Towards a global definition of responsible antibiotic use: results of an international multidisciplinary consensus procedure.

Background: Conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project, this study aimed to identify key elements for a global definition of responsible antibiotic use based on diverse stakeholder input. Methods: A three-step RAND-modified Delphi method was applied. First, a systematic review of antibiotic stewardship literature and relevant organization web sites identified definitions and synonyms of responsible use. Identified elements of definitions were presented by questionnaire to a multidisciplinary international stakeholder panel for appraisal of their relevance. Finally, questionnaire results were discussed in a consensus meeting. Results: The systematic review and the web site search identified 17 synonyms (e.g. appropriate, correct) and 22 potential elements to include in a definition of responsible use. Elements were grouped into patient-level (e.g. Indication, Documentation) or societal-level elements (e.g. Education, Future Effectiveness). Forty-eight stakeholders with diverse backgrounds [medical community, public health, patients, antibiotic research and development (R&D), regulators, governments] from 18 countries across all continents participated in the questionnaire. Based on relevance scores, 21 elements were retained, 9 were rephrased and 1 was added. Together, the 22 elements and associated best-practice descriptions comprise an exhaustive list of elements to be considered when defining responsible use. Conclusions: Combination of concepts from the literature and stakeholder opinion led to an international multidisciplinary consensus on a global definition of responsible antibiotic use. The widely diverging perspectives of stakeholders providing input should ensure the comprehensiveness and relevance of the definition for both individual patients and society. An aspirational goal would be to address all elements.

Progress in the Fight Against Multidrug-Resistant Bacteria 2005-2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance.

From a public health perspective, new antibacterial agents should be evaluated and approved for use before widespread resistance to existing agents emerges. However, for multidrug-resistant pathogens, demonstration of superior efficacy of a new agent over a current standard-of-care agent is routinely feasible only when epidemic spread of these dangerous organisms has already occurred. One solution to enable proactive drug development is to evaluate new antibiotics with improved in vitro activity against MDR pathogens using recently updated guidelines for active control, noninferiority trials of selected severe infections caused by more susceptible pathogens. Such trials are feasible because they enroll patients with infections due to pathogens with a "usual drug resistance" phenotype that will be responsive to widely registered standard-of-care comparator antibiotics. Such anticipatory drug development has constructively reshaped the antibiotic pipeline and offers the best chance of making safe and efficacious antibiotics available to the public ahead of epidemic resistance.

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.

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.

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.

Use of daptomycin for treatment of Staphylococcus aureus infections.

Gram-positive bacteria such as Staphylococcus aureus are important human pathogens. An increasing proportion of S. aureus are methicillin resistant. For decades, methicillin-resistant S. aureus infections have been treated with vancomycin, but susceptibility is decreasing, and tissue penetration and safety profile (especially nephrotoxicity) is not ideal. Consequently, there is a great need for the development of antibiotics with demonstrated efficacy and safety for infections caused by S. aureus and other Gram-positive pathogens. One such antibiotic is daptomycin, which has a unique mechanism of action and potent, rapid bactericidal activity, without causing cell lysis. Daptomycin has demonstrated significant efficacy in the treatment of complicated skin and skin structure infections, as well as methicillin-susceptible and methicillin-resistant S. aureus bacteremia, including right-sided endocarditis. Other attributes include an excellent safety profile, low potential for resistance, and once-daily dosing.

Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections.

The increasing incidence of serious infections caused by antibiotic-resistant Gram-positive bacteria has led to the development of new spectrum-specific agents. One such agent is Cubicin (daptomycin for injection), the first member of a new class of antibacterials called cyclic lipopeptides. Daptomycin has rapid, concentration-dependent bactericidal activity against most clinically significant Gram-positive pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate and -resistant S. aureus. This cyclic lipopeptide has a unique mechanism of action and exhibits a relatively prolonged concentration-dependent postantibiotic effect in vitro. In September 2003 the US FDA approved daptomycin for the treatment of complicated skin and skin-structure infections. With its once-daily dosing, excellent safety profile and low potential for resistance, daptomycin is a welcome new addition to the armamentarium against Gram-positive infections.

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.

Development potential of rifalazil.

Rifalazil represents a new generation of ansamycins that contain a unique four-ring structure. Originally rifalazil was developed as a therapeutic agent to replace rifampin as part of a multiple drug regimen in the treatment of tuberculosis. As a result of its superior antimicrobial activity and high intracellular levels, rifalazil has potential to treat indications caused by the intracellular pathogen, Chlamydia trachomatis, which causes non-gonococcal urethritis and cervicitis, often leading to pelvic inflammatory disease. Rifalazil also has potential to treat the related microorganism, Chlamydia pneumoniae, which may be involved in chronic inflammatory processes thought to be partly responsible for atherosclerosis. Due to its favourable antimicrobial spectrum and other positive attributes, rifalazil may also prove valuable in the treatment of gastric ulcer disease, caused by Helicobacter pylori, and antibiotic-associated colitis, the result of toxin production following the growth of Clostridium difficile in the colon. The potential value of rifalazil in the treatment of these indications will be assessed in human clinical trials.

Microbiología:mecanismo de las enfermedades infecciosas, enfoque mediante resolución de problemas / Mechanisms of microbial disease

Enfermedades infecciosas:genética de las bacterias, biología de los agentes infecciosas, defensas del huésped, subversión microbiana a las defensas. Clasificación de las bacterias, virus, hongos y parásitos. Fisiopatología de las enfermedades infecciosas. Organos afectados. Enfermedades de transmisión sexual. Infecciones en el huésped comprometido. SIDA. Infecciones congénitas y neonatales. Zoonosis. Fiebre de origen desconocido. Infección hospitalaria e iatrogénica. enfermedades transmitidas por los alimentos. Nutrición e infecciones. Principios de epidemiología

Microbiología:mecanismo de las enfermedades infecciosas, enfoque mediante resolución de problemas / Mechanisms of microbial disease

Enfermedades infecciosas:genética de las bacterias, biología de los agentes infecciosas, defensas del huésped, subversión microbiana a las defensas. Clasificación de las bacterias, virus, hongos y parásitos. Fisiopatología de las enfermedades infecciosas. Organos afectados. Enfermedades de transmisión sexual. Infecciones en el huésped comprometido. SIDA. Infecciones congénitas y neonatales. Zoonosis. Fiebre de origen desconocido. Infección hospitalaria e iatrogénica. enfermedades transmitidas por los alimentos. Nutrición e infecciones. Principios de epidemiología