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.

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.

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.

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.

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.

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.

Observation of D+ --> etae + nue.

Using a 281 pb-1 data sample collected at the psi(3770) resonance with the CLEO-c detector at the Cornell Electron Storage Ring, we report the first observation of D+ --> etae + nue. We also set upper limits for D+ --> eta'e + nue and D + --> varphie + nue that are about 2 orders of magnitude more restrictive than those obtained by previous experiments.

J/psi and psi(2S) Radiative Transitions to eta_{c}.

Using 2.45x10;{7} psi(2S) decays collected with the CLEO-c detector at the Cornell Electron Storage Ring we present the most precise measurements of magnetic dipole transitions in the charmonium system. We measure B(psi(2S)-->gammaeta_{c})=(4.

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.

Objective: The objective was to evaluate whether daptomycin treatment of cellulitis or erysipelas would result in faster resolution compared with vancomycin.

Design: The study was a prospective, evaluator-blinded, multi-centre trial.

Search for lepton flavor violation in upsilon decays.

In this Letter, we describe a search for lepton flavor violation (LFV) in the bottomonium system. We search for leptonic decays Upsilon(nS)-->mutau (n=1, 2, and 3) using the data collected with the CLEO III detector. We identify the tau lepton using its leptonic decay nu_{tau}nu[over ]_{e}e and utilize multidimensional likelihood fitting with probability density function shapes measured from independent data samples.

Observation of Upsilon(2S)-->etaUpsilon(1S) and search for related transitions.

We report the first observation of Upsilon(2S)-->etaUpsilon(1S), with a branching fraction B=(2.1(-0.6)+0.

Precision measurement of the mass of the hc(1P1) state of charmonium.

A precision measurement of the mass of the h_{c}(1P1) state of charmonium has been made using a sample of 24.5x10;{6} psi(2S) events produced in e;{+}e;{-} annihilation at the Cornell Electron Storage Ring (CESR). The reaction used was psi(2S)-->pi;{0}h_{c}, pi;{0}-->gammagamma, h_{c}-->gammaeta_{c}, and the reaction products were detected in the CLEO-c detector.

Measurement of the eta'-meson mass using J/psi-->gammaeta'.

We measure the mass of the eta;{'} meson using psi(2S)-->pi;{+}pi;{-}J/psi, J/psi-->gammaeta;{'} events acquired with the CLEO-c detector operating at the CESR e;{+}e;{-} collider. Using three decay modes, eta;{'}-->rho;{0}gamma, eta;{'}-->pi;{+}pi;{-}eta with eta-->gammagamma, and eta;{'}-->pi;{+}pi;{-}eta with eta-->pi;{+}pi;{-}pi;{0}, we find M_{eta;{'}}=957.793+/-0.

Search for very light CP-odd Higgs Boson in radiative decays of Upsilon(1S).

We search for a non-SM-like CP-odd Higgs boson (a(1)(0)) decaying to tau(+)tau(-) or mu(+)mu(-) in radiative decays of the Upsilon(1S). No significant signal is found, and upper limits on the product branching ratios are set. Our tau(+)tau(-) results are almost 2 orders of magnitude more stringent than previous upper limits.

Observation of chicJ radiative decays to light vector mesons.

Using a total of 2.74 x 10(7) decays of the psi(2S) collected with the CLEO-c detector, we present a study of chi(cJ)-->gammaV, where V=rho(0), omega, phi. The transitions chi(c1)-->gammarho(0 and chi(c1)-->gammaomega are observed with B(chi(c1)-->gammarho(0))=(2.

Observation of J/psi-->3gamma.

We report the first observation of the decay J/psi-->3gamma. The signal has a statistical significance of 6sigma and corresponds to a branching fraction of B(J/psi-->3gamma)=(1.2+/-0.

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.

Study of the decays D0-->pi{-}e{+}nu{e}, D{0}-->K{-}e{+}nu{e}, D{+}-->pi{0}e{+}nu{e}, and D{+}-->K0e{+}nu{e}.

By using 1.8x10{6} DDpairs, we have measured B(D{0}-->pi{-}e{+}nu{e})=0.299(11)(9)%, B(D{+}-->pi{0}e{+}nu{e})=0.

Determination of the strong phase in D0-->K+pi- using quantum-correlated measurements.

We exploit the quantum coherence between pair-produced D0 and D[over]0 in psi(3770) decays to study charm mixing, which is characterized by the parameters x and y, and to make a first determination of the relative strong phase delta between D0-->K+pi- and D[over]0-->K+pi-. Using 281 pb(-1) of e+e- collision data collected with the CLEO-c detector at Ecm=3.77 GeV, as well as branching fraction input and time-integrated measurements of RM identical with (x2 + y2)/2 and RWS identical with Gamma(D0-->K+pi-)/Gamma(D[over]0-->K+pi-) from other experiments, we find cosdelta=1.

First observation of the decay Ds+-->pn.

Using e+e--->Ds*-Ds+ data collected near the peak Ds production energy, Ecm=4170 MeV, with the CLEO-c detector, we present the first observation of the decay Ds+-->pn. We measure a branching fraction B(Ds+-->pn)=(1.30+/-0.

Absolute measurement of hadronic branching fractions of the Ds+ meson.

The branching fractions of D(s)(+/-) meson decays serve to normalize many measurements of processes involving charm quarks. Using 298 pb(-1) of e(+)e(-) collisions recorded at a center of mass energy of 4.17 GeV, we determine absolute branching fractions for eight D(s)(+/-) decays with a double tag technique.

Measurement of the absolute branching fraction of Ds+ --> tau+ nutau decay.

Using a sample of tagged D(s)(+) decays collected near the D(s)(*+/-)D(s)(-/+) peak production energy in e(+)e(-) collisions with the CLEO-c detector, we study the leptonic decay D(s)(+)-->tau(+)nu(tau) via the decay channel tau(+)-->e(+)nu(e)nu(tau). We measure B(D(s)(+)-->tau(+)nu(tau))=(6.17+/-0.