Cubist Pharmaceuticals (United States)

Abstract Satisfiability modulo theories (SMT) solvers are widely used to ensure the correctness of safety- and security-critical applications. Therefore, being able to trust a solver’s results is crucial. One way to increase trust is to generate independently checkable proof certificates, which record the reasoning steps done by the solver. A key challenge with this approach is that it is difficult to efficiently and accurately produce proofs for reasoning steps involving term rewriting rules. Previous work showed how a domain-specific language, Rare, can be used to capture rewriting rules for the purposes of proof production. However, in that work, the Rare rules had to be trusted, as the correctness of the rules themselves was not checked by the proof checker. In this paper, we present IsaRare, a tool that can automatically translate Rare rules into Isabelle/HOL lemmas. The soundness of the rules can then be verified by proving the lemmas. Because an incorrect rule can put the entire soundness of a proof system in jeopardy, our solution closes an important gap in the trustworthiness of SMT proof certificates. The same tool also provides a necessary component for enabling full proof reconstruction of SMT proof certificates in Isabelle/HOL. We evaluate our approach by verifying an extensive set of rewrite rules used by the cvc5 SMT solver.

Fisher, Jane MsC; Linder, Adam MD, PhD; Caironi, Pietro MD; Russell, James A. MD Author Information

A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira coupling-cycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 h. The structure of the heterocyclic ring system was confirmed through single-crystal X-ray crystallography.

ObjectivesEstimate the prevalence of genital warts (GW) and GW-related healthcare resource use and costs among male and female patients seeking treatment in South Korea.DesignTo estimate GW prevalence, physicians in five major South Korean regions recorded daily logs of patients (n=71 655) seeking care between July 26 and September 27, 2011. Overall prevalence estimates (and 95% CIs) were weighted by the estimated number of physicians in each specialty and the estimated proportion of total patients visiting each specialist type. Healthcare resource use was compared among different specialties. Corresponding p values were calculated using Mann-Whitney U tests.SettingThe database covers 5098 clinics and hospitals for five major regions in South Korea: Seoul, Busan, Daegu, Gwangju and Daejeon.ParticipantsPrimary care physicians (general practice/family medicine), obstetricians/gynaecologists, urologists and dermatologists with 2–30 years’ experience.ResultsThe estimated overall GW prevalence was 0.7% (95% CI 0.7% to 0.8%). Among women, GW prevalence was 0.6% (95% CI 0.6% to 0.7%); among men prevalence was 1.0% (95% CI 0.9% to 1.0%), peaking among patients aged 18–24 years. Median costs for GW diagnosis and treatment for male patients were US$58.2 (South Korean Won (KRW) ₩66 857) and US$66.3 (KRW₩76 113) for female patients.ConclusionsThe estimated overall GW prevalence in South Korea was 0.7% and was higher for male patients. The overall median costs associated with a GW episode were higher for female patients than for male patients.

Purpose Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia patients treated with current antibiotic therapies have exhibited poor outcomes, increased hospital length of stay, and higher costs of care. Twenty-eight-day mortality rate of 32% was reported with vancomycin therapy for MRSA hospital-acquired pneumonia (HAP) and MRSA health care–associated pneumonia (HCAP) from the same institution. The purpose of this study was to compare the epidemiology and effectiveness of ceftaroline versus alternative antibiotic therapies: linezolid, vancomycin, and/or cefepime, in hospitalized patients with MRSA HAP or HCAP based on clinical outcomes. Methods Through retrospective matched case-control study design, the Infectious Diseases Society of America– and Centers for Disease Control and Prevention–defined MRSA HCAP or HAP consecutive hospitalized subjects treated with either ceftaroline fosamil (CPT-F) or alternative antibiotics were compared. Primary outcomes were 28-day mortality and 14-day clinical evaluation. Secondary outcomes included duration of hospitalization, complications with treatment, and clinical response to therapy switches. Results Overall, 40 cases of MRSA HAP or HCAP treated with CPT-F were matched to 109 control subjects treated with either vancomycin or linezolid based on age, intensive care unit status, and type of pneumonia infection. The CPT-F cohort had a 10% (n = 4) 28-day mortality rate, and 91% (n = 32) had 14-day clinical success/cure (±1 day) from diagnosis of pneumonia for the 35 evaluable cases. Of the 4 patients who died, 3 had debilitating comorbid conditions and an overall APACHE (Acute Physiology and Chronic Health Evaluation) II score greater than 20. Of those failing on standard antibiotic therapy, 50% (n = 20) were switched to CPT-F; subsequently, all (n = 20) switched patients cleared pneumonia. The overall success rate with CPT-F was 90% versus 75% for comparators. Conclusions Treatment of MRSA pneumonia with CPT-F is associated with overall lower 28-day mortality than earlier studies with other agents. These data suggest a possible benefit in the use of CPT-F for therapy of MRSA hospital-acquired and health care–associated pneumonia.

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.

To the Editor: Cubicin (daptomycin for injection; Cubist Pharmaceuticals, Lexington, MA) is a cyclic lipopeptide antibacterial indicated in the United States for the treatment of complicated skin and skin structure infections and Staphylococcus aureus bloodstream infections, including those with right-sided infective endocarditis.1 Daptomycin’s prescribing information states that parenteral drug products should be inspected visually for particulate matter prior to administration, however, medical inquiries regarding the use of filters after reconstitution are common.1 Cubist conducted a study to evaluate the compatibility of reconstituted daptomycin with 5 commercially available syringe filters, based on comparison of both appearance and high-performance liquid chromatography (HPLC) potency of the filtered solution to an unfiltered control. Compatibility was defined for the filtered samples as no visible difference in the appearance versus the unfiltered control and no more than a 5% decrease in potency from the unfiltered control. Ten vials of daptomycin lot CDC079 were reconstituted with 10 mL of 0.9% sodium chloride for injection USP and pooled into a clear container. Fifteen milliliters of the pooled solution was first removed using an unfiltered syringe and transferred into a scintillation vial as a control sample. Utilizing a syringe with each of the syringe filters listed in Table 1, 15 mL of the pooled solution was withdrawn through the syringe. The filter was subsequently removed, and the filtered material was transferred into 1 of 5 scintillation vials. After visual inspection of each solution, the color and clarity of each were recorded and any discrepancy between the filtered solutions and the control solution was documented. Potency analysis was subsequently performed for each solution by reverse-phase HPLC using a C8 column, with a qualified daptomycin reference standard, lot 010903A. Table 1. Compatibility of daptomycin with selected syringe filters Analysis of the solutions demonstrated that the 5 filters tested did not impact the appearance of the solution (ie, no visual differences were observed between the filtered samples and the unfiltered control) or cause a significant decrease in potency (the percent difference from the control ranged from 0.39% to 2.23%, meeting the acceptance criteria defined in the protocol). All 5 filters evaluated in this study are considered compatible with reconstituted daptomycin.

Antimicrobial stewardship programs are increasingly recognized as critical in optimizing the use of antimicrobials. Consequently, more physicians, pharmacists, and other healthcare providers are developing and implementing such programs in a variety of healthcare settings. The purpose of this guidance document is to outline the knowledge and skills that are needed to lead an antimicrobial stewardship program. It was developed by antimicrobial stewardship experts from organizations that are engaged in advancing the field of antimicrobial stewardship.