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New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Shionogi.

Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, -2.6% [95% confidence interval, -10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. NCT01737320.

Background. The value of rapid, panel-based molecular diagnostics for positive blood culture bottles (BCBs) has not been rigorously assessed. We performed a prospective randomized controlled trial evaluating outcomes associated with rapid multiplex PCR (rmPCR) detection of bacteria, fungi, and resistance genes directly from positive BCBs. Methods. A total of 617 patients with positive BCBs underwent stratified randomization into 3 arms: standard BCB processing (control, n = 207), rmPCR reported with templated comments (rmPCR, n = 198), or rmPCR reported with templated comments and real-time audit and feedback of antimicrobial orders by an antimicrobial stewardship team (rmPCR/AS, n = 212). The primary outcome was antimicrobial therapy duration. Secondary outcomes were time to antimicrobial de-escalation or escalation, length of stay (LOS), mortality, and cost. Results. Time from BCB Gram stain to microorganism identification was shorter in the intervention group (1.3 hours) vs control (22.3 hours) (P < .001). Compared to the control group, both intervention groups had decreased broad-spectrum piperacillin-tazobactam (control 56 hours, rmPCR 44 hours, rmPCR/AS 45 hours; P = .01) and increased narrow-spectrum β-lactam (control 42 hours, rmPCR 71 hours, rmPCR/AS 85 hours; P = .04) use, and less treatment of contaminants (control 25%, rmPCR 11%, rmPCR/AS 8%; P = .015). Time from Gram stain to appropriate antimicrobial de-escalation or escalation was shortest in the rmPCR/AS group (de-escalation: rmPCR/AS 21 hours, control 34 hours, rmPCR 38 hours, P < .001; escalation: rmPCR/AS 5 hours, control 24 hours, rmPCR 6 hours, P = .04). Groups did not differ in mortality, LOS, or cost. Conclusions. rmPCR reported with templated comments reduced treatment of contaminants and use of broad-spectrum antimicrobials. Addition of antimicrobial stewardship enhanced antimicrobial de-escalation. Clinical Trials Registration. NCT01898208.

In patients with complicated urinary tract infection, clinical and microbiologic treatment success was significantly better with cefepime–taniborbactam (β-lactam and β-lactamase inhibitor) than with meropenem.

The hospital environment is a reservoir for the transmission of microorganisms. The effect of improved cleaning on patient-centred outcomes remains unclear. We aimed to evaluate the effectiveness of an environmental cleaning bundle to reduce health care-associated infections in hospitals. The REACH study was a pragmatic, multicentre, randomised trial done in 11 acute care hospitals in Australia. Eligible hospitals had an intensive care unit, were classified by the National Health Performance Authority as a major hospital (public hospitals) or having more than 200 inpatient beds (private hospitals), and had a health-care-associated infection surveillance programme. The stepped-wedge design meant intervention periods varied from 20 weeks to 50 weeks. We introduced the REACH cleaning bundle, a multimodal intervention, focusing on optimising product use, technique, staff training, auditing with feedback, and communication, for routine cleaning. The primary outcomes were incidences of health-care-associated Staphylococcus aureus bacteraemia, Clostridium difficile infection, and vancomycin-resistant enterococci infection. The secondary outcome was the thoroughness of cleaning of frequent touch points, assessed by a fluorescent marking gel. This study is registered with the Australian and New Zealand Clinical Trial Registry, number ACTRN12615000325505. Between May 9, 2016, and July 30, 2017, we implemented the cleaning bundle in 11 hospitals. In the pre-intervention phase, there were 230 cases of vancomycin-resistant enterococci infection, 362 of S aureus bacteraemia, and 968 C difficile infections, for 3 534 439 occupied bed-days. During intervention, there were 50 cases of vancomycin-resistant enterococci infection, 109 of S aureus bacteraemia, and 278 C difficile infections, for 1 267 134 occupied bed-days. After the intervention, vancomycin-resistant enterococci infections reduced from 0·35 to 0·22 per 10 000 occupied bed-days (relative risk 0·63, 95% CI 0·41–0·97, p=0·0340). The incidences of S aureus bacteraemia (0·97 to 0·80 per 10 000 occupied bed-days; 0·82, 0·60–1·12, p=0·2180) and C difficile infections (2·34 to 2·52 per 10 000 occupied bed-days; 1·07, 0·88–1·30, p=0·4655) did not change significantly. The intervention increased the percentage of frequent touch points cleaned in bathrooms from 55% to 76% (odds ratio 2·07, 1·83–2·34, p<0·0001) and bedrooms from 64% to 86% (1·87, 1·68–2·09, p<0·0001). The REACH cleaning bundle was successful at improving cleaning thoroughness and showed great promise in reducing vancomycin-resistant enterococci infections. Our work will inform hospital cleaning policy and practice, highlighting the value of investment in both routine and discharge cleaning practice. National Health and Medical Research Council (Australia).

In this trial involving 387 patients with Staphylococcus aureus bacteremia, ceftobiprole, a cephalosporin active against methicillin-sensitive and -resistant S. aureus , was noninferior to daptomycin.

In this cluster-randomized study at ICUs in six hospitals, chlorhexidine-impregnated washcloths were associated with significantly lower rates of bloodstream infections and acquisition of multidrug-resistant organisms than were nonantimicrobial washcloths. Multidrug-resistant organisms (MDROs), including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), have become endemic in many acute care and long-term care facilities. 1 – 5 Infections with these organisms are often difficult to treat, owing to a dwindling armamentarium of active antimicrobial agents. The Centers for Disease Control and Prevention (CDC) has promulgated a variety of strategies, including hand hygiene and the use of isolation precautions, to limit the spread of these organisms among patients, but these strategies require consistent adherence to practices by large numbers of health care personnel during frequent patient encounters and can be difficult to sustain. 6 In . . .

Background. In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal β-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. Methods. In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. Results. We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%–102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. Conclusions. Combining an antistaphylococcal β-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).

Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. UK National Institute for Health Research Health Technology Assessment.

PurposeTo assess clinical impact and perform cost-consequence analysis of the broadest multiplex PCR panels available for the rapid diagnosis of bloodstream infections (BSI).MethodsSingle-center, randomized controlled trial conducted from June 2019 to February 2021 at a French University hospital with an institutional antimicrobial stewardship program. Primary endpoint was the percentage of patients with optimized antimicrobial treatment 12 h after transmission of positivity and Gram stain results from the first positive BC.ResultsThis percentage was significantly higher in the multiplex PCR (mPCR) group (90/105 = 85.7% %, CI95% [77.5 ; 91.8] vs. 68/107 = 63.6%, CI95% [53.7 ; 72.6]; p < 10− 3) at interim analysis, resulting in the early termination of the study after the inclusion of 309 patients. For patients not optimized at baseline, the median time to obtain an optimized therapy was much shorter in the mPCR group than in the control group (6.9 h, IQR [2.9; 17.8] vs. 26.4 h, IQR [3.4; 47.5]; p = 0.001). Early optimization of antibiotic therapy resulted in a non-statistically significant decrease in mortality from 12.4 to 8.8% (p = 0.306), with a trend towards a shorter median length of stay (18 vs. 20 days; p = 0.064) and a non-significant reduction in the average cost per patient of €3,065 (p = 0.15). mPCR identified all the bacteria present in 88% of the samples.ConclusionDespite its higher laboratory cost, the use of multiplex PCR for BSI diagnosis leads to early-optimised therapy, seems cost-effective and could reduce mortality and length of stay. Their impact could probably be improved if implemented 24/7.