Rethinking the role of metronidazole in veterinary medicine

This article discusses the appropriate and inappropriate uses of metronidazole, highlights current research that contradicts our older assumptions, and prompts some questioning to determine if this drug is an ideal choice.

When your patients have diarrhea, a course of metronidazole (Flagyl) might be the appropriate treatment. However, this antibiotic has become a knee-jerk response to cases of diarrhea based on good theory and historical practice, rather than scientific evidence. A growing body of evidence-based research suggests that metronidazole is much less effective for some gastrointestinal conditions than previously thought. In addition to potential adverse side effects, we now know that metronidazole can cause unhealthy long-term changes in a pet’s gut microbiome.1,2

Because metronidazole has activity against several diarrhetic agents, it has become the most frequently-used antibiotic for nonspecific diarrhea.3 But in some cases, it may be the wrong choice. Several studies have found that metronidazole doesn’t help inflammatory bowel disease (IBD)4 or acute diarrhea in dogs.5

So is metronidazole the right treatment for your patients? Or could we be doing more harm than good by prescribing it?

When is metronidazole the right choice?

Metronidazole is an extremely useful antibiotic and antiprotozoal agent that’s been around since the 1950s. In both human and veterinary medicine, it has cured life-threatening anaerobic infections. Being bactericidal, metronidazole has the potential to work faster and more efficiently than other antibiotics (e.g. clindamycin).

  • Metronidazole is effective against Bacteroides fragilis, a normal gut and mouth commensal that can be isolated from wound infections, abscesses, pyothorax, and cholangiohepatitis.  Metronidazole has historically been used for suspected anaerobic osteomyelitis, especially involving the jaw and mouth.6 However, more recent reviews suggest suboptimal bone penetration.7
  • Metronidazole works well against Clostridioides — a genus of bacteria that includes C. difficile, a well-known cause of antibiotic-associated diarrhea in humans and an implicated cause in animals.8–10 With regards to acute, nonspecific, canine diarrhea cases given metronidazole, a one-to-two-day shorter recovery has been reported.11
  • In pets, metronidazole has been used to treat Helicobacter gastritis. However, resistance is problematic.12–14 When polymicrobial sepsis is suspected, it’s a valuable and inexpensive addition to the arsenal to broaden anaerobic coverage. Whether used for Helicobacter or sepsis, metronidazole is combined with other medications, which can complicate interpretation of in vitro culture and sensitivities.
  • Historically, metronidazole was effective against Giardia.15 However, resistance has developed, so again, combination therapy is often recommended for refractory infections.16

A new study urges caution in choosing metronidazole

Along with the pathogens, most antibiotics also alter the commensal populations needed for health. As a result, important gut microbiome populations can be decimated, leading to dysbiosis. A new study published this year in the Journal of Veterinary Internal Medicine calls attention to metronidazole’s dramatic effects on the canine gut microbiome.1

Healthy dogs were medicated with a 14-day course of metronidazole; more than 50% developed diarrhea during treatment. The gut microbiome composition changed significantly, and included decreases in important beneficial bacteria, such as Fusobacteria — one of the dominant phyla of bacteria in the gut microbiomes of dogs and cats — and reductions in overall richness (the number of different bacterial species present). Effects were not temporary: four weeks post metronidazole, microbiome changes had not fully resolved, compromising healthy gut function.

The authors recommend that veterinarians adopt a more cautious approach when using metronidazole, particularly in dysbiotic patients.

Questions to ask when considering metronidazole for a patient

While metronidazole is shown to be an appropriate choice for some conditions, in other cases, it may not be as effective as we have assumed. Consider whether metronidazole will be beneficial for your patient. Here are some questions to ask:

Does my patient need antibiotics?

In many cases of canine diarrhea, the answer may be no. Though some health issues, such as life-threatening bacterial infections, do require antibiotics, other conditions may resolve with supportive care alone.

For example, dogs with hemorrhagic gastroenteritis are often given antibiotics, but according to veterinary consensus guidelines, antibiotics are appropriate for this condition only when sepsis is present.17,18 Researchers have found that as long as sepsis is not involved, even hemorrhagic gastroenteritis responds just as well to supportive care as to antibiotics.19

In fact, several studies have shown that metronidazole can actually make diarrhea worse, not only by reducing populations of “good” anaerobic bacteria, but also by altering the intestinal mucus.20,21

What are the possible side effects of metronidazole?

Most medications have potential adverse side effects. Metronidazole has a very bitter taste and often causes excessive salivation, drooling, gagging, or frothing at the mouth, especially in cats. In both cats and dogs, the drug may also cause nausea and hyporexia. Pets taking metronidazole may eat less than usual or refuse meals altogether. Vomiting and diarrhea are also relatively common. More serious, though less common, adverse effects include lethargy, weakness, hepatopathy, central nervous system signs such as nystagmus, head tilt, loss of balance and coordination, stumbling, knuckling, or even seizures. Teratogenicity has been recorded in rodents, though not humans.22 Rare idiosyncratic reactions in dogs have included pancytopenia.23 In cats, metronidazole has been found to cause reversible DNA damage to lymphocytes.24 Given long term and at a high dose in female mice, tumor-promoting effects are documented, and its carcinogenic potential has been questioned in people.25,26

Does your patient have any conditions that would make a bad reaction more likely?

Metronidazole should not be used when a patient has had an adverse reaction to it in the past. While some medications have been shown to increase the metabolism of metronidazole (e.g. prednisone and phenobarbital), no medications have been shown to clearly decrease metabolism.27 Don’t use metronidazole if your patient might be pregnant.28 If your patient has liver disease, metronidazole should be used very cautiously and at a lowered dose. It should also be used cautiously in any animal with a compromised nervous system or suspected neoplasia.

Are there any supplements that can be combined with metronidazole to improve the outcome for my patient?

  • Certain probiotics may help support better outcomes and reduce side effects. In a study of shelter dogs with diarrhea, a combination of the probiotic Enterococcus faecium SF68 and metronidazole led to better overall results than metronidazole alone.29
  • When silymarin (an anti-inflammatory flavonoid derived from milk thistle seed) was combined with metronidazole to treat Giardia in another study, dogs had better appetite, less intermittent vomiting, and less weight loss than when receiving metronidazole alone.30
  • Adding the yeast Saccharomyces boulardii to a pet’s food may reduce the risk of antibiotic-associated diarrhea.31 S. boulardii is a probiotic that works by supporting beneficial gut bacteria and inhibiting the growth of pathogenic bacteria.

What are the alternatives to metronidazole?

Are there alternatives to metronidazole for treating aspects of your patient’s gastrointestinal (GI) signs? Hippocrates is often credited with the maxim, “Let thy food be thy medicine and medicine be thy food.” Veterinarians have long used dietary modification in disease management. Given the plethora of amassing scientific evidence, diet is cemented as the foundation of health. For example, diarrhea often equates with dysbiosis. Prebiotic fibers such as inulin and psyllium may help by feeding beneficial bacterial populations while also firming up the stool. As mentioned previously, probiotic blends can help resolve diarrhea and support gut function. Empirical evidence for the use of phytonutrients like carvacrol (extracted from oregano, thyme and several other plants) is accumulating.32–38

Other symptomatic treatments include anti-nausea medications, proton pump inhibitors (to reduce acid production), motility inhibitors (to reduce cramping and the sense of urgency), bile acid sequestrants (to control bile acid malabsorption in chronic diarrhea cases), and vitamin B12 (cobalamin, which is often deficient in chronic diarrhea cases).39–42 While some of these approaches may also cause changes to the gut microbiome, those changes will generally be less profound than the effects associated with metronidazole.

Lastly, if your patient’s microbiome is significantly dysbiotic, the introduction of beneficial microbes via fecal microbiota transplantation (FMT) — i.e. Microbiome Restoration Therapy (MBRT) — can help by seeding the gut with a whole healthy community of dog- or cat-specific bacteria. Recent studies have found that FMT improves restoration of the gut microbiome from antibiotic exposure; one of these studies also found that probiotics may impair its recovery.43,44

Inappropriate uses of metronidazole

Because past research has found metronidazole to be effective against certain causes of diarrhea in dogs, it has become many veterinarians’ go-to treatment for diarrhea in general. The problem is that there isn’t much scientific evidence that metronidazole actually helps some of the conditions it’s being used for. And yet, even without strong scientific evidence of its effectiveness, metronidazole has become the most commonly prescribed antimicrobial agent for acute diarrhea in dogs.3 Here are three common situations in which research has found metronidazole to be the wrong choice.

Giardia infection

In the past, metronidazole was commonly used to treat infections caused by the protozoan parasites Giardia and Tritrichomonas, which are known to cause diarrhea in cats and dogs. Over time, however, both these organisms have developed metronidazole resistance, so this medication by itself is no longer a curative treatment for these protozoal infections. 46

Inflammatory bowel disease (IBD)

Because metronidazole has a positive effect on Crohn’s disease in humans, it is often used for diarrhea in dogs with IBD and other chronic diseases of the intestines, usually in combination with the steroid prednisone.47 However, researchers established in 2010 that metronidazole doesn’t actually add any benefit in this scenario: prednisone plus metronidazole is no more effective for IBD than prednisone by itself.4

Acute diarrhea

Because of its historical effectiveness against such diarrhea-inducing agents as Giardia and C. diff, metronidazole has been increasingly used by veterinarians to manage diarrhea due to other causes. But there is little evidence that it actually helps acute, nonspecific diarrhea (diarrhea with an undetermined cause) — a category that represents the majority of diarrhea cases in both cats and dogs.

In the veterinary sphere, there is some evidence that metronidazole reduces the time it takes for acute diarrhea to resolve. However, a study in dogs found that this reduction amounted to only a couple of days. And as the authors pointed out, most cases of diarrhea in dogs resolve in a few days “regardless of treatment.”11

Another study that looked at treating acute diarrhea in dogs found no significant difference between metronidazole and a placebo. The authors concluded that the use of metronidazole for such cases “should be discouraged until evidence-based data demonstrate a difference in treatment outcome.”48

Summary recommendations

We encourage veterinarians to discuss these issues with their clients. Metronidazole and other antibiotics can be valuable tools in treating a sick pet, but it’s important to make sure the chosen drug’s effectiveness in a given situation is supported by scientific evidence. And if your patient already suffers from an imbalanced gut microbiome, due to chronic GI issues or other health problems, antibiotics should be used only if absolutely necessary.

Additionally, testing your patient’s microbiome after a course of antibiotics (see sidebar) is recommended, especially if GI signs linger. Identifying and correcting any dysbiosis can make an enormous difference in your patient’s long-term health and happiness.

*Affiliated with AnimalBiome

°Affiliated with Condensed Light

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2Igarashi H, Maeda S, Ohno K, Horigome A, Odamaki T, Tsujimoto H. Effect of oral administration of metronidazole or prednisolone on fecal microbiota in dogs. PLoS One. 2014;9(9):e107909.

3Singleton DA, Noble PJM, Sánchez-Vizcaíno F, et al. Pharmaceutical Prescription in Canine Acute Diarrhoea: A Longitudinal Electronic Health Record Analysis of First Opinion Veterinary Practices. Front Vet Sci. 2019;6:218.

4Jergens AE, Crandell J, Morrison JA, et al. Comparison of oral prednisone and prednisone combined with metronidazole for induction therapy of canine inflammatory bowel disease: a randomized-controlled trial. J Vet Intern Med. 2010;24(2):269-277.

5Chaitman J, Ziese A-L, Pilla R, et al. Fecal Microbial and Metabolic Profiles in Dogs With Acute Diarrhea Receiving Either Fecal Microbiota Transplantation or Oral Metronidazole. Front Vet Sci. 2020;7:192.

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10Chon J-W, Seo K-H, Bae D, Park J-H, Khan S, Sung K. Prevalence, toxin gene profile, antibiotic resistance, and molecular characterization of Clostridium perfringens from diarrheic and non-diarrheic dogs in Korea. J Vet Sci. 2018;19(3):368-374.

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21Wlodarska M, Willing B, Keeney KM, et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. Infect Immun. 2011;79(4):1536-1545.

22Sheehy O, Santos F, Ferreira E, Berard A. The use of metronidazole during pregnancy: a review of evidence. Curr Drug Saf. 2015;10(2):170-179.

23Weiss DJ. Bone marrow necrosis in dogs: 34 cases (1996-2004). J Am Vet Med Assoc. 2005;227(2):263-267.

24Sekis I, Ramstead K, Rishniw M, et al. Single-dose pharmacokinetics and genotoxicity of metronidazole in cats. J Feline Med Surg. 2009;11(2):60-68.

25Bendesky A, Menéndez D, Ostrosky-Wegman P. Is metronidazole carcinogenic? Mutat Res. 2002;511(2):133-144.

26Adil M, Iqbal W, Adnan F, et al. Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions? Curr Drug Metab. 2018;19(11):902-909.

27Eradiri O, Jamali F, Thomson AB. Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn’s disease. Biopharm Drug Dispos. 1988;9(2):219-227.

28Pichler L. Teratogenicity in dogs and cats-a review for practitioners and toxicologists. Wien Tierarztl Monatsschr. 2007;94(9/10):214.

29Fenimore A, Martin L, Lappin MR. Evaluation of Metronidazole With and Without Enterococcus Faecium SF68 in Shelter Dogs With Diarrhea. Top Companion Anim Med. 2017;32(3):100-103.

30Chon S-K, Kim N-S. Evaluation of silymarin in the treatment on asymptomatic Giardia infections in dogs. Parasitol Res. 2005;97(6):445-451.

31McFarland LV, Surawicz CM, Greenberg RN, et al. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol. 1995;90(3):439-448.

32Mousavi S, Schmidt A-M, Escher U, et al. Carvacrol ameliorates acute campylobacteriosis in a clinical murine infection model. Gut Pathog. 2020;12:2.

33Yuan W, Seng ZJ, Kohli GS, Yang L, Yuk H-G. Stress Resistance Development and Genome-Wide Transcriptional Response of Escherichia coli O157:H7 Adapted to Sublethal Thymol, Carvacrol, and trans-Cinnamaldehyde. Appl Environ Microbiol. 2018;84(22). doi:10.1128/AEM.01616-18

34Gaur S, Kuhlenschmidt TB, Kuhlenschmidt MS, Andrade JE. Effect of oregano essential oil and carvacrol on Cryptosporidium parvum infectivity in HCT-8 cells. Parasitol Int. 2018;67(2):170-175.

35Giovagnoni G, Rossi B, Tugnoli B, et al. Thymol and Carvacrol Downregulate the Expression of Salmonella typhimurium Virulence Genes during an In Vitro Infection on Caco-2 Cells. Microorganisms. 2020;8(6). doi:10.3390/microorganisms8060862

36Sánchez C, Aznar R, Sánchez G. The effect of carvacrol on enteric viruses. Int J Food Microbiol. 2015;192:72-76.

37Katsoulos PD, Karatzia MA, Dovas CI, et al. Evaluation of the in-field efficacy of oregano essential oil administration on the control of neonatal diarrhea syndrome in calves. Res Vet Sci. 2017;115:478-483.

38Mooyottu S, Flock G, Upadhyay A, Upadhyaya I, Maas K, Venkitanarayanan K. Protective Effect of Carvacrol against Gut Dysbiosis and Clostridium difficile Associated Disease in a Mouse Model. Front Microbiol. 2017;8:625.

39Senderovich H, Ghassem Khani E. The Role of Bile Acid Sequestrant in Diarrhea Management: Too Good to Be True? Clin Gastroenterol Hepatol. 2018;02(03). doi:10.21767/2575-7733.1000048

40Enright EF, Griffin BT, Gahan CGM, Joyce SA. Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism. Pharmacol Res. 2018;133:170-186.

41Toresson L, Steiner JM, Olmedal G, Larsen M, Suchodolski JS, Spillmann T. Oral cobalamin supplementation in cats with hypocobalaminaemia: a retrospective study. J Feline Med Surg. 2017;19(12):1302-1306.

42Toresson L, Steiner JM, Spodsberg E, et al. Effects of oral versus parenteral cobalamin supplementation on methylmalonic acid and homocysteine concentrations in dogs with chronic enteropathies and low cobalamin concentrations. Vet J. 2019;243:8-14.

43Taur Y, Coyte K, Schluter J, et al. Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci Transl Med. 2018;10(460). doi:10.1126/scitranslmed.aap9489

44Suez J, Zmora N, Zilberman-Schapira G, et al. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018;174(6):1406-1423.e16.

45Martinez-Lopez LM, Pepper A, Pilla R, Woodward A, Suchodolski J, Mansfield C. Effect of Sequentially Fed High Protein, Hydrolysed Protein, and High Fibre Diets on The Faecal Microbiota of Healthy Dogs: A Cross-Over Study. Published online 2020.

46Upcroft P, Upcroft JA. Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin Microbiol Rev. 2001;14(1):150-164.

47Sprockett D, Fischer N, Boneh RS, et al. Treatment-Specific Composition of the Gut Microbiota Is Associated With Disease Remission in a Pediatric Crohn’s Disease Cohort. Inflammatory Bowel Diseases. 2019;25(12):1927-1938. doi:10.1093/ibd/izz130

48Shmalberg J, Montalbano C, Morelli G, Buckley GJ. A Randomized Double Blinded Placebo-Controlled Clinical Trial of a Probiotic or Metronidazole for Acute Canine Diarrhea. Front Vet Sci. 2019;6:163.

49Rossi G, Pengo G, Caldin M, et al. Comparison of microbiological, histological, and immunomodulatory parameters in response to treatment with either combination therapy with prednisone and metronidazole or probiotic VSL#3 strains in dogs with idiopathic inflammatory bowel disease. PLoS One. 2014;9(4):e94699.

50Niina A, Kibe R, Suzuki R, et al. Improvement in Clinical Symptoms and Fecal Microbiome After Fecal Microbiota Transplantation in a Dog with Inflammatory Bowel Disease. Vet Med (Auckl). 2019;10:197-201.

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Dr. Holly Ganz is a microbiologist turned entrepreneur. In 2016, she left academic research at UC Davis to create AnimalBiome, a company that provides microbiome assessments for dogs and cats and creates restorative remedies to help promote healthy guts. Dr. Ganz received her PhD from UC Davis, where she studied co-evolution between microbes and animals. After receiving her doctorate, she was a post-doctoral fellow at UC Berkeley, where she studied how bacterial pathogens survive in soil to infect wildlife. She subsequently applied microbial genomics to study the canine oral microbiome, as a visiting scientist at the UC Davis School of Veterinary Medicine. Dr. Ganz is dedicated to improving animal health and wellness through applying the latest innovations in microbiology.
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Dr. Dawn Kingsbury has practiced general and specialty companion animal medicine around the world. She met Holly Ganz while studying for her PhD. Being chief veterinary officer at AnimalBiome aligns with Dr. Kingsburty’s interests -- host-microbe interactions, precision medicine, and One Health -- while allowing her to promote microbiome analysis as a non-invasive, clinically actionable tool and to cultivate evolving microbiome restoration strategies.
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Ellen Barber is a writer and editor with more than 20 years of experience serving corporations, publishers, and organizations in the fields of business, investment, investment management, and education. Grounded in the humanities, she has also spent time in the worlds of grant administration and medical research. She regularly contributes to AnimalBiome’s pet health blog posts.

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