Barry I. Eisenstein

The Safety and Efficacy of Daptomycin for the Treatment of Complicated Skin and Skin-Structure Infections

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.

Tackling antibiotic resistance

The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates

Objectives In a prospective, randomized trial, daptomycin was non-inferior to standard therapy for Staphylococcus aureus bacteraemia and right-sided endocarditis. Since rates of infection due to methicillin-resistant S. aureus (MRSA) infection are increasing and treatment outcomes for bacteraemia caused by MRSA are generally worse than those observed with methicillin-susceptible S. aureus bacteraemia, clinical characteristics and treatment results in the trial’s pre-specified subset of patients with MRSA were analysed. Methods Clinical characteristics and outcomes of patients receiving daptomycin were compared with those receiving vancomycin plus low-dose gentamicin. Success was defined as clinical improvement with clearance of bacteraemia among patients who completed adequate therapy, received no potentially effective non-study antibiotics and had negative blood cultures 6 weeks after end of therapy. Results Twenty of the 45 (44.4%) daptomycin patients and 14 of the 43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9%; confidence interval −8.3 to 32.1). Success rates for daptomycin versus vancomycin/gentamicin were 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-sided MRSA endocarditis. Cure rates in patients with septic emboli and in patients who received pre-enrolment vancomycin were similar between treatment groups. However, in both treatment groups, success rates were lower in the elderly (≥75 years). Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients; among these patients, MICs of ≥2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. The clinical course of several patients may have been influenced by lack of surgical intervention. Conclusions Daptomycin was an effective alternative to vancomycin/gentamicin for MRSA bacteraemia or right-sided endocarditis.

A comprehensive regulatory framework to address the unmet need for new antibacterial treatments

To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure.

Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD.

Daptomycin has been approved and successfully launched for the treatment of complicated skin and skin-structure infections caused by gram-positive pathogens [1] and bacteremia and right-sided endocarditis due to Staphylococcus aureus, including strains that are resistant to methicillin or other antibiotics [2]. The development of the drug, however, was not straightforward; it involved a cast of characters, including scientists at Eli Lilly and at Cubist Pharmaceuticals. Of most importance, the development of daptomycin involved the tenacious leadership of Dr. Francis Tally. As a tribute to Dr. Tally, we attempt to reconstruct the path of daptomycin from the mountain to the clinic.

Interference with the Mannose Binding and Epithelial Cell Adherence of Escherichia coli by Sublethal Concentrations of Streptomycin

When Escherichia coli was grown in sublethal concentrations of streptomycin, mannose binding activity and epithelial cell adherence of the E. coli cultures at stationary phase were significantly reduced in the drug-grown organisms. In a strain whose minimal inhibitory concentrations was 30 mug/ml, the percentage of reduction in mannose binding activity was dose related over a range of concentrations between 0.5 and 10 mug/ml streptomycin. Concomitant with the drug-induced suppression of mannose binding activity, antigenic and ultrastructural alterations on the surface of the drug-grown organisms were observed by agglutination tests and electron microscopy, respectively. The streptomycin effect was reversible, required actively growing organisms, and was most apparent in the early log-phase of growth. High doses of antibiotic were ineffective when added to cultures which had acquired mannose binding activity. An isogenic derivative with high-level resistance to streptomycin was obtained as a single-step mutation from the test E. coli strain. Whereas the isogenic mutant possessed mannose binding activity and adhering ability similar to the parent strain, it was resistant to the streptomycin-induced suppression of the two activities at enormous concentrations (up to 10,000 mug/ml) of streptomycin. Taken together the results suggest that the suppression of epithelial cell adherence and mannose binding activity of E. coli grown in sublethal concentrations of streptomycin is a result of classic mechanisms of drug action upon the bacterial ribosome. The results support the possibility that antibiotics may act through mechanisms other than inhibition of growth and bacterial killing to eradicate bacteria from mucosal surfaces.

The efficacy and safety of daptomycin vs. vancomycin for the treatment of cellulitis and erysipelas

Background:  Results from previous trials suggest that daptomycin may result in faster clinical improvement than penicillinase‐resistant penicillins or vancomycin for patients with complicated skin and skin structure infections.

The evolution of the regulatory framework for antibacterial agents

The rising tide of antibacterial resistance and the lack of a diverse, vibrant pipeline of novel antibacterial agents is a global crisis that impairs our ability to treat life‐threatening infections. The recent introduction of a tiered approach to the regulatory framework in this area offers one path to resolving some of the challenges. By drawing heavily on the predictive power of the related sciences of pharmacokinetics and pharmacodynamics, smaller, focused clinical trial programs have become possible for agents that might not otherwise have been possible to progress. There are limitations to these pathways, and they are not easy to implement, but making reliable noninferiority‐based approaches available is critical to reinvigorating the global antibiotic pipeline. With the recognition of these ideas by key regulatory authorities in recent guidance, the next challenges in this area will focus on interpretive breakpoints, the extent of data in the prescribing information, ensuring that multiple agents can be progressed, and the challenge of the antibiotic business model.

Daptomycin versus ciprofloxacin in the treatment of Complicated urinary tract infection due to Gram-positive bacteria

Background: Complicated urinary tract infections (UTIs) due to Gram-positive pathogens are of increasing concern because of steadily emerging resistance to standard antibiotic therapy. Daptomycin is the first available agent of a new class of antibiotics, the cyclic lipopeptides, which have bactericidal activity against a broad range of Gram-positive pathogens including organisms resistant to methicillin, vancomycin, and other currently available agents. The purpose of this study was to compare the efficacy and safety of daptomycin with ciprofloxacin in the treatment of adult patients with complicated, Gram-positive UTIs. Methods: A total of 68 adult patients with complicated UTIs predominantly caused by Gram-positive pathogens were enrolled in an open-label, microbiologist-blinded trial. Complicated UTI was defined as pyuria and bacteriuria (≥105 colony-forming units/mL), and at least 1 underlying urinary tract complication, such as recent urinary tract surgery, postvoiding residual volume, neurogenic bladder, calculi (renal, ureteral, or bladder), urinary tract obstruction, surgically reconstructed bladder, or bladder diverticulum. Patients were randomized to receive intravenous daptomycin (4 mg/kg every 24 hours) or intravenous ciprofloxacin (400 mg every 12 hours) for 5 to 14 days. The primary efficacy end points were microbiologic and clinical response at the test-of-cure visit. The major statistical objective was to demonstrate noninferiority of daptomycin to ciprofloxacin. Results: For the microbiologically evaluable population, bacteriologic eradication at test-of-cure was 83% for daptomycin and 85% for ciprofloxacin (95% confidence interval [ciprofloxacin-daptomycin]: −17.7, 21.4). Clinical success rates at test-of-cure were 93% and 94%, respectively (95% confidence interval: −13.6, 12.2). Successful clinical outcome at the follow-up visit was maintained in 93% of daptomycin patients and in 86% of ciprofloxacin patients (95% confidence interval: −23.3, 8.5). Enterococcus faecalis and Staphylococcus aureus, the most common Gram-positive pathogens, were eradicated at 82% and 75%, respectively, in the daptomycin group and at 86% and 75%, respectively, in the ciprofloxacin group. Overall, there was a significantly lower incidence of adverse events in the daptomycin group than in the ciprofloxacin group, primarily due to fewer gastrointestinal disorders for daptomycin (95% confidence interval: 0.7, 28.7). There was no reported muscle pain or weakness in the entire safety population. Conclusion: Although low enrollment compromised the statistical power of the study, a trend toward equivalent efficacy between intravenous daptomycin and intravenous ciprofloxacin was observed. Daptomycin warrants further investigation as a potential agent for the treatment of complicated UTI due to Gram-positive pathogens.

The Challenge of Antimicrobial Resistance: New Regulatory Tools to Support Product Development

The antibiotic pipeline is thin and lacks diversity, particularly for agents targeting Gram‐negative pathogens. The reasons for our anemic global development pipeline are often summarized as (i) discovery of new antibiotics is difficult, (ii) clinical development of new antibiotics is difficult, and (iii) the economics for new antibiotics are unfavorable for the developer. Here, we review recent efforts directed at the second of these challenges.