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Acute canine diarrhea: is it time to rethink our treatment approach?

Publication
Article
dvm360dvm360 June 2022
Volume 53
Issue 6
Pages: 72

Examining the impact of antibiotic use on the gastrointestinal microbiome

acute canine diarrhea

Photographee.eu / stock.adobe.com

Content sponsored by Vetoquinol

Noteworthy new research bucking trends in traditional treatment

Because acute diarrhea is one of the most common concerns for small animal veterinary patients at general, emergency, and specialty hospitals, appropriate diagnostic workup and treatment is key. However, this is often trumped by the client’s desire for limited expenditure and a quick fix, and demand for immediate treatment often supersedes acceptance on the part of clients that most cases of uncomplicated acute diarrhea resolve spontaneously.1 Despite a paucity of evidence supporting use in clinically stable, healthy patients with non-septic acute diarrhea and few studies suggesting potential benefit within this patient subset, a recent study nevertheless identified systemic antimicrobials as the most prescribed pharmaceutical agent.2-9

In addition to the mounting evidence that antibiotics provide no significant benefit in terms of shortening duration of clinical signs or hospitalization, we know that their use can lead to adverse gastrointestinal signs and put patients at risk for long-term antimicrobial resistance, further potentiating longstanding ill effects on the intestinal gut microbiota.8-14 These effects can be wide-ranging, as the gut microbiome not only affects the host metabolism but also interacts with the immune system, protects against potential pathogens, and directly or indirectly affects many physiologic functions.12,15-18 For these reasons, it is prudent to avoid indiscriminate antibiotic use. Following recent trends in human literature, a paradigm shift in the management of acute uncomplicated diarrhea in dogs may involve interventions to support a healthy intestinal microbiome, including symptomatic management of diarrhea, therapeutic dietary modification, and the use of prebiotics, probiotics, symbiotic therapy (prebiotics and probiotics), and antidiarrheal probiotic pastes (ADPPs) in lieu of strategies involving the administration of antibiotics.

How to decide if/when to use antibiotics

In 2018, the Working Group of the Federation of International Societies of Pediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) published Universal Recommendations for the Management of Acute Diarrhea in Non-Malnourished Children, which advised against the routine use of antibiotics for the treatment of acute enteropathy.19 Despite similarities in the presenting populations, standard approaches in human medicine are geared toward management and prevention of progressive symptoms (without pharmaceutical intervention), while no standardized protocols or official guidelines exist for the management of canine and feline acute diarrhea. This often leads to inconsistencies in treatment recommendations, which are left to the discretion of clinicians, given that the exact etiology of presenting signs is rarely identified and few cases have a disease-specific targeted therapy.

Unfortunately, underlying etiologies causing similar presentations may be complex and include acute intestinal inflammation (gastroenterocolitis), infectious agents (endoparasites, bacteria, fungi, viruses, protozoa), dietary indiscretion, secondary extraintestinal organ dysfunction or inflammation, metabolic disturbances, endocrine diseases, and even patient stress, among many possible causes.20 As with all patients, obtaining a complete history and performing a thorough physical exam is crucial to ensuring appropriate management. In obtaining history, it is important to confirm that the duration of signs is indeed acute (less than one week long) rather than a flare-up of a more chronic process (of more than 2 weeks in duration), which may influence diagnostic and treatment recommendations. If not identified in a timely manner, life-threatening conditions can present or develop even with acute, sometimes seemingly mild, cases of acute diarrhea. Considering patient signalment, age, weight, current medications, preexisting comorbidities, and hemodynamic stability (hydration status, vital and perfusion parameters) and thoroughly understanding the potential for ongoing losses will significantly impact management.

Screening young, unvaccinated animals that are not receiving monthly heartworm and flea prevention for canine parvovirus and endoparasite infection may be straightforward; however, the decision to begin antibiotic therapy should be guided by targeted diagnostics confirming disease presence and an understanding of the anamnesis and anticipated progression. In confirmed cases of canine and feline parvovirus, antibiotics are unavoidable because of the immunological incompetence derived from viral bone marrow suppression with high risk of intestinal bacterial translocation. Appropriate fecal screening may obviate the prescription of antimicrobials in a stable, parvovirus-negative patient. Such antibiotic stewardship is not only important for improving patient outcomes but remains pivotal for reducing subsequent environmental contamination and potential exposure of the general population to multidrug-resistant, potentially zoonotic pathogens.

But owners say they want metronidazole/tylosin; what’s the harm?

Despite sparse historical evidence that metronidazole may reduce the time it takes for acute diarrhea to resolve in dogs, even the authors of these studies note that most cases of canine diarrhea resolve in a few days “regardless of treatment.” Caution should be raised when owners say, “it worked before, just give me another week,” especially if “only one dose” was needed to resolve the signs, as this temporal association could be simply coincidental. In the veterinary field, historical belief in beneficial outcomes may have been grounded in a perception that metronidazole possesses colonic anti-inflammatory properties (due to studies in human patients with Crohn disease) or that clinical signs associated with acute diarrhea or hematochezia increase the likelihood that an infectious process is involved and/or that the intestinal mucosal integrity is lost (increasing the risk of bacteremia).21 In attempting to rationalize use, an owner’s misguided assumption may be that an antibiotic would selectively target enteropathogenic bacteria responsible for causing acute clinical signs, leading to more rapid resolution of clinical signs. Although distressing to owners and clinicians alike, despite the presence of hematochezia, the consensus recommendations are against antibiotic use as no evidence corroborates benefit in cases of acute hemorrhagic diarrhea syndrome (AHDS) without signs of bacterial translocation with subsequent sepsis.12 On the contrary, it has been demonstrated that administration of antibiotics in dogs presenting with AHDS did not significantly improve severity of clinical signs, fecal consistency, and duration of hospitalization when compared to placebo.9 In truth, multiple canine and feline studies have demonstrated broad spectrum antibiotics markedly derange the fecal metabolome and reduce its diversity, with modifications persisting up to 4 years reported in human medicine.11,22-26

Although it was previously common for antibiotics such as metronidazole and tylosin to be included in an outpatient or inpatient treatment plan, increasing evidence-based research has identified significant short-term and long-term consequences of indiscriminate antibiotic use in both human and small animal patients.8 This is highlighted by emerging evidence identifying the impact of a short course or even a single-dose of an antibiotic on the entire gut microbiome, which is made up of bacteria, archaea, viruses, and eukaryotic organisms.12,14,17,24 Adverse clinical effects are believed to be due to the negative effects of antibiotics on these organisms, leading to alterations of the metabolome and opportunistic colonization by pathogenic bacteria.

A robust, diverse microbiome can act as in a pro- and anti-inflammatory capacity, maintaining a delicate balance and preventing excessive inflammation while promptly responding to control opportunistic pathogenic bacterial overgrowth or infections. Many diseases, systemic or localized, impact or are impacted by the gut microbiome, and are associated with dysbiosis (alterations in the composition of the gut microbiota that result in functional changes in the microbial transcriptome, proteome, or metabolome).27 In a study evaluating the long-term effects of tylosin in healthy dogs, those exposed to the antibiotic exhibited decreased bacterial diversity and fecal dysbiosis, with measurement of dysbiosis index not uniformly resolving post-discontinuation of treatment.28 In a prospective evaluation of dogs treated with metronidazole for 7-14 days, a minimum 4-week effect of metronidazole on fecal microbiome and metabolome was identified.24 In fact, despite reducing populations of the potentially pathogenic order Clostridiales (C. perfringens and C. difficile), reductions in Clostridium cluster XIVa, IV, and XVIII, which are important producers of short-chain fatty acids, may reduce innate anti-inflammatory effects through the induction of regulatory T cells in the intestinal cells. Importantly, although previous studies have suggested an association between increased levels of Clostridium in the feces of dogs suffering from acute and chronic diarrhea, this does not indicate causation and should not be used to contend that antibiotics be administered.29

If I can’t prescribe an antibiotic, what can I use?

The growing concerns regarding frequent antibiotic use in human and veterinary medicine highlight the trend toward seeking out alternative and/or synergistic strategies to manage acute diarrhea. However, client satisfaction is largely based on their confidence treatment plans will expedite patient recovery; few if any clients will be satisfied without clear expectations or an understanding of the treatment plan. Symptomatic therapies, including motility inhibitors to reduce cramping and urgency, may provide relief to distressed patients and owners seeking rapid resolution of signs, but they can also affect the gut microbiome (albeit less profoundly than antibiotics) and have limited prospective studies clearly identifying indication for use.

With amassing evidence cementing diet as the foundation of health in both human and veterinary patients, it is logical that dietary modification remain the basis of management of acute diarrhea. Given the strong interplay between nutritional intake and microbiota diversity, health, and function, highly digestible (ie, protein digestibility ≥87% and fat and carbohydrate digestibility ≥90%), low-residue food with moderate levels of fat (<14% dry matter basis) has been the cornerstone of prescription diets. The addition of small amounts (<5% DM basis) of soluble fiber (psyllium husks, apple pectin, soy fiber) or mixed solubility fiber (pea fiber, beet pulp) may normalize intestinal motility, improve water balance, and support a more healthy microbiota, whereas fiber higher quantities (7-15% DM basis) can normalize intestinal transit time, add ingestible bulk and retain excess water, buffer enterotoxins, and provide intraluminal stimuli to reestablish the coordinated actions of enzyme delivery, digestion, and absorption.20

Probiotics are supplements or foods that contain viable microorganisms with a proven benefit to the host, whereas prebiotics are supplements or foods (often dietary fibers or carbohydrates) that selectively stimulate the growth and/or activity of indigenous microorganisms. The use of probiotics is based on their ability to help reestablish microbial–host balance in the digestive system after disruption of normal function by stress, infection, or medical therapy. In a randomized double-blind clinical trial, dogs presenting with acute diarrhea achieved acceptable fecal consistency after 3.5 ± 2.2 days when receiving probiotic, 4.6 ± 2.4 days with oral metronidazole, and 4.8 ± 2.9 days with placebo (no statistically significant differences).8 Even without colonizing the intestine, bacteria administered with probiotics can modify intestinal microbiota composition and metabolism, conveying beneficial effects via counteraction of dysbiosis. In a study performed in dogs with acute uncomplicated idiopathic diarrhea, probiotic administration (Bifidobacterium animalis strain AHC7) allowed for a shorter resolution time and a lower proportion of patients receiving metronidazole when compared with the control group (placebo).30 Similarly, probiotic interventions containing ≥ 1 strain of Enterococcus faecium (strains SF68 and 4b1707), Bacillus coagulans, Lactobacillus acidophilus, and Bifidobacterium animalis have been shown to decrease the incidence of diarrhea in healthy dogs.31 Lastly, in patients previously treated with antibiotics, recent studies have identified a more rapid recovery of the fecal microbiome and overall metabolome composition in those that received synbiotics as compared to placebo.11,32

In addition to the modulation of the microbiota, it is helpful to use substances that facilitate reparative processes and have anti-inflammatory effects, as acute diarrhea can damage and inflame the intestinal barrier. Antidiarrheal probiotic pastes offer an advantage over other treatments commonly used for managing acute diarrhea, such as antimicrobials and dietary modification, for whose efficacy there is no evidence. ADPPs can act through such mechanisms as inhibition of pathogen growth and modulation of gastrointestinal immune function, gastrointestinal microbiome, and gastrointestinal motility, and may facilitate the binding of water and toxins.31

Kaolin/pectin formulations (such as Pro-Pectalin) have gained popularity for symptomatic therapy of diarrhea. Kaolin, an aluminum silicate, and pectin, a carbohydrate extracted from the rind of citrus fruits, act synergistically as a demulcent and an adsorbent in the treatment of diarrhea by binding bacterial toxins (endotoxins and enterotoxins) within the GI tract. In placebo-controlled clinical trials, treatment with ADPP was associated with significantly shorter duration of diarrhea (ADPP: median, 32 hours; 95% confidence interval [CI], 2-118; n = 51; placebo: median, 47 hours; 95% CI, 4-167; n = 58; P=.008) and a more rapid rate of resolution of diarrhea (1.60 times faster), and it required fewer additional medical interventions for non-improvement or worsening clinical signs (3.5% and 14.8% of dogs, respectively).31 The results suggest that these options had a favorable clinical outcome compared to antibiotics and are a valid antibiotic-sparing approach to the management of acute diarrhea.

References

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