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 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. Patients were randomised to receive daptomycin 4 mg/kg once daily or vancomycin according to standard of care for 7-14 days. PATIENTS: Adults diagnosed with cellulitis or erysipelas requiring hospitalisation and intravenous antibiotic therapy were eligible for enrolment. RESULTS: The clinical success rates were 94.0% for daptomycin and 90.2% for vancomycin (95% confidence interval for the difference, -6.7%, 14.3%). There were no statistically significant differences between treatment arms in the time to resolution or improvement in any of the predefined clinical end-points. Both daptomycin and vancomycin were well tolerated. CONCLUSIONS: There was no difference in the rate of resolution of cellulitis or erysipelas among patients treated with daptomycin or vancomycin. Daptomycin 4 mg/kg once daily appeared to be effective and safe for treating cellulitis or erysipelas.

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=1.03(-0.17)(+0.31)+/-0.06, where the uncertainties are statistical and systematic, respectively. By further including other mixing parameter measurements, we obtain an alternate measurement of cosdelta=1.10+/-0.35+/-0.07, as well as x sindelta=(4.4(-1.8)(+2.7)+/-2.9)x10(-3) and delta=(22(-12-11)(+11+9)) degrees .

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. In particular we determine the branching fraction B(D(s)(+)-->K(-)K(+}pi(+))=(5.50+/-0.23+/-0.16)%, where the uncertainties are statistical and systematic, respectively. We also provide partial branching fractions for kinematic subsets of the K(-)K(+)pi(+) decay mode.

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+/-0.36(-0.16)+0.12)x10(-3). This is the first observation of a charmed meson decaying into a baryon-antibaryon final state.

Treatment of staphylococcal infections with cyclic lipopeptides.

Daptomycin is the first of a new class of antibiotics, the cyclic lipopeptides, for which a novel mechanism of action is hypothesised. Owing to its mode of action, daptomycin is rapidly bactericidal without being bacteriolytic, is active against static- and growing-phase bacteria, and has a low resistance rate in vitro. Phase III clinical trials have demonstrated that daptomycin is as effective as standard therapy for the treatment of complicated skin and soft-tissue infections associated with Gram-positive infections, and daptomycin-treated patients benefited from a reduced time to clinical resolution. Daptomycin has also been shown to be as effective as standard therapy in the treatment of bacteraemia associated with Staphylococcus aureus, with or without endocarditis. These results indicate that daptomycin is a useful therapeutic option for treating Gram-positive infections, particularly those caused by S. aureus.

Treatment challenges in the management of complicated skin and soft-tissue infections.

Complicated skin and soft-tissue infections (cSSTIs) are a significant clinical problem, partially owing to increasing resistance of infecting bacteria to current antibiotic therapies. Two case studies that illustrate complications that can arise when treating cSSTIs are outlined, and methods that can be used to address the problem and the final treatment outcome are detailed. Although these are specific examples, intolerance of and bacterial resistance to current antibacterial therapies are problems that are often seen in the clinical setting and must be addressed appropriately. The use of new antibiotic agents is one potential solution to these problems, and some of these agents are highlighted. Selecting the most appropriate therapy for an infection is often crucial for patient welfare. This article presents some potential approaches to the treatment of cSSTIs.

Study of exclusive charmless semileptonic B decays and |Vub|.

We study semileptonic B decay to the exclusive charmless states pi, rho/omega, eta, and eta;{'} using the 16 fb(-1) CLEO Upsilon(4S) data sample. We find B(B0-->pi-l+nu)=(1.37+/-0.15stat+/-0.11sys)x10(-4) and B(B0-->rho-l+nu)=(2.93+/-0.37stat+/-0.37sys)x10(-4) and find evidence for B+-->eta'l+nu, with B(B+-->eta'l+nu)=(2.66+/-0.80stat+/-0.56sys)x10(-4). From our B-->pilnu rate for q2>16 GeV2 and lattice QCD, we find |Vub|=(3.6+/0.4stat+/0.2syst-0.4thy+0.6)x10(-3) [corrected]

Precision determination of the D0 mass.

A precision measurement of the D0 meson mass has been made using approximately 281 pb(-1) of e+e- annihilation data taken with the CLEO-c detector at the psi(3770) resonance. The exclusive decay D0-->K_{S}phi has been used to obtain M(D0)=1864.847+/-0.150(stat)+/-0.095(syst) MeV. This corresponds to M(D0D*0)=3871.81+/-0.36 MeV, and leads to a well-constrained determination of the binding energy of the proposed D0D*0 molecule X(3872), as Eb=0.6+/-0.6 MeV.

Experimental limits on weak annihilation contributions to decays.

We present the first experimental limits on high-q2 contributions to charmless semileptonic decays of the form expected from the weak annihilation (WA) decay mechanism. Such contributions could bias determinations of /Vub/ from inclusive measurements of B-->Xulupsilon. Using a wide range of models based on available theoretical input we set a limit of GammaWA/Gammab-->u<7.4% (90% confidence level) on the WA fraction, and assess the impact on previous inclusive determinations of /Vub/.

New measurements of Cabibbo-suppressed decays of mesons with the CLEO-c detector.

Using of data collected with the CLEO-c detector, we report on first observations and measurements of Cabibbo-suppressed decays of D mesons in the following six decay modes: pi+ pi- pi0 pi0, pi+ pi+ pi- pi- pi0, pi+ pi0 pi0, pi+ pi+ pi- pi0, eta pi0, and omega pi+ pi-. Improved branching fraction measurements in eight other multipion decay modes are also presented. The measured D --> pi pi rates allow us to extract the ratio of isospin amplitudes A(DeltaI = (3/2) / A(DeltaI = (1/2)) = 0.420 +/- 0.014(stat) +/- 0.016(syst) and the strong phase shift of delta1 = (86.4 +/- 2.8 +/- 3.3) degrees, which is quite large and now more precisely determined.

Observation of psi(3770) --> pi pi J/psi and measurement of Gamma ee[psi(2S)].

We observe signals for the decays psi(3770) --> XJ/psi from data acquired with the CLEO detector operating at the CESR e+ e- collider with square root of s = 3773 MeV. We measure the following branching fractions Beta(psi(3770) --> XJ/psi and significances: (189 +/- 20 +/- 20) x 10(-5) (11.6sigma) for X = pi+ pi-, (80 +/- 25 +/- 16) x 10(-5) (3.4sigma) for X = pi0 pi0, and (87 +/- 33 +/- 22) x 10(-5) (3.5sigma) for X = eta, where the errors are statistical and systematic, respectively. The radiative return process e+ e- --> gamma psi(2S) populates the same event sample and is used to measure Gamma ee[psi(2S)] = (2.54 +/- 0.03 +/- 0.11) keV.

Dielectron widths of the Gamma(1S,2S,3S) resonances.

We determine the dielectron widths of the Gamma(1S), Gamma(2S), and Gamma(3S) resonances with better than 2% precision by integrating the cross section of e+e- -->Gamma over the e+e- center-of-mass energy. Using e+e- energy scans of the Gamma resonances at the Cornell Electron Storage Ring and measuring Gamma production with the CLEO detector, we find dielectron widths of 1.252+/-0.004(sigma(stat))+/-0.019(sigma(syst)) keV, 0.581+/-0.004+/-0.009 keV, and 0.413+/-0.004+/-0.006 keV for the Gamma(1S), Gamma(2S), and Gamma(3S), respectively.

Absolute branching fraction measurements for D+ and D0 inclusive semileptonic decays.

We present measurements of the inclusive branching fractions for the decays D+-->Xe+ nu(e) and D0-->Xe+ nu(e), using 281 pb(-1) of data collected on the psi(3770) resonance with the CLEO-c detector. We find B(D0-->Xe+ nu(e)) = (6.46+/-0.17+/-0.13)% and B(D+-->Xe+ nu(e)) = (16.13+/-0.20+/-0.33)%. Using the known D meson lifetimes, we obtain the ratio Gamma(D+)sl/Gamma(D0)sl = 0.985+/-0.028+/-0.015, confirming isospin invariance at the level of 3%. The positron momentum spectra from D+ and D0 have consistent shapes.

Branching fractions for psi(2S)-to-J/psi transitions.

We describe new measurements of the inclusive and exclusive branching fractions for psi(2S) transitions to J/psi using e(+)e(-) collision data collected with the CLEO detector operating at CESR. All branching fractions and ratios of branching fractions reported here represent either the most precise measurements to date or the first direct measurements. Indirectly and in combination with other CLEO measurements, we determine B(chi(cJ) --> gamma(J/psi)) and B[psi(2S) --> light hadrons].

Observation of 1(-)0(-) final states from psi(2S) decays and e(+)e(-) annihilation.

Using CLEO data collected from CESR e(+)e(-) collisions at the psi(2S) resonance and nearby continuum at sqrt[s]=3.67 GeV, we report the first significantly nonzero measurements of light vector-pseudoscalar hadron pair production (including rhopi, omegapi, rhoeta, and K(*0)K0 ) and the pi(+)pi(-)pi(0) final state, both from psi(2S) decays and direct e(+)e(-) annihilation.

First observation and Dalitz analysis of the D0-->K(0)Setapi(0) decay.

Using 9.0 fb(-1) of integrated luminosity in e(+)e(-) collisions near the Upsilon(4S) mass collected with the CLEO II.V detector we report the first observation of the decay D0-->K(0)(S)etapi(0). We measure the ratio of branching fractions, BR(D0-->K(0)(S)etapi(0))BR / (D0-->K(0)(S)pi(0))=0.46+/-0.07+/-0.06. We perform a Dalitz analysis of 155 selected D0-->K(0)(S)etapi(0) candidates and find leading contributions from a(0)(980)K(0)(S) and K(*)(892)eta intermediate states.

Branching fractions of tau leptons to three charged hadrons.

From electron-positron collision data collected with the CLEO detector operating at Cornell Electron Storage Ring near sqrt[s]=10.6 GeV, improved measurements of the branching fractions for tau decays into three explicitly identified hadrons and a neutrino are presented as B(tau(-)-->pi(-)pi(+)pi(-)nu(tau))=(9.13+/-0.05+/-0.46)%, B(tau(-)-->K-pi(+)pi(-)nu(tau))=(3.84+/-0.14+/-0.38) x 10(-3), B(tau(-)-->K-K+pi(-)nu(tau))=(1.55+/-0.06+/-0.09) x 10(-3), and B(tau(-)-->K-K+K-nu(tau))<3.7 x 10(-5) at 90% C.L., where the uncertainties are statistical and systematic, respectively.

Measurement of B(D+-->K(*0)l(+)nu(l)).

Using 13.53 fb(-1) of CLEO data, we have measured the ratios of the branching fractions R(+)(e),R(+)(mu) and the combined branching fraction ratio R(+)(l), defined by R(+)(l)=[B(D+-->K(*0)l(+)nu(l))]/[B(D+-->K-pi(+)pi(+))]. We find R(+)(e)=0.74+/-0.04+/-0.05, R(+)(mu)=0.72+/-0.10+/-0.05, and R(+)(l)=0.74+/-0.04+/-0.05, where the first and second errors are statistical and systematic, respectively. The known branching fraction B(D+-->K-pi(+)pi(+)) leads to B(D+-->K(*0)e(+)nu(e))=(6.7+/-0.4+/-0.5+/-0.4)%, B(D+-->K(*0)mu(+)nu(mu))=(6.5+/-0.9+/-0.5+/-0.4)%, and B(D+-->K(*0)l(+)nu(l))=(6.7+/-0.4+/-0.5+/-0.4)%, where the third error is due to the uncertainty in B(D+-->K-pi(+)pi(+)).

Experimental investigation of the two-photon widths of the chi(c0) and the chi(c2) mesons.

Using 12.7 fb(-1) of data collected with the CLEO detector at CESR, we observed two-photon production of the cc states chi(c0) and chi(c2) in their decay to pi(+)pi(-)pi(+)pi(-). We measured gamma(gammagamma)(chi(c))xB(chi(c)-->pi(+)pi(-)pi(+)pi(-)) to be 75+/-13(stat)+/-8(syst) eV for the chi(c0) and 6.4+/-1.8(stat)+/-0.8(syst) eV for the chi(c2), implying gamma(gammagamma)(chi(c0)) = 3.76+/-0.65(stat)+/-0.41(syst)+/-1.69(br) keV and gamma(gammagamma)(chi(c2)) = 0.53+/-0.15(stat)+/-0.06(syst)+/-0.22(br) keV. Also, cancellation of dominant experimental and theoretical uncertainties permits a precise comparison of gamma(gammagamma)(chi(c0))/gamma(gammagamma)(chi(c2)), evaluated to be 7.4+/-2.4(stat)+/-0.5(syst)+/-0.9(br), with QCD-based predictions.