Safety and Efficacy of a New Formulation of Trimethoprim Sulfadiazine in Horses

A novel proprietary oral suspension of trimethoprim/sulfadiazine underwent safety and efficacy studies for an FDA new animal drug approval. The antimicrobial had no serious adverse effects on clinical, laboratory, or pathologic parameters of mature horses when administered at up to five times the intended combined dosage of 24 mg/kg twice daily for 30 consecutive days. Horses with lower respiratory tract infections caused by Streptocccus equi subsp. zoopidemicus were treated with combined trimethoprim/ sulfadiazine (TMP/SDZ) oral suspension at a dosage of 24 mg/kg q 12 h for 10 days. The TMP/SDZ suspension effectively treated the clinical signs of respiratory infection and elimination of the organism from the respiratory tract. Authors’ addresses: Iowa State University, College of Veterinary Medicine, 1600 S. 16th Street, Ames, IA 50011-1250 (McClure); East Tennessee Clinical Research, Inc., 80 Copper Ridge Road, Rockwood, TN 37854 (Reinemeyer); Biotechnical Services Inc., 4610 West Commercial Drive, North Little Rock, AK 72116 (Koenig); and Aurora Pharmaceuticals, 1196 Hwy. 3 South, Northfield, MI 55057 (Hawkins); e-mail: mcclures@iastate.edu.

1. Introduction

Potentiated sulfonamides combine sulfa with a diaminopyrimidine, utilizing the synergistic mechanisms of action of these drugs. Trimethoprim and sulfadiazine both function as bacteriostatic antimicrobials by interfering with folate metabolism in bacteria. The two antimicrobials function synergistically to inhibit bacterial DNA synthesis, reducing the potential for the development of antimicrobial resistance compared to either drug used alone. Potentiated sulfonamides are routinely used in equine practice for broad spectrum antibiotic therapy, particularly in the treatment of lower respiratory tract infections. This drug combination is popular because it can be administered orally.

Although paste formulations approved for horses are labeled for once daily administration at 30 mg/kg body weight, pharmacokinetic data for the potentiated sulfonamides suggest that twice daily dosing is more appropriate to maintain therapeutic plasma levels above the minimum inhibitory concentration (MIC). A combined study of field effectiveness and pharmacokinetics conducted in 26 horses with lower respiratory disease determined that the time-concentration profile of sulfadiazine in horses did not demonstrate linearity with increasing dosage. Increased dosages of the potentiated sulfa did not result in a significantly greater t > MIC for either active moiety, particularly for sulfadiazine, where the plasma C_max was actually lower for the higher dose regimen. The 30 mg/kg q 12 h dosing regimen had no clinical advantage over 24 mg/kg q 12 h and the latter was associated with fewer incidents of antibiotic-associated loose feces. 

Based on this information, a proprietary oral suspension formulation of trimethoprim plus sulfadiazine (TMP/SDZ) has been developed, with label recommendations for dosing at 24 mg/kg body weight twice daily for 10 consecutive days. Because the formulation was different than those previously approved, the FDA requested a New Animal Drug Application. Two separate studies as part of this application are presented here. A controlled clinical study to determine the margin of safety of the suspension at dosages of 1x, 3x, and 5x the label recommendation, administered for 30 days (three times the recommended duration), and a broad field trial on the clinical efficacy of the anti-microbial on Streptocccus equi subsp. Zoopidemicus bronchopneumonia.

2. Safety Study

Objective

To evaluate the safety of a novel trimethoprim/sulfadiazine oral suspension in horses up to 5X the normal dose for 30 days.

Design

Blinded, randomized, controlled margin of safety study.

Animals

Thirty-two healthy horses.

Procedures

Dose multiples of 0x, 1x, 3x, or 5x the recommended dosage of 24 mg/kg bwt were administered at 12-hour intervals for a total of 30 days; three times the recommended treatment duration of 10 days. Daily health observations and fecal consistency was scored. Clinicopathologic data were obtained pretreatment and on days 6, 13, 20, and 29. At the completion of the 30-day period, complete necropsies were performed.

Results

Loose feces was the most common observation that was likely related to TMP/SDZ treatment. The incidence of loose feces was greater in groups treated with higher dosages of TMP/SDZ. All episodes were self-limiting and no horses were treated for diarrhea. Significant differences between the TMP/SDZ-treated animals and the control group were observed for albumin, creatinine, and gamma-glutamyl transferase (GGT) concentrations. These changes did not exhibit a correlation to dosage and none were considered clinically significant. All gross pathologic observations noted during necropsy were considered to represent normal biological variation, or were related to conditions existing prior to treatment, primarily to parasitic activity.

Conclusions and Clinical Relevance

No serious adverse effects on the clinical, laboratory, or pathologic parameters of mature horses were found when administered at up to five times the intended combined dosage of 24 mg/kg twice daily for 30 consecutive days.

2. Efficacy Study

Objective

To evaluate the effectiveness of a novel trimethoprim and sulfadiazine oral suspension in the treatment of naturally acquired Streptococcus equi subsp. zooepidemicus (Strep. zoo.) related pneumonia in horses under field use conditions.

Design

A randomized blinded placebo controlled field efficacy study.

Animals

Two hundred seventy horses that met inclusion criteria from 5 different sites.

Procedures

Horses with lower respiratory tract infections caused by Streptococcus equi subsp. zooepidemicus were treated with a novel formulation of combined trimethoprim/sulfadiazine oral suspension at a dosage of 24 mg/kg twice a day for 10 days.

Results

Of the 119 horses receiving treatment, 58% (69/119) were considered successes, compared to only 15% (9/61) of the saline control horses. Many of the failures were apparent by day 5 with 41% (25/61) of the control horses failing at day 5 compared to only 7.6% (9/119) of treated horses. By day 10, 46% (28/61) of the control horses had met the failure criteria compared to only 9.2% (11/119) of the treated horses. There were no adverse events associated with the TMP/SMZ administration. The fecal consistency scores assessed twice daily throughout the study period showed no significant differences between treatment groups.

Conclusions and Clinical Relevance

Improved bioavailability allows a 20% lower dose than previously published. The novel TMP/SDZ suspension effectively treated the clinical signs of respiratory infection and eliminated the organism from the respiratory tract.

Acknowledgments

Conflict of Interest

These studies were funded by Aurora Pharmaceuticals LLC, Northfield, MN. Dr. Scott McClure served as a paid investigator in the broad field trial. Dr. Craig Reinemeyer served as a paid investigator in the safety studies. Dr. Robbin Koenig served as a paid employee of Biotechnical Services Incorporated to facilitate FDA submission. [...]