Novel Use of Rifabutin and Rifapentine to Treat Methicillin-Resistant Staphylococcus aureus in a Rat Model of Foreign Body Osteomyelitis

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Due to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection (PJI). Here, we evaluated rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a K-wire implanted in each. After four weeks of infection, rifampin, rifabutin, or rifapentine were administered alone or with vancomycin. Tibiae and K-wires were cultured and medians reported as log10 cfu/gram of bone or log10 cfu/K-wire, respectively.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Rifampin, rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02 and 0.10 log10 cfu/gram, respectively) than did no treatment (4.36 log10 cfu/gram) (p≤0.0198) or vancomycin alone (4.64 log10 cfu/gram) (p≤0.0235). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 cfu/gram of K-wire, respectively. In contrast, rifampin, rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 cfu/K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal PJIs.</jats:p> </jats:sec>

Activity of Omadacycline in Rat Methicillin-Resistant Staphylococcus aureus Osteomyelitis

“…Addition of rifampin is recommended in some scenarios due to its activity against staphylococcal biofilms (41,42) and intracellular staphylococci (42), and ability to penetrate bone tissue (43). We have shown in multiple studies that rifampin is active in orthopedic MRSA rat models; however, we have observed several instances of selection of rifampin resistance with rifampin monotherapy (25,29,30), including three animals in the current study. The rate of reported rifampin resistance varies from study to study, both in our work and in the literature, varying with rifampin dose and model type.…”

“…A vancomycin AUC/MIC ratio between 400 and 600 is recommended for humans ( 26 ); with a MIC of 1 μg/ml, the vancomycin AUC/MIC was 368, slightly lower than this goal range. However, higher doses in rats have been shown to cause toxicity ( 27 ).…”

“…The strain studied in vivo is a clinical MRSA isolate (IDRL-6169) that was isolated from a periprosthetic hip infection at Mayo Clinic (Rochester, MN) and has been shown to produce infection in previous osteomyelitis studies ( 24 , 27 , 33 , 35 – 39 ). Susceptibility testing was performed with omadacycline (Paratek Pharmaceuticals, Inc., Boston, MA), vancomycin (Sigma-Aldrich, St. Louis, MO), and rifampin (Sigma-Aldrich), as follows.…”

In Vitro Activity of Rifampin, Rifabutin, and Rifapentine against Enterococci and Streptococci from Periprosthetic Joint Infection

“…Rifampin is an antibiotic with antibiofilm activity used in the management of staphylococcal periprosthetic joint infection (PJI) with irrigation and debridement with component retention (IDCR) ( 1 , 2 ); some patients are unable to receive rifampin due to drug interactions or intolerance. We recently showed that rifabutin and rifapentine, which have more favorable drug interaction/side effect profiles than rifampin, have in vitro activity against planktonic and biofilm states of rifampin-susceptible PJI-associated staphylococci ( 3 ), and that these rifamycins are as active as rifampin in combination therapy regimens in experimental rat Staphylococcus aureus foreign body osteomyelitis ( 4 ). After staphylococci, streptococci and enterococci combined are the most common causes of PJI, accounting for up to 20% of cases ( 5 – 8 ).…”

A Case Series of Rifabutin Use in Staphylococcal Prosthetic Infections

“…Rifampin exhibits potent induction of multiple cytochrome P450 (CYP450) enzymes and P-glycoprotein (P-gp) transport system proteins, which causes interactions with commonly prescribed medications that may warrant dose adjustment or switch to another therapeutic agent altogether during concomitant rifampin therapy ( 6 , 8 ). Rifabutin, though used less commonly than rifampin in clinical settings, is another rifamycin that exhibits potent in vitro antistaphylococcal activity as well as fewer CYP450 enzyme interactions and no induction of P-gp proteins ( 5 , 6 , 9 ). Recently, Tuloup et al studied a model-based analysis comparing rifampin and rifabutin drug-drug interaction profiles and concluded that interactions caused by rifampin were twice as potent as those caused by rifabutin ( 10 ).…”