Reports of Retrospective Studies

Clinical use of metronidazole in horses: 200 cases (1984-1989)

Raymond W. Sweeney, VMD; Corinne R. Sweeney, DVM; Janice Weiher, BS

Summary: Case records of 200 horses treated with metronidazole were reviewed. Horses were treated for respiratory tract infections (90 cases), peritonitis or abdominal abscess (39 cases), celiotomy (49 cases), orthopedic infections (6 cases), and miscellaneous soft tissue infections (16 cases). Bacteria of the genus Bac­teroides were most prevalent (55 of 167 anaerobic isolates). Metronidazole was always used in combina­tion with other antimicrobial drugs.

Only 4 of the 200 horses had signs of adverse ef­fects associated with metronidazole treatment. Those 4 horses had poor appetite that resolved when met­ronidazole treatment was discontinued.

Metronidazole (1-2-hydroxyethyl-2-methyl-5-nitroimidazole) is an antibacterial agent used

for the treatment of infections caused by anaerobic protozoa and bacteria. The importance of anaero­bic bacterial infections in horses has been described, l-3 and the resistance of anaerobic bac­terial pathogens (isolated from human patients) to commonly used antimicrobial agents has been recognized. 4-6 Metronidazole has a broad spectrum of antibacterial activity against anaerobes in vi­tro, 5-7 and the successful use of metronidazole for the treatment and prevention of anaerobic infec­tions in human patients has been described. 7- 10

The pharmacokinetics of metronidazole in the horse have been described, 11 ·12 but reports of the clinical use of metronidazole are scarce. 13·14 The purpose of the study reported here was to review the clinical use of metronidazole in horses in an attempt to describe the response to treatment and the rate of complications associated with metron­idazole usage.

Criteria for Selection of Cases Records of horses admittted to the George D.

Widener Hospital for Large Animals, New Bolton Center, University of Pennsylvania School of Vet-

From the Department of Clinical Studies,School of Veteri­nary Medicine, University of Pennsylvania, New Bolton Center, 382 W Street Rd, Kennett Square, PA 19348.

The authors thank Pam Spencer for statistical assistance.

JAVMA, Vol 198, No. 6, March 15, 1991

erinary Medicine between July 31, 1984 and June 1, 1989 were reviewed. Case records of horses treated with metronidazole were evaluated. The diagnosis, duration of treatment, bacteriologic cul­ture results, concurrent antimicrobial treatment, clinical outcome, and complications were re­viewed.

Results There were 21,058 horses admitted to the

hospital during the period studied. Records from 200 horses treated with metronidazole were re­trieved. An additional 19 horses were treated with metronidazole during this period but were not in­cluded in the study because of incomplete or un­available case records. There were 103 males and 97 females. The mean age was 5.2 years (sD = 4.9 years), with a range of 2 weeks to 30 years, and 15 horses were < 6 months old. The breed distribu­tion was as follows: 105 Thoroughbred, 60 Stan­dardbred, 11 Quarter Horse, 8 Arabian, 6 Warm­blood, 2 Morgan, 2 Appaloosa, 2 Paint Horse, and 4 ponies. There were 2 cases in the second half of 1984, 23 in 1985, 48 in 1986, 50 in 1987, 51 in 1988, and 26 in the first 5 months of 1989.

The most common dosage of metronidazole used was 15 mg/kg of body weight given q 6 h in 162 cases and q 8 h in 4 cases. A dosage of 20 to 25 mg/kg was used q 6 h in 21 horses and q 12 h in one horse. A dosage of 7. 5 mg/kg q 6 h (the dos­age in people) was used in 12 cases. The drug was administered orally to 196 of the 200 horses. Of those 196 horses, 9 with a gastrointestinal problem were given the drug IV and 13 were given the drug (crushed tablets suspended in water) per rectum because of ileus or intestinal obstruction. Four horses were given metronidazole only per rectum.

Infections involving the respiratory or gas­trointestinal systems (where anaerobic bacteria are known to reside and anaerobic infections can fre­quently develop) were most commonly treated with metronidazole (Table 1). The 6 miscellaneous diagnoses not specified included protozoa! myeli­tis, fever of unknown origin, hepatitis, perforated esophagus, salmonellosis, and open diagnosis. Met­ronidazole was used prophylactically in 49 celiot-

Reports of Retrospective Studies 1045

Table 1-Duration of treatment, outcome, and anaerobic bacterial culture results in 200 horses treated with metronidazole

No. of Duration of treatment Culture- Pos Neg Diagnosis cases (range) positive* Survivet Survive:!:

Respiratory 90 Pleuropneumonia/Lung abscess 87 16 ± 26 (1 to 217) 36/76 18/36 36/40 Upper respiratory tract 3 6.3 ± 2.5 (4 to 9) 1/1 1/1

Gastrointestinal 88 Peritonitis/ Abdominal abscess 39 9.7 ± 6.9 (1 to 37) 8/23 4/8 9/15 Celiotomy (colic) 49 5.8 ± 2.5 (2 to 15) 0/6 6/6

Orthopedic 6 Septic arthritis 2 14 (9 to 19) 2/2 1/2 Osteomyelitis 4 16.2 ± 11.3 (6 to 27) 1/4 1/1 1/3

Soft tissue 10 Urachal/umbilical abscess 2 26.5 (21 to 32) 2/2 2/2 Abscess/cellulitis 8 7.3 ± 3.3 (4 to 14) 4/7 4/4 3/3

Miscellaneous 6 10 ± 4.0 (4 to 16) 0/3 2/3

*No. of horses with positive anaerobic culture result/No. of horses with anaerobic cultures submitted. tNo. of horses that survived with positive anaerobic culture result/total No. of horses with positive culture result. :l:No. of horses that survived with negative anaerobic culture result/total No. of horses with negative culture result.

Duration of treatment is expressed as mean No. of days ± so.

Table 2-Anaerobic bacterial isolates from 54 horses treated with metronidazole

Diagnosis (No. of cases with each isolate)*

Anaerobic isolate PP/LA(36) URT(1) PER/AA(B) ARTH(2) DSTED(1) UMB(2) ST(4)

Bacteroides fragi/is 3 0 2 2 1 1 1 Bacteroides oralis 4 0 0 0 0 0 0 Bacteroides sp 33 1 3 0 0 1 3 C/ostridium sp 19 0 0 0 0 1 1 Eubacterium sp 5 0 1 1 0 0 1 Fusobacterium necrophorum 0 0 1 0 0 0 0 Fusobacterium sp 8 0 1 0 0 0 1 Peptostreptococcus sp 17 0 3 0 0 0 1 Streptococcus sp 2 0 0 0 0 0 0 Proprionobacterium sp 3 0 0 0 0 0 0 Unidentified anaerobes 30 7 4 0 0 0 5

*PP/LA= pleuropneumonia/lung abscess; URT = upper respiratory tract (sinusitis); PER/AA= peritonitis/abdominal abscess; ARTH = septic arthritis; OSTEO = osteomyelitis; UMB = umbilicaljurachal abscess; ST = soft tissue abscess/cellulitis.

Numbers in parentheses indicate total number of cases of each disease.

omy cases, in which intestine was compromised or incised and leakage of resident anaerobic bacteria into the peritoneal cavity was possible.

Anaerobic bacterial culturing was performed15

for 124 of the 200 horses; 54 cultures were posi­tive. From many specimens, more than one anaer­obe was cultured; 167 organisms were isolated from the 54 horses (Table 2). Mixed infections were most common; 51 of the 54 horses with anaerobes also had aerobic bacteria isolated from the same specimen. Bacteria of the genus Bacteroi­des were most prevalent (55 of 167 isolates). An­timicrobial susceptibility testing was not performed on anaerobic bacteria. Of the 40 horses with pleu­ropneumonia with negative anaerobic bacterial culture results, 36 survived; significantly fewer (18 of36 horses) with positive anaerobic culture results survived (P < 0. 01, x2 test). Among horses with peritonitis, the difference in the survival rates for horses with positive culture results (4/8) and neg­ative. culture results (9/15) was not significant.

Metronidazole was always used in combina­tion with other antimicrobial drugs, including aqueous penicillin and gentamicin (159 of 200 horses), penicillin and amikacin (21 horses), tri­methoprim-sulfa (15 horses, various sulfas, de-

1046 Reports of Retrospective Studies

pending on product used). Of the 180 horses ini­tially treated with metronidazole, penicillin, and an aminoglycoside (amikacin or gentamicin), 48 were switched to treatment with metronidazole and tri­methoprim-sulfa for continued oral treatment after parenteral antimicrobial treatment was discontin­ued. Deleterious drug interactions were not ob­served in these horses. Other antimicrobials used with metronidazole, in lesserfrequency, included ampicillin, erythromycin, neomycin, and rifampin.

Complications attributed to metronidazole were rare. Of the 200 horses treated with metron­idazole, only 4 had complications attributed to metronidazole. These four horses had reduced ap­petite that improved or resolved within 24 hours after administration of the drug was discontinued. One additional horse developed mild, self-limiting diarrhea, but this horse was concurrently treated with a liquid diet that is known to cause diarrhea in some horses, and the diarrhea resolved while the horse was still being medicated with metronida­zole.

Discussion Metronidazole was used most commonly to

treat horses with infections of the respiratory tract

JAVMA, Vol 198, No. 6, March 15, 1991

and abdominal cavity, or in cases in which con­tamination of the abdomen with intestinal contents was considered possible. Metronidazole was fre­quently used in cases of pleuropneumonia, because of the known prevalence of anaerobic infections at these sites, 1·3 and also because of the known res­ident anaerobic bacterial flora in the upper respi­ratory tract than can result in contamination or in­fection with anaerobes. Similarly, metronidazole was frequently used to treat horses with peritonitis (or prevent peritonitis), because leakage of anaer­obic bacteria from the gastrointestinal tract can re­sult in anaerobic infection of the abdominal cavity. Additional evidence of anaerobic infection, such as foul breath odor and ultrasonographic findings, give even stronger indication for metronidazole treatment in cases of pleuropneumonia.1·3

Metronidazole was always used in combina­tion with antimicrobials with antibacterial activity against aerobic bacteria. Of the 54 horses with positive anaerobic culture results, 94.4% als? had aerobic bacteria isolated from the same specimen. Although metronidazole has bactericidal activity against some facultative anaerobic bacteria (when tested under anaerobic conditions), the activity is not uniform, and additional antimicrobials should be used.7 Bacteria of the genus Bacteroides were most prevalent in this study, and these (not just B fragilis) commonly are resistant to penicillin be­cause of j3-lactamase production. 5·6 Although sim­ilar data are not available for Bacteroides isolates of equine origin, and antimicrobial susceptibility test­ing was not performed on anaerobic bacte~a iso­lated in this report, possible resistance might be expected and metronidazole could b~ 1:1sed if anaerobic infection is considered a possibhty. Be­cause anaerobic bacterial culture results are usually not available for several days after specimen sub­mission, we recommend empiric treatment with metronidazole at the onset of treatment in severe cases of pleuropneumonia, because of the known prevalence of anaerobic infections (especially Bac­teroides sp) in those horses.

The dosage of metronidazole used most fre­quently in the horses of this report was 15 i_nglkg, PO q 6 h. This dosage was recommended m one

' 12 f report 11 although in another study, a dosage o ' 12 25 mg/kg q 12 h was suggested to be adequate.

Only one horse in our study was medicated with 25 mg/kg q 12 h, so response to treatment of the 2 dosages cannot be compared. Therapeutic c?ncen­trations of metronidli.zole in serum and pentoneal fluid are rapidly achieved with oral administration, and IV administration is necessary only if oral

. d b ·1 11 12 M 'd treatment is prevente y i eus. ' etrom a-zole was used IV in some horses in this study, when the need for antianaerobic bacterial treatment was determined during surgery (eg, enterotomy), or when postoperative ileus prevented its use by the oral route. Although metronidazole is well ab­sorbed when administered per rectum to human

JAVMA, Vol 198, No. 6, March 15, 1991

patients, i6 the bioavailability of this drug when ad­ministered per rectum to the horse is not known. Posttreatment serum concentration of metronida­zole was not obtained in the horses in this study. Adverse effects following administration per rec­tum were not observed.

In a review of pleuropneumonia, 1 anaerobic bacterial infections were confirmed in 21 of 46 horses (45.7%) from which specimens wer~ s1:1b­mitted for anaerobic bacteriologic culture, similar to the prevalence in the cases reported here (47.3%). A group of horses not treated with met­ronidazole was not available for comparison of clinical outcome in this report. However, in the reviewl of horses with pleuropneumonia (not treated withmetronidazole), 7 of21 horses (33.3%) with positive anaerobic bacterial culture results survived, compared with 18 of 36 (50%) in our study. Although improved survival may be in part attributable to improved antianaerobic bacterial treatment with metronidazole, other improvements in patient care might have affected survival rates. Even with metronidazole, the surtjval rate for horses with a positive anaerobic bacterial culture result (50%) was less than that for horses with a negative result (90%).

Complications or adverse effects attributable to metronidazole treatment in horses are appar­ently rare. Gastrointestinal side effects, in particu­lar nausea and vomiting, develop in 5 to 10% of human patients treated with metronidazole. 7 Ap­petite suppression was apparent in 4 .of t?e 200 horses (2%) in this report. Other comphcanons ~e­ported in people include dark urine, rash, ~nd with prolonged or high-dose treatment, convulsi~ns and peripheral neuropathy. 7 Acute CNS dy~funcnon h~s been reported in dogs treated with metrom­dazole.11 Comparable adverse effects were not ob­served in these horses. Postanesthetic hindlimb paralysis in 2 horses treated ~th api:roxima~e~y 3 mg of metronidazole/kg by mtrapentoneal mJeC­tion at the time of celiotomy14 may have been as­sociated with anesthesia and recumbency. Several horses in this study were medicated with higher doses while under anesthesia, with no adverse ef­fects.

Metronidazole has been used with few adverse effects in 200 horses with various conditions. Pro­longed duration of treatment (up to 21_7 d~ys) a~d treatment with metronidazole in combmanon with other antimicrobials (especially penicillin, genta­micin, and trimethoprim-sulfa) caused no apparent adverse effects. We believe that the survival rate for horses with anaerobic infections, particularly anaerobic pleuropneumonia, has improved since the usage of metronidazole was instituted in our hospital.

References 1. Sweeney CR, Divers TJ, Benson CE. Anaerobic bacteria

in 21 horses with pleuropneumonia. ] Am Vet Med Assoc 1985;187:721-724.

Reports of Retrospective Studies 104 7

2. Hirsh DC, "Biberstein EL, Jang SS. Obligate anaerobes in clinical veterinary practice.] Clin Microbial 1979;10:188-191.

3. Reimer JM, Reef VB, Spenser PA. Ultrasonography as a diagnostic aid in horses with anaerobic bacterial pleuropneu­monia and/or pulmonary abscessation: 27 cases (1984-1986). ] Am Vet Med Assoc 1989;194:278-282.

4. Rosenblatt JE, Stewart PR. Lack of activity of sul­famethoxazole and trimethoprim against anaerobic bacteria. Antimicrob Agents Chemother 1974;6:93-97.

5. Collignon PJ, Munro R, Morris G, Susceptibility of anaerobic bacteria to antimicrobial agents. Pathology 1988;20: 48-52.

6. Aldridge KE, Henderberg A, Schiro DD, et al. Suscep­tibility of Bacteroides fragilis group isolates to broad-spectrum beta-lactams, clindamycin, and metronidazole: rates of resis­tance, cross-resistance, and importance ofbeta-lactamase pro­duction. Adv Ther 1988;5:273-282.

7. Scully BE. Metronidazole. Med Clin North Am 1988;72:613-621.

8. Wilkens TD, West SEH. Therapy of anaerobic infec­tions. Infection l 983;1 l:Sl05-Sl08.

9. Willis AT, Mee WM, Ferguson IR, et al. Metronidazole in the prevention and treatment of Bacteroides infections in sur­gical patients, in Proceedings. Int Metronidazole Conf l 976;377-384.

10. Eykyn S, Phillips I. Intravenous metronidazole in the treatment of anaerobic sepsis, in Proceedings. Int Metronidazole Conf 1976;393-403.

11. Sweeney RW, Sweeney CR, Soma LR, et al. Pharma­cokinetics of metronidazole given to horses by intravenous and oral routes. Am] Vet Res 1986;47:1726-1729.

12. Baggot JD, Wilson WD, Hietala S. Clinical pharma­cokinetics of metronidazole in horses. ] Vet Pharmaco1 Ther 1988; 11:417-420.

13. Kirkpatrick CE, Skand DI:. Giardiasis in a horse.] Am Vet Med Assoc 1985;187:163-164.

14. Owen Rh ap Rh, Jagger DW, Quan-Taylor, R. Possi­ble adverse reaction to metronidazole in the horse (letter). Vet Rec 1985;117:534.

15. Leannette EH, BalowsA, HauslerWJ, et al. Manual of clinical microbiology. 4th ed. Washington, DC: American So­ciety for Microbiology, l 985;413-4 33.

16. Ioannides L, Somogyi A, Spicer J, et al. Rectal admin­istration of metronidazole provides therapeutic plasma levels in postoperative patients. N Engl] Med 1981;305:1569-1570.

17. Dow SW, LeCouteur RA, Poss Ml, et al. Central ner­vous system toxicosis associated with metronidazole treatment of dogs; five cases (1984-1987).] Am Vet Med Assoc 1989; 195: 365-368.

New Veterinary Biological Products

Product name

Haemophilus somnus-Pasteurella haemolytica-multocida-salmonella typhimurium bacterin, (Texas Vet Lab, Inc, San Angelo, TX 76903)

Species and indications for use

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Route of administration

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1048 Reports of Retrospective Studies JAVMA, Vol 198, No. 6, March 15, 1991