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Background Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI). Methods Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator. Results Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator. Conclusions We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease–specific DOOR endpoints.

BackgroundElizabethkingia anophelis is an emerging Gram-negative nonlactose fermenter in the health care setting, where it causes life-threatening infections in immunocompromised patients. We aimed to characterize the molecular mechanisms of antimicrobial resistance and evaluate the utility of contemporary antibiotics with the intent to offer targeted therapy against an uncommonly encountered pathogen.MethodsWhole-genome sequencing (WGS) was conducted to accurately identify isolate species and elucidate the determinants of β-lactam resistance. Antimicrobial susceptibility testing was performed using broth microdilution and disk diffusion assays. To assess the functional contribution of the major metallo-β-lactamase (MBL) encoding genes to the resistance profile, blaBlaB was cloned into pBCSK(-) phagemid vector and transformed into Escherichia coli DH10B.ResultsWGS identified the organism as E. anophelis. MBL genes blaBlaB-1 and blaGOB-26 were identified, in addition to blaCME-2, which encodes for an extended-spectrum β-lactamase (ESBL). Plasmids were not detected. The isolate was nonsusceptible to all commonly available β-lactams, carbapenems, newer β-lactam β-lactamase inhibitor combinations, and to the combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI). Susceptibility to the novel siderophore cephalosporin cefiderocol was determined. A BlaB-1 transformant E. coli DH10B isolate was obtained and demonstrated increased minimum inhibitory concentrations to cephalosporins, carbapenems, and CAZ-AVI, but not ATM.ConclusionsUsing WGS, we accurately identified and characterized an extensively drug-resistant E. anophelis in an immunocompromised patient. Rapid evaluation of the genetic background can guide accurate susceptibility testing to better inform antimicrobial therapy selection.

Background Ceftazidime-avibactam (caz-avi), a novel β-lactam/β-lactamase inhibitor, is commonly utilized for carbapenem-resistant gram-negative infections (CR-GNI). However, the benefits vs risks of combining caz-avi with other agents are unclear. Methods In this retrospective cohort study, inpatients with CR-GNI treated with caz-avi were identified at 9 U.S. hospitals. The impact of caz-avi monotherapy (MT) or combination therapy (CT; i.e., any concomitant use of gram-negative-active antibiotics) was studied using logistic regression, controlling for baseline patient and hospital factors. The primary outcome was in-hospital mortality or discharge to hospice (death), and secondary outcomes were length of stay (LOS), resolution of infectious signs and symptoms (clinical response), 90-day recurrent infection and future caz-avi–resistant organism. An adjusted odds ratio (aOR) with 95% confidence interval (CI) was used to assess the primary and secondary outcomes. Results 328/499 (65.7%) patients received caz-avi as targeted therapy for a CR-GNI. Overall patients treated with MT and CT were similar at baseline and had comparable baseline demographics although patients treated with CT were more likely to be in the ICU and receive a concomitant empiric in vitro-concordant antibiotic (table 1). The most common organism was Klebsiella spp. (44.6%) followed by Pseudomonas aeruginosa (27.7%) (table 2). Concomitant gram-negative agents are shown in table 3. Overall, 92 (28.1%) patients died and CT (vs MT) displayed similar adjusted mortality risk (27.7% vs 28.7%; aOR [95%CI]: 0.67 [0.34-1.33]) and LOS (19 [9, 37] and 20 [9, 42.5] days). CT (vs MT) was associated with greater odds of clinical response (aOR: 2.25 [95%CI:1.15-4.41]). Among survivors, similar rates of 90-day recurrent infection (50/154 (32.5%) were observed in CT vs 18/82 (22.0%) in MT group (p=0.09) and 5 (2.19%) patients had future infection with a caz-avi–resistant pathogen (3 in CT and 2 in MT group). Conclusion Compared to patients with CR-GNI treated with caz-avi alone, those who received CT including caz-avy had similar survival and LOS but higher clinical response. The role of CT in the era of novel antibiotics warrants additional study. Disclosures Helen W. Boucher, MD, American Society of Microbiology: Honoraria|Elsevier: Honoraria|Sanford Guide: Honoraria.

Background Desirability of outcome ranking (DOOR) uses an ordinal ranking system to evaluate global outcomes in clinical trial participants by incorporating safety and efficacy assessments into a single endpoint. In this study, we developed and applied a DOOR endpoint for cIAI clinical trials. Methods We reviewed 10 Phase 3 noninferiority trials for cIAI with electronic patient-level data (n=5473 participants) submitted to the FDA between 2005-2021. Extending previous work [CID. 2019:68(10):1691-8)], we developed an expanded cIAI-specific DOOR endpoint based on clinically meaningful events captured in trial datasets and those that were unique to patients with cIAI. Using this DOOR endpoint, we assigned each participant a DOOR rank, estimated the probability that a participant in the study treatment arm in each trial would have a more desirable DOOR rank than if assigned to the comparator arm, and analyzed individual components of clinical experience in each trial. Results Based on analysis of available data, we noted heterogeneity in definitions of “indeterminate” clinical outcomes, and significant diversity and increased incidence of infectious complications (ICs), serious adverse events (SAEs), and surgical/percutaneous procedures in participants without clinical cure. These informed the expansion of the DOOR endpoint for cIAI to include clinical efficacy outcomes, ICs, SAEs, and additional procedures (Table 1). The DOOR distributions between treatment and comparator arms in all 10 trials were similar. DOOR probability estimates for the 10 trials ranged from 44.5% to 50.3% but were not nominally statistically significant. Component analyses in two trials showed that the study treatment was nominally statistically inferior to the comparator with regard to SAEs and clinical failure, respectively (Fig. 1b, 1c). Table 1.cIAI-Specific DOOR EndpointFigure 1.Forest plot listing the DOOR probabilities and probability for each DOOR component from 3 trials. Trial 1 has no significant differences between the treatment arms in the component analysis (A). The study treatment arm was shown to be nominally statistically inferior for SAEs in Trial 2 (B) and for clinical failure in Trial 3 (C). Conclusion We developed a cIAI-specific DOOR endpoint to better elucidate the events that participants experienced in these trials. The component analysis allowed more nuanced evaluation of the factors that contributed to the composite DOOR probability estimate and provided a visual display of the risk-benefit assessment of a study treatment vs. the comparator. Our study was limited by its retrospective approach and trial design heterogeneity. Disclosures Deborah Collyar, B.Sci, Apellis Pharmaceuticals, Inc.: Advisor/Consultant|Kinnate Biopharma: Advisor/Consultant|M2GEN: Advisor/Consultant|Maxis Clinical Sciences: Advisor/Consultant|Parexel: Honoraria|Pfizer: Honoraria|Roundtable Analytics, Inc.: Ownership Interest Sarah B. Doernberg, MD, MAS, Basilea: Clincal events committee|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Regeneron: Grant/Research Support|Shinogi: Clincal events committee Scott R. Evans, Ph.D., M.S., Abbvie: DSMB|Akouos: DSMB|Apellis: DSMB|AstraZeneca: Advisor/Consultant|Atricure: Advisor/Consultant|Becton Dickenson: Advisor/Consultant|Breast International Group: DSMB|Candel: DSMB|ChemoCentrix: Advisor/Consultant|Clover: DSMB|DayOneBio: DSMB|DeGruyter: Editor|Duke University: DSMB|Endologix: Advisor/Consultant|FHI Clinical: DSMB|Genentech: Advisor/Consultant|Horizon: Advisor/Consultant|International Drug Development Institute: Advisor/Consultant|Janssen: Advisor/Consultant|Lung Biotech: DSMB|Neovasc: Advisor/Consultant|NIH: Grant/Research Support|Nobel Pharma: Advisor/Consultant|Nuvelution: DSMB|Pfizer: DSMB|Rakuten: DSMB|Roche: DSMB|Roivant: Advisor/Consultant|SAB Biopharm: DSMB|SVB Leerink: Advisor/Consultant|Takeda: DSMB|Taylor & Francis: Book royalties|Teva: DSMB|Tracon: DSMB|University of Penn: DSMB|Vir: DSMB Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant Henry Chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Sumathi Nambiar, MD MPH, Johnson and Johnson: Stocks/Bonds Helen W. Boucher, MD, American Society of Microbiology: Honoraria|Elsevier: Honoraria|Sanford Guide: Honoraria.

Infection is the second leading cause of death in patients with cancer. Loss of efficacy in antibiotics due to antibiotic resistance in bacteria is an urgent threat against the continuing success of cancer therapy. In this review, the authors focus on recent updates on the impact of antibiotic resistance in the cancer setting, particularly on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This review highlights the health and financial impact of antibiotic resistance in patients with cancer. Furthermore, the authors recommend measures to control the emergence of antibiotic resistance, highlighting the risk factors associated with cancer care. A lack of data in the etiology of infections, specifically in oncology patients in United States, is identified as a concern, and the authors advocate for a centralized and specialized surveillance system for patients with cancer to predict and prevent the emergence of antibiotic resistance. Finding better ways to predict, prevent, and treat antibiotic-resistant infections will have a major positive impact on the care of those with cancer.

Background There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. Methods Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. Results In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P Conclusions Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. Clinical Trial Registration NCT03354598.

Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P, Imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam for treating hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), with a comparable tolerability profile. Imipenem/cilastatin/relebactam is an efficacious treatment option for nosocomial pneumonia, including HABP/VABP in mechanically ventilated and critically ill, high-risk patients.

SARS-CoV-2 transmission in K-12 schools was rare during in 2020-2021; few studies included CDC-recommended screening of asymptomatic individuals. We conduct a prospective observational study of SARS-CoV-2 screening in a mid-sized suburban public school district, to evaluate the incidence of asymptomatic COVID-19, document frequency of in-school transmission, and characterize barriers and facilitators to asymptomatic screening in schools. Staff and students undergo weekly pooled testing using home-collected saliva samples. Identification of >1 case in a school prompts investigation for in-school transmission and enhancement of safety strategies. With layered mitigation measures, in-school transmission even before student or staff vaccination is rare. Screening identifies a single cluster with in-school staff-to-staff transmission, informing decisions about in-person learning. The proportion of survey respondents self-reporting comfort with in-person learning before versus after implementation of screening increases. Costs exceed $260,000 for assays alone; staff and volunteers spend 135-145 hours per week implementing screening., Graphical Abstract, Reports of rare SARS-CoV-2 transmission in K-12 schools are limited by lack of asymptomatic screening. Doron et al. report that public-school screening for asymptomatic SARS-CoV-2 in 2020-21 provides valuable data about in-school transmission risk and informs decisions about in-person learning, but human and financial resource requirements are high.

Background Neutropenia is a serious complication following heart transplantation (OHT); however, risk factors for its development and its association with outcomes is not well described. We sought to study the prevalence of neutropenia, risk factors associated with its development, and its impact on infection, rejection, and survival. Methods A retrospective single-center analysis of adult OHT recipients from July 2004 to December 2017 was performed. Demographic, laboratory, medication, infection, rejection, and survival data were collected for 1 year post-OHT. Baseline laboratory measurements were collected within the 24 hours before OHT. Neutropenia was defined as absolute neutrophil count ≤1000 cells/mm3. Cox proportional hazards models explored associations with time to first neutropenia. Associations between neutropenia, analyzed as a time-dependent covariate, with secondary outcomes of time to infection, rejection, or death were also examined. Results Of 278 OHT recipients, 84 (30%) developed neutropenia at a median of 142 days (range 81-228) after transplant. Factors independently associated with increased risk of neutropenia included lower baseline WBC (HR 1.12; 95% CI 1.11-1.24), pre-OHT ventricular assist device (1.63; 1.00-2.66), high-risk CMV serostatus [donor positive, recipient negative] (1.86; 1.19-2.88), and having a previous CMV infection (4.07; 3.92-13.7). Conclusions Neutropenia is a fairly common occurrence after adult OHT. CMV infection was associated with subsequent neutropenia, however, no statistically significant differences in outcomes were found between neutropenic and non-neutropenic patients in this small study. It remains to be determined in future studies if medication changes in response to neutropenia would impact patient outcomes.

U.S. Efforts to Curb Antibiotic Resistance Demonstrating that large-scale efforts to control antibiotic resistance have saved lives would help secure ongoing and expanded funding and support in thi...

Background The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance, Imipenem/relebactam (IMI/REL) is a suitable treatment option for serious gram-negative infections, including those caused by carbapenem-nonsusceptible pathogens in high-risk patients. IMI/REL may be preferable to colistin-based therapy, given comparable efficacy but IMI/REL’s significantly lower nephrotoxicity and improved overall tolerability.

Background Infections caused by antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae, have increased in frequency, resulting in significant patient morbidity and mortality. The Infectious Diseases Society of America continues to propose legislative, regulatory, and funding solutions to address this escalating crisis. This report updates the status of development and approval of systemic antibiotics in the United States as of late 2018. Methods We performed a review of the published literature and on-line clinical trials registry at www.clinicaltrials.gov to identify new systemically acting orally and/or intravenously administered antibiotic drug candidates in the development pipeline, as well as agents approved by the US Food and Drug Administration since 2012. Results Since our 2013 pipeline status report, the number of new antibiotics annually approved for marketing in the United States has reversed its previous decline, likely influenced by new financial incentives and increased regulatory flexibility. Although our survey demonstrates progress in development of new antibacterial drugs that target infections caused by resistant bacterial pathogens, the majority of recently approved agents have been modifications of existing chemical classes of antibiotics, rather than new chemical classes. Furthermore, larger pharmaceutical companies continue to abandon the field, and smaller companies face financial difficulties as a consequence. Conclusions Unfortunately, if 20 × '20 is achieved due to efforts embarked upon in decades past, it could mark the apex of antibiotic drug development for years to come. Without increased regulatory, governmental, industry, and scientific support and collaboration, durable solutions to the clinical, regulatory, and economic problems posed by bacterial multidrug resistance will not be found.

BackgroundData suggest that COVID-19 transmission in K-12 schools is uncommon, but few studies have confirmed this using widespread screening of asymptomatic individuals.ObjectiveTo evaluate the incidence of asymptomatic COVID-19, document the frequency of in-school transmission, and confirm feasibility of widespread asymptomatic screening in schools.DesignProspective observational studySettingSingle mid-sized suburban school district including 10 schools and a central office.ParticipantsDistrict staff and studentsInterventionsAsymptomatic screening PCR for SARS-CoV-2MeasurementsConcurrent with a hybrid model and layered mitigation, weekly pooled testing of staff and secondary students was offered using saliva samples collected at home. Identification of >1 case in a school prompted investigation for possible in-school transmission. Staff and families were surveyed about satisfaction with the screening program.ResultsFrom weeks 1-18, rates of incident COVID-19 in the surrounding community rose steadily. Weekly staff and student screening identified 0-7 asymptomatic cases/week. In week 7, 5 cases were identified among staff who shared an office setting. Enhancements to mitigation strategies were undertaken. The proportion of survey respondents self-reporting comfort with in-person learning before versus after implementation of screening increased.LimitationsBecause screening testing was not mandatory, the results from the participating population might not represent the entire school community.ConclusionsIn this school district with layered mitigation measures, in-school transmission was rare. The program identified a cluster with in-school staff-to-staff transmission and spurred enhancement of safety strategies. A weekly COVID-19 screening program can provide critical data to inform mitigation efforts, and provides school-specific, current data to inform decisions about in-person learning models. Screening provided reassurance and identified asymptomatic cases.FundingThe Wellesley Education Foundation provided funding for the testing.

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.

Background Understanding social and scientific drivers of antibiotic resistance is critical to help preserve antibiotic efficacy. These drivers include exposure to subinhibitory antibiotic concentrations in the environment and clinic. Objectives To summarize and quantify the relationship between subinhibitory fluoroquinolone exposure and antibiotic resistance and mutagenesis to better understand resistance patterns and mechanisms. Methods Following PRISMA guidelines, PubMed, Web of Science and Embase were searched for primary in vitro experimental studies on subinhibitory fluoroquinolone exposure and bacterial antibiotic resistance and mutagenesis, from earliest available dates through to 2018 without language limitation. A specifically developed non-weighted tool was used to assess risk of bias. Results Evidence from 62 eligible studies showed that subinhibitory fluoroquinolone exposure results in increased resistance to the selecting fluoroquinolone. Most increases in MIC were low (median minimum of 3.7-fold and median maximum of 32-fold) and may not be considered clinically relevant. Mechanistically, resistance is partly explained by target mutations but also changes in drug efflux. Collaterally, resistance to other fluoroquinolones and unrelated antibiotic classes also develops. The mean ± SD quality score for all studies was 2.6 ± 1.8 with a range of 0 (highest score) to 7 (lowest score). Conclusions Low and moderate levels of resistance and efflux changes can create an opportunity for higher-level resistance or MDR. Future studies, to elucidate the genetic regulation of specific resistance mechanisms, and increased policies, including surveillance of low-level resistance changes or genomic surveillance of efflux pump genes and regulators, could serve as a predictor of MDR development.

Trichodysplasia spinulosa (TS) is a rare skin condition caused by trichodysplasia spinulosa-associated polyomavirus (TSPyV). It affects immunosuppressed patients, and

This Viewpoint reviews the FDA's May 2020 Emergency Use Authorization of the antiviral drug remdesivir for treatment of COVID-19 and discusses the need for a transparent distribution plan of a drug not otherwise available in the US and for which demand will likely exceed supply [ABSTRACT FROM AUTHOR] Copyright of JAMA: Journal of the American Medical Association is the property of American Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

The year 2019 brought about a multitude of innovations in clinical infectious diseases. With the continued rise of antimicrobial resistance (AMR), advances in diagnostics and newly available antibiotics offer additional strategies for combating this threat, but the broken antibiotic market serves as an impediment to further developments. The IDSA and other stakeholders are working to create novel pull incentives to stabilize the pipeline. Ongoing needs include developing optimal stewardship practices, including by using narrow-spectrum antibiotics and shorter durations of therapy. In the area of solid organ transplantation, early data from transplanting Hepatitis C virus (HCV)-infected organs are encouraging and the American Society of Transplantation (AST) released new guidelines addressing several key issues. Lastly, 2019 saw a resurgence in Measles emphasizing the importance of vaccination., In 2019, there were numerous new developments in clinical infectious diseases. We discuss strategies for combatting the ever-evolving threat of antimicrobial resistance, updates in solid organ transplantation guidelines, as well as the resurgence of measles.

Clinical trials for Staphylococcus aureus bloodstream infections (SAB) are broadly grouped into 2 categories: registrational trials intended to support regulatory approval of antibiotics for the treatment of SAB and strategy trials intended to inform clinicians on the best treatment options for SAB among existing antibiotics. Both types of SAB trials are urgently needed but have been limited by cost, complexity, and regulatory uncertainty. Here, we review key SAB trial design considerations for investigators, sponsors, and regulators.

BackgroundIn the randomized controlled RESTORE-IMI 1 clinical trial (NCT02452047), imipenem/cilastatin (IMI) with relebactam (IMI/REL) was as effective as colistin plus IMI for the treatment of imipenem-nonsusceptible gram-negative infections. Differences in nephrotoxicity were observed between treatment arms. As there is no standard definition of nephrotoxicity used in clinical trials, we conducted analyses to further understand the renal safety profile of both treatments.MethodsNephrotoxicity was retrospectively evaluated using 2 acute kidney injury assessment criteria (Kidney Disease Improving Global Outcomes [KDIGO] and Risk, Injury, Failure, Loss, and End-stage Kidney Disease [RIFLE]). Additional outcomes included time to onset of protocol-defined nephrotoxicity and incidence of renal adverse events.ResultsOf 47 participants receiving treatment, 45 had sufficient data to assess nephrotoxicity (IMI/REL, n = 29; colistin plus IMI, n = 16). By KDIGO criteria, no participants in the IMI/REL but 31.3% in the colistin plus IMI group experienced stage 3 acute kidney injury. No IMI/REL-treated participants experienced renal failure by RIFLE criteria, vs 25.0% for colistin plus IMI. Overall, the time to onset of nephrotoxicity varied considerably (2–22 days). Fewer renal adverse events (12.9% vs 37.5%), including discontinuations due to drug-related renal adverse events (0% vs 12.5%), were observed in the IMI/REL group compared with the colistin plus IMI group, respectively.ConclusionsOur analyses confirm the findings of a preplanned end point and provide further evidence that IMI/REL had a more favorable renal safety profile than colistin-based therapy in patients with serious, imipenem-nonsusceptible gram-negative bacterial infections.ClinicalTrials.gov IdentifierNCT02452047.

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Antimicrobial resistance threatens health and global security, with an estimated 162,000 deaths per year in the United States caused by multidrug-resistant infections.1 Surveillance and stewardship...

Patient management is not based on a single decision. Rather, it is dynamic: based on a sequence of decisions, with therapeutic adjustments made over time. Adjustments are personalized: tailored to individual patients as new information becomes available. However, strategies allowing for such adjustments are infrequently studied. Traditional antibiotic trials are often nonpragmatic, comparing drugs for definitive therapy when drug susceptibilities are known. COMparing Personalized Antibiotic StrategieS (COMPASS) is a trial design that compares strategies consistent with clinical practice. Strategies are decision rules that guide empiric and definitive therapy decisions. Sequential, multiple-assignment, randomized (SMART) COMPASS allows evaluation when there are multiple, definitive therapy options. SMART COMPASS is pragmatic, mirroring clinical, antibiotic-treatment decision-making and addressing the most relevant issue for treating patients: identification of the patient-management strategy that optimizes the ultimate patient outcomes. SMART COMPASS is valuable in the setting of antibiotic resistance, when therapeutic adjustments may be necessary due to resistance.

This updated section of the guideline from the Infectious Diseases Community of Practice of the American Society of Transplantation reviews the screening of donor and candidate prior to solid organ transplantation. Screening of donor and candidate is vital for optimizing post-transplant outcomes. Risk assessment based on detailed history and appropriate diagnostic evaluation is essential. Serologic screening for certain viral infections is important and aids in immunization counseling and risk mitigation of recipients. In addition to serology, nucleic acid testing for hepatitis B, hepatitis C and human immunodeficiency virus has been required for deceased and living donors. Certain endemic exposure may warrant additional evaluation beyond recommended standard testing. Diagnosed infection in the donor or recipient warrants treatment as well as additional testing and/or prophylaxis to mitigate risk for post-transplant complications. Certain infections in the immediate pre-transplant period may warrant delay of transplantation.

Background A 60-year-old woman with acute myeloid leukemia developed fever and cough post induction chemotherapy. Meropenem and vancomycin were administered as empiric therapy. A bloodstream infection due to resistant E. meningoseptica was initially identified. Ceftazidime-avibactam and aztreonam (ATM) were next administered. Minocycline and trimethoprim/sulfamethoxazole (TMP/SMX) were added as the patient deteriorated and died ten days later. Methods MIC testing /disc diffusion assays were done according to CLSI guidelines. Whole genome sequencing (WGS) was performed, assembled, and annotated using PATRIC.org and compared to Institute Pasteur cgMLST instance of the BIGSdb database tool. Resistant genes and plasmids were identified by the Center for Genomic epidemiology. Results Core genome MLST and average nucleotide identity of 99.46% revealed the organism as E. anophelis, not E. meningoseptica. The WGS assembly resulted in 118 contigs with a chromosome of 4,110,726 bp. Plasmids were not identified. Resistance genes blaB11, blaGOB-13 (a metallo beta-lactamase) and blaCME-1 were detected. E. anophelis was resistant to multiple drug classes including aminoglycosides, vancomycin, cephalosporins, and carbapenems. Mechanism based susceptibility testing using double-disc diffusion assays demonstrated susceptibility to cefiderocol (MIC 1 µg/ml), minocycline, TMP/SMX, linezolid, and modestly wider zones of inhibition with the addition of ATM. Susceptibility results are shown in Table 1. Antimicrobial susceptibility testing using various BLIs and combinations with Aztreonam Conclusion This is one of the first reports describing E. anophelis in immunocompromised hosts. More thorough testing methods are needed for distinguishing between species in the Elizabethkingia genus in hospital settings as there is concern that this may represent a novel opportunistic infection. Per CDC, E. anophelis outbreaks have occurred in three Midwestern states in 2016. Vigilance is warranted to the role of this pathogen in immunocompromised hosts. Disclosures Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)

Background Sulopenem is a broad-spectrum IV and oral penem antibiotic being developed for the treatment of infections caused by multidrug-resistant bacteria. Overall and Clinical Success in Patients with an Uncomplicated UTI at Test of Cure (TOC) and End of Treatment (EOT) Methods 1,671 adult women with pyuria, bacteriuria, and signs and symptoms of uUTI were randomized to sulopenem etzadroxil/probenecid bid for 5 days or ciprofloxacin bid for 3 days. Two independent primary analyses, each with a separate alpha assigned, were incorporated into the design of the study with the primary endpoint being overall success (combined clinical and microbiologic success) at the Test of Cure (TOC) visit. In the micro-MITTR population (patients with baseline pathogen resistant to ciprofloxacin), sulopenem was compared for superiority over ciprofloxacin; in the micro-MITTS population (patients with baseline pathogen susceptible to ciprofloxacin), the two agents were compared for non-inferiority. Using a pre-specified hierarchical testing procedure (Westfall 2001), the primary efficacy endpoint was then to be further tested if either superiority or non-inferiority was declared in the MITTR or MITTS populations, respectively. Results In the micro-MITTR population, sulopenem demonstrated superiority to ciprofloxacin (p < 0.001). In the micro-MITTS population, sulopenem was not non-inferior to ciprofloxacin for the primary endpoint, driven primarily by the higher rate of asymptomatic bacteriuria post treatment in patients on sulopenem. In the combined analysis of all randomized patients with an organism identified at baseline (MITTR+MITTS), sulopenem was non-inferior to ciprofloxacin. Treatment emergent adverse events occurred more frequently in sulopenem patients (all, 24.8% vs 13.9%; related, 17.0% vs 6.2%), accounted for by a higher incidence of self-limited diarrhea (12.4% vs 2.5%). Serious adverse events were similar on each regimen. Conclusion Sulopenem was superior to ciprofloxacin for the treatment of adult women with uUTI due to quinolone non-susceptible pathogens. Sulopenem was not non-inferior in the treatment of quinolone susceptible pathogens, driven by a lower rate of asymptomatic bacteriuria in patients receiving ciprofloxacin, but was non-inferior in the combined population of patients. Disclosures Michael W. Dunne, MD, Iterum Therapeutics (Employee, Shareholder) Anita F. Das, PhD, Iterum Therapeutics (Consultant) Michael Zelasky, BS, Iterum Therapeutics (Employee) Karthik Akinapelli, BS, Iterum Therapeutics (Employee) Steven I. Aronin, MD, Iterum Therapeutics (Employee)

Introduction Dalbavancin is a new lipoglycopeptide that is active against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. It has a half-life of 14.4 days, permitting intravenous treatment of acute bacterial skin and skin structure infections without the need for daily dosing. Objective The objective of these analyses was to compare the adverse event profile of dalbavancin with that of the comparator agents in the treatment of skin and skin structure infections. Methods Data on adverse events and laboratory assessments collected from 3002 patients enrolled in seven late-stage, randomized clinical trials were analyzed for patients receiving dalbavancin or a comparator antibiotic. Results Overall adverse event rates were similar or lower for patients receiving dalbavancin (799/1778; 44.9 %) compared with those receiving comparator agents (573/1224; 46.8 %, p = 0.012). The most common treatment-emergent adverse events were nausea, headache, diarrhea, constipation, vomiting, rash, urinary tract infection, pruritus, and insomnia. The duration and timing of the onset of adverse events were similar for patients receiving dalbavancin relative to the comparators. Conclusion Dalbavancin exhibits a favorable overall safety profile for treatment of acute bacterial skin and skin structure infections due to Gram-positive bacteria.

Purpose Neutropenia is a serious complication following heart transplantation (OHT) however risk factors for its development and its association with outcomes is not well described. We sought to study the prevalence of neutropenia, risk factors associated with its development and its impact on infection, rejection and survival. Methods A retrospective single center analysis of adult OHT recipients from July 2004 to December 2017 was performed. Demographic, laboratory, medication, infection, rejection and survival data were collected for 1 year post-OHT. Baseline lab measurements were collected within the 24 hours before OHT. Neutropenia was defined as absolute neutrophil count ≤ 1000 mm3. Cox proportional hazards models explored associations with time to first neutropenia. Associations of neutropenia, analyzed as a time-dependent covariate, with secondary outcomes of time to infection, rejection or death were also examined. Results Of 278 OHT recipients, 84 (30%) developed neutropenia within a median of 142 days (81-228 days) after transplant. More than half (56%) of those with neutropenia were treated with GCSF. Most infections were CMV disease whether they occurred before (14/22, 64%) or after (8/9, 89%) neutropenia or in the absence of neutropenia (20/40, 50%). Factors associated with increased risk of neutropenia are in Table 1. Neutropenia was not significantly associated with secondary outcomes of infection (N=9), rejection (N=10) or death (N=4), however numbers were small. Conclusion Neutropenia is a fairly common occurrence after adult OHT. Infection was associated with subsequent neutropenia, however no statistically significant differences in outcomes (infection, rejection, death) were found between neutropenic and non-neutropenic patients in this small study. It remains to be determined if medication changes in response to neutropenia impact patient outcomes. Supported by an unrestricted grant by Merck, NIH CTSA award: UL1TR002544 and Tupper Research Fund at Tufts Medical Center.

Background Desirability of outcome ranking (DOOR) is an innovative approach in clinical trials to evaluate the global benefits and risks of an intervention. We developed and validated a DOOR endpoint for Staphylococcus aureus bloodstream infection (BSI) through a survey to infectious diseases clinicians and secondary analysis of trial data. Methods We administered a survey of 20 cases of S. aureus BSI, asking respondents to rank outcomes by global desirability. Correlations and percentage of pairwise agreement among rankings were estimated to inform development of a DOOR endpoint, which was applied to 2 prior S. aureus BSI trials. The probability that a patient randomly assigned to experimental treatment would have a better DOOR ranking than if assigned to control was estimated. Results were also analyzed using partial credit, which is analogous to scoring an academic test, assigning 100% to the most desirable outcome, 0% to the least, and "partial credit" to intermediate ranks. Results Forty-two recipients (97%) completed the survey. The DOOR endpoint fitting these rankings (r = 0.89; 95% confidence interval, 0.67 to 0.94) incorporated survival plus cumulative occurrence of adverse events, cure, infectious complications, and ongoing symptoms. Tailored versions of this endpoint were applied to 2 S. aureus BSI trials, and both demonstrated no benefit of the experimental treatment using DOOR and partial credit analysis. Conclusions Using S. aureus BSI as an exemplar, we developed a DOOR endpoint that can be used as a template for development of DOOR endpoints for other diseases. Future trials can incorporate DOOR to allow for global assessment of patient experience.

Importance The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, −6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, −3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, −1.8 days [95% CI, −3.1 to −0.6]). Conclusions and Relevance Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration ClinicalTrials.gov Identifier:NCT01191840

BackgroundInfective endocarditis (IE) often requires surgical intervention. An increasingly common cause of IE is injection drug use (IDU-IE). There is conflicting evidence on whether postoperative mortality differs between people with IDU-IE and people with IE from etiologies other than injection drug use (non–IDU-IE). In this manuscript, we compare short-term postoperative mortality in IDU-IE vs non–IDU-IE through systematic review and meta-analysis.MethodsThe review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Publication databases were queried for key terms included in articles up to September 2017. Randomized controlled trials, prospective cohorts, or retrospective cohorts that reported on 30-day mortality or in-hospital/operative mortality following valve surgery and that compared outcomes between IDU-IE and non–IDU-IE were included.ResultsThirteen studies with 1593 patients (n = 341 [21.4%] IDU-IE) were included in the meta-analysis. IDU-IE patients more frequently had tricuspid valve infection, Staphylococcus infection, and heart failure before surgery. Meta-analysis revealed no statistically significant difference in 30-day postsurgical mortality or in-hospital mortality between the 2 groups.ConclusionsDespite differing preoperative clinical characteristics, early postoperative mortality does not differ between IDU-IE and non–IDU-IE patients who undergo valve surgery. Future research on long-term outcomes following valve replacement is needed to identify opportunities for improved healthcare delivery with IDU-IE.

Acute bacterial skin and skin structure infections (ABSSSI) have increased in incidence and severity. The involvement of resistant organisms, particularly methicillin-resistant Staphylococcus aureus, presents additional challenges. The lipoglycopeptide dalbavancin has a prolonged half-life, high protein binding, and excellent tissue levels which led to its development as a once-weekly treatment for ABSSSI. In the pivotal DISCOVER 1 and DISCOVER 2 trials, dalbavancin proved non-inferior to vancomycin followed by linezolid when used sequentially for ABSSSI, forming the basis for its recent approval in the US and Europe for ABSSSI.A literature search of published pharmacologic and clinical data was conducted to review the chemistry, pharmacodynamics, and pharmacokinetics of dalbavancin. We also discuss its development process, highlighting efficacy and safety data from pertinent clinical trials and the role it could play in the current clinical landscape.DISCOVER 1 and DISCOVER 2 demonstrated dalbavancin's non-inferiority to vancomycin followed by linezolid for ABSSSI and confirmed its safety and tolerability. They were among the first trials to use new, early primary efficacy endpoints, and dalbavancin was among the first agents designated a Qualified Infectious Disease Product for expedited review. Dalbavancin may prove to be a valuable option for ABSSSI patients in whom conventional therapy is limited.

Pathogen-directed therapy targeting multidrug-resistant bacteria in pneumonia can be a challenge. We reviewed the recent literature on bacterial resistance, diagnostic methods, and treatment strategies to guide pathogen-directed therapy of respiratory infections.Antibiotic resistance is a growing problem in both community and nosocomial settings. Macrolide resistance in Streptococcus pneumoniae varies geographically, ranging from 45 to 88%, and has been associated with prior antibiotic use. Methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative bacilli remain the main targets for pathogen-directed therapy in patients with hospital-acquired and ventilator-associated pneumonia. Rapid molecular tests show promise to facilitate pathogen-directed therapy. Improved antibiotic use with the right drug and optimal dose is a key strategy in tackling antimicrobial resistance. Evidence supporting de-escalation for hospital-acquired and ventilator-associated pneumonia has been increasing. To date, no convincing evidence exists to support combination therapy for severe infections due to carbapenem-resistant Gram-negative bacilli. Aerosolized therapy might provide additive benefits to parenteral therapy, but requires further study.Pathogen-directed therapy guided by in-vitro microbiological data is a safe approach for the treatment of respiratory infections due to antibacterial-resistant bacteria. Further research should focus on the role of rapid diagnostic tools, new antibiotics, and novel immunotherapy for respiratory infection.

Increasing resistance to antimicrobial agents has led to international pledges to increase funding for public health initiatives as well as for research and development to combat this grave threat....

Despite progress in antimicrobial drug development, a critical need persists for new, feasible pathways to develop antibacterial agents to treat people infected with drug-resistant bacteria. Infections due to resistant gram-negative bacilli continue to cause unacceptable morbidity and mortality rates. Antibacterial agents have been historically studied in noninferiority clinical trials that focus on a single site of infection (eg, complicated urinary tract infections, intra-abdominal infections), yet these designs may not be optimal, and often are not feasible, for study of infections caused by drug-resistant bacteria. Over the past several years, multiple stakeholders have worked to develop consensus regarding paths forward with a goal of facilitating timely conduct of antimicrobial development. Here we advocate for a novel and pragmatic approach and, toward this end, present feasible trial designs for antibacterial agents that could enable conduct of narrow-spectrum, organism-specific clinical trials and ultimately approval of critically needed new antibacterial agents.

Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection.We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome.Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus.Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).

Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies.

Background Clinical trials of new antibacterial agents in patients with carbapenem-resistant infections are critical but challenging to conduct. One challenge is identifying the study population by microbiological (micro) criteria; patients need to be identified locally to initiate effective treatment rapidly, but data standardization requires central laboratory confirmation. REL is a novel β-lactamase inhibitor that can restore imipenem activity against many imipenem-NS Gram-negative pathogens. Here we compare a supplemental analysis population based on local microbiology data (SmMITT eligibility) with the primary analysis population (mMITT) from the RESTORE-IMI 1 trial (NCT02452047) of IMI/REL vs. IMI+CST. Methods Randomized, active-controlled, double-blind, phase 3 trial enrolled adults with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI). Patients were mMITT-eligible if pathogens were imipenem-NS (but CST- and IMI/REL-susceptible) based on central laboratory minimum inhibitory concentration (MIC). SmMITT comprised mMITT plus all patients who met inclusion criteria only based on local laboratory MIC. Results The SmMITT population (n = 41 [28 IMI/REL; 13 IMI+CST]) comprised 31 from mMITT plus 10 based on local MIC; 12/41 (29%) had HABP/VABP, 8/41 (20%) cIAI, and 21/41 (51%) cUTI. The majority of differences in central vs. local MIC were 1–2 dilutions; similar numbers of patients were excluded from mMITT due to imipenem susceptibility (n = 5) or IMI/REL-NS (n = 4); 1 patient was CST-NS. Baseline characteristics, including infecting pathogens, were comparable in SmMITT and mMITT (SmMITT: 68% male; 46% ≥65 y; 24% APACHE II score >15; 22% creatinine clearance Conclusion Consistency of results was demonstrated across two analysis populations in a trial of resistant pathogens. This analysis provides results supportive of expected future clinical use of IMI/REL when treatment decisions will be made based on local laboratory results. Disclosures K. Kaye, Merck & Co., Inc.: Consultant and Research Contractor, Research grant. Melinta, Achaogen, Allergan: Consultant, Consulting fee. T. File, Bio Merieux, Curetis, Melinta, Merck, MotifBio, Nabriva, Paratek, Pfizer: Consultant, Consulting fee. H. W. Boucher, Merck & Co., Inc.: Scientific Advisor, Consulting fee. M. Brown, Merck & Co., Inc.: Employee, Salary. A. Aggrey, Merck & Co., Inc.: Employee, Salary. I. Khan, Merck & Co., Inc.: Employee, Salary. H. K. Joeng, Merck & Co., Inc.: Employee, Salary. R. Tipping, Merck & Co., Inc.: Employee, Salary. J. Du, Merck & Co., Inc.: Employee, Salary. K. Young, Merck & Co., Inc.: Employee, Salary and Stock options. J. Butterton, Merck & Co., Inc.: Employee, Salary and Stock. N. A. Kartsonis, Merck & Co., Inc.: Employee, Salary and Stocks. A. Paschke, Merck & Co., Inc.: Employee and Shareholder, Salary.

Background Nephrotoxicity is a common complication of CST-based therapy, limiting its use to treat carbapenem-resistant bacterial infections. REL is a novel β-lactamase inhibitor that restores imipenem activity against many imipenem-NS strains of Gram-negative pathogens. IMI/REL was shown to be as effective but better tolerated than IMI+CST in the phase 3 RESTORE-IMI 1 study (NCT02452047), including a lower incidence of treatment-emergent nephrotoxicity (prespecified secondary endpoint). Here we present additional renal safety data from that trial. Methods Randomized, active-controlled, double-blind, phase 3 trial in adults with infections caused by ≥1 imipenem-NS (but CST- and IMI/REL-susceptible) pathogen. Treatment (2:1) was IMI/REL or IMI+CST for 5–21 days in complicated intra-abdominal infection and complicated urinary tract infection and 7–21 days in hospital-acquired/ventilator-associated bacterial pneumonia. For baseline serum creatinine (Cr) 1.2 mg/dL OR decrease in Cr clearance [CrCl] ≥50%; for Cr ≥1.2 mg/dL, nephrotoxicity was defined as an increase in serum Cr ≥1 mg/dL OR decrease from baseline in CrCl ≥20% OR need for renal replacement therapy. KDIGO and RIFLE criteria of acute kidney injury (AKI) were applied to the data; renal-related adverse events (AEs) were analyzed. Results A total of 47 patients were randomized, treated (31 IMI/REL, 16 IMI+CST), and included in this analysis. A significantly smaller percentage of patients in the IMI/REL than the IMI+CST group experienced protocol-defined nephrotoxicity (% difference: −45.9 [95% CI: −69.1, −18.4]; P = 0.002) during study treatment and the 14-day follow-up period (table). These results were confirmed by applying KDIGO and RIFLE criteria, with no patients in the IMI/REL group in stage 3 AKI or failure compared with 31.3% and 25.0%, respectively, in the IMI+CST group. Fewer renal AEs, including discontinuations due to renal events, were observed in the IMI/REL group. Conclusion IMI/REL demonstrates a more favorable renal safety profile compared with CST-based therapy, as demonstrated by a lower incidence of treatment-emergent nephrotoxicity and AKI with IMI/REL across several different analyses. Disclosures M. Brown, Merck & Co., Inc.: Employee, Salary. J. Motsch, Heidelberg University: Research Contractor, Research grant. K. Kaye, Merck & Co., Inc.: Consultant and Research Contractor, Research grant. Melinta, Achaogen, Allergan: Consultant, Consulting fee. T. File, Bio Merieux, Curetis, Melinta, Merck, MotifBio, Nabriva, Paratek, Pfizer: Consultant, Consulting fee. H. W. Boucher, Merck & Co., Inc.: Scientific Advisor, Consulting fee. N. Vendetti, Merck & Co., Inc.: Employee, Salary. A. Aggrey, Merck & Co., Inc.: Employee, Salary. H. K. Joeng, Merck & Co., Inc.: Employee, Salary. R. Tipping, Merck & Co., Inc.: Employee, Salary. J. Du, Merck & Co., Inc.: Employee, Salary. D. D. Depestel, Merck & Co., Inc.: Employee, Salary. J. Butterton, Merck & Co., Inc.: Employee, Salary and Stock. N. A. Kartsonis, Merck & Co., Inc.: Employee, Salary and Stocks. A. Paschke, Merck & Co., Inc.: Employee and Shareholder, Salary.

Infections caused by antibiotic-resistant bacteria, especially the "ESKAPE" pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's "10 × '20 Initiative."

The authors summarize key aspects of the problem of antimicrobial resistance and share their views about an appropriate response to this international threat to public health.