This study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistant Staphylococcus aureus (MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.
BC-3781 is a novel semisynthetic pleuromutilin antibiotic inhibiting bacterial protein synthesis. BC-3781 has completed a phase 2 clinical trial in acute bacterial skin and skin structure infections (ABSSSI). Its antibacterial spectrum additionally covers the predominant pathogens causing community-acquired bacterial pneumonia (CABP). In this study, the antibacterial activity of BC-3781 was evaluated against a contemporary collection of 10,035 bacterial isolates predominately causing ABSSSI and CABP, among other infections, collected within the SENTRY Antimicrobial Surveillance Program worldwide in 2010. BC-3781 exhibited potent activity against organisms commonly isolated from ABSSSI such as Staphylococcus aureus (MIC 50/90 , 0.12/0.12 g/ ml; 99.8% inhibited at <0.5 g/ml), beta-hemolytic streptococci (MIC 50/90 , 0.03/0.03 g/ml; 99.3% inhibited at <0.5 g/ml), and coagulase-negative staphylococci (CoNS; MIC 50/90 , 0.06/0.12 g/ml; 97.8% inhibited at <1 g/ml). BC-3781 displayed similar MIC distributions among methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) S. aureus strains. BC-3781 was also active against Enterococcus faecium, with 76.3% of vancomycin-susceptible and 97.0% of vancomycin-resistant isolates being inhibited at BC-3781 concentrations of <1 g/ml. Beta-hemolytic and viridans group streptococci were highly susceptible to BC-3781, with 99.3% and 96.7% of isolates inhibited at <0.5 g/ml, respectively. Further, activity of BC-3781 against Streptococcus pneumoniae (MIC 50/90 , 0.12/0.25 g/ml), Haemophilus influenzae (MIC 50/90 , 1/2 g/ml), and Moraxella catarrhalis (MIC 50/90 , 0.12/0.25 g/ml) was not negatively influenced by -lactamase production or resistance to other antimicrobial classes tested. In all, BC-3781 displayed a very potent antibacterial profile including the most prevalent bacterial pathogens causing ABSSSI and CABP, thus warranting further clinical development of this antibiotic in these and possibly other indications.
BC-3781 was very active against organisms commonly associated with CARTIs and its activity was not negatively influenced by resistance to other antimicrobials.
Lefamulin was evaluated against various Streptococcus pneumoniae serotypes that were collected from adults with lower respiratory tract infections. Lefamulin exhibited MIC 50 and MIC 90 values of 0.12 and 0.25 g/ml, respectively, against the entire collection (n ؍ 822). Similar results were obtained for lefamulin against each of the most common serotypes as well as against multidrug-resistant isolates and strains that are nonsusceptible to ceftriaxone or erythromycin. These data support the clinical development of lefamulin for the treatment of community-acquired respiratory tract infections.
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