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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.

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.

Osteomyelitis is a difficult-to-treat disease that can require both surgical debridement and a prolonged course of antimicrobial therapy. Current standard of care for the antimicrobial treatment of osteomyelitis is fraught with multiple challenges and limitations. Patients typically require the insertion of an indwelling catheter for single or multiple daily intravenous antibiotic infusions for up to 6 weeks. Currently, there are treatment guidelines for only vertebral osteomyelitis, indicating the complexity of the condition. Oritavancin is a long-acting, second-generation lipoglycopeptide, administered intravenously once per week, which has potential to be a useful alternative in the treatment of osteomyelitis. This article reviews occurrence and outcomes of off-label oritavancin use for treatment of osteomyelitis as described in case reports. Analysis included 23 patients treated for osteomyelitis with single- or multiple-dose oritavancin. Overall, clinical cure or improvement was achieved in 87% of patients, and adverse events were mild and reported in only two patients. Clinical efficacy was demonstrated in 81.8% of methicillin-resistant Staphylococcus aureus (MRSA), 71.4% of methicillin-sensitive S. aureus (MSSA), 50% of vancomycin-resistant Enterococcus (VRE), and in the single case of Streptococcus pyogenes. Oritavancin has shown efficacy against Gram-positive pathogens in osteomyelitis, and offers a possible outpatient treatment option for osteomyelitis patients. Future studies are needed to determine dosing frequency in osteomyelitis patients.

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: 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.

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.

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.

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.

Everyone is aware that antibiotic resistance is a major clinical, and economic, problem. Recent publications have foretold huge costs and clinical disasters if we do not better manage the tools we ...

Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. In 2007 there were over 2000 HAE-related emergency department (ED) visits, nearly one-half of which culminated in a hospitalization. This study examines epidemiology and outcomes of hospital ED visits among HAE patients. We evaluated epidemiology, resource use, and discharge destinations of HAE (International Classification of Diseases, Version 9, clinical modification [ICD-9-CM] code 277.6) ED visits within the Nationwide Emergency Department Sample, part of Agency for Healthcare Research and Quality Healthcare Costs and Utilization Project, in 2006 and 2007. In 2006-2007, there were 5040 ED visits with HAE, of which 2705 (53.7%) had HAE as the principal diagnosis (HAE-PD). The mean age for all HAE visits was 38.2 years, and women accounted for 56.5% of all HAE visits. When HAE was not the primary reason for the visit, abdominal pain was the most prevalent (10%) presenting diagnosis. Two thousand fifty-nine (40.9%) resulted in a hospitalization. Although of all HAE ED visits that did not require a hospitalization, the vast majority was discharged routinely home, further care either at a skilled nursing facility or at home was required after 45 (0.9%) of all the HAE visits and 10 (0.4%) of the HAE-PD visits. Mean HAE ED visits costs were $1479 (95% confidence interval, $1028-1929). HAE ED visit volume is substantial. Although likely representing a fraction of the entire HAE population, prevention and acute treatment strategies aimed at those at risk for frequent exacerbations and disproportionate resource use need to be examined.

The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established.

Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. There are ∼6000 HAE cases in the United States, nearly one-half of whom suffer a monthly exacerbation. Little is known about hospital use patterns by patients with HAE attacks in the United States. This study was designed to examine burden, epidemiology, and outcomes of hospitalizations among HAE patients. We evaluated epidemiology, resource use, and discharge destinations of HAE (ICD-9-CM code 277.6) hospitalizations within the NIS, part of Agency's for Healthcare Research and Quality Healthcare Costs and Utilization Project in 2004 through 2007. There were 10,125 hospitalizations with HAE, of which 3216 (31.8%) had HAE as the principal diagnosis (HAE-PD). Two-thirds of all HAE hospitalizations were among women, and 60% were white. Hypertension was the most common comorbidity (26.9%, all HAE, and 28.0%, HAE-PD). Mortality was 1.4% in HAE and 0.3% in the HAE-PD group. Mean hospital length of stay (3.7, 95% CI 3.0-4.4 days vs. 5.0, 95% CI 4.6-5.4 days) and costs ($4,760, 95% CI $3,612-$5,907 vs. $8,383, 95% CI $7,432-$9,334) were lower in HAE-PD than in the HAE cohort. Although >80% in each group were discharged home routinely, 15.9% of HAE and 4.9% of HAE-PD required either home health care or a transfer to another short-term hospital or a skilled nursing facility. HAE hospitalization volume is substantial. Because diagnostic uncertainty is likely, HAE and its related resource use may be underestimated. HAE prevention strategies need to be examined in the context of these outcomes.

Physicians need a better understanding of outcomes of these infections., We evaluated the annual rate (cases/10,000 hospitalizations) of pediatric hospitalizations with Clostridium difficile infection (CDI; International Classification of Diseases, 9th revision, clinical modification code 008.45) in the United States. We performed a time-series analysis of data from the Kids’ Inpatient Database within the Health Care Cost and Utilization Project during 1997–2006 and a cross-sectional analysis within the National Hospital Discharge Survey during 2006. The rate of pediatric CDI-related hospitalizations increased from 7.24 to 12.80 from 1997 through 2006; the lowest rate was for children

The use of noninferiority clinical trials is problematic unless one can establish the benefit of the active control versus no treatment. In community-acquired pneumonia, there are no placebo-controlled clinical trials establishing the benefit of antibiotic treatment, because the observed benefit of sulfapyridine and, subsequently, penicillin was established before the advent of randomized clinical studies. Historical data and observational cohort studies have established the marked decrease in mortality resulting from antimicrobial therapy; however, mortality is not a suitable end point for contemporary clinical trials for mild-to-moderate community-acquired pneumonia that is treated with oral antimicrobial drugs in ambulatory patients. There are historical clinical data that describe the timing of spontaneous recovery in patients with documented pneumonia caused by Streptococcus pneumoniae. In addition, there is one contemporary clinical trial that demonstrated superiority in clinical response of levofloxacin versus a cephalosporin regimen of ceftriaxone and/or cefuroxime for treatment of mild-to-moderate community-acquired pneumonia. Using either the historical data or the superiority study of levofloxacin, one can justify a noninferiority margin of 10% for the per-protocol population and 15% for the microbiologically evaluable population for future noninferiority clinical trials for mild-to-moderate community-acquired pneumonia.

The appropriate management of Clostridium difficile infection (CDI) has become a growing clinical and economic issue, as a new epidemic strain with enhanced virulence is causing increased morbidity and mortality. Presently, only two antibiotics (metronidazole and vancomycin) are routinely used to treat CDI. Both increasing disease severity and recurrent infections have been an impetus not only to develop new agents, but also to better recognize which patients are at highest risk for treatment failure and/or recurrence so that treatments can be optimized from the outset. The availability of a standardized and validated system for stratifying CDI severity could improve patient management and potentially accelerate the development of new treatment agents.

Antibiotic development has decreased significantly, in part because of recent changes in regulatory requirements in the United States. These changes both decrease the probability of technical and regulatory success for a new antibiotic for which marketing approval is sought and motivate the pharmaceutical industry to focus its research efforts on other therapeutic areas. There is a growing, unmet clinical need for new antibiotics, because of bacterial resistance to approved drugs; however, there are few candidates in development, especially new oral agents for treatment of community-acquired respiratory infections. The answers to important questions about the benefit of antibacterial treatment for community-acquired pneumonia and the publication of clear guidance for future clinical studies will support future investments. We discuss the underlying issues and offer some alternative strategies to enable improvements in clinical trial design for community-acquired pneumonia.

Respiratory tract infections (RTIs) form a substantial clinical and financial burden, with the increasing complication of antimicrobial resistance. This resistance may compromise the use of many empirically prescribed antimicrobials. The new respiratory fluoroquinolones have been developed to overcome this burgeoning resistance. This group includes gemifloxacin, an enhanced-affinity fluoroquinolone that has been approved for clinical use in several countries and is characterised as a potent dual-acting agent with excellent in vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration for 90% of strains (MIC90)=0.03-0.06 microg/mL). Gemifloxacin given once daily for 5-7 days has been shown to be non-inferior to, or in some instances superior to, comparator agents for the treatment of common lower RTIs. Moreover, it is generally well tolerated and is as safe as many frequently empirically prescribed antimicrobials. In addition, studies have shown gemifloxacin to be a cost-effective agent for some lower RTIs.

The aim of this study was to describe the rates of antimicrobial susceptibility of Staphylococcus aureus from skin and wound infections reported from nine regions of the USA during 2005-07 and to identify the regional variation in patterns of resistance.The Surveillance Network (TSN) comprises 296 laboratories across the nine census regions of the USA. TSN laboratories reported the susceptibility data for six antimicrobials by isolate with source and other relevant data. Antimicrobial susceptibility data were analysed by individual drug resistance, multidrug resistance and geographical distribution of resistance phenotypes.There were over 380 000 isolates of S. aureus tested and reported for the period 2005-07. Methicillin resistance was observed in 57.8% in 2007, with little change from 2005. There was little difference in rates of methicillin resistance between community and hospital strains, although strains from intensive care units (ICUs) tended to be slightly more resistant overall. Resistance to other antimicrobials was also reported. A regional variation in resistance rates was noted with the highest rates in the Central states and lowest in the New England and Mid-Atlantic regions. There was high activity observed with trimethoprim/sulfamethoxazole and gentamicin. Linezolid resistance was rare. Oxacillin resistance was similar among paediatric and elderly cohorts, whereas ciprofloxacin and clindamycin resistance was significantly (P0.01) more common in elderly patients when compared with both paediatric and adult populations. Less than a third of all isolates showed no resistance mechanism, 30.3%. Three distinct resistance phenotypes accounted for 46% of all resistant strains. Overall, there were more highly drug-resistant isolates from the ICU with four, five or six drug-resistant phenotypes accounting for over a third of all strains.S. aureus has become methicillin-resistant in both the community and hospital settings; however, little change has been seen in the past 3 years. Multiresistant strains now are seen in all settings, but due to regional variation, empirical therapy should be guided by local susceptibility patterns. Currently, among the agents studied, only trimethoprim/sulfamethoxazole, gentamicin and linezolid exhibit susceptibility rates of95%.