Is Rifampin (Rifampicin) Essential for the Treatment of Rhodococcus equi Infections in Foals? A Critical Review of the Role of Rifampin

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 .

Keywords: Rhodococcus; foals; horses; macrolides; rifampicin; rifampin.

FIGURE 1

Diagram showing the complex interactions between rifampin and major classes of drug‐transporting proteins and drug metabolizing enzymes (cytochrome P450 enzymes). Rifampin is a prototype ligand for the nuclear pregnane X receptor (PXR) that complexes with retinoid X receptor (RXR) and in turn regulates multidrug transport proteins, both efflux carriers () and drug‐uptake carriers () found primarily in drug‐eliminating organs, including the kidney, liver, brain, intestinal lumen, testes, adrenal gland, pregnant uterus, tumour cells, and epithelial cells. CYPs, cytochrome P450 enzymes; MRPs, multidrug resistance‐associated proteins; OATPs, organic anion‐transporting polypeptides; OCTs, organic cation transporter; PELF, pulmonary epithelial lining fluid; P‐gp, P‐glycoproteins.

FIGURE 2

Forest plot of blinded and double‐blinded randomized clinical trials investigating treatment for subclinical, mild‐to‐moderate bronchopneumonia, in endemic Rhodococccus equi facilities, sorted in ascending order of the mean abscess score (cm) in the placebo (control) group. Each clinical trial is represented by a separate line (Treatment, reference), including the number of foals in each group and a visual representation of the relative risk estimate (solid black square) and 95% confidence intervals (horizontal bars on either side of the solid black squares). Random‐effects meta‐regression model of overall Risk Ratio (relative risk) predictions represented as black diamonds, including 95% confidence intervals. Horizontal dotted line represents the division between monotherapy and combination therapy clinical trials. Vertical dotted line represents the “no‐effect” level of the relative risk estimates (i.e., no clinical difference between treatment and placebo group). Azi, azithromycin; Doxy, doxycycline; fail, number of foals not recovered, and required to change antimicrobial treatment; Recov, number of foals successfully recovered without the need to change antimicrobial treatment; Rifa, rifampin.

FIGURE 3

Plot of absolute risk difference versus the mean abscess score (cm) from the placebo (control) group, calculated from blinded and double‐blinded randomized clinical trials investigating treatment for subclinical, mild‐to‐moderate bronchopneumonia, in endemic Rhodococcus equi facilities. Size of the circles reflects the sample size of the randomized clinical trial (see the legend). Horizontal dotted line represents the “no‐effect” level of the absolute risk difference (i.e., no clinical difference between treatment and placebo group). Below the dotted line shows better drug treatment efficacy relative to placebo.