Efficacy and Safety of Eravacycline in Obese Patients: A Post Hoc Analysis of Pooled Data From the IGNITE1 and IGNITE4 Clinical Trials.

BACKGROUND: The increasing prevalence of obesity worldwide merits an examination of the efficacy and safety profiles of agents dosed by weight. METHODS: Data for patients (n = 1037) were obtained from the pooled IGNITE1 and IGNITE4 randomized double-blind trials in which patients with complicated intra-abdominal infections received eravacycline 1 mg/kg (actual body weight [ABW]) every 12 hours or comparator (ertapenem 1 g every 24 hours or meropenem 1 g every 8 hours) intravenously. This post hoc analysis evaluated clinical cure rates, adverse events, and drug discontinuation rates stratified by body mass index (BMI) categories of BMI >40 kg/m2 (Obese, Class III), BMI 35-39.9 kg/m2 (Obese, Class II), BMI 30-34.9 kg/m2 (Obese, Class I), BMI 25-29.9 kg/m2 (Overweight), BMI 18.5-24.9 kg/m2 (Healthy weight), and BMI <18.5 kg/m2 (Underweight). RESULTS: Clinical cure rates were high across BMI categories and ranged from 82% to 94% in the eravacycline group and 88.5%-100% in the comparator group. Similar cure rates were observed among eravacycline-treated healthy weight (126/134; 94%), overweight (127/146; 87%), and obese (BMI ≥30 kg/m2; 110/129; 85.3%) patients. In the comparator group, a similar proportion of patients demonstrated clinical response (healthy weight [132/145; 91%], overweight [130/144; 90.3%], and obese [115/129; 89.1%]). Of the treatment-emergent adverse events that occurred in eravacycline-treated obese patients, a larger proportion were gastrointestinal-related (ie, nausea and vomiting); however, discontinuation rates were low and similar between eravacycline and carbapenems. CONCLUSIONS: This post hoc analysis demonstrates the therapeutic utility and acceptable safety profile of eravacycline dosed by ABW in obese patients (BMI ≥30 kg/m2).

An Evaluation of Treatment Patterns and Associated Outcomes Among Adult Hospitalized Patients With Lower-Risk Community-Acquired Complicated Intra-abdominal Infections: How Often Are Expert Guidelines Followed?

BACKGROUND: Expert guidelines discourage use of antipseudomonal ß-lactams and fluoroquinolones in lower-risk patients with community-acquired complicated intra-abdominal infection (CA cIAI). Compliance with these recommendations across US hospitals is unclear. This study sought to determine treatment patterns and associated outcomes among adult hospitalized lower-risk patients with CA cIAI. METHODS: A study using data from the Premier Healthcare Database (10/2015-12/2017) was performed. Inclusion criteria: age ≥18 years; hospitalized; had a cIAI at admission; and received antibiotics within the first 4 hospital days. Patients were excluded if they were high risk, were transferred from another health care facility, had a recent hospital admission, or received dialysis within 30 days of admission. Empiric antibiotic treatment patterns and associated outcomes were quantified. RESULTS: Overall, 46 722 (66%) patients with cIAIs met the lower-risk CA IAI study criteria. Among lower-risk CA IAI patients, the mean (SD) age was 53.4 (18.2) years, and 71% had a Charlson Comorbidity Index score of 0. The most common diagnosis was acute appendicitis with peritonitis (59.7%). Among lower-risk CA IAI patients, 54% received piperacillin/tazobactam, 20% received a fluoroquinolone (FQ), 11% received ceftriaxone, and 7% received ampicillin/sulbactam. Overall, the median hospital length of stay was 4 days and median costs were $12 345 USD. Nearly 90% of patients were discharged home, and <1% died. Outcomes were similar across all empiric treatments received. CONCLUSIONS: Overuse of antipseudomonal ß-lactams and fluoroquinolones was commonplace among lower-risk CA IAI patients. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics.

Safety, Pharmacokinetics, and Drug-Drug Interaction Potential of Intravenous Durlobactam, a ß-Lactamase Inhibitor, in Healthy Subjects.

Durlobactam (DUR; also known as ETX2514) is a novel ß-lactamase inhibitor with broad activity against Ambler class A, C, and D ß-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a cohort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR ranging from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug interaction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii (This study has been registered at ClinicalTrials.gov under identifier NCT02971423.).

Carbapenem Treatment and Outcomes Among Patients With Culture-Positive Complicated Intra-abdominal Infections in US Hospitals: A Retrospective Cohort Study.

BACKGROUND: Carbapenems are a frequent firstline therapy in complicated intra-abdominal infections (cIAIs). We examined the microbiology, epidemiology, and outcomes among patients hospitalized in the United States with culture-positive cIAIs in the context of their exposure to empiric carbapenem treatment (ECT). METHODS: We performed a multicenter retrospective cohort study of Premier database of ~180 hospitals, 2013-2017. Using an International Classification of Diseases (ICD)-9/10-based algorithm, we identified all culture-positive adult patients hospitalized with cIAI and examined their microbiology, epidemiology, and outcomes. RESULTS: Among 4453 patients with cIAIs, 3771 (84.7%) had a gram-negative (GN) and 1782 (40.0%) a gram-positive organism; 1185 (26.6%) received ECT. Compared with those on non-ECT, patients on ECT were less frequently admitted from home (82.5% vs 86.0%) or emergently (76.0% vs 81.4%; P < .05 for each); E. coli were less frequent, whereas P. aeruginosa and Enterococcus spp. were more prevalent and resistance to third-generation cephalosporins (C3R; 10.1% vs 5.1%; P < .001) and carbapenems (CR; 3.6% vs 1.2%; P < .001) was more common. In adjusted analyses, ECT was associated with no rise in mortality, shorter postinfection length of stay (-0.59 days; 95% confidence interval [CI], -1.15 to -0.03), but higher postinfection costs ($3844; 95% CI, $1921 to $5767) and risk of Clostridioides difficile (odds ratio, 2.15; 95% CI, 1.02 to 4.50). CONCLUSIONS: Among patients hospitalized with cIAI, the majority were gram-negative. Despite a 10% prevalence of C3R, fully one-quarter of all empiric regimens contained a carbapenem. ECT was a marker for slightly lower postinfection length of stay, but higher costs and risk of hospital complications.

Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance.

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum ß-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.

Trends in resistant Enterobacteriaceae and Acinetobacter species in hospitalized patients in the United States: 2013-2017.

BACKGROUND: Trends in antimicrobial resistance help inform infection control efforts. We examined trends in resistance for Enterobacteriaceae and Acinetobacter spp. from 2013 to 2017 in hospitalized US patients. METHODS: We analyzed antimicrobial susceptibility of non-duplicate isolates in hospitalized patients (not limited to hospital-acquired infections) in the US BD Insights Research Database. Resistance profiles of interest were extended-spectrum beta-lactamase (ESBL)-producing, multidrug resistant (MDR), and carbapenem-nonsusceptible (Carb-NS) phenotypes of Enterobacteriaceae, and MDR and Carb-NS Acinetobacter spp. Time series models were used to evaluate the patterns of resistance trends in rate per 100 hospital admissions and proportion per isolates tested. RESULTS: More than 1 million Enterobacteriaceae isolates were obtained from 411 hospitals; 12.05% were ESBL, 1.21% Carb-NS, and 7.08% MDR. Urine was the most common source. For Acinetobacter spp. (n = 19,325), 37.48% were Carb-NS, 47.66% were MDR, and the most common source was skin/wound cultures. Trend analyses showed that the rates of ESBL and Carb-NS Enterobacteriaceae per 100 hospital admissions increased significantly between 2013 and 2017. Rates of MDR Enterobacteriaceae and Carb-NS and MDR Acinetobacter spp. decreased during this time period. Trends in proportions of resistant isolates generally mirrored trends in rates per 100 hospital admissions. MDR Enterobacteriaceae and Carb-NS and MDR Acinetobacter spp. were more common in winter than summer. CONCLUSIONS: In this large-scale study of patients in US hospitals, rates of ESBL and Carb-NS Enterobacteriaceae per 100 hospital admissions increased between 2013 and 2017. MDR Enterobacteriaceae and MDR and Carb-NS Acinetobacter spp. isolates decreased over this period. These data support continuing infection control and stewardship efforts and the development of new therapeutic options.

National prevalence estimates for resistant Enterobacteriaceae and Acinetobacter species in hospitalized patients in the United States.

OBJECTIVES: To determine antimicrobial nonsusceptibility rates for Enterobacteriaceae and Acinetobacter spp. in US hospitals. METHODS: We analyzed antimicrobial susceptibilities of non-duplicate Enterobacteriaceae and Acinetobacter spp. isolates reported in 2017 from 375 US hospitals in the BD Insights Research Database. Logistic and Poisson regression modeling methods were used to estimate proportions of resistant isolates and rates per 1000 hospital admissions. National projections were generated based on raking (weighting) methods. RESULTS: The nationwide proportions of resistant isolates in inpatients were an estimated 12.6%, 6.6%, and 1.2% for Enterobacteriaceae with extended-spectrum beta-lactamase (ESBL), multidrug resistant (MDR), and carbapenem-nonsusceptible (Carb-NS) phenotypes, respectively, and 42.4% and 34.5% for Acinetobacter spp. with MDR and Carb-NS phenotypes. Resistance varied by geographic region and hospital size/type. Estimated nationwide rates per 1000 hospital admissions ranged from a high of 7.1 for ESBL Enterobacteriaceae to a low of 0.3 for Carb-NS Acinetobacter spp. The estimated number of isolates occurring in US inpatients each year was 290,220 ESBL, 173,984 MDR, and 30,194 Carb-NS for Enterobacteriaceae and 12,274 MDR and 9,991 Carb-NS for Acinetobacter spp. CONCLUSIONS: National prevalence estimates suggest high levels of antimicrobial resistance and a substantial number of patients with resistant Enterobacteriaceae and Acinetobacter spp. in US hospitals.

Antimicrobial Resistance in Neisseria gonorrhoeae: Proceedings of the STAR Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting.

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG; (ii) the US National Strategy for combating antimicrobial-resistant bacteria; (iii) surveillance needs, challenges, and novel technologies; (iv) plasmid-mediated and chromosomally mediated mechanisms of AMR in NG; (v) novel therapeutic (eg, sialic acid analogs, factor H [FH]/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (eg, peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives, and collaborations across academic and commercial research and public health programs.

IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections.

BACKGROUND: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum ß-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. METHODS: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. RESULTS: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. CONCLUSIONS: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. CLINICAL TRIALS REGISTRATION: NCT01844856.

Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea.

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).

Suppressor of IKKepsilon forms direct interactions with cytoskeletal proteins, tubulin and α-actinin, linking innate immunity to the cytoskeleton.

Suppressor of IKKepsilon (SIKE) is associated with the type I interferon response of the innate immune system through TANK-binding kinase 1 (TBK1). Originally characterized as an endogenous inhibitor of TBK1 when overexpressed in viral infection and pathological cardiac hypertrophic models, a mechanistic study revealed that SIKE acts as a high-affinity substrate of TBK1, but its function remains unknown. In this work, we report that scratch assay analysis of parental and SIKE CRISPR/Cas9 knockout HAP1 cells showed an ~ 20% decrease in cell migration. Investigation of the SIKE interaction network through affinity purification/mass spectrometry showed that SIKE formed interactions with cytoskeletal proteins. In immunofluorescence assays, endogenous SIKE localized to cytosolic puncta in both epithelial and myeloid cells and to nuclear puncta in myeloid cells, while in epithelial cells additional staining occurred in stress fiber-like structures and adjacent to the plasma membrane. Using cellular markers, co-occurrence of SIKE fluorescence with actin, α-actinin, and ezrin was detected. Reciprocal immunoprecipitation revealed a SIKE:tubulin interaction sensitive to the phosphorylation state of SIKE, but a SIKE:α-actinin interaction was unchanged by SIKE phosphorylation. In vitro precipitation assays confirmed a direct SIKE interaction with tubulin and α-actinin. These results indicate that SIKE may promote cell migration by directly associating with the cytoskeleton. In this role, SIKE may mediate cytoskeletal rearrangement necessary in innate immunity, but also link a key catalytic hub, TBK1, to the cytoskeleton. DATABASE: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD007262.

In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione.

Antimicrobial resistance in Neisseria gonorrhoeae has severely limited the number of treatment options, and the emergence of extended-spectrum cephalosporin resistance threatens the effectiveness of the last remaining recommended treatment regimen. This study assessed the in vitro susceptibility of N. gonorrhoeae to ETX0914, a novel spiropyrimidinetrione that inhibits DNA biosynthesis. In vitro activity was determined by agar dilution against 100 N. gonorrhoeae isolates collected from men presenting with urethritis in the USA during 2012-2013 through the Gonococcal Isolate Surveillance Project. The minimum inhibitory concentration (MIC) that inhibited growth in 50% (MIC50) and 90% (MIC90) of isolates was calculated for each antimicrobial agent. ETX0914 demonstrated a high level of antimicrobial activity against N. gonorrhoeae, including isolates with decreased susceptibility or resistance to currently available agents. The ability of ETX0914 to inhibit the growth of N. gonorrhoeae was similar to ceftriaxone, which is currently recommended in combination with azithromycin to treat gonorrhoea. The data presented in this study strongly suggest that ETX0914 should be evaluated in a clinical trial for the treatment of N. gonorrhoeae.

Update on Treatment Options for Gonococcal Infections.

The incidence of Neisseria gonorrhoeae infections in the United States has grown over the past decade. The most recent data provided by the Centers for Disease Control and Prevention (CDC) indicate that reported cases have increased by almost 10% over the last 5 years. In conjunction with this rise, the presence of multidrug-resistant strains of N. gonorrhoeae has also emerged. The 2015 CDC guidelines recommend dual therapy with intramuscular ceftriaxone and oral azithromycin as first-line treatment, although components of this regimen are met with a high level of resistance. Although ceftriaxone resistance has not yet been reported in the United States, it is only a matter of time before such isolates are detected, thus ushering in a new era of difficult-to-manage uncomplicated gonococcal infection. The potential public health crisis and patient-associated sequelae (e.g., pelvic inflammatory disease, epididymitis, and human immunodeficiency virus infection) linked with untreatable gonorrhea are cause for great concern. To try to stem this tide, a number of new agents targeted against N. gonorrhoeae are being investigated in clinical trials. In this article, we review the various agents, both currently available and under clinical investigation, and provide recommendations for the management of gonococcal infections.

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.

Assessment of Outpatient and Inpatient Antibiotic Treatment Patterns and Health Care Costs of Patients with Complicated Urinary Tract Infections.

PURPOSE: The goal of this study was to examine treatment patterns, utilization, and costs for complicated urinary tract infections (UTIs) requiring inpatient/emergency department (ED) and outpatient care. METHODS: This observational study evaluated inpatient/ED-treated and outpatient-treated patients (aged ≥18 years) with complicated UTIs from 2 large US administrative claims databases (HealthCore Integrated Research Environment and Premier Perspective Database). Patient identification depended on treatment setting: outpatients had 2 UTI diagnosis-related office visits and 2 claims for different antibiotics within 30 days, and inpatients had a UTI-related hospitalization/ED visit after 1 UTI diagnosis-related office visit plus 2 claims for different antibiotics within 30 days. The index date for outpatients was the date of the first office visit; for inpatients, it was the date of admission/ED visit. Both cohorts had continuous insurance eligibility. Outcomes were assessed by using univariate and multivariate statistics. FINDINGS: The study sample included 1118 inpatient/ED patients (76.6% female subjects; mean age, 62.4 years) and 41,605 outpatients (85.8% female subjects; mean age, 52.3 years). Mean (SD) pharmacy costs were $2971 ($7650) for inpatient/ED patients and $1882 ($3120) for outpatients during the full treatment period. Index hospitalization/ED averaged $38,422 ($51,161). Mean all-cause 90-day follow-up costs for the inpatient/ED cohort were $34,100 ($71,621) and $11,345 ($34,313) for the outpatient cohort. IMPLICATIONS: Relative to outpatient-treated patients, inpatient/ED-treated patients were older, sicker, had higher costs across treatment periods, and had reduced antibiotic use at a lower rate during the 90-day follow-up. Strategies to avoid preventable inpatient/ED visits may help reduce costs in the management of outpatients with complicated UTIs.

Evaluation of programmatic changes to an antimicrobial stewardship program with house officer feedback.

RATIONALE, AIMS AND OBJECTIVES: A collegial relationship between prescribers and antimicrobial stewards, along with an appreciation of the importance of antimicrobial stewardship, is essential for optimal functioning of an antimicrobial stewardship program (ASP). Programmatic adjustments based on feedback may be beneficial to the success of ASPs. The objective of this study is to assess the experience of house officers with the ASP and the effect of programmatic improvements. METHODS: A survey of house officers at an academic medical centre was conducted assessing their experience with the ASP before (2008) and after (2010) programmatic interventions were instituted. RESULTS: Of 225 house officer surveys sent, we received 97 responses (88% from medical doctors). The majority indicated that ASP was either very or somewhat important in fighting antibiotic resistance (100%), improving patient care (97%), preventing medication errors (91%) and containing health care costs (89%). Ninety-one per cent indicated either a very good or good educational experience with the ASP. The ASP often reminded respondents of a patient's allergy (31%), to adjust for renal function (78%), and 38% were prevented from making a medication error. Comparing 2008 and 2010, a higher proportion of respondents in 2010 said they had a very good or good educational experience with ASP [84% versus 98%, odds ratio (OR) = 8.40, P = 0.022] and a lower proportion of respondents reported confusion about ASP procedures (59% versus 39%, OR = 0.43, P = 0.048). CONCLUSIONS: House officer feedback resulted in ASP policy changes which improved the ASP experience.

Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data.

OBJECTIVES AND METHODS: The present study's objective was to evaluate serotonin toxicity with concomitant use of linezolid or comparators and serotonergic agents from 20 Phase III and IV comparator-controlled clinical studies on treatment of various Gram-positive infections. All reported adverse events were evaluated for serotonin toxicity using exact and surrogate terms consistent with Sternbach Criteria and Hunter Serotonin Toxicity Criteria. RESULTS: Baseline demographics and co-morbidities were similar between linezolid and comparator groups. No patients in either group were reported to have adverse events identified as serotonin toxicity. Among the patients receiving at least one serotonergic agent, 9 of the 2208 (0.41%) linezolid patients and 3 of the 2057 (0.15%) comparator patients met the Sternbach Criteria [risk ratio (RR) 2.79; 95% confidence interval (95% CI) 0.76-10.31]; 3 (0.14%) of the linezolid patients and 1 (0.05%) of the comparator patients met the Hunter Serotonin Toxicity Criteria (RR 2.79; 95% CI 0.29-26.85). No patients met both criteria. Most patients meeting criteria for serotonin toxicity had past or present co-morbidities that may have contributed to or overlapped with reported adverse events. CONCLUSIONS: While the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk appears to be low. Based on the large database of Phase III and IV studies included in our analysis, we did not find enough evidence to conclude that linezolid-induced serotonin toxicity was different from that of comparators.

The role of primary care prescribers in the diagnosis and management of community-associated methicillin-resistant Staphylococcus aureus skin and soft tissue infections.

Nosocomial infections caused by methicillin-resistant Staphylococcus aureus were first reported in the United States in the early 1960s. Beginning in the 1990s, healthy individuals from the community with no risk factors for resistant bacteria began presenting with methicillin-resistant Staphylococcus aureus infections, acquiring the name "community-associated methicillin-resistant Staphylococcus aureus" (CA-MRSA). CA-MRSA has a tendency to affect the skin and skin structures, generally in the form of abscesses and furuncles, carbuncles, and cellulitis. Cases of invasive infections including bacteremia, endocarditis, and necrotizing pneumonia have also been reported. A patient complaint of a "spider bite" is frequently associated with CA-MRSA. CA-MRSA and the traditional health care-associated methicillin-resistant Staphylococcus aureus are distinguished by their genetic composition, virulence factors, and susceptibility patterns to non-beta-lactam antibiotics. Appropriate management of CA-MRSA skin and skin structure infections includes incision and drainage of infected tissue and appropriate antimicrobial therapy. It has been suggested that when prevalence of CA-MRSA within a community eclipses 10%-15%, empiric use of non-beta-lactam antibiotics with in vitro activity against CA-MRSA be initiated when treating skin and skin structure infections. CA-MRSA retains susceptibility to a range of older antibiotics available in oral formulations such as minocycline, doxycycline, sulfamethoxazole-trimethoprim, moxifloxacin, levofloxacin, and clindamycin. Local susceptibility patterns and individual patient factors should guide the selection of antibiotics.