Enhanced antimicrobial stewardship based on rapid phenotypic antimicrobial susceptibility testing for bacteraemia in patients with haematological malignancies: a randomized controlled trial

ObjectivesRecently, rapid phenotypic antimicrobial susceptibility testing (AST) based on microscopic imaging analysis has been developed. The aim of this study was to determine whether implementation of antimicrobial stewardship programmes (ASP) based on rapid phenotypic AST can increase the proportion of patients with haematological malignancies who receive optimal targeted antibiotics during early periods of bacteraemia.MethodsThis randomized controlled trial enrolled patients with haematological malignancies and at least one positive blood culture. Patients were randomly assigned 1:1 to conventional (n = 60) or rapid phenotypic (n = 56) AST. The primary outcome was the proportion of patients receiving optimal targeted antibiotics 72 hr after blood collection for culture.ResultsThe percentage receiving optimal targeted antibiotics at 72 hr was significantly higher in the rapid phenotypic AST group (45/56, 80.4%) than in conventional AST group (34/60, 56.7%) (relative risk (RR) 1.42, 95% confidence interval (CI) 1.09–1.83). The percentage receiving unnecessary broad-spectrum antibiotics at 72 hr was significantly lower (7/26, 12.5% vs 18/60, 30.0%; RR 0.42, 95% CI 0.19–0.92) and the mean time to optimal targeted antibiotic treatment was significantly shorter (38.1, standard deviation (SD) 38.2 vs 72.8, SD 93.0 hr; p < 0.001) in the rapid phenotypic AST group. The mean time from blood collection to the AST result was significantly shorter in the rapid phenotypic AST group (48.3, SD 17.6 vs 83.1, SD 22.2 hr).DiscussionASP based on rapid phenotypic AST can rapidly optimize antibiotic treatment for bacteraemia in patients with haematological malignancy. Rapid phenotypic AST can improve antimicrobial stewardship in immunocompromised patients.     

Herbal treatment with uva ursi extract versus fosfomycin in women with uncomplicated urinary tract infection in primary care: a randomized controlled trial

ObjectiveWe explored whether initial treatment with the herbal drug uva ursi (UU) reduces antibiotic use in women with uncomplicated urinary tract infection (UTI) without increasing symptom burden and complication frequency compared with antibiotic treatment.MethodsA double-blind randomized controlled trial was conducted in 42 family practices in Germany. The participants were adult women with suspected uncomplicated UTIs receiving either UU 105 mg 3 × 2 tablets for 5 days (intervention) or fosfomycin a 3-g single dose (control), and their respective placebos. Participants and investigators were blinded. The primary outcome included (1) antibiotic courses day 0–28 as superiority, and (2) symptom burden (sum of daily symptom scores) day 0–7, as non-inferiority outcome (margin 125%). Clinicaltrials.gov: NCT03151603.ResultsOverall, 398 patients were randomly allocated to groups receiving UU (n = 207) and fosfomycin (n = 191). The number of antibiotic courses was 63.6% lower (95% CI 53.6%–71.4%; p < 0.0001) in the UU group than in the fosfomycin group. The ratio of total symptom burden in the UU group compared with control was 136.5% (95% CI 122.7–151.9; p 0.95), failing non-inferiority. Eight women developed pyelonephritis in the UU group compared with two in the fosfomycin group (mean difference 2.8; 95% CI 0.2–5.9; p 0.067). Adverse events were similar between the groups.DiscussionIn women with uncomplicated UTIs, initial treatment with UU reduced antibiotic use but led to a higher symptom burden and more safety concerns than fosfomycin.     

Antibiotics for lower respiratory tract infection in children presenting in primary care (ARTIC-PC): the predictive value of molecular testing

ObjectivesThis study aimed to assess whether the presence of bacteria or viruses in the upper airway of children presenting with uncomplicated lower respiratory tract infection (LRTI) predicts the benefit of antibiotics.MethodsChildren between 6 months and 12 years presenting to UK general practices with an acute LRTI were randomized to receive amoxicillin 50 mg/kg/d for 7 days or placebo. Children not randomized (ineligible or clinician/parental choice) could participate in a parallel observational study. The primary outcome was the duration of symptoms rated moderately bad or worse. Throat swabs were taken and analyzed for the presence of bacteria and viruses by multiplex PCR.ResultsSwab results were available for most participants in the trial (306 of 432; 71%) and in the observational (182 of 326; 59%) studies. Bacterial pathogens potentially sensitive to amoxicillin (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) were detected among 51% of the trial placebo group and 49% of the trial antibiotic group. The median difference in the duration of symptoms rated moderately bad or worse between antibiotic and placebo was similar when potentially antibiotic-susceptible bacteria were present (median: –1 day; 99% CI, –12.3 to 10.3) or not present (median: –1 day; 99% CI, –4.5 to 2.5). Furthermore, bacterial genome copy number did not predict benefit. There were similar findings for all secondary outcomes and when including the data from the observational study.DiscussionThere was no clear evidence that antibiotics improved clinical outcomes conditional on the presence or concentration of bacteria or viruses in the upper airway. Before deploying microbiologic point-of-care tests for children with uncomplicated LRTI in primary care, rigorous validating trials are needed.     

Effect of discontinuation of an antimicrobial stewardship programme on the antibiotic usage pattern

ObjectivesThis study aimed to analyse the effect of discontinuation of antimicrobial stewardship programme (ASP) activity on the usage pattern of antibiotics.MethodsAn interrupted time-series analysis assessing the trends in antibiotic use was conducted between September 2015 and August 2019 in an 859-bed university-affiliated hospital in Korea, where all ASP activities were discontinued in March 2018. The major activity of the ASP was a restrictive antibiotic programme.ResultsThe use of restrictive antibiotics increased immediately after the discontinuation of the ASP by 41.06 days of therapy (DOT)/1000 patient-days in the general ward (95% confidence interval (CI) 21.04–61.08) and by 391.04 DOT/1000 patient-days in the intensive care unit (ICU) (95%CI 207.56–574.51). In addition, there were positive changes in the slope for the use of restrictive antibiotics in the general ward (7.06 DOT/1000 patient-days per month, 95%CI 4.63–9.50) and ICU (35.95 DOT/1000 patient-days per month, 95%CI 18.70–53.19). The use of broad-spectrum antibiotics in the general ward significantly decreased (–87.54 DOT/1000 patient-days, 95%CI –149.29 to –25.79). For non-broad-spectrum antibiotics, there were positive changes in the slope in the general ward (16.54 DOT/1000 patient-days per month, 95%CI 12.99–20.09) and ICU (12.85 DOT/1000 patient-days per month, 95%CI 2.32–23.38).ConclusionsAfter discontinuation of the ASP, antibiotic usage patterns rapidly returned to the patterns prior to the implementation of the programme.     

Analysis of antibiotics discontinuation during bone marrow suppression in childhood,adolescent and young adult patients with febrile neutropenia

BackgroundAntibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia.ProcedureWe analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery.ResultsRecurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0–27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics <0.011 × 10⁹/L, neutrophil count at start of antibiotics ≥0.061 × 10⁹/L, febrile onset following <1 day after onset of neutropenia, and incomplete remission of original disease were independent risk factors for recurrent fever.ConclusionsDiscontinuation of antibiotics while pediatric patients were still neutropenic was almost safe. However, physicians should note the risk factors of recurrent fever.     

Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic,multicentre, randomized,controlled trial

ObjectivesMany transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB.MethodsWe performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months.ResultsOne hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50–1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20–41, versus 6, interquartile range 0–15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003).ConclusionsApplying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.     

Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized,controlled trial

ObjectiveTo prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes.MethodsA randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis.Results248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments.Conclusions7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.     

Time to antibiotic administration and patient outcomes in community-acquired pneumonia: results from a prospective cohort study

ObjectivesCommunity-acquired pneumonia (CAP) is a frequently occurring disease linked to high mortality and morbidity. Previous studies indicated that the administration of antibiotics within 4 hrs of admission can improve key patient outcomes associated with CAP, such as mortality and time to clinical stability. However, the results have been heterogeneous and may not be applicable to all healthcare settings. Therefore, we designed a cohort study to estimate the impact of timely antibiotic administration on outcomes in patients admitted with CAP.MethodsThe impact of antibiotic administration within 4 hrs of admission and other covariates were estimated for 30-day mortality, stability within 72 hrs, 30-day readmission and time to discharge, using multivariable regression models. Sensitivity analyses were performed on a subset of patients with the most severe CAP and a propensity score matched cohort.ResultsIn total, 2264 patients were included. Of these, 273 (12.1%) died within 30 days of admission, 1277 (56.4%) were alive and stable within 72 hrs and 334 (14.8%) were discharged alive and readmitted within 30 days. Median length of hospital stay was 5 days (interquartile range 3–8). In all models, the administration of antibiotics within 4 hrs of admission had no significant effect on the outcomes. The adjusted odds ratios (OR) derived from the multivariable models for 30-day mortality, stability within 72 hrs and 30-day readmission were 1.01 (95% confidence interval (CI) 0.76; 1.33), 0.88 (95% CI 0.74; 1.05) and 1.05 (95% CI 0.82; 1.34). The adjusted hazard ratio (HR) for time to discharge was 1.00 (95% CI 0.91; 1.10).DiscussionA strict 4-hr threshold for antibiotic administration in all patients admitted with CAP is not reasonable. Instead, our results suggested that patients should be triaged and prioritized according to age, comorbidities, clinical condition and pneumonia severity.     

Comparison of methods for measuring antibiotic consumption in an intensive care unit

Hospitals worldwide are working on minimizing unnecessary use of antimicrobials. To assess actual changes of antimicrobial usage, correct and precise measurements are necessary. This study aimed to compare data on the purchase of antibiotics from the pharmacy and the administration of antibiotics to patients, respectively, in an intensive care unit (ICU). Data were obtained from the Neurointensive Care Unit (NICU) at Rigshospitalet, Denmark. During a 23‐month period, comprising 10 770 bed‐days (BD), the ward purchased 16 908 defined daily doses (DDD) of antibiotics from the pharmacy, and 15 130 DDD and 41 304 individual doses were administered. Intraclass correlation coefficients (ICCs) were calculated; control and runcharts and a Bland–Altman plot were constructed. Pharmacy sales and drug administration data showed no systematic variation over time with a monthly overestimation of pharmacy sales data of 10% (95% confidence interval (CI), 6.20–14.3%) for all antibiotics, and 7% (95% CI: 1.81–11.1%) for broad‐spectrum antibiotics. The antibiotic consumption, without bed‐days, has a clinically acceptable ICC of >0.70 and no systematic difference is suggested by the Bland–Altman plot. In this study of a large NICU, whose antibiotic consumption varied at random, pharmacy sales data were an acceptable approximation of the actual summarized drug consumption.     

Antibiotic prescribing in patients with COVID-19: rapid review and meta-analysis

BackgroundThe proportion of patients infected with SARS-CoV-2 that are prescribed antibiotics is uncertain, and may contribute to patient harm and global antibiotic resistance.ObjectiveThe aim was to estimate the prevalence and associated factors of antibiotic prescribing in patients with COVID-19.Data SourcesWe searched MEDLINE, OVID Epub and EMBASE for published literature on human subjects in English up to June 9 2020.Study Eligibility CriteriaWe included randomized controlled trials; cohort studies; case series with ≥10 patients; and experimental or observational design that evaluated antibiotic prescribing.ParticipantsThe study participants were patients with laboratory-confirmed SARS-CoV-2 infection, across all healthcare settings (hospital and community) and age groups (paediatric and adult).MethodsThe main outcome of interest was proportion of COVID-19 patients prescribed an antibiotic, stratified by geographical region, severity of illness and age. We pooled proportion data using random effects meta-analysis.ResultsWe screened 7469 studies, from which 154 were included in the final analysis. Antibiotic data were available from 30 623 patients. The prevalence of antibiotic prescribing was 74.6% (95% CI 68.3–80.0%). On univariable meta-regression, antibiotic prescribing was lower in children (prescribing prevalence odds ratio (OR) 0.10, 95% CI 0.03–0.33) compared with adults. Antibiotic prescribing was higher with increasing patient age (OR 1.45 per 10 year increase, 95% CI 1.18–1.77) and higher with increasing proportion of patients requiring mechanical ventilation (OR 1.33 per 10% increase, 95% CI 1.15–1.54). Estimated bacterial co-infection was 8.6% (95% CI 4.7–15.2%) from 31 studies.ConclusionsThree-quarters of patients with COVID-19 receive antibiotics, prescribing is significantly higher than the estimated prevalence of bacterial co-infection. Unnecessary antibiotic use is likely to be high in patients with COVID-19.     

The effect of preoperative oral antibiotic use on the risk of periprosthetic joint infection after primary knee or hip replacement: a retrospective study with a 1-year follow-up

ObjectivesAntibiotics are used for various reasons before elective joint replacement surgery. The aim of this study was to investigate patients' use of oral antibiotics before joint replacement surgery and how this affects the risk for periprosthetic joint infection (PJI).MethodsPatients having a primary hip or knee replacement in a tertiary care hospital between September 2002 and December 2013 were identified (n = 23 171). Information on oral antibiotic courses purchased 90 days preoperatively and patients' chronic diseases was gathered. Patients with a PJI in a 1-year follow-up period were identified. The association between antibiotic use and PJI was examined using a multivariable logistic regression model and propensity score matching.ResultsOne hundred and fifty-eight (0.68%) cases of PJI were identified. In total, 4106 (18%) joint replacement operations were preceded by at least one course of antibiotics. The incidence of PJI for patients with preoperative use of oral antibiotics was 0.29% (12/4106), whereas for patients without antibiotic use it was 0.77% (146/19 065). A preoperative antibiotic course was associated with a reduced risk for subsequent PJI in the multivariable model (OR 0.40, 95% CI 0.22–0.73). Similar results were found in the propensity score matched material (OR 0.34, 95% CI 0.18–0.65).ConclusionsThe use of oral antibiotics before elective joint replacement surgery is common and has a potential effect on the subsequent risk for PJI. Nevertheless, indiscriminate use of antibiotics before elective joint replacement surgery cannot be recommended, even though treatment of active infections remains an important way to prevent surgical site infections.     

Novel point-of-care biomarker combination tests to differentiate acute bacterial from viral respiratory tract infections to guide antibiotic prescribing: a systematic review

BackgroundAcute respiratory tract infections (RTIs) are the most common reason to seek medical care, with many patients receiving inappropriate antibiotics. Novel testing approaches to identify aetiology at the point-of-care are required to accurately guide antibiotic treatment.ObjectiveTo assess the diagnostic accuracy of biomarker combinations to rapidly differentiate between acute bacterial or viral RTI aetiology.Data sourcesMEDLINE, Embase and Web of Science databases were searched to February 2021.Study eligibility criteriaDiagnostic accuracy studies comparing accuracy of point-of-care and rapid diagnostic tests in primary or secondary care, consisting of biomarker combinations, to identify bacterial or viral aetiology of RTI.MethodsRisk of bias was assessed using the QUADAS-2 tool. Sensitivity and specificity of tests reported by more than one study were meta-analysed using a random effects model.ResultsTwenty observational studies (3514 patients) were identified. Eighteen were judged at high risk of bias. For bacterial aetiologies, sensitivity ranged from 61% to 100% and specificity from 18% to 96%. For viral aetiologies, sensitivity ranged from 59% to 97% and specificity from 74% to 100%. Studies evaluating two commercial tests were meta-analysed. For ImmunoXpert, the summary sensitivity and specificity were 85% (95% CI 75%–91%, k = 4) and 86% (95% CI 73%–93%, k = 4) for bacterial infections, and 90% (95% CI 79%–96%, k = 3) and 92% (95% CI 83%–96%, k = 3) for viral infections, respectively. FebriDx had pooled sensitivity and specificity of 84% (95% CI 75%–90%, k = 4) and 93% (95% CI 90%–95%, k = 4) for bacterial infections, and 87% (95% CI 72%–95%; k = 4) and 82% (95% CI 66%–86%, k = 4) for viral infections, respectively.ConclusionCombinations of biomarkers show potential clinical utility in discriminating the aetiology of RTIs. However, the limitations in the evidence base, due to a high proportion of studies with high risk of bias, preclude firm conclusions. Future research should be in primary care and evaluate patient outcomes and cost-effectiveness with experimental study designs.Clinical trialPROSPERO registration number: CRD42020178973.     

Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre,prospective cohort study

ObjectivesThe aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods.MethodsPatients 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.ResultsWe 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.ConclusionsImpact 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.Clinical Trial registrationNCT01208519.     

Antibiotic use from formal and informal healthcare providers in the Democratic Republic of Congo: a population-based study in two health zones

ObjectiveIn the Democratic Republic of Congo and other low-resource countries, community-acquired pathogens are increasingly resistant to most locally available antibiotics. To guide efforts to optimize antibiotic use to limit antibiotic resistance, we quantified healthcare provider–specific and community-wide antibiotic use.MethodsFrom household surveys, we estimated monthly healthcare visit rates by provider. From healthcare visit exit surveys, we estimated prevalence, defined daily doses, and access/watch/reserve distribution of antibiotic use by provider. Combining both, we estimated community-wide antibiotic use rates.ResultsOf 88.7 (95% CI 81.9–95.4) healthcare visits per 1000 person-months (n = 31221), visits to private clinics (31.0, 95% CI 30.0–32.0) and primary health centres (25.5, 95% CI 24.6–26.4) were most frequent. Antibiotics were used during 64.3% (95% CI 55.2–73.5%, 162/224) of visits to private clinics, 51.1% (95% CI 45.1–57.2%, 245/469) to health centres, and 48.8% (95% CI 44.4–53.2%, 344/454) to medicine stores. Antibiotic defined daily doses per 1000 inhabitants per day varied between 1.75 (95% CI 1.02–2.39) in rural Kimpese and 10.2 (95% CI 6.00–15.4) in (peri) urban Kisantu, mostly explained by differences in healthcare utilisation (respectively 27.8 versus 105 visits per 1000 person-months), in particular of private clinics (1.23 versus 38.6 visits) where antibiotic use is more frequent. The fraction of Watch antibiotics was 30.3% (95% CI 24.6–35.9%) in private clinics, 25.6% (95% CI 20.2–31.1%) in medicine stores, and 25.1% (95% CI 19.0–31.2%) in health centres. Treatment durations <3 days were more frequent at private clinics (5.3%, 9/169) and medicine stores (4.1%, 14/338) than at primary health centres (1.8%, 5/277).DiscussionPrivate healthcare providers, ubiquitous in peri-urban settings, contributed most to community-wide antibiotic use and more frequently dispensed Watch antibiotics and shortened antibiotic courses. Efforts to optimize antibiotic use should include private providers at community level.