4. DISCUSSION
Our results suggest that metronidazole treatment can shorten the duration of diarrhea in some dogs with acute nonspecific diarrhea. Overall, the duration of diarrhea was decreased by approximately 1.5 days in metronidazole‐treated dogs as compared to placebo‐treated dogs (P = .04). This statistical difference could be of clinical relevance because a 1.5 day decrease in clinical signs would be appealing for clients challenged with managing a diarrheic pet. However, the results of our study do not establish whether or not metronidazole should be utilized as a first line drug for acute diarrhea because many additional factors must be considered. Most dogs (88.2%) have resolution of diarrhea within 1 week even in the absence of treatment. Also, metronidazole is not approved by the Food and Drug Administration for veterinary purposes despite its commonplace usage in companion animal medicine.29 Acute diarrhea is a common reason owners seek veterinary care, and widespread antimicrobial treatment could impact both veterinary and human health by promoting bacterial resistance.19 Additionally, evidence suggests that metronidazole treatment dramatically alters the intestinal microbiome of normal dogs, and some of these changes persist for an indefinite time period.30 Dietary modifications or probiotic treatment might yield clinically advantageous effects comparable to those of metronidazole and preclude the need for antimicrobial treatment.5, 10, 31, 32 These and other important issues require further consideration, but they were beyond the scope of our study.
Management strategies for acute diarrhea in dogs have garnered considerable attention in recent years.1, 2, 3, 4, 5, 10, 11, 12, 13 Probiotics have been studied extensively, but with inconsistent results. Various formulations have been documented to decrease the duration of acute diarrhea by 0.6,5 0.9,12 1,32 and 2.7 days31 as compared to placebo‐treated dogs. Other studies have shown no treatment effects, and a recent systematic review suggested that the overall clinical benefit of probiotic therapy is potentially unimportant.18, 33 Short‐term dietary modifications often are recommended in dogs with acute diarrhea, but strong evidence for this practice is lacking.1, 2 Studies of metronidazole treatment of acute diarrhea in dogs are limited.10, 18 Concurrent treatments frequently are administered in clinical studies of acute diarrhea, different fecal scoring scales often are utilized, and the definition of diarrhea resolution is not uniform.10, 18, 32 Consequently, interpretation and application of results are challenging. A previous randomized controlled clinical trial failed to document a benefit of metronidazole treatment as compared to placebo in dogs with acute nonspecific diarrhea.18 The reasons for conflicting results are unclear. The average durations of time until diarrhea resolution in both metronidazole (4.6 days) and placebo (4.8 days) treated dogs from the aforementioned study were longer than the average durations of time reported in our study, which suggests that the study populations may not be similar. Different designs and methodologies could have contributed to discordant study results. In the previous trial, some dogs did not have fecal flotations performed, clinicians were permitted to treat dogs with an anthelmintic at their discretion, and owners were not required to document daily fecal scores.18 We also utilized a different fecal scoring system, which has not been used routinely in studies of dogs despite widespread use in clinical trials of humans.24, 25, 26 The Bristol fecal chart appeared to perform adequately because all dogs had fecal scores of 6 or 7 at baseline, and all dogs had scores ≤4 at the time of study termination. Regardless, continued clinical research is needed to better characterize treatment approaches for dogs with acute diarrhea.
Clostridium perfringens is likely to be involved in the pathogenesis of various diarrheal syndromes in dogs.16, 32, 34 Both C. perfringens enterotoxin and cpe are more commonly detected in dogs with diarrhea than in non‐diarrheic dogs.34, 35 Similarly, the cpb2 gene recently was identified in a larger number of C. perfringens isolates from diarrheic dogs as compared to non‐diarrheic dogs.36 Additional C. perfringens genes and associated toxins also seem to be involved in specific forms of disease such as acute hemorrhagic diarrhea syndrome.16 Although C. perfringens and its toxins often are associated with acute diarrhea, it is still unclear if this bacteria is a cause or consequence of the intestinal disease.34, 35, 37 We did not evaluate C. perfringens in a healthy population of dogs, but previous studies have shown that isolation rates are similar in diarrheic and non‐diarrheic dogs, and the C. perfringens toxins associated with diarrhea also can be identified in healthy, non‐diarrheic dogs.34, 35, 36, 37, 38 Further complicating matters, the presence of toxin‐encoding genes does not always correlate to the presence of actual toxins.34, 35 These findings pose obvious diagnostic challenges for individual cases. Our study was not designed to establish a relationship between C. perfringens and acute diarrhea, but we still thought it was important to consider the effects of metronidazole treatment on C. perfringens carriage given the potential associations with acute diarrhea that have been observed in other studies. The frequency at which C. perfringens was detected by fecal culture in our population of diarrheic dogs (87.1%) is similar to previous reports, as is the frequency of cpe and cpb2 identification.34, 35, 39 More importantly, metronidazole treatment resulted in negative fecal cultures for C. perfringens in approximately 80% of dogs with positive cultures at baseline. This finding is in contrast to the nearly 80% of control dogs that remained positive for C. perfringens growth on day 7. These findings are in agreement with previous reports that suggest metronidazole is an effective treatment for most C. perfringens isolates.14, 40
Our inclusion criteria, which selected clinically stable dogs that were still eating and drinking, may have excluded dogs with nongastrointestinal or metabolic diseases. This conclusion is further supported by the normal biochemical evaluations that were performed in 18 dogs. However, comprehensive diagnostic testing was not performed in many dogs of the present study, and heterogeneous etiologies for acute diarrhea could have been represented in the study population. Although this could be perceived as a limitation, extensive diagnostic testing such as abdominal ultrasound examination and various molecular‐based diagnostic fecal panels are of questionable utility in clinically stable dogs with acute diarrhea.7, 8, 34 Each dog in our study did undergo repeated fecal diagnostic tests to ensure that gastrointestinal parasitism and parvovirus infection were not present, and baseline characteristics were similar between test and control populations. Also, none of the potential confounding factors considered in the multivariable analysis were found to be related to the duration of diarrhea. Another limitation is that long‐term monitoring was not performed as part of this study, and acute diarrhea might be an early manifestation of a more chronic disease process. The sample size of 31 is small for a randomized controlled clinical trial, and different results might be obtained with a larger population. Severe protocol deviations led to exclusion of 2 dogs, which was not unanticipated given the requirements for owners to document numerous fecal scores and return for a repeat clinical evaluation. However, we did not expect 22% of dogs screened for enrollment to be affected by gastrointestinal parasitism given that our study population received routine veterinary care. Lower parasitism prevalence rates have been reported in some studies, but these results reflect convenience samples from both healthy and diarrheic dogs.41, 42 Regional prevalence studies are not available for the State of Michigan, but a similar prevalence rate has been reported in diarrheic dogs in other regions.43 Although not an intended study aim, the high rate of gastrointestinal parasitism underscores the importance of fecal flotations in dogs with acute diarrhea.
In summary, metronidazole treatment modestly decreased the duration of diarrhea in this population of dogs with acute nonspecific diarrhea. Metronidazole treatment also decreased C. perfringens carriage although the relationship of C. perfringens with acute diarrhea was not investigated. The usage of metronidazole should be carefully considered in cases of acute diarrhea because our results do not preclude the possibility that other treatments could be similarly or even more effective. The impact of widespread antimicrobial usage for a condition that is frequently self‐limiting also needs to be considered. Future studies are needed to substantiate our results and address these concerns before metronidazole treatment of acute diarrhea in dogs can be categorically recommended.