Abstract
Rifampin is an enigma among antimicrobials. Blood and tissue compartment concentrations are a "moving target" along the treatment course due to the complex pharmacodynamic interactions within the body. Rifampin concomitant therapies are for the prevention and treatment of Rhodococcus equi infection in foals, for nearly 40 years. The necessity of rifampin concomitant therapies is based on beliefs that both antimicrobials (e.g., rifampin plus macrolide) penetrate into pulmonary abscesses and intracellular compartments above R. equi minimum inhibitory concentrations (MICs), as well as better efficacy, compared with other approaches, and limiting the rate of antimicrobial resistance to either single agent. However, rifampin acts as a perpetrator drug for many co-administered drugs. This critical review evaluates the available evidence for rifampin use in foals with R. equi , concerning pharmacokinetic/pharmacodynamic characteristics of rifampin in foals, in vitro microbiological studies and selection of antimicrobial resistance, as well as an analysis of randomized clinical trials. Rifampin is a nuclear pregnane X receptor activator, which results in strong negative drug interactions towards itself and other drugs, for drug-absorption routes either by upregulation of presystemic elimination mechanisms (e.g., intestinal and hepatic CYP3A4), or functional drug-absorption carriers (e.g., intestinal P-glycoprotein) and/or inhibition of intestinal and/or hepatic drug-uptake carriers (e.g., OATP1B1, OATP2B1, MRP2). Chronic rifampin administration results in decreases in the serum and target site/s concentrations of many parent drugs, including itself. Rifampin concomitant therapies do not demonstrate a significant advantage over monotherapy with macrolides, in randomized controlled blinded and double-blinded clinical trials for subclinical, and mild-to-moderate bronchopneumonia in foals with pulmonary abscesses, regardless of initial pulmonary abscess score. Efficacy of rifampin concomitant therapies for severe Rhodococcus equi pneumonia has not been fully investigated, but there is sufficient accumulated evidence in foals to raise major concerns about the incorrect use of rifampin in equine medicine. These concerns include rifampin as a bacteriostatic antibiotic against R. equi , with changing pharmacokinetics during treatment that decreases parent/coparent concentrations as well as the risk of selecting for multi-resistant R. equi .