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Single-dose pharmacokinetics of orally administered metronidazole and intravenously administered imipenem in healthy horses and computer-based simulation of pleural fluid concentrations with multiple dosing

Taisuke Kuroda DVM, PhD1, Shun-ichi Nagata DVM, PhD2, Norihisa Tamura DVM, PhD1, Yuta Kinoshita DVM, PhD1, Hidekazu Niwa DVM, PhD1, Hiroshi Mita DVM1, Takuto Minami DVM, PhD3, Kentaro Fukuda DVM1, Seiji Hobo DVM, PhD4, and Atsutoshi Kuwano DVM, PhD1
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  • 1 1Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi 329-0412, Japan.
  • | 2 2Laboratory of Racing Chemistry, Tochigi 320-0856, Japan.
  • | 3 3Equine Hospital, Ritto Training Center, Japan Racing Association, Ritto-shi, Shiga 520-3085, Japan.
  • | 4 4Department of Domestic Animal Internal Medicine, Clinical Veterinary Science, Veterinary Medicine, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan

Abstract

OBJECTIVE

To determine plasma pharmacokinetics of metronidazole and imipenem following administration of a single dose PO (metronidazole, 15 mg/kg) or IV (imipenem, 10 mg/kg) in healthy Thoroughbreds and simulate pleural fluid concentrations following multiple dose administration every 8 hours.

ANIMALS

4 healthy Thoroughbreds.

PROCEDURES

Metronidazole and imipenem were administered, and samples of plasma and pleural fluid were collected at predetermined time points. Minimum concentrations of metronidazole and imipenem that inhibited growth of 90% of isolates (MIC90), including 22 clinical Bacteroides isolates from horses with pleuropneumonia, were calculated. For the computer simulation, the target ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was > 70, and the target percentage of time per day that the pleural fluid concentration of imipenem exceeded the MIC90 was > 50%.

RESULTS

Mean ± SD pleural fluid concentrations of metronidazole and imipenem were 12.7 ± 3.3 μg/mL and 12.1 ± 0.9 μg/mL, respectively, 1 hour after administration and 4.9 ± 0.85 μg/mL and 0.3 ± 0.08 μg/mL, respectively, 8 hours after administration. For both antimicrobials, concentrations in the pleural fluid and plasma were similar. The ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was 84.9, and the percentage of time per day the pleural fluid concentration of imipenem exceeded the MIC90 was 70.9%.

CONCLUSIONS AND CLINICAL RELEVANCE

Results suggested that administration of metronidazole (15 mg/kg, PO, q 8 h) or imipenem (10 mg/kg, IV, q 8 h) resulted in their accumulation in the pleural fluid in healthy horses and concentrations were likely to be effective for the treatment of pneumonia and pleuropneumonia caused by Bacteroides spp.

Abstract

OBJECTIVE

To determine plasma pharmacokinetics of metronidazole and imipenem following administration of a single dose PO (metronidazole, 15 mg/kg) or IV (imipenem, 10 mg/kg) in healthy Thoroughbreds and simulate pleural fluid concentrations following multiple dose administration every 8 hours.

ANIMALS

4 healthy Thoroughbreds.

PROCEDURES

Metronidazole and imipenem were administered, and samples of plasma and pleural fluid were collected at predetermined time points. Minimum concentrations of metronidazole and imipenem that inhibited growth of 90% of isolates (MIC90), including 22 clinical Bacteroides isolates from horses with pleuropneumonia, were calculated. For the computer simulation, the target ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was > 70, and the target percentage of time per day that the pleural fluid concentration of imipenem exceeded the MIC90 was > 50%.

RESULTS

Mean ± SD pleural fluid concentrations of metronidazole and imipenem were 12.7 ± 3.3 μg/mL and 12.1 ± 0.9 μg/mL, respectively, 1 hour after administration and 4.9 ± 0.85 μg/mL and 0.3 ± 0.08 μg/mL, respectively, 8 hours after administration. For both antimicrobials, concentrations in the pleural fluid and plasma were similar. The ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was 84.9, and the percentage of time per day the pleural fluid concentration of imipenem exceeded the MIC90 was 70.9%.

CONCLUSIONS AND CLINICAL RELEVANCE

Results suggested that administration of metronidazole (15 mg/kg, PO, q 8 h) or imipenem (10 mg/kg, IV, q 8 h) resulted in their accumulation in the pleural fluid in healthy horses and concentrations were likely to be effective for the treatment of pneumonia and pleuropneumonia caused by Bacteroides spp.

Contributor Notes

Address correspondence to Dr. Kuroda (taisuke.kuroda@equinst.go.jp).