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Background Disruptions to gut microbiota composition can result in dysbiosis and subsequent intestinal colonization by opportunistic pathogens such as Clostridioides difficile.1,2 The incidence of Clostridioides difficile infection (CDI) in persons ≥ 65 years old is greater than in those < 65 years old,3 with 1 in 11 CDI patients ≥ 65 years old dying within 1 month of diagnosis.4 We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in patients with recurrent CDI (rCDI) who were ≥ 65 years old with comorbidities. This is a subgroup analysis of the PUNCH CD3 trial (NCT03244644), a prospective, multicenter, randomized, double-blind, placebo-controlled phase 3 trial. Methods Participants enrolled in PUNCH CD3 were ≥ 18 years old with documented rCDI who completed standard-of-care antibiotic therapy prior to treatment with RBX2660 or placebo. Treatment success was defined as remaining recurrence-free 8 weeks after intervention. In this subgroup analysis, we assessed outcomes of participants ≥ 65 years old with underlying cardiac disorders, chronic kidney disease (CKD), and gastrointestinal (GI) disorders. The treatment-emergent adverse events (TEAEs) were summarized for the double-blind treatment period within 8 weeks and censored if a patient received open-label RBX2660 after CDI recurrence. Results In the modified intent-to-treat population, 119 of 262 participants (45%) were ≥ 65 years old. Of these 119 participants, 42% had a cardiac disorder, 19% had CKD, and 61% had a GI disorder; the respective RBX2660 treatment success rates were 69%, 68%, and 67% (Figure 1). In the total safety population, the overall incidence of TEAEs was 52% with RBX2660 treatment compared to 44% with placebo treatment; mild events accounted for most of the difference (40% vs 30%) (Table 1). The overall incidence of TEAEs was 51% in RBX2660-treated participants ≥ 65 years old and 61%, 68%, and 51% in those participants with a cardiac disorder, CKD, or GI disorder, respectively. Most TEAEs were mild or moderate in severity and related to a pre-existing condition. Conclusion RBX2660 is safe and efficacious across a range of medically complex patients and consistently reduced rCDI in adults ≥ 65 years old, regardless of baseline comorbidities. Disclosures Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Stuart Johnson, M.D., Ferring Pharmaceuticals: Membership on Ferring Publication Steering Committee|Ferring Pharmaceuticals: Employee|Summit Plc: Advisor/Consultant Adam Harvey, PhD, Ferring Pharmaceuticals: Employment.

Background Recurrence of Clostridioides difficile infection (rCDI) is common - up to 35% of patients may recur. RBX2660 is a microbiota restoration therapy to reduce rCDI. Here we report 8 weeks HRQL results using the Clostridioides difficile Health-related Quality-of-Life Questionnaire (Cdiff32), a disease-specific instrument, from PUNCH CD3 (a randomized, double-blinded, placebo-controlled RBX2660 Phase 3 trial, NCT03244644). Methods Cdiff32 includes three domains (physical, mental, and social) and a total score (all range from 0 to 100 [100 best possible]). Changes in Cdiff32 from baseline to week 8 were compared between RBX2660 and placebo (PBO) using unadjusted and adjusted analyses controlling for baseline score, demographic and disease characteristics. Per trial protocol, missing data were imputed via last observation carried forward (LOCF); as-observed data were also analyzed. Patients experiencing recurrence after blinded treatment received open-label RBX2660 per physician discretion; these participants were excluded unless, per LOCF, data were available from the blinded period for week 8 use. Results A total of 206 patients (140 RBX2660, 66 PBO) were included, with similar age (mean±SD) 61.1±16.9 yrs (RBX2660) and 57.3±16.4 yrs (PBO) and baseline Cdiff32 scores. More than half of the patients had multiple comorbidities. Cdiff32 scores improved significantly from baseline to weeks 1, 4, and 8 for both arms, with greater improvements for RBX2660 through week 8 (Figs. 1 & 2). At week 8, statistical differences were found for mental domain (unadjusted: 8.01±3.64; adjusted: 7.07, 95% confidence interval: [0.28, 13.86], both P< 0.05) and total score (adjusted: 6.11, [0.14, 12.08], P< 0.05), all favoring RBX2660. Results were similar for the as-observed analyses, with the adjusted physical domain also statistically favoring RBX2660. Conclusion Most patients in this study reported improved HRQL. Improvements were observed in both arms, but RBX2660-treated patients had more robust and sustained improvements with statistically significant differences in Cdiff32 scores. This study suggests that microbiome restoration therapy might positively affect HRQL; future research may link these improvements directly with microbiota changes. Disclosures Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Erik R. Dubberke, MD, MSPH, Abbott: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Seres: Advisor/Consultant|Summit: Advisor/Consultant|Synthetic Biologics: Grant/Research Support Amy Guo, PhD, Ferring Pharmaceuticals: Employee Adam Harvey, PhD, Ferring Pharmaceuticals: Employment Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received consulting fees from Ferring for the conduct of this study. Mirko Fillbrunn, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Lindy Bancke, PharmD, Rebiotix, a Ferring Company: Employee Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support.

Summary Background Recurrent Clostridioides difficile infection (CDI) is one of the most common and challenging infections to treat in healthcare facilities. Faecal microbiota transplantation (FMT) is recommended as a definitive treatment option. Methods We performed a retrospective review of 50 patients from January 2015 to December 2019 who underwent FMT for recurrent CDI. Primary outcome was recurrence of CDI within 12-weeks of FMT and secondary outcomes were the need for repeat FMT, serious adverse outcomes related to FMT and all-cause mortality. Results Fifty charts were reviewed, of which 47 cases comprising 17 immunocompromised patients treated with FMT via retention enema were included in the study. The majority of the patients had ≥3 recurrent CDIs (62%). Nine (19%) patients failed to respond to the first FMT and five underwent repeat FMT within four to 12 weeks. The cure rate was 81% after the first FMT (38/47) and 91% after the second FMT treatment (43/47). Serious adverse events occurred in 2% and all-cause mortality was 2% at 90-day follow up. Conclusion Our study demonstrated the safety and efficacy of FMT administered via retention enema, a simple bedside procedure, for the treatment and prevention of recurrent non-severe and severe CDI with an overall cure rate of 91%.

Clostridioides difficile is a dangerous human pathogen because it can grow to high numbers in the intestine, cause colitis with its potent toxins, and persist as spores. C. difficile infection (CDI) is the primary hospital-acquired infection in North America and Europe, and it now is a global disease. Even with newer laboratory tests, there still is confusion on accurately diagnosing this disease. Three guidelines from three different healthcare-affiliated societies have recently been published. Consensus consolidated recommendations from these guidelines should be recognized by healthcare professionals, who need to understand why this disease continues to be difficult to diagnose and need a clear understanding of the advantages and limitations of current tests. Hopefully, these combined efforts will lead to an improvement in the recognition of this pathogen and a reduction in the suffering and economic loss caused by CDI.

Antimicrobial resistance (AR) is escalating worldwide with the potential for dire consequences, global travel contributes to the dissemination of resistant pathogens from one region to another. The World Health Organization identified the rapid emergence and prevalence of carbapenem-resistant Gram-negative species, includingThis review describes key carbapenem-resistant (CR) Gram-negative species, changes in current global and regional trends, AR surveillance and reporting, and identifies drivers of change, specifically travel. Finally, we review clinical implications and challenges of treating CR infections which exist due to widespread dissemination of CR bacteria. A literature search was conducted using PubMed, Google Scholar, Ebsco, and ProQuest (from 2000 to December 2019).The level of global travel is increasing, and antimicrobial resistance continues to disseminate worldwide. Healthcare providers risk assessment for AR needs to consider a patient's recent travel history, including pre-travel and intra-travel antimicrobial prescription, and potential exposure based on geography. Patient education, healthcare provider awareness, and access to data and surveillance resources are critical to inform antimicrobial selection and improve health outcomes.

Omadacycline is a novel aminomethylcycline antimicrobial, US FDA approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is not susceptible to common tetracycline resistance mechanisms, and has demonstrated efficacy against a broad spectrum of pathogens including resistant isolates, which are increasing in prevalence and complexity. It is available in both intravenous and oral formats, and can be administered in single, once daily doses or multiple doses, with no dosing adjustments required for sex, age, hepatic or renal impairment. It can be a good option for patients with low treatment adherence, and oral therapy may be used to reduce length of hospitalization for iv. treatment. This article reviews the in vitro and in vivo activity, PK/PD profile, integrated data from clinical trials including clinical efficacy and safety profile, and looks to future application of omadacycline.

Background and Objective Community-acquired bacterial pneumonia (CABP) affects millions of people each year in the USA. The majority of patients with CABP are treated in the community setting with empirical antimicrobial therapy. Delafloxacin is an anionic fluoroquinolone approved for the treatment of adult patients with CABP. This de novo analysis sought to estimate the budget impact of delafloxacin in the treatment of adult patients with CABP in the outpatient setting from the payer’s perspective. Methods A budget impact model (BIM) was developed from the perspective of a US third-party payer to estimate the cost of introducing delafloxacin for the outpatient treatment of CABP over a 1-year time horizon. Population, clinical, and cost inputs were based on the available literature, clinical trial data, and real-world evidence studies. Scenario analyses were conducted to evaluate the potential budget impact among COPD/asthma patients based on the findings from the phase III trial of delafloxacin for CABP, which indicated that patients with COPD or asthma may experience improved effectiveness with delafloxacin compared to moxifloxacin. Results In the base-case analysis, with a hypothetical plan of 1,000,000 members, the model estimated that adding delafloxacin to the formulary resulted in a total budget impact of $58,987. This increase was mainly attributed to treatment acquisition costs. In the scenario analysis that was restricted to COPD/asthma patients, adding delafloxacin to the formulary was estimated to result in a total budget impact of $5,042. Conclusion The results of the budget impact analyses provide conservative estimates of the impact of adding delafloxacin to outpatient formularies in substitution of moxifloxacin. Electronic supplementary material The online version of this article (10.1007/s40261-020-00938-y) contains supplementary material, which is available to authorized users.

Background Oritavancin is a FDA-approved single-dose IV therapy for the treatment of acute bacterial skin and skin structure infections caused (or suspected to be caused) by certain Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Published data describing the outcomes of patients with skin and soft tissue infections (SSTIs) who received oritavancin beyond its pivotal phase III clinical trials are scant. Objective The purpose of this report was to describe the results of two separate multicenter observational cohort studies that described the outcomes associated with two unique real-world usage patterns of oritavancin. Methods The first cohort (n = 115) examined patients 18 years or older who were treated with oritavancin at three outpatient sites for SSTIs caused by suspected or confirmed Gram-positive pathogens, including MRSA, to avoid hospital admission. Patients were included if they had not been discharged from the inpatient setting within the previous 24 h and received their single-dose oritavancin treatment at a hospital-based outpatient infusion center. The primary outcomes measured were 30-day healthcare costs and admissions (all cause and infection related). The second cohort (n = 151) was a multicenter, retrospective chart review of adult patients who were discharged early from seven hospitals in 2015 on oritavancin for SSTIs. The primary outcome was readmission of patients within 30 days (all cause and infection related). Results In cohort 1, 30-day mean healthcare costs were USD 3698. In the study of patients who started oritavancin in the outpatient setting, 7 patients (6.1%) were admitted to hospital within 30 days of the index treatment, and 3 of those (2.6% overall) were deemed to be due to an infection. In cohort 2, all-cause and infection-related 30-day readmission rates were 6.6% and 2.6%, respectively, among patients who received oritavancin at hospital discharge. Conclusions Findings from these studies suggest that oritavancin may be a potentially useful agent to avoid hospitalization or shorten hospital length of stay among appropriate SSTI patients. Future comparator studies are required to properly ascertain the outcomes and potential benefits associated with oritavancin relative to other commonly used antibiotics in patients with SSTIs.

Background: Antibiotic resistance is an evolving issue which requires constant review. Susceptibility breakpoints are revised in line with new microbiological and pharmacological data. Susceptibility breakpoints for carbapenems and Enterobacterales were revised in response to the rise in resistance and the potential for standard doses of carbapenems to provide the necessary antibiotic exposure and to accurately identify rates of carbapenem resistance.Objectives: This review sought to identify real-world implications associated with lack of testing and reporting current carbapenem breakpoints and potential barriers that may impede implementation of these strategies.Methods: A literature review was conducted using PubMed and Google Scholar electronic databases.Results: The failure to adopt revised breakpoints incurs negative clinical outcomes and carries increased cost implications. However, there were several impediments highlighted which are barriers for laboratories to implement breakpoint updates.Conclusion: Possible practical steps to implement revised breakpoints which apply to carbapenems and Enterobacterales are proposed. The challenge for laboratories is to be aware and implement these changes to provide accurate and relevant susceptibility results for clinicians.

Background: The APEKS-cUTI study demonstrated the non-inferiority of cefiderocol to imipenem−cilastatin in the primary endpoint of the composite of clinical and microbiological outcome in patients with complicated urinary tract infections (cUTIs). We piloted a structured patient interview (SPI) to evaluate clinical outcomes based on patient-reported symptoms while conducting this pivotal randomized, double-blind, phase-2 study. The objectives were to assess the value of the SPI, using its performance relative to physician assessment, and also to strengthen the value of patient-reported measures in conducting clinical trials for cUTI treatment. Methods: In addition to the protocol-defined clinical and microbiological outcomes, patients randomized in the APEKS-cUTI study were interviewed by the investigator or qualified study personnel at screening/baseline, early assessment (EA), end of treatment (EOT), test of cure (TOC), and follow-up (FUP). The 14-element questionnaire graded cUTI symptoms as absent or present, and if present, as mild, moderate, or severe. Changes in post-baseline symptoms based on patients’ responses were rated by the interviewer. The overall clinical outcome was evaluated based on the responses provided by patients at each time point. Results: Among the 371 patients in the modified intention-to-treat population, the rate of SPI completion in each treatment arm exceeded 90% at each time point. SPI-assessed clinical cure rates were 89.7% in the cefiderocol arm and 84.9% in the imipenem–cilastatin arm. There was substantial agreement between SPI evaluation and investigator global assessment of clinical outcome at TOC and FUP, with lower agreement at EA and EOT. Conclusion: This analysis suggests that patient-reported symptoms can be effectively captured in hospitalized patients with cUTI in a clinical trial setting. Development of a validated patient-reported outcome for use in such a setting is warranted. Registration: NCT02321800 (registered on 22 December 2014).

Over 25 years ago Professor Cookson [1] opined that ‘damage limitation policies such as control of antibiotic prescribing are the sensible way forward.‘ In an effort to provide such stewardship con...

Background The aim of this survey was to assess the attitudes of physicians toward antibiotic prescribing and explore their knowledge about antimicrobial resistance (AMR) in ambulatory care settings. Methods We conducted a cross-sectional survey that was administered to physicians who work primarily in ambulatory care settings in the United States. The survey was self-administered, voluntary, and anonymous, and was delivered through electronic mail and online forums using a 35-item questionnaire. Results The survey was completed by 323 physicians. Ninety-nine percent of respondents agreed that AMR is a national problem, but only 63% agreed that AMR is a local problem within their own facilities. Ninety-four percent of the respondents reported that each antibiotic prescription can impact AMR; however, 23% still believed that aggressive prescribing is necessary to avoid clinical failures. Factor perceived to have a low to moderate impact on the physicians’ choice of antibiotic was the presence of prescription guidelines (54%). Top measures reported to be effective in reducing the emergence of AMR were institution specific guidelines (94%), institution specific antibiogram (92%), educating health care providers (87%), and regular audits and feedback on antibiotic prescribing (86%). Conclusions AMR awareness campaigns and antibiotic stewardships incorporating interactive education and feedback, along with input of local experts, are critically needed to address the problem of AMR in both inpatient and ambulatory settings.

Background Through improved understanding of the structure-activity relationship attributes of fluoroquinolones, molecule development has improved efficacy, safety, and tolerability of the class. Adverse events (AEs) associated with the fluoroquinolones are well defined and a prospective part of the development process. However, not all fluoroquinolones have the same AE profile with different substitutions on the core molecule resulting in differences in side effects and spectrum of activity. Unique structural attributes of delafloxacin (DLX) may differentiate its AE profile compared to other fluoroquinolones. This analysis compared the incidence of AEs between DLX and vancomycin/aztreonam across two phase 3 ABSSSI studies in order to provide a broader overview of DLX safety. Methods Safety events occurring in all subjects in the pivotal phase 3 trials were pooled to provide a broad overview of DLX safety. Results DLX was safe and well-tolerated in the pooled phase 3 ABSSSI trial population of 741 subjects. Treatment-emergent AEs (TEAEs) were seen in the DLX group versus the comparator group at 45.1% and 47.7%, respectively. Most were mild or moderate in severity. Treatment-related TEAEs were reported in the DLX group versus the comparator group at rates of 22.1% and 26.1%, respectively. Conclusions Available data show DLX is well tolerated in both intravenous and oral formulation for the treatment of ABSSSI and does not appear to be associated with increased risk of AEs associated with other fluoroquinolones. It remains important to monitor for potential AEs that have been observed with other fluoroquinolones.

Background For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed. Methods This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included. Results Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP. Conclusions A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics., In cUTI trial data from 6 new antibiotics targeting MDR Gram-negative infections, proportion of acute pyelonephritis (AP) varied; influencing population demographics and baseline microbiology. Smaller proportion of AP resulted in older patient population, fewer females, less E coli, and lower treatment success.

The role of empirical and even directed antimicrobial management of patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is problematic; antibiotics are used frequently among these patients to treat confirmed or suspected coinfection or just the symptoms. In the rapidly changing clinical landscape of SARS-CoV-2, there is minimal guidance for selecting appropriate treatment versus non-antimicrobial treatment, and clinicians are pressed to make daily decisions under the stress of absence of data while watching patients deteriorate. We review current data and patterns of antimicrobial use and the potential approach for antimicrobial stewardship in the context of SARS-CoV-2.

As COVID-19 sweeps through the nation, turning hospitals into war zones, overwhelming healthcare personnel and essentially disrupting our healthcare framework, we envision the aftermath with cautio...

Background Stenotrophomonas maltophilia is an opportunistic pathogen observed in both nosocomial and community-onset infections. S. maltophilia is intrinsically resistant to many currently available broad-spectrum antibiotics and is often not included in antimicrobial resistance surveillance studies or stewardship programs’ guidelines. Methods A retrospective cohort study of patients with S. maltophilia bloodstream infection (BSI) in the United States was conducted using the 2010–2015 US Premier Healthcare Database. This study described patient characteristics, infection characteristics, antibiotic treatment, and discharge status. Results S. maltophilia was the most common carbapenem-resistant, gram-negative pathogen causing BSIs in this database. Of 486 unique patients with S. maltophilia BSI, 44.6% were assessed as community-onset, 95% of cultures were susceptible to trimethoprim-sulfamethoxazole (TMP-SMX), and 84% were susceptible to fluoroquinolones; 39.1% of patients received a potentially effective antibiotic (fluoroquinolone, doxycycline, ceftazidime, minocycline, or TMP-SMX) during the empiric treatment period (≤3 days post–index culture date), whereas 85.8% received a potential effective antibiotics during the definitive treatment period. The most common antibiotic received as definitive treatment was levofloxacin (48.9%). TMP-SMX was used infrequently empirically (10.5%) and in 38.3% during the definitive period. Compared with BSIs caused by other carbapenem-resistant gram-negative pathogens, S. maltophilia BSIs were more likely to be community-onset, and were more likely to be discharged to home and to have a lower mortality rate. Conclusions This study demonstrated that patients at risk for S. maltophilia BSI are highly variable and that standard of care is not clearly defined, leading to questions regarding the appropriateness of antibiotic treatment among patients. Further efforts are needed to better recognize and treat S. maltophilia BSI.

Background Antibiotic treatment failure is common among patients with community-acquired pneumonia (CAP) who are managed in the outpatient setting and is associated with higher mortality and increased health care costs. This study’s objectives were to quantify the occurrence of antibiotic treatment failure (ATF) and to evaluate clinical and economic outcomes between CAP patients who experienced ATF relative to those who did not. Methods Retrospective analysis of the MarketScan Commercial & Medicare Supplemental Databases was performed, identifying patients ≥18 years old, with a pneumonia diagnosis in the outpatient setting, and who received a fluoroquinolone, macrolides, beta-lactam, or tetracycline. ATF was defined as any of the following events within 30 days of initial antibiotic: antibiotic refill, antibiotic switch, emergency room visit, or hospitalization. Outcomes included 30-day all-cause mortality and CAP-related health care costs. Results During the study period, 251 947 unique patients met inclusion criteria. The mean age was 52.2 years, and 47.7% were male. The majority of patients received a fluoroquinolone (44.4%) or macrolide (43.6%). Overall, 22.1% were classified as ATFs. Among 18–64-year-old patients, 21.2% experienced treatment failure, compared with 25.7% in those >65 years old. All-cause mortality was greater in the antibiotic failure group relative to the non–antibiotic failure group (18.1% vs 4.6%, respectively), and the differences in 30-day mortality between antibiotic failure groups increased as a function of age. Mean 30-day CAP-related health care costs were also higher in the patients who experienced treatment failure relative to those who did not ($2140 vs $54, respectively). Conclusions Treatment failure and poor outcomes from outpatient CAP are common with current guideline-concordant CAP therapies. Improvements in clinical management programs and therapeutic options are needed.

Community-acquired pneumonia (CAP) is a significant global health problem and leading cause of death and hospitalization in both the US and abroad. Increasing macrolide resistance among Streptococcus pneumoniae and other pathogens results in a greater disease burden, along with changing demographics and a higher preponderance of comorbid conditions. Areas covered: This review summarizes current data on the clinical and economic burden of CAP, with particular focus on community-acquired bacterial pneumonia (CABP). Incidence, morbidity and mortality, and healthcare costs for the US and other regions of the world are among the topics covered. Major factors that are believed to be contributing to the increased impact of CABP, including antimicrobial resistance, the aging population, and the incidence of comorbidities are discussed, as well as unmet needs in current CABP management. Expert commentary: The clinical and economic burden of CABP is staggering, far-reaching, and expected to increase in the future as new antibiotic resistance mechanisms emerge and the world's population ages. Important measures must be initiated to stabilize and potentially decrease this burden. Urgent needs in CABP management include the development of new antimicrobials, adjuvant therapies, and rapid diagnostics.

The emergence of antimicrobial resistance threatens current clinical practice across a range of infection types. Delafloxacin, a non-zwitterionic fluoroquinolone recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections, has been developed to address some of these challenges. Uniquely delafloxacin has increased intracellular penetration and enhanced antibacterial activity under acidic conditions, an environment seen in many infection sites including abscesses. Delafloxacin is active against a wide range of Gram-positive and -negative species including methicillin-resistant Staphylococcus aureus and many fluoroquinolone-resistant strains. Additionally, according to preclinical and clinical trial data, well-known adverse events related to fluoroquinolone class do not appear to occur with this new molecule. Delafloxacin has been studied in acute bacterial skin and skin structure infections with >1400 patients exposed to both intravenous and oral formulation for up to 14 days and has shown noninteriority to vancomycin with or without aztreonam. For its interesting microbiological and pharmacokinetic/pharmacodynamics characteristics and for its safety profile, delafloxacin represents a very promising option for the treatment of infections caused by multidrug-resistant pathogens.

Summary Background Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection. Methods We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935. Findings Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation. Interpretation Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted. Funding Wellcome Trust and Summit Therapeutics.

The current treatment options for patients with community-acquired pneumonia (CAP) often present a trade-off between the potential for treatment failure and safety concerns. We set out to investigate real-world outcomes associated with the use of currently available antimicrobial treatment options for CAP in both the outpatient and inpatient (non-intensive care unit [ICU]) settings.This claims-based retrospective study included adult patients diagnosed with CAP and treated with antibiotic therapies, including any oral fluoroquinolone, macrolide, or beta-lactam monotherapy in the outpatient setting, and intravenous (IV) levofloxacin or IV azithromycin/ceftriaxone in the inpatient setting. Generalized linear model (GLM) regression was used to determine total charges for inpatient stay, the length of stay, and days of inpatient therapy. For outpatients, rates of adverse events (AEs), treatment failure, and hospitalization were compared by type of initial antibiotic therapy using logistic regression multivariate models that controlled for baseline characteristics.A total of 441,820 outpatients and 33,287 inpatients treated for CAP between 2007 and 2012 were included in this analysis. In the outpatient setting, fluoroquinolone therapy led to a higher rate of documented AEs (adjusted odds ratio [OR]: 1.23; 95% confidence interval [CI]: 1.20-1.25; p 0.0001) but a lower rate of retreatment (adjusted OR: 0.9; 95% CI: 0.87-0.94; p 0.0001) compared with macrolides. Both AEs and retreatment in these patients were associated with increased costs. For patients treated with the IV macrolide/beta-lactam combination compared with IV fluoroquinolone in the inpatient setting, a significantly longer length of stay in hospital (4.71 vs. 4.38 days; p 0.0001) and greater overall costs ($3,535 more per stay; p 0.0001) were observed.In both the inpatient and outpatient settings, the development of additional efficacious treatment options that have a reduced AE burden for patients with CAP may be warranted.

We describe 9 patients at a medical center in Detroit, Michigan, USA, with severe acute respiratory syndrome coronavirus 2 and Clostridioides difficile. Both infections can manifest as digestive symptoms and merit screening when assessing patients with diarrhea during the coronavirus disease pandemic. These co-infections also highlight the continued importance of antimicrobial stewardship.

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients.

Antibiotic resistance has been emerged as a major global health problem. In particular, gram-negative species pose a significant clinical challenge as bacteria develop or acquire more resistance mechanisms. Often, these bacteria possess multiple resistance mechanisms, thus nullifying most of the major classes of drugs. Novel approaches to this issue are urgently required. However, the challenges of developing new agents are immense. Introducing novel agents is fraught with hurdles, thus adapting known antibiotic classes by altering their chemical structure could be a way forward. A chemical addition to existing antibiotics known as a siderophore could be a solution to the gram-negative resistance issue. Siderophore molecules rely on the bacterial innate need for iron ions and thus can utilize a Trojan Horse approach to gain access to the bacterial cell. The current approaches to using this potential method are reviewed.

Background Cefiderocol (CFDC) is a new siderophore cephalosporin with potent in vitro activity against a broad range of Gram-negative (GN) pathogens, including carbapenem-nonsusceptible (Carb-NS) strains. We evaluated the in vitro activity of CFDC and comparator agents against recent clinical Carb-NS GN respiratory isolates collected from North America and Europe as part of the multi-national SIDERO-WT surveillance program. Methods A total of 2831 Carb-NS GN respiratory isolates collected from 2014 to 2017 were tested centrally (IHMA, Inc., Schaumburg, IL). Minimum inhibitory concentrations (MIC) were determined for CFDC, cefepime (FEP), ceftazidime–avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to the 2018 CLSI guidelines. CFDC MICs were tested in iron-depleted cation-adjusted Mueller–Hinton broth, and interpreted according to the 2018 CLSI provisional breakpoints. Carb-NS strains were defined as MEM MIC of ≥2 µg/mL for Enterobacteriaceae (ENB) and of ≥4 µg/mL for nonfermenters (NF). Results CFDC exhibited predictable in vitro activity against 2807 clinically relevant Carb-NS GN isolates (214 ENB, 1086 A. baumannii complex, 693 P. aeruginosa, 794 S. maltophilia, and 20 Burkholderia cepacia) isolated from respiratory infections. CFDC was the most active agent against Carb-NS ENB with 97.7% susceptibility followed by 78.0% CZA, 59.4% CST, and 16.4% CIP. Against Carb-NS A. baumannii complex, CFDC demonstrated 94% susceptibility vs. 83.7% for CST. CFDC was the most active agent against Carb-NS P. aeruginosa with 99.9% susceptibility followed by 97.8% CST, 77.6% C/T, and 77.5% CZA. 99.7% of S. maltophilia and 100% of B. cepacia isolates had CFDC MICs of ≤4 µg/mL. The MIC90s of tested compounds for clinically relevant pathogens are shown in the table. Conclusion In a multinational collection of Carb-NS GN respiratory isolates, CFDC demonstrated potent in vitro activity with MIC90 of ≤4 µg/mL for all clinically relevant ENB and NF. These findings suggest that CFDC can be a potential option for the treatment of respiratory infections caused by Carb-NS ENB, A. baumannii complex, P. aeruginosa, S. maltophilia, and B. cepacia. Disclosures All authors: No reported disclosures.

Although there was a flurry of new antifungal drugs approved in the early part of the last decade, the growing need for newer agents to treat systemic fungal infections has escalated due to increasing resistance to the 2 main classes of drugs developed to date and shifts in the etiology of these diseases. In addition to this microbial shift, there are more at-risk patients who are being managed in increasingly heroic ways and are thus highly susceptible to these more common resistant fungi and yeasts. However, as we acknowledge the need for new drugs to treat these desperately ill patients, there is a basic problem facing the pharmaceutical industry as it tries to balance the conundrum of antifungal development. Globally there is a relatively low, but growing, number of systemic fungal infections, which creates significant hurdles in conducting clinical trials in a timely and economical manner. In the United States, there have been some significant moves to easing these hurdles and, potentially, to bringing new drugs to the clinic more quickly and efficiently. We will discuss the current unmet clinical need and the current US regulatory positions to encourage further investment in this critical field.

Antimicrobial resistance has become a global problem. Many pathogens are becoming multidrug-resistant with the attendant increased risk of failure of standard therapies and the under-recognised outcomes such as increased morbidity, mortality, length of hospitalization and costs of treatment. Areas covered: We undertook a review of the literature using standard search engines including PubMed, Google Scholar, Scopus and internet sources. Key search terms included antimicrobial resistance, antibiotic resistance, bacterial resistance, clinical outcomes, economic consequences, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus. Expert commentary: Antimicrobial resistance among the five-species presented demonstrates a major, and increasing, deleterious impact seen in each of the key outcomes measured. These negative changes, at a personal, health system and Societal levels, further emphasise the growing problem of increasing antimicrobial resistance at a global level and the vital need for new antimicrobials.

Background Based on the 2009 US FDA guidance, patient-reported outcome (PRO) measures are recommended in clinical study designs for certain indications to evaluate response to therapy from the patient’s perspective, and a PRO was recommended in the final complicated urinary tract infection (cUTI) guidance in 2014. Several PRO tools have been rigorously validated, but currently, no tool exists for evaluating cUTI. We included a “structured patient interview (SPI)“ while conducting a randomized, double-blind, study (NCT02321800) investigating cefiderocol (CFDC) vs. imipenem–cilastatin (IPM/CS) in cUTI patients to support the physician’s assessment of clinical response. Methods Patients, who were fully alert and oriented, were interviewed at randomization, end of treatment, test of cure (TOC), and follow-up (FUP) by the same interviewer. The questionnaire identified the presence or absence of relevant symptoms pertinent to cUTI. Responses were graded as none, or if present, mild, moderate, or severe. Investigator assessment included objective measures of clinical outcome(s) and was performed independently from the patient-reported symptoms collected in the SPI. Changes in the patient’s responses were compared with the investigator’s assessment at randomization and at each study visit. A kappa correlation coefficient comparing the SPI and physician’s clinical assessment was calculated at each evaluation time point. Results Based on investigator assessment, 89.7% (226 out of 252 patients) in the CFDC arm and 87.4% (104 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 2.39%; 95% CI: –4.66; 9.44) at TOC. Based on the SPI responses, 89.7% (226 out of 252 patients) in the CFDC arm and 84.9% (101 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 4.96%; 95% CI: –2.48; 12.39) in favor of CFDC. The correlation between SPI evaluation and physician’s assessment of clinical outcomes was very high at TOC and FUP visits (Kappa coefficients: 0.820 and 0.766, respectively). Conclusion The strong correlation between patients’ reported symptoms collected in the SPI and investigator assessment showed that SPI responses could be a useful alternative measure of clinical outcomes in cUTI studies. Disclosures All authors: No reported disclosures.