M
etronidazole is an antibacte-rial and antiprotozoal agentthat is also used for its anti-inflammatory properties. Various saltsof metronidazole with improvedpalatability are now available for vet-erinary patients.
PHARMACOLOGY
Metronidazole is bactericidalagainst obligate anaerobic bacteria.The drug manifests its biologic activi-ty through reduction of its nitrogroup within nitroreductase-produc-ing cells.
1
During reduction, certainshort-lived highly toxic intermediatederivatives of the parent compoundare formed; these derivatives disruptbacterial DNA. Although a similarmechanism of action is suspected, theantiprotozoal mechanism of metron-idazole is not well understood. Well absorbed following oral ad-ministration, metronidazole is not ex-tensively protein bound and is widely distributed in tissue and body fluids,including abscesses.
2
Metronidazole isprimarily metabolized in the liver.The major metabolite, 2-hydroxy-methylmetronidazole, has significantantibacterial and antiprotozoal activi-ty. Approximately 20% of an oraldose is excreted unchanged in theurine. In dogs with normal renal andhepatic function, the elimination half-life of metronidazole is 4 to 5 hours.
3
Metronidazole’s half-life is essentially unchanged in humans with renal im-pairment.
2
Its half-life in cats has notbeen determined but is thought to belonger than in dogs.In the United States, only the hy-drochloride (HCl) salt of metronida-zole is approved for use. Despite itsuniversal therapeutic value, the tasteof metronidazole HCl is uniformly unpalatable to all animal species. Hu-mans report a bitter, unpleasant me-tallic taste after administration. Catspredictablydemonstrate salivationand head shaking after receiving met-ronidazole HCl. Not all salts of met-ronidazole, however, are equally bit-ter. Metronidazole benzoate, alsoknown as benzoyl metronidazole, hasbeen approved for use in Europe andMexico for many years and has been widely used in many animal speciesbecause of its improved palatability.The molecular weight of metroni-dazole benzoate is approximately 275.3 D, whereas the molecular weight of metronidazole HCl is 171.2D. Because of the larger benzoatemolecule, doses of metronidazoleHCl must be multiplied by a factor of 1.6 to convert to metronidazole ben-zoate. Cats and birds accept the ben-
Small Animal/Exotics
Compendium
December 2000
zoate salt much more willingly thanthey accept metronidazole HCl anddo not seem to be stressed by its ad-ministration.
INDICATIONS
Metronidazole is effective against avariety of obligate anaerobic bacteriaas well as such anaerobic protozoa as
Giardia
and
Trichomonas
.
2,4
Metroni-dazole has no known activity againstaerobic rods or cocci and is inactiveagainst fungi and viruses.
1,3
In vitroand in vivo studies indicate that met-ronidazole has antiinflammatory pro-perties and affects neutrophil motility,lymphocyte transformation, and someaspects of cell-mediated immunity.
5,6
These immunomodulatory effects arebelieved to be partially responsible foramelioration of clinical signs, particu-larly in cases of enterocolitis and oro-pharyngeal infections.Metronidazole is indicated for thetreatment of anaerobic infections, in-cluding periodontitis/stomatitis, os-teomyelitis, soft tissue infections, andintraabdominal sepsis.
7–9
The agent iscommonly prescribed for the manage-ment of giardiasis, canine colitis, andantibiotic-responsive enteropathy.
10–12
Metronidazole may be indicated, ei-ther alone or in conjunction with im-munosuppressive agents, for canine
Reid Groman, DVMUniversity of Pennsylvania
PHARM PROFILE
METRONIDAZOLE
Pharm Profile
introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like
Pharm Profile
to cover a particular agent, please contact column editor Gigi Davidson, BS, RPh, North Carolina State University,4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email gigi_davidson@ncsu.edu.
and feline inflammatory bowel dis-ease.
13,14
The drug is often—but notinvariably—an effective treatment forclostridial colitis.
a,15
In conjunction with other medications, metronida-zole may be beneficial in the treat-ment of
Helicobacter
-associated gastri-tis
16
; however, it has limited value asthe sole therapeutic agent in the man-agement of
Helicobacter
infection.
17
Metronidazole may be given to pa-tients with hepatic encephalopathy for short-term suppression of bacterialflora in the large bowel.
18
ADVERSE EFFECTS
Untoward effects of metronidazoleadministration occur infrequently inveterinary medicine, although lethargy,anorexia, vomiting, and diarrhea areoccasionally reported.
3
Hepatotoxicity is possible, and thus caution should beused in patients with hepatic dysfunc-tion.
3
Ptyalism and anorexia can beseen following oral administration incats.
3
Neurotoxic signs may developfollowing short-term use and withchronic moderate- to high-dose thera-py.
19
Neurologic signs are occasionally reported in patients receiving metron-idazole at conventional dosing regi-mens. Pancreatitis has been rarely re-ported in humans after metronidazoleadministration
20
; however, this adverseeffect has not been reported in dogs.
ACUTE TOXICITY
The appearance of abnormal neu-rologic signs, including nystagmus,ataxia, seizures, and rigidity, demandsprompt discontinuation of therapy.Most patients improve within 5 to 7days after cessation of therapy, al-though weeks and sometimes monthsmay be required for complete resolu-tion of neurotoxic effects. No specificantidote for metronidazole overdoseexists. Although a large portion of metronidazole HCl is excreted un-changed in the urine, metronidazolebenzoate, like all benzene moieties,must be conjugated with glucuronideto facilitate elimination. Because thismetabolic pathway is inefficient incats, acute toxicity from overdoses of metronidazole benzoate is a possibility.Bedford and Clarke
21
experimental-ly induced benzoate toxicity in cats by introducing varying concentrations(0.25% to 1%) of benzoic acid infoodstuff. These investigators showedthat 450 mg/kg was the maximumpermissible single oral dose of benzoicacid in cats. The highest level thatcould safely be fed daily was 200mg/kg. These studies also showedthat benzoic acid accumulates withchronic use. Doses above 200 mg/kg/day produced signs of cumulative tox-icity (e.g., hyperesthesia, depression,and apprehension) within 48 to 72hours and sometimes caused death.Therefore, the risk of toxicity increas-es with the duration of therapy. By extrapolating these data
21
to metron-idazole benzoate (40% benzoic acid),it can be supposed that a dose of 500mg/kg/day would be toxic to catsbased on the benzoic acid moiety.
DRUG INTERACTIONS
Metronidazole blocks the metabo-
Compendium
December 2000Small Animal/Exotics
a
Willard M: Personal communication,Texas A&M University, 2000.
CLIENT COUNSELING INFORMATION
I
Metronidazole is a safe antibacterial agent for use in dogs and cats.
I
Side effects are unusual but include nausea, anorexia, diarrhea, and sali-vation (cats).
I
Any neurologic signs should be reported to the prescribing veterinarianat once.
I
Use of this drug in food-producing animals is specifically banned by theFDA.
Interested in writing for
COMPENDIUM
?
For small animal articles,please contactDr. Douglass Macintire(email macindk@vetmed.auburn.edu;phone 334-844-6032).For exotics articles,please contactDr. Branson Ritchie(phone 706-542-6316;emailbritchie@vet.uga.edu).
Compendium
December 2000Small Animal/Exotics
G.D. Searle & Co.) is approved only for vaginal infections in human wom-en and has no indication (and has notbeen evaluated for use) in veterinary patients.Metronidazole solution (500 mg/100 ml) for intravenous use is pack-aged in ready-to-use, 100-ml single-dose plastic containers (individually packaged in boxes of 24; Flagyl
®
I.V.RTU
®
, SCS Pharmaceuticals, Chica-go, IL). The drug is also available asa lyophilized powder (which must bediluted and reconstituted for intra-venous administration) in single-dosevials; each vial contains 500 mg met-ronidazole equivalent (individually packaged in boxes of 10; Flagyl
®
I.V.,SCS Pharmaceuticals). The wholesaleprice varies depending on special or-ders and subcontracts. Metronidazolebenzoate is not approved for use inthe United States but is available pur-suant to a valid prescription filled by acompounding pharmacist.
STORAGE
Metronidazole tablets should bestored at temperatures below 30˚Cand protected from light. The cap-sules can be stored at controlled roomtemperature (15˚C to 30˚C) in an air-tight, light-resistant container. The
TABLE I
Metronidazole Doses in Dogs and Cats
IndicationDose
Anaerobic infection, antibiotic-responsive enteropathy, 10–15 mg/kg PO or intravenously,
a
two or three timesulcerative colitis, and inflammatory bowel disease daily Gastric helicobacteriosis15 mg/kg PO once or twice daily (dogs)62.5 mg/day PO (cats)
Giardia
infection50 mg/kg/day PO for 5 days (dogs)25 mg/kg/day PO for 5 days (cats)Hepatic encephalopathy7.5–10 mg/kg PO two or three times daily
a
When administering metronidazole intravenously, the lower end of the dosing range should be used and administration shouldtake 20 to 30 minutes.
PO
= orally.
lism of warfarin and thus increases theprothrombin time and the risk forsignificant bleeding.
3,22
Barbituratesmay enhance metabolism of metron-idazole, causing therapeutic failure.
3,23
The simultaneous administration of drugs that decrease microsomal liverenzyme activity (e.g., cimetidine) may prolong the half-life and decrease plas-ma clearance of metronidazole.
3
DOSAGE AND ADMINISTRATION
Metronidazole can be administeredorally or intravenously to treat anaer-obic infection, antibiotic-responsiveenteropathy, ulcerative colitis, and in-flammatory bowel disease in dogs andcats. Oral administration is indicatedfor hepatic encephalopathy, helico-bacteriosis, and
Giardia
infections(Table I).
PREPARATIONS
Metronidazole HCl is availablegenerically (numerous manufacturers)in 250- and 500-mg tablets; the wholesale price for these preparationsranges from $0.08 to $0.21/250-mgtablet and $0.16 to $0.46/500-mgtablet. The drug is also available in375-mg capsules (Flagyl
®
, G.D. Searle& Co., Chicago, IL). The 750-mg ex-tended-release tablet (Flagyl
®
ER,lyophilized powder may be reconsti-tuted with either bacteriostatic wateror 0.9% sodium chloride; the recon-stituted product may be clear to paleyellow, but no cloudiness should beobserved. Because the pH of the re-constituted product is low, 5 mEq of sodium bicarbonate should be addedto neutralize the pH. No bicarbonateor any other additives or solutionsneed to be added to the ready-to-useformulation.
REFERENCES
1.Ellison MJ: Vancomycin, metronidazole,and tetracyclines.
Clin Podiatr Med Surg
9(2):430–438, 1992.2.Bosso JA, Prince RA: Anti-anaerobic an-timicrobial agents.
Tex Heart Inst J
17(2):77–83, 1990.3.Plumb DC:
Veterinary Drug Handbook
. White Bear Lake, MN, Pharma Vet Pub-lishing, 1999, pp 424–427.4.Greene CE (ed): Appendix 8: Antimicro-bial drug formulary, in
Infectious Diseases of the Dog and Cat.
Philadelphia, WBSaunders Co, 1998, pp 875–877.5.Grove DI, Mahmoud AF, Warren KS:Suppression of cell-mediated immunity by metronidazole.
Int Arch Allergy Appl Immunol
54:422–427, 1977.6.Arndt H, Palitzch KD, Grisham MB:Metronidazole inhibits leukocyte-endo-thelial cell adhesion in rat mesenteric ven-ules.
Gastroenterology
106(5):1271– 1274,1999.7.Sarkiala E, Harvey C: Systemic antimi-
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