Trial of Vancomycin and Cefazolin as Surgical Prophylaxis in Arthroplasty.

BACKGROUND: The addition of vancomycin to beta-lactam prophylaxis in arthroplasty may reduce surgical-site infections; however, the efficacy and safety are unclear. METHODS: In this multicenter, double-blind, superiority, placebo-controlled trial, we randomly assigned adult patients without known methicillin-resistant Staphylococcus aureus (MRSA) colonization who were undergoing arthroplasty to receive 1.5 g of vancomycin or normal saline placebo, in addition to cefazolin prophylaxis. The primary outcome was surgical-site infection within 90 days after surgery. RESULTS: A total of 4239 patients underwent randomization. Among 4113 patients in the modified intention-to-treat population (2233 undergoing knee arthroplasty, 1850 undergoing hip arthroplasty, and 30 undergoing shoulder arthroplasty), surgical-site infections occurred in 91 of 2044 patients (4.5%) in the vancomycin group and in 72 of 2069 patients (3.5%) in the placebo group (relative risk, 1.28; 95% confidence interval [CI], 0.94 to 1.73; P = 0.11). Among patients undergoing knee arthroplasty, surgical-site infections occurred in 63 of 1109 patients (5.7%) in the vancomyin group and in 42 of 1124 patients (3.7%) in the placebo group (relative risk, 1.52; 95% CI, 1.04 to 2.23). Among patients undergoing hip arthroplasty, surgical-site infections occurred in 28 of 920 patients (3.0%) in the vancomyin group and in 29 of 930 patients (3.1%) in the placebo group (relative risk, 0.98; 95% CI, 0.59 to 1.63). Adverse events occurred in 35 of 2010 patients (1.7%) in the vancomycin group and in 35 of 2030 patients (1.7%) in the placebo group, including hypersensitivity reactions in 24 of 2010 patients (1.2%) and 11 of 2030 patients (0.5%), respectively (relative risk, 2.20; 95% CI, 1.08 to 4.49), and acute kidney injury in 42 of 2010 patients (2.1%) and 74 of 2030 patients (3.6%), respectively (relative risk, 0.57; 95% CI, 0.39 to 0.83). CONCLUSIONS: The addition of vancomycin to cefazolin prophylaxis was not superior to placebo for the prevention of surgical-site infections in arthroplasty among patients without known MRSA colonization. (Funded by the Australian National Health and Medical Research Council; Australian New Zealand Clinical Trials Registry number, ACTRN12618000642280.).

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.

Importance: Extended-spectrum ß-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum ß-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Comparison of Clostridium difficile Ribotypes Circulating in Australian Hospitals and Communities.

Clostridium difficile infection (CDI) is becoming less exclusively a health care-associated CDI (HA-CDI). The incidence of community-associated CDI (CA-CDI) has increased over the past few decades. It has been postulated that asymptomatic toxigenic C. difficile (TCD)-colonized patients may play a role in the transfer of C. difficile between the hospital setting and the community. Thus, to investigate the relatedness of C. difficile across the hospital and community settings, we compared the characteristics of symptomatic and asymptomatic host patients and the pathogens from these patients in these two settings over a 3-year period. Two studies were simultaneously conducted; the first study enrolled symptomatic CDI patients from two tertiary care hospitals and the community in two Australian states, while the second study enrolled asymptomatic TCD-colonized patients from the same tertiary care hospitals. A total of 324 patients (96 with HA-CDI, 152 with CA-CDI, and 76 colonized with TCD) were enrolled. The predominant C. difficile ribotypes isolated in the hospital setting corresponded with those isolated in the community, as it was found that for 79% of the C. difficile isolates from hospitals, an isolate with a matching ribotype was isolated in the community, suggesting that transmission between these two settings is occurring. The toxigenic C. difficile strains causing symptomatic infection were similar to those causing asymptomatic infection, and patients exposed to antimicrobials prior to admission were more likely to develop a symptomatic infection (odds ratio, 2.94; 95% confidence interval, 1.20 to 7.14). Our findings suggest that the development of CDI symptoms in a setting without establishment of hospital epidemics with binary toxin-producing C. difficile strains may be driven mainly by host susceptibility and exposure to antimicrobials, rather than by C. difficile strain characteristics.

The Potential Role of Social Media Platforms in Community Awareness of Antibiotic Use in the Gulf Cooperation Council States: Luxury or Necessity?

The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media campaigns worldwide have been launched; however, such campaigns can be costly and the outcomes are variable and difficult to assess. Social media platforms, including Twitter, Facebook, and YouTube, are now frequently utilized to address health-related issues. In many geographical locations, such as the countries of the Gulf Cooperation Council (GCC) States (Saudi Arabia, United Arab Emirates, Kuwait, Oman, Qatar, and Bahrain), these platforms are becoming increasingly popular. The socioeconomic status of the GCC states and their reliable communication and networking infrastructure has allowed the penetration and scalability of these platforms in the region. This might explain why the Saudi Ministry of Health is using social media platforms alongside various other media platforms in a large-scale public awareness campaign to educate at-risk communities about the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper discusses the potential for using social media tools as cost-efficient and mass education platforms to raise awareness of appropriate antibiotic use in the general public and in the medical communities of the Arabian Peninsula.

Clostridioides difficile Infection: Clinical Practice and Health Outcomes in 6 Large Tertiary Hospitals in Eastern Australia.

Background: Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality in both healthcare and community settings. We aimed to define the predisposing factors, risks for severe disease, and mortality determinants of CDI in eastern Australia over a 1-year period. Methods: This is an observational retrospective study of CDI in hospitalized patients aged ≥18 years in 6 tertiary institutions from 1 January 2016 to 31 December 2016. Patients were identified through laboratory databases and medical records of participating institutions. Clinical, imaging, and laboratory data were input into an electronic database hosted at a central site. Results: A total of 578 patients (578 CDI episodes) were included. Median age was 65 (range, 18-99) years and 48.2% were male. Hospital-onset CDI occurred in 64.0%. Recent antimicrobial use (41.9%) and proton pump inhibitor use (35.8%) were common. Significant risk factors for severe CDI were age <65 years (P < .001), malignancy within the last 5 years (P < .001), and surgery within the previous 30 days (P < .001). Significant risk factors for first recurrence included severe CDI (P = .03) and inflammatory bowel disease (P = .04). Metronidazole was the most common regimen for first episodes of CDI with 65.2% being concordant with Australian treatment guidelines overall. Determinants for death at 60 days included age ≥65 years (P = .01), severe CDI (P < .001), and antibiotic use within the prior 30 days (P = .02). Of those who received metronidazole as first-line therapy, 10.1% died in the 60-day follow-up period, compared to 9.8% of those who received vancomycin (P = .86). Conclusions: Patients who experience CDI are vulnerable and require early diagnosis, clinical surveillance, and effective therapy to prevent complications and improve outcomes.

Investigator-Driven Randomised Controlled Trial of Cefiderocol versus Standard Therapy for Healthcare-Associated and Hospital-Acquired Gram-negative Bloodstream Infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial.

BACKGROUND: Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection. METHODS: This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient's treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5-14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. DISCUSSION: With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent. TRIAL REGISTRATION: The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.

Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC ß-Lactamase-Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2).

BACKGROUND: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. METHODS: We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. RESULTS: Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, -12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC ß-lactamase genes identified were bla CMY-2, bla DHA-17, bla CMH-3, and bla ACT-17. No ESBL, OXA, or other carbapenemase genes were identified. CONCLUSIONS: Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. CLINICAL TRIALS REGISTRATION: NCT02437045.

Reporting of pre-enrolment screening with randomized clinical trials: A small item that could impact a big difference.

INTRODUCTION: Randomized controlled trials (RCTs), when conducted using ethical and transparent methods, become the ultimate standard for producing evidence-based knowledge in the field of medical research. We sought to determine the proportion of RCTs in which the number of screened patients is reported, and also to ascertain what predicted efficient screening (i.e., a high number of screened participants being enrolled). MATERIALS AND METHODS: Thirty-five RCTs from the Journals Clinical Infectious Diseases and The Lancet Infectious Diseases were reviewed from the time period of January 2012 to July 2013 using standardised criteria. RESULTS: From the 35 RCTs, 9 of 35 (26%) did not report the number of patients screened prior to recruitment. From the 26 studies that reported this screening figure, 10,215 (47%; range: 2-98%) of the screened participants (21,862) were subsequently enrolled. About 18.3% of those screened and not enrolled, met inclusion and exclusion criteria yet did not wish to participate in an RCT. Studies performed in developed countries and pediatric populations were more likely to have low rates of enrolment compared with the screened population although there was no statistical significance to these associations (P = 0.2 for both variables). CONCLUSION: Many reports of RCTs do not report screening figures, even though these add useful information about the feasibility of future trials.

Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial.

BACKGROUND: Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections. METHODS/DESIGN: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection. TRIAL REGISTRATION: The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).

Predictors of use of infection control precautions for multiresistant gram-negative bacilli in Australian hospitals: analysis of a national survey.

INTRODUCTION: Despite the global expansion of extended spectrum ß-lactamase-harboring Enterobacteriaceae (ESBL-E) and carbapenem-resistant Enterobacteriaceae (CRE), only limited research on the infection control management of patients with these organisms is available. METHODS: We present a national survey of infection control practices amongst adult acute-care hospitals in Australia, for ESBL-E, CRE, and the emerging threat of patients with overseas health care contact. RESULTS: In total, 97 health services responded, representing 9% of all eligible hospitals. The proportion of hospitals that reported use of contact precautions (CP) was 96% (93 out of 97) for ESBL-E, 81% (79 out of 97) for CRE, and 72% (48 out of 67) for patients transferred from an international hospital. For ESBL-E hospitals frequently employed risk-stratification to limit the use of CP (40 out of 97; 41%). On multivariate analysis predictors of a strategy to limit use of CP for ESBL-E were government funding (odds ratio, 4.8; P = .003) and a metropolitan location (odds ratio, 3.2; P = .014); predictors of any use of CP for CRE were location in an Australian state with a specific legislation on CRE (P = .030) and the presence of a written policy on CRE (P = .011). CONCLUSIONS: Infection control management of multiresistant gram-negative bacilli varied considerably across the Australian hospitals surveyed. A lower rate of reported CP use for CRE than for ESBL-E was unexpected and indicates a vulnerability in some Australian hospitals. Multivariate analysis revealed various drivers influencing infection control practice in Australia.