In vitro activity of ceftolozane/tazobactam in combination with other classes of antibacterial agents.

OBJECTIVES: Combination antibiotic therapy has been used successfully to treat some patients with bacterial infections. However, although certain combinations may result in beneficial synergistic activity, others may produce antagonistic effects resulting in poor treatment outcomes. Ceftolozane/tazobactam is an antibacterial agent with potent activity against Pseudomonas aeruginosa and many other Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. This study aimed to evaluate potential synergistic or antagonistic interactions between ceftolozane/tazobactam and a selection of antibacterial agents. METHODS: Chequerboard analyses were conducted with Escherichia coli, Klebsiella pneumoniae and P. aeruginosa isolates. RESULTS: Combinations of ceftolozane/tazobactam with aztreonam, amikacin, tigecycline and meropenem resulted in synergistic effects in some of the bacterial strains tested. The potency of ceftolozane/tazobactam against common Gram-negative pathogens was not compromised in the presence of other commonly prescribed antibacterial agents, and ceftolozane/tazobactam did not antagonise the activity of these other antibacterials. CONCLUSIONS: The synergy observed for some antibacterial combinations in this study supplements the currently available information for combination therapy and may suggest new directions for treating challenging cases. Some synergistic effects may be attributed, at least in part, to the ESBL-inhibitory activity of tazobactam, although this remains to be proven. The mechanisms of the other synergistic interactions observed also require further elucidation. Ceftolozane/tazobactam did not adversely affect the activity of, and was not affected by, other antibacterial agents given concurrently. In vivo studies will be needed to substantiate these results and to determine their clinical relevance.

Structure-Activity Relationship Studies of a Series of Semisynthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridium difficile-Associated Diarrhea.

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 µg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

Reduced pulmonary surfactant interaction of daptomycin analogs via tryptophan replacement with alternative amino acids.

Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids.

In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile.

CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence.