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.

Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies.

This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly. Overall, additive or indifferent effects with daptomycin combinations were observed; however, synergy was observed for certain isolates of vancomycin-resistant enterococci when exposed to daptomycin and rifampicin. Unexpected synergy was demonstrated against methicillin-resistant Staphylococcus aureus by daptomycin and beta-lactams. Most importantly, no in vitro antagonism of daptomycin with any other agent tested was confirmed in these studies. The most striking in vivo effects were noted in two different complicated infection models; i.e. osteomyelitis and implant infections, where rifampicin combinations with daptomycin increased efficacy and reduced the incidence of rifampicin resistance.

Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia.

OBJECTIVE: We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). METHODS: Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. RESULTS: After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, -13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%). CONCLUSIONS: Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

Detection of daptomycin-nonsusceptible strains using the Neo-Sensitab prediffusion method.

Two prediffusion methods with daptomycin (DAP) Neo-Sensitabs were evaluated against a challenge set of 30 Staphylococcus aureus isolates and 30 enterococci. DAP Neo-Sensitabs were prediffused for either 8 or 20 h on Mueller-Hinton agar. Inhibition zones were plotted versus Etest MIC values determined on the same prediffused agar. A generalization to the genus level of the manufacturer's suggested Neo-Sensitabs breakpoints for staphylococci and enterococci was used to interpret the results. DAP-susceptible and DAP-nonsusceptible enterococci, Enterococcus faecium in particular, were not reliably discriminated using a 20-h prediffusion method and the manufacturer's suggested breakpoints. Further development of this testing methodology, such as changing the format to a susceptibility screen followed by a confirmatory MIC, is needed to accurately categorize the DAP susceptibility of enterococcal isolates. Prediffusion for either 8 or 20 h with DAP Neo-Sensitabs discriminated between susceptible and nonsusceptible S. aureus with minimal errors. Both prediffusion methods also detected changes in MIC values between isogenic pairs of susceptible and nonsusceptible S. aureus. These results suggest that a multisite evaluation of either prediffusion method with DAP Neo-Sensitabs against a larger collection of S. aureus is warranted.

In vitro activity of daptomycin against multidrug-resistant Staphylococcus aureus and S. aureus with known virulence factors, including community-acquired methicillin-resistant isolates.

The in vitro activity of daptomycin was evaluated against 360 multidrug-resistant Staphylococcus aureus isolates (including hospital-acquired isolates) and multidrug-susceptible community-acquired methicillin-resistant S. aureus with known virulence genes. All isolates were inhibited at

In vitro activity of daptomycin against clinical isolates with reduced susceptibilities to linezolid and quinupristin/dalfopristin.

An initiative was taken to determine the in vitro activity of daptomycin against 85 Gram-positive isolates with reduced susceptibilities to linezolid and quinupristin/dalfopristin. Daptomycin had potent activity against all strains, with a Staphylococcus spp. minimum inhibitory concentration (MIC) < or =2 microg/mL and an Enterococcus spp. MIC < or =8 microg/mL. Resistance to linezolid and quinupristin/dalfopristin appears to be independent of reduced susceptibility to daptomycin.

Multicenter evaluation of the Etest and disk diffusion methods for differentiating daptomycin-susceptible from non-daptomycin-susceptible Staphylococcus aureus isolates.

Daptomycin is a novel cyclic lipopeptide that is approved by the U.S. Food and Drug Administration for the treatment of complicated skin and skin structure infections associated with Staphylococcus aureus and other gram-positive pathogens and also staphylococcal bacteremia, including right-sided endocarditis. The Clinical and Laboratory Standards Institute (CLSI) established "susceptible-only" interpretive criteria for broth microdilution (BMD) and disk diffusion (DD) testing of daptomycin in 2005. However, a series of S. aureus isolates have been recovered with daptomycin MICs in the nonsusceptible range (i.e., MICs of >1 microg/ml). The objective of this study was to determine the ability of the Etest and DD methods to differentiate daptomycin-susceptible from nonsusceptible isolates of S. aureus compared to the results of the CLSI BMD reference method. There was a good correlation between Etest MIC results and the results of BMD among laboratories (r = 0.86 to 0.88), with 95.3% of the Etest MICs within a +/-1 log(2) dilution of the BMD MIC result. A total of 92 of 102 (90.2%) non-daptomycin-susceptible isolates of S. aureus identified by BMD in two participating laboratories were also classified as nonsusceptible by Etest. However, the very major and major error rates reported by one of the participating laboratories were 13.5 and 4.0%, respectively, primarily due to the absence of an intermediate category. The DD method, however, did not reliably differentiate daptomycin-susceptible from non-daptomycin-susceptible isolates. In 2005, daptomycin disks were voluntarily removed from the market by Cubist Pharmaceuticals. The disk diffusion breakpoints were subsequently removed from the CLSI M100 standard in 2006.

Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections.

Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomycin has a unique mechanism of action that results in destruction of the membrane potential. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.

Daptomycin tested against 915 bloodstream isolates of viridans group streptococci (eight species) and Streptococcus bovis.

OBJECTIVES: To evaluate the activity of daptomycin tested against numerous species of viridans group streptococci and Streptococcus bovis, which are associated with wound infections, sepsis, cellulitis, endocarditis, abscesses and dental caries. The incidence of penicillin-resistant (non-susceptible) and MLS(B)-resistant strains among viridans group streptococci often varies by species. METHODS: The activity of daptomycin was compared with seven other antimicrobial classes using reference broth microdilution and disc diffusion methods tested against 915 bacteraemic isolates of streptococci (815 viridans group strains; 100 S. bovis). RESULTS: Among all species of viridans group streptococci and S. bovis, 99.9% of isolates were susceptible to daptomycin (MIC values, < or = 0.016-2 mg/L). In contrast, penicillin, erythromycin and tetracycline susceptibility varied widely between species. Erythromycin susceptibility was in the range 48.6-88.7%, penicillin susceptibility in the range 65.5-98.1% and tetracycline in the range 35.0-93.9%. The inter-method agreement between daptomycin and linezolid resistance (comparison agent) disc diffusion and broth microdilution test results was high, each showing near complete susceptibility (99.9%). CONCLUSIONS: Daptomycin is an active antimicrobial agent that has a usable potency against eight species of viridans group streptococci, as well as S. bovis, with all MIC values at < or =2 mg/L.