presenting overview or non-relevant information. |
Inclusion: | In vivo studies, studies with more than one animal, studies relevant to PICO question, studies including treatment with ronidazole plus placebo and/or alternative antiprotozoal drug. |
Search Outcome | ||||||
Database |
Number of results |
Excluded – in vitro studies |
Excluded – review article |
Excluded – not relevant to PICO |
Excluded – non-relevant conference proceedings |
Total relevant papers |
CAB Abstracts |
14 | 3 | 3 | 1 | 2 | 5 |
PubMed |
10 | 2 | 1 | 3 | 0 | 4 |
Scopus |
10 | 3 | 2 | 1 | 0 | 4 |
Total relevant papers when duplicates removed |
6 |
The author declares no conflict of interest.
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