rifampin and gamithromycin

Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative.. To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro.. Controlled, four-period, consecutive, single-dose and multiple-dose study.. Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4β-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1.. Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 μg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 μg × h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin.. Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated.. The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Biomarkers; Dogs; Drug Administration Schedule; Drug Interactions; Female; Half-Life; Horses; Macrolides; Madin Darby Canine Kidney Cells; Male; Rifampin

Gamithromycin is active in vitro against the bacterial agents most commonly associated with bronchopneumonia in older foals. However, the clinical efficacy and safety of this drug have not been investigated.. Gamithromycin is effective for the treatment of bronchopneumonia in foals.. One hundred and twenty-one foals on a farm endemic for infections caused by Rhodococcus equi.. In a controlled, randomized, and double blinded clinical trial, foals with ultrasonographic evidence of pulmonary abscesses (abscess score 8.0-20 cm) were randomly allocated in 3 treatment groups: (1) gamithromycin IM q7 days (n = 40); (2) azithromycin with rifampin, PO q24h (n = 40); or (3) no antimicrobial treatment (controls; n = 41). Physical examination and thoracic ultrasonography were performed by individuals unaware of treatment group assignment. Foals that worsened were removed from the study.. The proportion of foals that recovered without the need to be removed from the study was significantly higher for foals treated with gamithromycin (38 of 40) or azithromycin with rifampin (39 of 40) than for controls (32 of 41). Treatment with gamithromycin or with azithromycin-rifampin resulted in a significantly faster decrease in the clinical score and abscess score compared to the controls. Adverse reactions characterized by colic (n = 18) and hind limb lameness (n = 14) were observed only in foals treated with gamithromycin.. Gamithromycin was noninferior to azithromycin with rifampin for the treatment of bronchopneumonia in the study population but had a higher frequency of adverse reactions.

Topics: Abscess; Actinomycetales Infections; Animals; Anti-Bacterial Agents; Azithromycin; Bronchopneumonia; Double-Blind Method; Drug Therapy, Combination; Female; Horse Diseases; Horses; Macrolides; Male; Rhodococcus equi; Rifampin

Rhodococcus equi is responsible for foal pneumonia worldwide, with a significant economic impact on the production and breeding of horses. In Chile, the first case was reported in 2000, and since then, its incidence has been increasing. Distinctive characteristics of R. equi as an intracellular pathogen in macrophages, emergence of virulence plasmids encoding surface lipoprotein antigens, and appearance of antibiotic resistance against macrolides and rifampicin have significantly complicated the treatment of R. equi pneumonia in foals. Therefore, in vitro susceptibility studies of first-line and newer antibiotics against R. equi are the first step to establishing effective treatments and optimizing new therapeutic options. The aim of the present study is to determine the susceptibility profile of fourteen strains of R. equi isolated from foals in Chile to several antibiotics of the macrolide group including azithromycin, amikacin, tildipirosin and gamithromycin as well as others such as rifampicin, doxycycline and ceftiofur. Identification of R. equi in collected isolates from foals in Chile has been performed by CAMP test and PCR based on detecting of the gene encoding the 16 S rRNA. The presence of genes encoding virulence plasmids was also determined using PCR. Results obtained have demonstrated presence of virulent R. equi strains in Chile. In vitro susceptibility pattern to different antibiotics has shown better results for doxycycline and rifampicin similar to previous studies performed. Current macrolides have been evaluated in order to consider alternative treatment options in a context of emerging resistance to classic macrolides and rifampicin, obtaining better results with gamithromycin (MIC range of 0.125 to 128 mg/ml) than with tildipirosin (MIC range of 16 to 128 mg/ml). An adequate diagnosis of bacterial susceptibility based on antibiograms is necessary to treat the Rhodococcus equi infection in foals.

Topics: Animals; Anti-Bacterial Agents; Chile; Doxycycline; Horses; Macrolides; Rhodococcus equi; Rifampin