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Background: A significant increased risk of complications and mortality in immunocompromised patients affected by COVID-19 has been described. However, the impact of COVID-19 in solid organ transplant (SOT) recipients is an issue still on debate, due to conflicting evidence emerged from different observational studies. Objective: We performed a systematic review with meta-analysis to assess the clinical outcome in SOT recipients with COVID-19 compared to general population. Data source: PubMed-MEDLINE and Scopus were independently searched until 13 October 2021. Study eligibility criteria: Prospective or retrospective observational studies comparing clinical outcome in SOT recipients versus general populations affected by COVID-19. Primary endpoint was 30-day mortality. Participants: Patients with confirmed COVID-19. Intervention: Solid organ transplant recipients. Assessment of risk of bias: Quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Methods of data synthesis: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using a random-effect model with inverse variance method. Multiple subgroup and sensitivity analyses were conducted to investigate source of heterogeneity. Results: 3,501 articles were screened, and thirty-one observational studies (N=590,375; 5,759 SOT recipients vs. 584,616 general population) were included in the meta-analyses. No difference in 30-day mortality rate was found in primary analysis including studies providing adjustment for confounders (N=17; 3,752 SOT recipients vs. 159,745 general population; OR 1.13, 95%CI 0.94-1.35; I2=33.9%). No evidence of publication bias was reported. Higher risk of ICU admission (OR 1.56, 95%CI 1.03-2.63) and occurrence of acute kidney injury (OR 2.50 95%CI 1.81-3.45) was found in SOT recipients. Conclusions: No increased risk in mortality was found in SOT recipients affected by COVID-19 compared to general population when adjusted for demographic and clinical features and COVID-19 severity.

Background: Since the SARS-CoV-2 pandemic emerged, antimicrobial stewardship (AS) activities need to be diverted into COVID-19 management. Methods: In order to assess the impact of COVID-19 on AS activities, we analyzed changes in antibiotic consumption in moderate-to-severe COVID-19 patients admitted to four units in a tertiary-care hospital across three COVID-19 waves. The AS program was introduced at the hospital in 2018. During the first wave, COVID-19 forced the complete withdrawal of hospital AS activities. In the second wave, antibiotic guidance calibration for COVID-19 patients was implemented in all units, with enhanced stewardship activities in Units 1, 2, and 3 (intervention units). In a controlled before and after study, antimicrobial usage during the three waves of the COVID-19 pandemic was compared to the 12-month prepandemic unit (Unit 4 acted as the control). Antibiotic consumption data were analyzed as the overall consumption, stratified by the World Health Organization AWaRe classification, and expressed as defined-daily-dose (DDD) and days-of-therapy (DOT) per 1000 patient-day (PD). Results: In the first wave, the overall normalized DOT in units 2–4 significantly exceeded the 2019 level (2019: 587 DOT/1000 PD ± 42.6; Unit 2: 836 ± 77.1; Unit 3: 684 ± 122.3; Unit 4: 872, ± 162.6; p < 0.05). After the introduction of AS activities, consumption decreased in the intervention units to a significantly lower level when compared to 2019 (Unit 1: 498 DOT/1000 PD ± 49; Unit 2: 232 ± 95.7; Unit 3: 382 ± 96.9; p < 0.05). Antimicrobial stewardship activities resulted in a decreased amount of total antibiotic consumption over time and positively affected the watch class and piperacillin-tazobactam use in the involved units. Conclusions: During a pandemic, the implementation of calibrated AS activities represents a sound investment in avoiding inappropriate antibiotic therapy.

Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77-2.54), hospitalization (OR, 1.98; 95% CI, 1.15-3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38-2.26), and MV (OR, 2.17; 95% CI, 1.71-2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer., This work has been financed by the ORCHESTRA project under the European Union's Horizon 2020 research and innovation program Grant Agreement No. 101016167.

Background The outpatient setting is a key scenario for the implementation of antimicrobial stewardship (AMS) activities, considering that overconsumption of antibiotics occurs mainly outside hospitals. This publication is the result of a joint initiative by the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks, which is aimed at formulating a set of target actions for linking surveillance data with AMS activities in the outpatient setting. Methods A scoping review of the literature was carried out in three research areas: AMS leadership and accountability; antimicrobial usage and AMS; antimicrobial resistance and AMS. Consensus on the actions was reached through a RAND-modified Delphi process involving over 40 experts in infectious diseases, clinical microbiology, AMS, veterinary medicine or public health, from 18 low-, middle- and high-income countries. Results Evidence was retrieved from 38 documents, and an initial 25 target actions were proposed, differentiating between essential or desirable targets according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for all targets. Further to a second review, 6 statements were re-considered and 3 were deleted, leading to a final list of 22 target actions in the form of a practical checklist. Conclusions This White Paper is a pragmatic and flexible tool to guide the development of calibrated surveillance-based AMS interventions specific to the outpatient setting, which is characterized by substantial inter- and intra-country variability in the organization of healthcare structures, maintaining a global perspective and taking into account the feasibility of the target actions in low-resource settings.

BackgroundAntimicrobial surveillance and antimicrobial stewardship (AMS) are essential pillars in the fight against antimicrobial resistance (AMR), but practical guidance on how surveillance data should be linked to AMS activities is lacking. This issue is particularly complex in the hospital setting due to structural heterogeneity of hospital facilities and services. The JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks have joined efforts to formulate a set of target actions for linking surveillance data with AMS activities.MethodsA scoping review of the literature was carried out addressing research questions on three areas: (i) AMS leadership and accountability; (ii) antimicrobial usage and AMS; (iii) AMR and AMS. Consensus on the target actions was reached through a RAND-modified Delphi process involving over 40 experts in different fields from 18 countries.ResultsEvidence was retrieved from 51 documents. Initially 38 targets were proposed, differentiated as essential or desirable according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for 32 targets. Following a second consultation, 27 targets were approved, 11 were deleted and 4 were suggested for rephrasing, leading to a final approved list of 34 target actions in the form of a practical checklist.ConclusionsThis White Paper provides a pragmatic and flexible tool to guide the development of calibrated hospital-surveillance-based AMS interventions. The strength of this tool is that it is a comprehensive perspective that takes into account the hospital patient case-mix and the related epidemiology, which ultimately drives antimicrobial usage, and the feasibility in low-resource settings.

In recent years, there have been significant developments in rapid diagnostic techniques (RDTs) in microbiology for the diagnosis of infectious diseases. By providing a more rapid diagnosis, RDTs have the potential to affect diagnostic algorithms and therapeutic decisions. In addition to “antibiotic stewardship,” the term “diagnostic stewardship” has recently been coined in clinical practice and denotes the promotion of a rational implementation of diagnostic tests with a view to improving the quality of care and safely reducing cost. This review explores the advancement of diagnostic and antibiotic stewardship in the implementation of RDTs and describes the most relevant related clinical applications in Clostridioides difficile infections (CDIs), bloodstream infections (BSIs), and respiratory infections. An innovative evidence-based RDT diagnostic algorithm that varies according to the presence of pre-agreed institutional criteria significantly increases testing accuracy for differentiating CDIs from carriage status. Evidence on BSIs reveals that pairing RDTs and antibiotic stewardship eases timely and appropriate utilization of RDTs results that may improve the clinical outcomes by optimizing antibiotic use. Data on clinical implications of RDTs targeting antibiotic-resistant Gram-negative and respiratory infections are scarce and inconclusive. Intertwining the role of diagnostic and antibiotic stewardship is crucial to optimizing RDTs utilization, by ensuring that RDTs are rationally selected and implemented, and results correctly interpreted and applied to clinical practice. Further research is needed to explore the clinical implications of RDT implementation.

Antibiotic stewardship (AS) is a cornerstone of the fight against antimicrobial resistance; however, evidence on the best practice to improve antibiotic prescription in various hospital settings is still scarce. This study aimed to measure the efficacy of a non-restrictive AS intervention in the internal medicine area of a tertiary-care hospital across a 3-year period.The intervention comprised a 3-month 'intensive phase' based on education and guidelines provision, followed by 9 months of audits and feedback activities. The primary outcome was the overall antibiotic consumption measured as days of therapy (DOTs) and defined daily doses (DDDs). Secondary outcomes were carbapenem and fluoroquinolone consumption, all-cause in-hospital mortality, length of stay, incidence of Clostridioides difficile and carbapenem-resistant Enterobacterales bloodstream infections (CRE-BSIs). All outcomes were measured in the intervention wards comparing the pre-phase with the post-phase using an interrupted time-series model.A total of 145 337 patient days (PDs) and 14 159 admissions were included in the analysis. The intervention was associated with reduced DOTs*1000PDs (-162.2/P = 0.005) and DDDs*1000PDs (-183.6/P ≤ 0.001). A sustained decrease in ward-related antibiotic consumption was also detected during the post-intervention phase and in the carbapenem/fluoroquinolone classes. The intervention was associated with an immediate reduction in length of stay (-1.72 days/P0.001) and all-cause mortality (-3.71 deaths*100 admissions/P = 0.002), with a decreasing trend over time. Rates of Clostridioides difficile infections and CRE-BSIs were not significantly impacted by the intervention.The AS intervention was effective and safe in decreasing antibiotic consumption and length of stay in the internal medicine area. Enabling prescribers to judicious use of antimicrobials through active participation in AS initiatives is key to reach sustained results over time.

SARS-CoV-2 serological tests are used to assess the infection seroprevalence within a population. This study aims at assessing potential biases in estimating infection prevalence amongst healthcare workers (HCWs) when different diagnostic criteria are considered. A multi-site cross-sectional study was carried out in April–September 2020 amongst 1.367 Italian HCWs. SARS-CoV-2 prevalence was assessed using three diagnostic criteria: RT-PCR on nasopharyngeal swab, point-of-care fingerprick serological test (POCT) result and COVID-19 clinical pathognomonic presentation. A logistic regression model was used to estimate the probability of POCT-positive result in relation to the time since infection (RT-PCR positivity). Among 1.367 HCWs, 69.2% were working in COVID-19 units. Statistically significant differences in age, role and gender were observed between COVID-19/non-COVID-19 units. Prevalence of SARS-CoV-2 infection varied according to the criterion considered: 6.7% for POCT, 8.1% for RT-PCR, 10.0% for either POCT or RT-PCR, 9.6% for infection pathognomonic clinical presentation and 17.6% when at least one of the previous criteria was present. The probability of POCT-positive result decreased by 1.1% every 10 days from the infection. This study highlights potential biases in estimating SARS-CoV-2 point-prevalence data according to the criteria used. Although informative on infection susceptibility and herd immunity level, POCT serological tests are not the best predictors of previous COVID-19 infections for public health monitoring programmes.

Surgical site infections (SSIs) represent a potential complication in surgical procedures, mainly because clean/contaminated surgery involves organs that are normally colonized by bacteria. Dental, maxillo-facial and ear-nose-throat (ENT) surgeries are among those that carry a risk of SSIs because the mouth and the first respiratory tracts are normally colonized by a bacterial flora. The aim of this consensus document was to provide clinicians with recommendations on surgical antimicrobial prophylaxis in neonates (

Surgical site infections (SSIs) represent a potential complication in any type of surgery and can occur up to one year after the procedure in the case of implant placement. In the field of orthopedic and hand surgery, the rate of SSIs is a relevant issue, considering the need for the placement of synthesis devices and the type of some interventions (e.g., exposed fractures). This work aims to provide guidance on the management of peri-operative antibiotic prophylaxis for the pediatric and neonatal population undergoing orthopedic and hand surgery in order to standardize the management of patients and to reduce, on the one hand, the risk of SSI and, on the other, the development of antimicrobial resistance. The following scenarios were considered: (1) bloodless fracture reduction; (2) reduction of unexposed fracture and grade I and II exposed fracture; (3) reduction of grade III exposed fracture or traumatic amputation; (4) cruel fracture reduction with percutaneous synthesis; (5) non-traumatic amputation; (6) emergency intact skin trauma surgery and elective surgery without synthetic media placement; (7) elective orthopedic surgery with prosthetic and/or synthetic media placement and spinal surgery; (8) clean elective hand surgery with and without bone involvement, without use of synthetic means; (9) surgery of the hand on an elective basis with bone involvement and/or with use of synthetic means. This manuscript has been made possible by the multidisciplinary contribution of experts belonging to the most important Italian scientific societies and represents, in our opinion, the most complete and up-to-date collection of recommendations regarding the behavior to be adopted in the peri-operative setting in neonatal and pediatric orthopedic and hand surgery. The specific scenarios developed are aimed at guiding the healthcare professional in practice to ensure the better and standardized management of neonatal and pediatric patients, together with an easy consultation.

Dalbavancin is a second-generation lipoglycopeptide approved since 2014 to treat acute bacterial skin and skin-structure infections (ABSSSI). Dalbavancin is characterized by Gram-positive activity and novel pharmacokinetic properties allowing prolonged terminal half-life andonce weekly dosing . A good safety profile was reported in clinical trials .Dalbavancin safety and tolerability from trials and post-marketing studies were reviewed. While most reports included predominantly ABSSSI, two clinical trials and recent observational studies have explored the use of dalbavancin for off-label indications, mainly including bloodstream and osteoarticular infections.The occurrence of drug-related adverse effects (AE) was similar between dalbavancin and comparators in clinical trials enrolling patients with ABSSSI. Most common AE included gastrointestinal symptoms, infusion reaction, and hypersensitivity. Low rates of drug discontinuation and serious AE were reported across studies. In the past 5 years, several observational studies have reported safety data on the use of dalbavancin, confirming its favorable safety profile. Nevertheless, data from dalbavancin off-label use, often derived from prolonged (2 weeks) treatments with variable dosing regimens, were mainly retrospective and lacked comparators. Further research is required to allow a reliable analysis of short- and long-term dalbavancin-related AE in non-ABSSSI.

Objectives: Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. Methods: A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. Results: A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in high-income countries versus 59% (194/283) in upper-medium-income countries and 30% (118/196) in lower-middle-income countries/lower-income-countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of ‘combination therapy’ with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) requiring in vitro synergism. Conclusions: Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.

Scope: this guideline addresses the indications for direct testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in asymptomatic individuals in health care facilities, with the aim to prevent SARS-CoV-2 transmissions in these settings. The benefit of testing asymptomatic individuals to create a safe environment for patients and health care workers must be weighed against potential unintended consequences, including delaying necessary treatments owing to false positive results and lower quality of care owing to strict isolation measures. Methods: a total of nine PICOs (population, intervention, comparison, outcome) on the topic of testing asymptomatic individuals was selected by the panel members. Subsequently, a literature search for existing guidelines and systematic reviews was performed on PubMed, Epistemonikos, and RecMap using relevant filters available in each database. Data on article/recommendation type, setting, target population, intervention, and quality of the evidence were extracted. Credibility of the systematic reviews was evaluated using the AMSTAR tool, and level of agreement with available recommendation was evaluated with the AGREE II score. Because the evidence available from systematic reviews was deemed insufficiently updated to formulate relevant recommendations, an additional search targeting relevant guidance documents from major public health institutions and original studies was performed. Provisional recommendations were discussed via web conferences until agreement was reached, and final recommendations were formulated according to the grade approach. Recommendations: recommendations were formulated regarding systematic testing in asymptomatic individuals upon admission to a health care setting, during hospital stay, before elective procedures, and before scheduled nonsurgical procedures. Moreover, recommendations regarding testing of asymptomatic visitors, personal caregivers, and health care workers in health care facilities were presented. Recommendations also were given on contact tracing in asymptomatic patients or health care workers and the possibility of a negative screening test to shorten the quarantine period. Furthermore, if applicable, recommendations were specified to transmission rate and vaccination coverage., NA

The recent invasion of electric-powered personal mobility vehicles (e-PMVs) in many cities worldwide has disputed the transport sector and captured the attention of academics, practitioners, and public administrators. Indeed, these vehicles are believed to be sustainable transport alternatives. Therefore, understanding how to evaluate and monitor the related performance is crucial and may be addressed by suitable key sustainable parameters (KSPs) to inform on the excellences and criticalities of e-PMVs. Previous research has focused largely on “how to measure and manage” KSPs rather than “what to measure”. Conversely, as far as the authors know, no study investigated objective methods for identifying and selecting top KSPs. This paper covers this gap by proposing a cohesive approach, which identifies a long list of KSPs, defines their properties, involves experts to elicit judgments for each KSP, evaluates the long list, and returns the most promising set. This approach is demonstrated with an application based on an Italian survey. A circumscribed and relevant set of six overlapping KSPs is derived by merging two different approaches. These results may support the opportunity to assess the performance of e-PMVs among cities according to a common set of KSPs.

The impact of inappropriate empirical antibiotic therapy (IEAT) on the outcome of severe infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-Ent) remains unclear. Current evidence is limited by study design and lack of confounder control. The main objective of this study was to define the outcome of severe infections due to ESBL-Ent according to clinical parameters and place of infection acquisition. Adult hospitalised patients with ESBL-Ent infections were included in a 3-year multicentre prospective study. Primary outcomes were IEAT rates and crude mortality of severe infections, adjusted by place of acquisition [community-acquired infection (CAI), healthcare-associated infection (HCAI) and hospital-acquired infection (HAI)]. Among 729 patients, 519 (71.2%) were diagnosed with HAI, 176 (24.1%) with HCAI and 34 (4.7%) with CAI. Moreover, 32.9% of patients received IEAT; higher rates of IEAT were observed in pneumonia (23%) and deep surgical site infections (19%). HCAIs were more frequently associated with IEAT than HAIs (48.3% vs. 27.9%; OR = 1.7, 95% CI 1.2–2.4). The overall mortality rate for severe infections (n = 264) was 12.1% and was significantly higher in HCAIs (20%) than HAIs (10%) (RR = 2.3, 95% CI 1.01–5.3). IEAT significantly increased the risk of mortality in bloodstream infections (RR = 8.3, 95% CI 2–46.3). Rates of IEAT and overall mortality of ESBL-Ent severe infections were higher in HCAIs than HAIs. Prompt diagnosis of patients with severe HCAIs due to ESBL-Ent is essential since these infections receive high rates of IEAT and significantly higher mortality than HAIs [ClinicalTrials.gov Identifier: NCT00404625].

Background Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods We systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as “defined” when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens. Results A total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components. Conclusion The existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice.

Background: The combination of antibiotics has become the clinicians’ preferred strategy for the treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) although the evidence supporting its use is weak. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods: Comparative and non-comparative observational studies, randomized control trials (RCTs) and case series were considered eligible with no language restriction. Studies were included if reporting microbiologically-confirmed sepsis caused by Acinetobacter baumannii, Enterobacterales/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcome and targeted antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected to explore feasibility of pooling data on antibiotic regimens. Results: A total of 6306 records were retrieved and 134 studies (11546 patients) were included [54 studies on Acinetobacter, 52 on Enterobacterales/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas]. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective and 17 (13%) case series. Forty-one studies (31%) were multicentric. Ninety-two distinct regimens were identified with 47 (51%, 5863 patients) not reporting any details on combination. 30-day mortality was assessed in 65 (48%) studies while attributable mortality was reported only in 19 (14%).The NMAs were not applicable for any of selected outcomes given the presence of too many disconnected components. Conclusion: The existing evidence is too weak for allowing formulating any evidence-based therapeutic recommendation for combination of antibiotics to treat CR-GNB sepsis. Future studies must clearly define number, type, dosages, and in vitro activity of each antibiotic included in the regimen to drive recommendations for using combination of antibiotics that might be reliably applied into clinical practice.

Klebsiella pneumoniae has accumulated a wide range of resistance determinants and has evolved into a difficult-to-treat pathogen that poses an increasing healthcare threat. KPC is an important marker for extensively drug-resistant (XDR) organisms with limited treatment options. In response to the medical need for new treatment options, several new antibiotics have been developed and registered recently. The β-lactamase inhibitor (BLI) combinations ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam, the cephalosporin–siderophore conjugate cefiderocol, the aminoglycoside derivative plazomicin and the tetracycline derivative eravacycline, focus on carbapenem-resistant Enterobacterales. These modified agents from old antibiotic classes illustrate the challenges of this requirement to address class-specific resistance mechanisms while critical gaps and some cross-resistance within a class, or to unrelated antibiotic classes, remain. The diverse molecular mechanisms and increasing diversification of carbapenem resistance among Klebsiella isolates requires improved rapid molecular diagnostic capabilities and stringent stewardship programmes to preserve the efficacy of new antibiotics for as long as possible.

[Scope] These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy., [Methods] An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak)., [Recommendations] The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed., These guidelines were supported in part by ESCMID.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria.

Antimicrobial stewardship programmes are widely considered to be a core component of the response to the antimicrobial resistance threat. However, a positive impact of these interventions in terms of microbiological outcomes remains difficult to demonstrate, especially when focusing on specific resistant phenotypes. The first part of this review aims to explore the complex relationship between antibiotic exposure and resistance development in KPC-producing Klebsiella pneumoniae. In the second part we aim to summarize published examples of antimicrobial stewardship interventions intended to impact on the epidemiology of KPC-producing K. pneumoniae. For this purpose, a literature search was performed and seven studies were included in the review. Both restrictive and non-restrictive interventions were associated with an overall reduction in antibiotic consumption, and a decrease in carbapenem resistance rates was observed in five studies. The overall quality of the evidence was low, mainly due to the poor reporting of microbiological outcomes, lack of a control group and suboptimal study design. Although the link between antibiotic use and resistance development is supported by strong evidence, demonstrating the impact of antimicrobial stewardship interventions on microbiological outcomes remains difficult. Studies with adequate design and appropriate outcome measures are needed to further promote antimicrobial stewardship and elucidate which interventions are more successful for controlling the spread of KPC-producing K. pneumoniae.

PRAISE network: Maaike S. M. van Mourik, Stephanie M.van Rooden, Mohamed Abbas, Olov Aspevall, Pascal Astagneau, Marc J. M. Bonten, Elena Carrara, Aina Gomila-Grange, Sabine C. de Greeff , Sophie Gubbels, Wendy Harrison, Hilary Humphreys, Anders Johansson, Mayke B. G. Koek, Brian Kristensen, Alain Lepape, Jean-Christophe Lucet, Siddharth Mookerjee, Pontus Naucler, Zaira R. Palacios-Baena, Elisabeth Presterl, Miquel Pujol, Jacqui Reilly, Christopher Roberts, Evelina Tacconelli, Daniel Teixeira, Thomas Tängdén, John Karlsson Valik, Michael Behnke, PetraGastmeier., [Introduction] Healthcare-associated infections (HAI) are a major public health concern. Monitoring of HAI rates, with feedback, is a core component of infection prevention and control programmes. Digitalization of healthcare data has created novel opportunities for automating the HAI surveillance process to varying degrees. However, methods are not standardized and vary widely between different healthcare facilities. Most current automated surveillance (AS) systems have been confined to local settings, and practical guidance on how to implement large-scale AS is needed., [Methods] This document was written by a task force formed in March 2019 within the PRAISE network (Providing a Roadmap for Automated Infection Surveillance in Europe), gathering experts in HAI surveillance from ten European countries., [Results] The document provides an overview of the key e-health aspects of implementing an AS system of HAI in a clinical environment to support both the infection prevention and control team and information technology (IT) departments. The focus is on understanding the basic principles of storage and structure of healthcare data, as well as the general organization of IT infrastructure in surveillance networks and participating healthcare facilities. The fundamentals of data standardization, interoperability and algorithms in relation to HAI surveillance are covered. Finally, technical aspects and practical examples of accessing, storing and sharing healthcare data within a HAI surveillance network, as well as maintenance and quality control of such a system, are discussed., [Conclusions] With the guidance given in this document, along with the PRAISE roadmap and governance documents, readers will find comprehensive support to implement large-scale AS in a surveillance network., This network has been supported under the 7th transnational call within the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), Network Call on Surveillance (2018) and was thereby funded by ZonMw (grant 549007001). This project also received support from the COMBACTE MAGNET EPI-Net project funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement 115523 | 115620 | 115737 | 777362, resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. J.K.V. was supported by grants from Region Stockholm and Vinnova.

Objectives/Purpose The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level.Methods GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level. Results The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies. Conclusion In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

Objective There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria. Methods and analysis This protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE’s risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias. Dissemination This systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals. PROSPERO registration number CRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104).

Objectives/PurposeThe costs attributable to antimicrobial resistance (AMR) across human, animal, and environmental health remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network aimed to develop a global, One Health AMR Cost Framework, that can be used by countries, regions, and other entities to quantify the economic burden attributable to AMR.MethodsGAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. It operated by means of Delphi rounds, teleconferences (TCs) and face-to-face (F2F) meetings. It assumes a bottom-up cost estimate, at the National level, with a global scope across all One Health Areas.ResultsThe resulting framework consists of the epidemiological data and the direct and indirect cost components, linked by the likelihood of each AMR-related health state that imposes such costs, across all One Health Areas for a large number of relevant pathogens. It represents a first step towards more comprehensive analyses for comparing cost-effectiveness of AMR interventions at the local level as well as more harmonised analyses at the global level.ConclusionThis is the first full AMR costing framework to be developed for bacterial pathogens in human and animal health and the environment. It aims to provide guidance on the data items necessary to calculate AMR costs in a global, One Health perspective to facilitate harmonized, full economic analyses. It is only through building a realistic cost picture that we can make informed decisions about potential strategies and political priorities.

Supplemental Digital Content is available in the text., Objective: Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; P

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients’ group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients’ group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.

[Objectives/purpose] The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level., [Methods] GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level., [Results] The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies., [Conclusion] In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats., The creation of the GAP-ONE Network was supported under the framework of the Joint Programming Initiative on Antimicrobial Resistance and funded by the Italian Ministry of Health, within the JPIAMR 8th call, Virtual Research Initiative, 2018.

Purpose of review Combination therapy is a common strategy for treatment of multidrug resistant infections. Despite the strong twin rationales of improving efficacy and reducing resistance development, the evidence supporting this strategy remains controversial. The aims of this review are to assess the most recent studies supporting the use of combination therapy for treating infections because of carbapenem-resistant Enterobacteriaceae (CRE) and to highlight relevant areas for further research. Recent findings Evidence supporting the use of combination therapy for the treatment of CRE remains limited to in-vitro experiments and observational studies with considerable risk of bias. Very few antibiotic combinations have been tested in well designed randomized controlled trials, making it difficult to draw general conclusions for clinical practice. Summary Further studies are urgently needed to test the most promising synergistic combinations. New drugs potentially active against CRE should also to be tested in studies with adequate sample size and truly representative of the general patient population.

This systematic review assessed study-level determinants of non-covering (inappropriate) empirical antibiotic treatment (IEAT), focusing on the influence of study years and the prevalence of multidrug-resistant organisms (MDROs) in the study. Prospective and retrospective observational studies reporting on the association between IEAT and mortality in adult patients with microbiologically documented infections published between 2008–2016 were included. A meta-analysis of IEAT rates was conducted using a random-effects model. Subgroup analyses and mixed-effect single-covariate meta-regression were conducted to identify the association between clinical and methodological study-level covariates and IEAT rates. Heterogeneity was assessed using the I 2 measure of inconsistency. Multi-covariate meta-regression was conducted including variables with a P -value of I 2 = 97.7%). On multi-covariate analyses, the prevalence of any MDRO [odds ratio (OR) per 10% increase in prevalence = 1.11, 95% CI 1.07–1.15], Acinetobacter spp. specifically (OR = 1.99, 95% CI 1.22–3.25) and advancing study years were associated with IEAT rates (OR = 1.03, 95% CI 1.00–1.06 per year). MDRO rates were independently associated with mortality rates in the studies, adjusting to the rate of IEAT. The prevalence of MDROs, mainly multidrug-resistant Gram-negative bacteria, is significantly associated with the probability of prescribing IEAT and mortality rates in recent studies. We show how antibiotic resistance impacts patient management and outcomes.

Summary Background Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria. Methods For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I 2 method. Findings We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35–0·68; p Staphylococcus aureus (37%; 0·63, 0·45–0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53–0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54–0·88; p=0·0030), especially hand-hygiene interventions (0·34, 0·21–0·54; p Interpretation Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic-resistant bacteria. Funding German Center for Infection Research.

There is increasing evidence that psycho-social factors can influence antimicrobial prescribing practice in hospitals and the community, and represent potential barriers to antimicrobial stewardship interventions. Clinicians are conditioned both by emotional and cognitive factors based on fear, uncertainty, a set of beliefs, risk perception and cognitive bias, and by interpersonal factors established through social norms and peer and doctor–patient communication. However, a gap is emerging between research and practice, and no stewardship recommendation addresses the most appropriate human resource allocation or modalities to account for psycho-social determinants of prescribing. There is a need for translation of the evidence available from human behaviour studies to the design and implementation of stewardship interventions and policies at hospital and community levels. The integration of behaviour experts into multidisciplinary stewardship teams seems essential to positively impact on prescribers’ communication and decision-making competencies, and reduce inappropriate antibiotic prescribing.

Objectives: The aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum beta-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods. Methods: Patients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30 days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics. Results: We screened 10 034 patients collecting 28 322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29-4.40), age 60-69 years (HR 1.19; 95% CI 1.05-1.34), and spring season (HR 1.25; 95% CI 1.14-1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins. Conclusions: Impact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions. (c) 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Background People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad-spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines. Objectives To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences. Selection criteria We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30-day or end of follow-up all-cause mortality. Data collection and analysis Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta-analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel-Haenszel fixed-effect model. Main results We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. Authors' conclusions We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.