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The US burden of acute skin infections is substantial. While Staphylococcus aureus and Streptococcus spp. are the most common causes, gram-negative bacteria and mixed infections can occur in some settings. These mixed infections are more likely to result in inappropriate empiric antibiotic therapy. Important challenges remain in diagnosing and treating acute skin infections.

OBJECTIVE To determine the independent association between diabetes and surgical site infection (SSI) across multiple surgical procedures. DESIGN Systematic review and meta-analysis. METHODS Studies indexed in PubMed published between December 1985 and through July 2015 were identified through the search terms \"risk factors\" or \"glucose\" and \"surgical site infection.\" A total of 3,631 abstracts were identified through the initial search terms. Full texts were reviewed for 522 articles. Of these, 94 articles met the criteria for inclusion. Standardized data collection forms were used to extract study-specific estimates for diabetes, blood glucose levels, and body mass index (BMI). A random-effects meta-analysis was used to generate pooled estimates, and meta-regression was used to evaluate specific hypothesized sources of heterogeneity. RESULTS The primary outcome was SSI, as defined by the Centers for Disease Control and Prevention surveillance criteria. The overall effect size for the association between diabetes and SSI was odds ratio (OR)=1.53 (95% predictive interval [PI], 1.11-2.12; I2, 57.2%). SSI class, study design, or patient BMI did not significantly impact study results in a meta-regression model. The association was higher for cardiac surgery 2.03 (95% PI, 1.13-4.05) compared with surgeries of other types (P=.001). CONCLUSIONS These results support the consideration of diabetes as an independent risk factor for SSIs for multiple surgical procedure types. Continued efforts are needed to improve surgical outcomes for diabetic patients. Infect. Control Hosp. Epidemiol. 2015;37(1):88-99.

The intent of this document is to highlight practical recommendations in a concise format designed to assist acute-care hospitals in implementing and prioritizing their surgical-site infection (SSI) prevention efforts. This document updates the Strategies to Prevent Surgical Site Infections in Acute Care Hospitals published in 2014.1 This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Abstract Background ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. Results Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. Conclusions ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. Clinical Trial Registration NCT02753946 ZEUS, a Phase 2/3 trial, studied ZTI-01 (fosfomycin for injection) in the treatment of hospitalized adults with complicated urinary tract infection and acute pyelonephritis versus piperacillin-tazobactam. ZTI-01 was non-inferior to piperacillin-tazobactam and was well tolerated.

Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20–28) of these patients had died. Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. National Institutes of Health.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime–avibactam, imipenem–relebactam, meropenem–vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections. Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine- and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases—the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections.

Background. Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin–tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin–tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC. Methods. A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for ≥48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards. Results. A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73–6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001). Conclusion. The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination.

Resistant gram-negative bacteria (R-GNB) colonization in nursing home patients can cause clinical infection and intrafacility transmission. Limited data exist on the roles of age and function on R-GNB colonization. A secondary data analysis was performed from a cohort study of 896 patients admitted to 6 Michigan nursing homes between November 2013 and May 2018. Swabs obtained upon enrollment, weekly for 1 month, then monthly until nursing home discharge from 5 anatomical sites were cultured for GNB. R-GNB were defined as resistant to ciprofloxacin, ceftazidime, or imipenem. Patients with growth of the same R-GNB as the initial positive visit, from any anatomical site at any subsequent visit, were considered persistently colonized. Demographic data, antibiotic use, device use, and physical self-maintenance scales (PSMSs) were obtained upon enrollment. Characteristics were compared between patients with R-GNB colonization versus those without, and those with persistent R-GNB colonization versus those with spontaneous decolonization. Of 169 patients with a positive R-GNB culture and ≥2 subsequent study visits, 89 (53%) were transiently colonized and 80 (47%) were persistently colonized. Compared to uncolonized patients, persistent and transient R-GNB colonization were associated with higher PSMS score: 1.14 (95% confidence interval or CI, 1.05-1.23; = .002) and 1.10 (95% CI, 1.01-1.19; = .023), respectively. Persistent colonization was independently associated with longer duration of nursing home stay (1.02; 95% CI, 1.01-1.02; < .001). Higher readmission rate among persistently colonized patients was observed on unadjusted analysis. Persistent R-GNB colonization is associated with younger age, functional disability, and prolonged length of nursing home stay. In-depth longitudinal studies to understand new acquisition and transmission dynamics of R-GNB in nursing homes are needed.

IntroductionTreatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE.MethodsA total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings.ResultsWithin the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P < 0.001).ConclusionsMonotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT.Clinical Trials RegistrationNCT02168946.FundingThe Medicines Company.