Efficacy of a novel rifamycin derivative, ABI-0043, against Staphylococcus aureus in an experimental model of foreign-body infection

Abstract

We compared the efficacy of a novel rifamycin derivative, ABI-0043, with that of rifampin, alone and in combination with levofloxacin, against methicillin-susceptible Staphylococcus aureus ATCC 29213 in a guinea pig tissue-cage infection model. The MIC, logarithmic-growth-phase minimal bactericidal concentration, and stationary-growth-phase minimal bactericidal concentration of ABI-0043 were 0.001, 0.008, and 0.25 microg/ml, respectively; the corresponding concentrations of rifampin were 0.016, 0.8, and 3.6 microg/ml, respectively. After a single intraperitoneal dose of 12.5 mg/kg of body weight, the peak concentration in cage fluid was 1.13 micarog/ml of ABI-0043 and 0.98 microg/ml of rifampin. Five days after completion of treatment, levofloxacin administered alone (5 mg/kg/12 h) resulted in bacterial counts in cage fluid that were similar to those for untreated controls (>8.0 log(10) CFU/ml), whereas rifampin and ABI-0043 administered alone (12.5 mg/kg/12 h) decreased the mean titers of bacteria +/- standard deviations to 1.43 +/- 0.28 log(10) and 1.57 +/- 0.53 log(10) CFU/ml, respectively, in cage fluid. In combination with levofloxacin, both rifamycins cleared bacteria from the cage fluid. The cure rates of cage-associated infections with rifampin and ABI-0043 administered alone were 46% and 58%, respectively, and increased to 88% and 92% in combination with levofloxacin. Emergence of rifamycin resistance was observed in 42% of cages after ABI-0043 therapy and in 38% of cages after rifampin therapy; no emergence of resistance occurred with combination treatment with levofloxacin. In conclusion, ABI-0043 had cure rates comparable to that of rifampin. ABI-0043 in combination with a quinolone has the potential for treatment of implant-associated infections caused by susceptible strains of S. aureus, potentially without drug-drug interactions.

FIG. 1.

Chemical structure of rifampin and its derivative compound ABI-0043.

FIG. 2.

Pharmacokinetics in cage fluid after a single intraperitoneal dose (12.5 mg/kg) of rifampin (▪) and ABI-0043 (▴). Values are means ± standard deviations (n = 6). Horizontal lines indicate the corresponding MBC_log and MBC_stat values for S. aureus with rifampin (Rif) and ABI-0043 (ABI).

FIG. 3.

Treatment efficacy with different antimicrobial regimens. (A) Mean log₁₀ CFU/ml S. aureus in aspirated cage fluid during (day 4) and after treatment (day 9). (B) Cure rates of cage-associated infection determined by the fraction of explanted cages without growth of S. aureus in TSB. In both panels, numbers above the bars represent the numbers of culture-negative cage specimens/total numbers of cage fluid specimens. SD, standard deviation; LVX, levofloxacin; RIF, rifampin; ABI, ABI-0043; NS, not significant.