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In this trial involving 387 patients with Staphylococcus aureus bacteremia, ceftobiprole, a cephalosporin active against methicillin-sensitive and -resistant S. aureus , was noninferior to daptomycin.

Daptomycin is the first available agent from a new class of antibiotics, the cyclic lipopeptides, that has activity against a broad range of gram-positive pathogens, including organisms that are resistant to methicillin, vancomycin, and other currently available agents. Daptomycin (4 mg/kg intravenously [iv] every 24 h for 7–14 days) was compared with conventional antibiotics (penicillinase-resistant penicillins [4–12 g iv per day] or vancomycin [1 g iv every 12 h]) in 2 randomized, international trials involving 1092 patients with complicated skin and skin-structure infections. Among 902 clinically evaluable patients, clinical success rates were 83.4% and 84.2% for the daptomycin- and comparator-treated groups, respectively (95% confidence interval, -4.0 to 5.6). Among patients successfully treated with iv daptomycin, 63% required only 4–7 days of therapy, compared with 33% of comparator-treated patients (P < .0001). The frequency and distribution of adverse events were similar among both treatment groups. Overall, the safety and efficacy of daptomycin were comparable with conventional therapy.

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health 1 . Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action 2 , but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease 3 , causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon ( prdRAB ) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered ‘low risk’ for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics. Rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin.

Background Enterococcal infections represent 10% of intensive care unit (ICU)-acquired infections and are associated with adverse outcomes, particularly in the case of E. faecium infections. Some studies focusing on non-critically ill patients have cast doubt on the non-inferiority of daptomycin compared to other antibiotics for these infections. We aimed to describe antibiotic treatment practices for monomicrobial E. faecium bloodstream infections (BSI) in patients admitted to the ICU, and to identify factors associated with treatment failure. Methods This retrospective multicenter study included adult patients presenting with a monomicrobial E. faecium BSI during their stay in one of 11 ICUs of Paris University hospitals between 2017 and 2022. Patients receiving daptomycin as a definitive antibiotic regimen were compared to those receiving another molecule using competing-risks models and propensity score-based analyses. The primary outcome was a composite criterion of treatment failure including: (1) prolonged bacteremia (≥3days) under treatment and/or (2) relapse within 30 days after the end of treatment and/or (3) the need for salvage therapy within 30 days. Results Of the 166 included patients, 26 received daptomycin as a definitive antibiotic regimen, at a median dose of 10 [10-10] mg/kg/day and 140 patients received non-daptomycin-based regimens (vancomycin (69%), linezolid (19%) or a beta-lactam (11%)). Source of BSI was predominantly unknown (38%), digestive (37%) or an intravascular device (16%). All isolates were vancomycin-susceptible. Median daptomycin MIC was 3 [2-3.25] mg/L. Time to adequate antibiotic regimen (1 [0-2] vs 1 [0-2] days, p=0.22) and rates of source control (63% vs 43%, p=0.17) were not different between groups. Regarding primary outcome, daptomycin as a definitive antibiotic regimen was associated with a higher rate of treatment failure in the multivariate adjusted analysis using a Fine and Gray model (aSHR 2.53 [1.14-5.62], p=0.022). Sensitivity analyses using propensity score overlap weighting (HR 2.48 [1.05-5.86], p=0.038) or with only patients treated by vancomycin as comparators (aSHR 2.26 [1.00-5.10], p=0.051) yielded similar results. Conclusions In this multicenter retrospective cohort of critically ill patients with monomicrobial E. faecium bloodstream infections, use of daptomycin as the definitive antibiotic regimen was associated with a higher rate of treatment failure. Further prospective studies are needed.

Background. The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, “CPK elevation”) in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Methods. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Results. Significant relationships between the minimum concentration of drug (Cmin) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. Cmin (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a Cmin ⩾24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in Cmin, evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated Cmin to be a significant predictor of time to a CPK elevation (P ⩽ .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a Cmin ⩾24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. Conclusions. This analysis demonstrated that a daptomycin Cmin ⩾24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067.

Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. A total of 170 patients were included. The median (interquartile range) age was 60 years (50–74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10–18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Background. Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are associated with significant mortality. Daptomycin exhibits concentration-dependent activity vs VRE in vitro, yet the clinical impact of higher-dose strategies remains unclear. Methods. We performed a national retrospective cohort study of hospitalized Veterans Affairs patients treated with standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (≥10 mg/kg total body weight) daptomycin for VRE-BSI. Patient-related, microbiological, and outcomes data were abstracted from clinical databases. The primary outcome was overall survival, evaluated by Cox regression. Secondary outcomes included 30-day mortality, time to microbiological clearance, and creatine phosphokinase (CPK) elevation. Results. A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose (hazard ratio [HR], 2.68; 95% confidence interval; [CI], 1.33–3.06; P = .002) and medium-dose (HR, 2.66; 95% CI, 1.33–3.92; P = .003) daptomycin were associated with poorer survival. After adjusting for confounders, the relationship between poorer survival and standard-dose (adjusted HR [aHR], 2.58; 95% CI, 1.27–4.88; P = .004) and medium-dose (aHR, 2.52; 95% CI, 1.27–5.00; P = .008) daptomycin persisted. Thirty-day mortality was significantly lower among high-dose daptomycin–treated patients compared with other dosing strategies (risk ratio, 0.83; 95% CI, .74–.94; P = .015). Compared with standard-dose daptomycin, both medium-dose (HR, 0.78; 95% CI, .55–.90; P = .012) and high-dose daptomycin (HR, 0.70; 95% CI, .41–.84; P = .006) were associated with significantly improved microbiological clearance. No differene in the risk of CPK elevation was observed between the treatment groups (P = .504). Conclusions. High-dose daptomycin was associated with improved survival and microbiological clearance in VRE-BSI.

Background. Daptomycin has become a front-line antibiotic for multidrug-resistant Enterococcus faecium bloodstream infections (BSIs). We previously showed that E. faecium strains with daptomycin minimum inhibitory concentrations (MICs) in the higher end of susceptibility frequently harbor mutations associated with daptomycin resistance. We postulate that patients with E. faecium BSIs exhibiting daptomycin MICs of 3–4 μg/mL treated with daptomycin are more likely to have worse clinical outcomes than those exhibiting daptomycin MICs ≤2 μg/mL. Methods. We conducted a multicenter retrospective cohort study that included adult patients with E. faecium BSI for whom initial isolates, follow-up blood culture data, and daptomycin administration data were available. A central laboratory performed standardized daptomycin MIC testing for all isolates. The primary outcome was microbiologic failure, defined as clearance of bacteremia ≥4 days after the index blood culture. The secondary outcome was all-cause in-hospital mortality. Results. A total of 62 patients were included. Thirty-one patients were infected with isolates that exhibited daptomycin MICs of 3–4 μg/mL. Overall, 34 patients had microbiologic failure and 25 died during hospitalization. In a multivariate logistic regression model, daptomycin MICs of 3–4 μg/mL (odds ratio [OR], 4.7 [1.37–16.12]; P = .014) and immunosuppression (OR, 5.32 [1.20–23.54]; P = .028) were significantly associated with microbiologic failure. Initial daptomycin dose of ≥8 mg/kg was not significantly associated with evaluated outcomes. Conclusions. Daptomycin MICs of 3–4 μg/mL in the initial E. faecium blood isolate predicted microbiological failure of daptomycin therapy, suggesting that modification in the daptomycin breakpoint for enterococci should be considered.

Recent developments in next-generation sequencing technologies have brought recognition of microbial genomes as a rich resource for novel natural product discovery. However, owing to the scarcity of efficient procedures to connect genes to molecules, only a small fraction of secondary metabolomes have been investigated to date. Transformation-associated recombination (TAR) cloning takes advantage of the natural in vivo homologous recombination of Saccharomyces cerevisiae to directly capture large genomic loci. Here we report a TAR-based genetic platform that allows us to directly clone, refactor, and heterologously express a silent biosynthetic pathway to yield a new antibiotic. With this method, which involves regulatory gene remodeling, we successfully expressed a 67-kb nonribosomal peptide synthetase biosynthetic gene cluster from the marine actinomycete Saccharomonospora sp. CNQ-490 and produced the dichlorinated lipopeptide antibiotic taromycin A in the model expression host Streptomyces coelicolor. The taromycin gene cluster (tar) is highly similar to the clinically approved antibiotic daptomycin from Streptomyces roseosporus, but has notable structural differences in three amino acid residues and the lipid side chain. With the activation of the tar gene cluster and production of taromycin A, this study highlights a unique \"plug-and-play\" approach to efficiently gaining access to orphan pathways that may open avenues for novel natural product discoveries and drug development.