Impact of a prospective audit and feedback antimicrobial stewardship programme on carbapenem consumption: a quasi-experimental study (IPANEMA study).

OBJECTIVES: To test the hypothesis that a prospective audit and feedback (PAF) intervention combined with electronic tools will reduce carbapenem use without negatively affecting patient outcomes. METHODS: A quasi-experimental, pre-intervention and intervention study was performed conducted in the urology department of a university hospital. The intervention involved implementing a PAF within an antimicrobial stewardship programme with the aid of an electronic tool. The primary outcome was carbapenem use, assessed by DDD/100 patient-days (PD). Secondary outcomes included evaluating the effect of the intervention on overall antibiotic use measured by DDD/100 PD and days of therapy (DOT)/100 PD, as well as patient safety. The chi-squared test or t-test was used, and the Poisson model was employed to assess the association between the intervention and outcomes. RESULTS: A 9% decrease in carbapenem DDD/100 PD was observed during the intervention period (IR = 0.91; 95% CI = 0.85-0.97, P = 0.007). The proportion of patients who received carbapenem treatment dropped from 17.8% to 16.5% [incidence ratio (IR) = 0.95; 95% CI = 0.86-2.05, P = 0.31]. Carbapenem DOT/100 PD decreased from 12.4 to 11.0 (IR = 0.89; 95% CI = 0.83-0.94, P < 0.001). Overall antibiotic DDD/100 PD decreased by 3% (IR = 0.97; 95% CI = 0.94-0.99, P = 0.001) and DOT/100 PD by 7% (IR = 0.93; 95% CI = 0.91-0.95, P < 0.001). The incidence of infections caused by carbapenemase-producing microorganisms, Enterococcus faecium bacteraemia and Clostridioides difficile-associated diarrhoea episodes was similar in the pre-intervention and intervention periods. ESBL incidence rate decreased, but the differences were not statistically significant (3.94/1000 PD versus 2.88/1000 PD, P = 0.111). Length of hospital stay, in-hospital all-cause mortality, and 30 day readmission incidence remained unchanged. CONCLUSIONS: The implementation of PAF combined with an electronic tool was an effective and safe intervention for reducing carbapenem use.

Ceftolozane/tazobactam for difficult-to-treat Gram-negative infections: A real-world tertiary hospital experience.

OBJECTIVE: To evaluate the real-world clinical efficacy of ceftolozane/tazobactam (C/T) in difficult-to-treat infections caused by multi-drug resistant Gram-negative microorganisms, including carbapenem-resistant Pseudomonas aeruginosa. METHODS: Retrospective cohort study of adult patients treated with C/T for at least 48 hours for infections caused by multi-drug resistant Gram-negative bacteria in a tertiary hospital from May 2016 until August 2019. The primary outcome analysed was clinical failure, defined as a composite of symptomatology persistence after 7 days of C/T treatment, infection recurrence, and/or all-cause mortality within 30 days of follow-up. RESULTS AND DISCUSSION: 96 episodes of C/T treatment were included, mostly consisting of targeted treatments (83.9%) for the following sources of infection: intra-abdominal (22.6%), urinary tract (25.8%), skin and soft tissue (19.4%), hospital-acquired pneumonia (14%), and other (6.4%). The most frequently isolated bacteria were carbapenem-resistant (88, 94.6%). Clinical failure rate was 30.1%, due to persistent infection at day 7 (4.3%), recurrence of the initial infection (16.1%), or 30-day all-cause mortality (8.6%). Adverse events most frequently reported were Clostridium difficile infection (9%) and cholestasis (8%). WHAT IS NEW AND CONCLUSION: C/T showed a favourable clinical profile for difficult-to-treat multidrug-resistant and carbapenem-resistant Gram-negative infections, regardless of the source of infection.

Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial.

BACKGROUND: We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. METHODS: A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. RESULTS: Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). CONCLUSIONS: Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events. CLINICAL TRIALS REGISTRATION: NCT01898338.

Predictors of Infliximab Trough Concentrations in Inflammatory Bowel Disease Patients Using a Repeated-Measures Design.

BACKGROUND AND AIMS: Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design. METHODS: We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (Cmin) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t1/2), and central elimination rate constant (K10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX Cmin and PK parameters. RESULTS: We collected 429 Cmin measurements from 112 patients. The median of the Cmin values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K10, and t1/2 values were 4.77 mL/kg/day (3.88-5.90), 0.09 days (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX Cmin, AUC, CL, and K10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K10. Patients receiving concurrent immunosuppressive therapy had higher Cmin and AUC values and lower CL and K10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in Cmin values during the study period. CONCLUSIONS: In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX Cmin, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.

External Evaluation of Population Pharmacokinetic Models of Infliximab in Patients With Inflammatory Bowel Disease.

BACKGROUND: Infliximab (IFX) trough levels vary markedly between patients with inflammatory bowel disease (IBD), which is important for clinical response. The aim of this study was to evaluate the performance of previously developed population pharmacokinetic models in patients with IBD for dose individualization for Crohn disease (CD) and ulcerative colitis in our clinical setting. METHODS: The authors collected 370 trough levels prospectively from 100 adult patients with IBD who were undergoing IFX treatment between July 2013 and August 2016. The external evaluation included prediction- and simulation-based diagnostics [prediction-corrected visual predictive check, prediction- and variability-corrected visual predictive check, and normalized prediction distribution error tests]. RESULTS: In prediction-based diagnostics, the authors observed a nonsignificant overall mean relative bias of -6.87% and an acceptable imprecision of 8.45%. Approximately 100% of the prediction error was within ±30%, indicating satisfactory predictability. Simulation-based diagnostics indicated model misspecification; thus, the model may not be appropriate for simulation-based applications. CONCLUSIONS: While simulation-based diagnostics provided unsatisfactory results, the prediction-based diagnostics demonstrate that the population pharmacokinetic model developed by Fasanmade et al for CD can be used to predict and design individualized IFX dose regimens that meet the individual needs of patients with CD and ulcerative colitis.

Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: an easy method for clinical use.

Continuous infusion (CI) of beta-lactams could optimize their pharmacokinetic/pharmacodynamic indices, especially in difficult-to-treat infections. PURPOSE: To validate an easy-to-use method to guide beta-lactams dosage in CI (formula). METHODS: A retrospective analysis was conducted of a prospectively collected cohort (n = 24 patients) with osteoarticular infections caused by Gram-negative bacilli (GNB) managed with beta-lactams in CI. Beta-lactams dose was calculated using a described formula (daily dose = 24 h × beta-lactam clearance × target "steady-state" concentration) to achieve concentrations above the MIC. We correlated the predicted concentration (Cpred = daily dose/24 h × beta-lactam clearance) with the patient's observed concentration (Cobs) measured by UPLC-MS/MS (Spearman's coefficient). RESULTS: The most frequent microorganism treated was P. aeruginosa (21 cases; 9 MDR). Beta-lactams in CI were ceftazidime (n = 14), aztreonam (7), and piperacillin/tazobactam (3), mainly used in combination (12 with colistin, 5 with ciprofloxacin) and administered without notable side effects. The plasma Cobs was higher overall than Cpred; the Spearman correlation between both concentrations was rho = 0.6 (IC 95%: 0.2-0.8) for all beta-lactams, and rho = 0.8 (IC 95%: 0.4-1) for those treated with ceftazidime. CONCLUSIONS: The formula may be useful in clinical practice for planning the initial dosage of beta-lactams in CI, while we await a systematic therapeutic drug monitoring. The use of beta-lactams in CI was safe.

The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation.

INTRODUCTION: Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients. PARTICIPANTS AND METHODS: In a cohort of 272 kidney transplant recipients, associations between functional genetic variants (CYP3A4*22 and CYP3A5*3) and dose-adjusted predose Tac concentrations (C0) and daily doses of Tac at days 5-7 and 15 and 1, 3, 6 and 12 months after renal transplantation were evaluated. Patients were genotyped and clustered according to both CYP3A4*22 and CYP3A5*3 allelic status: poor (PM) (CYP3A4*22 carriers with CYP3A5*3/*3), intermediate (IM) (CYP3A4*1/*1 with CYP3A5*3/*3 or CYP3A4*22 carriers with CYP3A5*1 carriers) and extensive CYP3A-metabolizers (EM) (CYP3A4*1/*1 and CYP3A5*1 carriers). RESULTS: EM had an 88% lower dose-adjusted C0 compared with IM. PM had a 26% higher dose-adjusted C0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C0>15 ng/ml) was significantly higher in PM (43.5%) compared with EM (0%) at days 5-7 after transplantation (P=0.01). About 30% of EM had subtherapeutic exposure (C0<5 ng/ml) at days 5-7 after transplantation (P=0.001). CONCLUSION: The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure.

Measurement of ceftazidime concentration in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. Application to critically ill patients and patients with osteoarticular infections.

Ceftazidime is an antibiotic belonging to the third generation of the cephalosporin family. It is indicated in the treatment of serious, simple or mixed bacterial infections, and its administration in continuous or intermittent infusion allows optimization of the concentration of antibiotic to keep it above the minimum inhibitory concentration. We developed and validated a chromatographic method by ultra-performance liquid chromatography-tandem mass spectrometry to measure ceftazidime concentration in human plasma. Following extraction with acetonitrile and 1,2-dichloroethane, the chromatographic separation was achieved using an Acquity ® UPLC ® BEH(TM) (2.1 × 100 mm i.d., 1.7 µm) reverse-phase C18 column, with a water-acetonitrile linear gradient containing 0.1% formic acid at a 0.4 mL/min flow rate. Ceftazidime and its internal standard (cefotaxime) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode using mass-to-charge transitions of 547.0 → 467.9/396.1 and 456.0 → 395.8/324.1, respectively. The limit of quantification was 0.58 mg/L and linearity was observed in the range 0.58-160 mg/L. Coefficients of variation and absolute relative biases were <9.8 and 8.4%. The mean recovery for ceftazidime was 74.4 ± 8.1%. Evaluation of the matrix effect showed ion enhancement, and no carry-over was observed. The validated method could be applied to daily clinical laboratory practice to measure the concentration of ceftazidime in plasma.

De novo use of a generic formulation of tacrolimus versus reference tacrolimus in kidney transplantation: evaluation of the clinical results, histology in protocol biopsies, and immunological monitoring.

The use of generic formulations of immunosuppressive drugs in renal transplantation has been and still is a controversial subject. The lack of clinical studies about safety and efficacy in transplant patients is one of the factors restricting the diffusion of generic drugs in the renal transplant field. Since March 2013, our transplant unit has incorporated generic tacrolimus (Adoport(®) ; Sandoz), replacing the one we were currently using (Prograf(®) ; Astellas). When carrying out our retrospective analysis comparing the two different formulations, we evaluated several clinical results: tacrolimus trough concentrations (C0) at 5-7 days; 1, 3, and 6 months post-transplantation; concentration/dose ratio at 6 months; acute rejection incidence; delayed graft function (DGF); renal function (as CKD-EPI); and proteinuria at 6 months in 120 patients (1:1 ratio of Prograf(®) versus Adoport(®) ), noticing no important differences. We also evaluated the results of protocol biopsies at 6 months in a subgroup of patients, thus verifying the safety and efficacy of this particular generic drug versus the reference product on a histological basis as well. No difference in the development of dnDSA (de novo donor-specific antibody) was found between the two groups.

Short-Term Exposure to Ambient Air Pollution and Antimicrobial Use for Acute Respiratory Symptoms.

Importance: Ambient air pollution and antimicrobial resistance pose significant global public health challenges. It is not known whether ambient air pollution is associated with increased consumption of antimicrobials. Objective: To assess whether a short-term association exists between ambient air pollution levels and antimicrobial consumption among the general population seeking primary care consultations for acute respiratory symptoms. Design, Setting, and Participants: This 2-stage cross-sectional ecological time series analysis study using data on daily ambient air pollution and antimicrobial consumption was conducted in the 11 largest cities in Catalonia, Spain, from June 23, 2012, to December 31, 2019, among all inhabitants aged 12 years or older. Statistical analysis was performed from November 2022 to December 2023. Exposures: Daily ambient air pollution (particulate matter of 10 µg/m3 [PM10], particulate matter of 2.5 µg/m3 [PM2.5], and nitrogen dioxide [NO2]). Main Outcomes and Measures: The main outcome was antimicrobial consumption associated with primary care consultations for acute respiratory symptoms in the 30 days before and after the dispensing of the antimicrobial. Antimicrobial consumption was measured as defined daily doses (DDDs) per 1000 inhabitants per day. Results: Among 1 938 333 inhabitants (median age, 48 years [IQR, 34-65 years]; 55% female participants), there were 8 421 404 antimicrobial dispensations, with a median of 12.26 DDDs per 1000 inhabitants per day (IQR, 6.03-15.32 DDDs per 1000 inhabitants per day). The median adjusted morbidity score was 2.0 (IQR, 1.0-5.0). For the 1 924 814 antimicrobial dispensations associated with primary care consultations for acute respiratory symptoms, there was a significant correlation between increases of 10 µg/m3 in the concentration of the 3 pollutants studied and heightened antimicrobial consumption at day 0 (PM10: relative risk [RR], 1.01 [95% CI, 1.01-1.02]; PM2.5: RR, 1.03 [95% CI, 1.01-1.04]; NO2: RR, 1.04 [95% CI, 1.03-1.05]). A delayed association emerged between increases in PM2.5 concentration and antimicrobial consumption between day 7 (RR, 1.00 [95% CI, 1.00-1.01]) and day 10 (RR, 1.00 [95% CI, 1.00-1.01]) after exposure. Conclusions and Relevance: In this 2-stage cross-sectional study using ecological time series analysis, short-term exposure to air pollution was associated with increased antimicrobial use associated with primary care consultations for acute respiratory symptoms in the general population. This finding could contribute to informing policy decisions aimed at reducing air pollution and its associated risks, thereby promoting respiratory health and reducing antimicrobial use.

Determination of ertapenem in plasma and ascitic fluid by UHPLC-MS/MS in cirrhotic patients with spontaneous bacterial peritonitis.

Objectives: Spontaneous bacterial peritonitis is a frequent severe complication in cirrhotic patients with ascites. Carbapenem antibiotics are currently the treatment of choice for patients with hospital-acquired or healthcare-related infections. However, there is limited evidence available on the efficacy of ertapenem in cirrhotic patients with spontaneous bacterial peritonitis. As a result, the pharmacokynetics and pharmacodynamics of this antibiotic are still unknown. The objective of this study was to develop and validate measurement procedures based on liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine ertapenem concentrations in plasma and ascitic fluid. Methods: Samples were pretreated by acetronile protein-precipitation. Chromatographic separation is performed on a C18 reversed-phase Acquity®-UPLC®-BEHTM column (2.1 × 100 mm id, 1.7 µm) using a non-linear gradient of water/acetonitrile containing 0.1 % of formic acid at a flow rate of 0.4 mL/min. Ertapenem and its internal standard (ertapenem-D4) are detected by tandem mass spectrometry using positive electrospray ionization and multiple reaction monitoring, and using 476.2 â†’ 346.0/432.2 as mass transition for ertapenem and 480.2 â†’ 350.0 for its internal standard. Results: No significant interferences or carry-over contamination were observed. Imprecisions, absolute relative bias, matrix effects and normalized recoveries were ≤14.5 %, ≤9.3 % (92.8-104.5) % and (98.8-105.8) %, respectively. Chromatographic measurement procedures were linear from (0.50-100) mg/L. Conclusions: The measurement procedures based on UHPLC-MS/MS developed and validated in this study could be useful in pharmacokynetic and pharmacodynamic studies in subjects with liver cirrhosis who develop spontaneous bacterial peritonitis treated with ertapenem.

An Ocean between the Waves: Trends in Antimicrobial Consumption in Hospitalized Patients with COVID-19.

We assessed the antibiotic use in SARS-CoV-2-infected patients during four different waves of the COVID-19 pandemic, as well as its trends over the period and associated risk factors. We performed a cross-sectional retrospective analysis nested in a prospectively collected cohort of hospitalized adult patients with COVID-19 at a university hospital in Spain. A total of 2415 patients were included in this study, among whom 1120 corresponded to the first wave. The highest percentage of patients receiving some sort of antibiotic treatment was higher during the first wave (77.6%) than during the others; nevertheless, our calculation of the average DOT (days of antibiotic treatment) per 100 patient days of stay found that the highest antibiotic prescription rate corresponded to the second pandemic wave (61.61 DOT/100 patient days), which was associated with a higher ICU admission rate and a lower SpO2/FiO2 ratio at admission. After the second wave, the prescription rates presented a steady downward trend. With regard to the use of specific antibiotic families, amoxicillin/clavulanate was the most used antibiotic in our cohort (14.20 DOT/100 patient days) due to a high prescription rate during the first wave. According to the "AWaRe" WHO classification, antibiotics corresponding to the "Watch" group were the most prescribed (27.92 DOT/100 patient days). The antibiotic use rate fell progressively, but it remained high during all four waves analyzed. In conclusion, antibiotic use was high throughout all the waves that were analyzed, despite a relatively low incidence of bacterial coinfection and superinfection. Efforts should be made to keep antimicrobial stewardship programs active, especially in complicated epidemiological situations, such as the SARS-CoV-2 pandemic.

Impact of an antimicrobial stewardship program indicator on the appropriateness of the empiric antibiotic treatment of urinary source Escherichia coli bacteraemia.

A prospective multicentre study was carried out between 2017 and 2021 to assess (1) the appropriateness of the empirical treatment to the local guidelines of urinary source Escherichia coli bacteraemia, (2) the appropriateness of empirical treatment to antibiotic sensitivity results and (3) the degree of error in the local guidelines regarding the antibiotic sensitivity reported in acute care hospitals enrolled in the vigilància de les infeccions relacionades amb l'atenció sanitària de Catalunya program. During the study period, 79.0% of the empirical treatments analysed complied with the guidelines and 88.1% were appropriate in view of the in vitro activity of the isolated strain. The rate of appropriateness rose from 73.8% in 2017 to 81.0% in 2021 (P < 0.001). The degree of error in the recommendations regarding the in vitro activity of the isolated strains was 5.9% and remained stable during the study period. Antibiotic families correctly prescribed according to the guidelines were third-generation cephalosporins (54.9%), carbapenems (16.8%) and combinations of penicillins and beta-lactamase inhibitors (16.4%). Of the 8009 E. coli strains, 19.0% were extended-spectrum beta-lactamases producers, 36.8% were resistant to quinolones and 0.5% were resistant to carbapenems. The broad implementation of an antimicrobial stewardship program with quality indicators of antibiotic use improved compliance to local guidelines in the empiric treatment of urinary tract E. coli bacteraemia. The degree of error in local guidelines was low but higher in more complex hospitals and in healthcare-associated infections. Guidelines need to be constantly updated with the use of epidemiological data, rapid diagnostic tests and the analysis of patient risk factors specific to each geographical area.

Multiplex real-time PCR in non-invasive respiratory samples to reduce antibiotic use in community-acquired pneumonia: a randomised trial.

We assessed whether multiplex real-time PCR plus conventional microbiological testing is safe and more effective than conventional microbiological testing alone for reducing antibiotic use in community-acquired pneumonia (CAP). In this randomised trial, we recruited adults hospitalised with CAP at four Spanish hospitals. Patients were randomly assigned (1:1) to undergo either multiplex real-time PCR in non-invasive respiratory samples plus conventional microbiological testing or conventional microbiological testing alone. The primary endpoint was antibiotic use measured by days of antibiotic therapy (DOT). Between February 20, 2020, and April 24, 2023, 242 patients were enrolled; 119 were randomly assigned to multiplex real-time PCR plus conventional microbiological testing and 123 to conventional microbiological testing alone. All but one of the patients allocated to multiplex real-time PCR plus conventional microbiological testing underwent PCR, which was performed in sputum samples in 77 patients (65.2%) and in nasopharyngeal swabs in 41 (34.7%). The median DOT was 10.04 (IQR 7.98, 12.94) in the multiplex PCR plus conventional microbiological testing group and 11.33 (IQR 8.15, 16.16) in the conventional microbiological testing alone group (difference -1.04; 95% CI, -2.42 to 0.17; p = 0.093). No differences were observed in adverse events and 30-day mortality. Our findings do not support the routine implementation of multiplex real-time PCR in the initial microbiological testing in hospitalised patients with CAP. Clinicaltrials.gov registration: NCT04158492.

Long-Term Effects of a Stepwise, Multimodal, Non-Restrictive Antimicrobial Stewardship Programme for Reducing Broad-Spectrum Antibiotic Use in the ICU.

Information on the long-term effects of non-restrictive antimicrobial stewardship (AMS) strategies is scarce. We assessed the effect of a stepwise, multimodal, non-restrictive AMS programme on broad-spectrum antibiotic use in the intensive care unit (ICU) over an 8-year period. Components of the AMS were progressively implemented. Appropriateness of antibiotic prescribing was also assessed by monthly point-prevalence surveys from 2013 onwards. A Poisson regression model was fitted to evaluate trends in the reduction of antibiotic use and in the appropriateness of their prescription. From 2011 to 2019, a total of 12,466 patients were admitted to the ICU. Antibiotic use fell from 185.4 to 141.9 DDD per 100 PD [absolute difference, -43.5 (23%), 95% CI -100.73 to 13.73; p = 0.13] and broad-spectrum antibiotic fell from 41.2 to 36.5 [absolute difference, -4.7 (11%), 95% CI -19.58 to 10.18; p = 0.5]. Appropriateness of antibiotic prescribing rose by 11% per year [IRR: 0.89, 95% CI 0.80 to 1.00; p = 0.048], while broad-spectrum antibiotic use showed a dual trend, rising by 22% until 2015 and then falling by 10% per year since 2016 [IRR: 0.90, 95% CI 0.81 to 0.99; p = 0.03]. This stepwise, multimodal, non-restrictive AMS achieved a sustained reduction in broad-spectrum antibiotic use in the ICU and significantly improved appropriateness of antibiotic prescribing.

Efficacy of extended infusion of ß-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients (BEATLE): a randomised, multicentre, open-label, superiority clinical trial.

OBJECTIVES: The efficacy of extended infusions (EI) of ß-lactam antibiotics for optimising outcomes in febrile neutropenia is unclear. We assessed whether the administration of ß-lactams was more effective in EI than in intermittent infusion (II) for the treatment of febrile neutropenia. METHODS: We performed a randomised, open-label, superiority clinical trial of patients with febrile neutropenia at four Spanish university hospitals. Patients undergoing haematopoietic stem cell transplantation or with acute leukaemia receiving chemotherapy who required empirical antibiotic treatment for febrile neutropenia were randomly assigned (1:1) to receive EI of ß-lactam or II after a first dose in bolus. The choice of antipseudomonal ß-lactam was left to the discretion of the attending physician. The primary endpoint was treatment success at day 5, defined as defervescence without modifying the antibiotic treatment. Secondary endpoints included adverse events, attainment of the pharmacokinetic/pharmacodynamic target of 50, 75 and 100%ƒuT>MIC, and 30-day mortality. RESULTS: Between November 19, 2019 and June 22, 2022, 295 patients we screened for eligibility, of whom 150 were randomly assigned to receive EI (n=77) or II (n=73) of the antipseudomonal ß-lactam of choice. In the intention-to-treat analysis, treatment success at day 5 was achieved in 39/77 patients (50.6%) receiving EI versus 46/73 patients (63.0%) receiving II (risk difference -12.4%; 95% confidence interval, -29.4 to 4.7, p=0.17). The pharmacokinetic/pharmacodynamic targets of 75 and 100% ƒuT>MIC for empirical treatment were achieved more frequently in the EI group. No statistically-significant differences were found between groups in terms of adverse events or 30-day mortality. CONCLUSIONS: Our findings do not support the routine use of empirical EI of ß-lactams in febrile neutropenia. Further studies should consider the clinical heterogeneity of febrile neutropenia and focus on patients with sepsis/septic shock and microbiologically documented infections, particularly those with infections caused by microorganisms less susceptible to ß-lactams.

Reducing the duration of antibiotic therapy in surgical patients through a specific nationwide antimicrobial stewardship program. A prospective, interventional cohort study.

BACKGROUND: Guidelines recommend 5-7 days of antibiotic treatment in patients with surgical infection and adequate source control. This nationwide stewardship intervention aimed to reduce the duration of treatments in surgical patients to <7 days. METHODS: Prospective cohort study evaluating surgical patients receiving antibiotics ≥7 days in 32 hospitals. Indication for treatment, quality of source control, type of recommendations issued, and adherence to the recommendations were analysed. Temporal trends in the percentages of patients with treatment >7 days were evaluated using a linear regression model and Pearson's correlation coefficients. RESULTS: A total of 32 499 patients were included. Of these, 13.7% had treatments ≥7 days. In all, 3912 stewardship interventions were performed, primarily in general surgery (90.7%) and urology (8.1%). The main types of infection were intra-abdominal (73.4%), skin/soft tissues (9.8%) and urinary (9.2%). The septic focus was considered controlled in 59.9% of cases. Out of 5458 antibiotic prescriptions, the most frequently analysed drugs were piperacillin/tazobactam (21.7%), metronidazole (11.2%), amoxicillin/clavulanate (10.3%), meropenem (10.7%), ceftriaxone (9.3%) and ciprofloxacin (6.7%). The main recommendations issued were: treatment discontinuation (35.0%), maintenance (40.0%) or de-escalation (15.5%), and the overall adherence rate was 91.5%. With adequate source control, the most frequent recommendation was to terminate treatment (51.2%). Throughout the study period, a significant decrease in the percentage of prolonged treatments was observed (Pc=-0.69;P < 0.001). CONCLUSIONS: This stewardship programme reduced the duration of treatments in surgical departments. Preference was given to general surgery services, intra-abdominal infection, and beta-lactam antibiotics, including carbapenems. Adherence to the issued recommendations was high.

Cross-Sectional Survey on the Current Role of Clinical Pharmacists among Antimicrobial Stewardship Programmes in Catalonia: Much Ado about Nothing.

BACKGROUND: Antimicrobial resistance killed 1.27 million people in 2019, so urgent actions are desperately needed. Antimicrobial stewardship programmes (ASPs) are essential to optimize antimicrobial use. The objective was to acknowledge the current role of clinical pharmacists engaged in ASP activities in Catalonia. METHODS: This was a cross-sectional survey shared through the Catalan Infection Control Programme (VINCat). The survey consisted of four sections and was sent by e-mail. RESULTS: A total of 69.0% of the centres answered. Pharmacists dedicated a median of 5.0 h per week (2.1 h/week/100 acute care beds), representing 0.15 full time equivalents. The ASP lacked information technology (IT) support, as only 16.3% of centres automatically calculated defined daily doses and days of therapy. Those with less than 15% of their time available for ASPs conducted fewer clinical activities, especially prospective audits and feedback. Those without official infectious diseases training also performed fewer clinical activities, but training was less determinant than IT support or time. Pharmacists performed interventions mostly through annotation in the medical records. CONCLUSIONS: Clinical pharmacists from Catalonia dedicated to ASPs present an important lack of time and IT support to perform clinical activities. Pharmacists should also improve their clinical skills and try to conduct clinical advice to prescribers, either by phone or face-to-face.

Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study.

Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (Cmin) in patient serum of between 1-5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation (ECMO) support, and data regarding voriconazole PK changes during ECMO are scarce. Our study compared voriconazole PKs in patients with and without ECMO support in a retrospective cohort of critically-ill patients. Fifteen patients with 26 voriconazole Cmin determinations in the non-ECMO group and nine patients with 27 voriconazole Cmin determinations in the ECMO group were recruited. The ECMO group had lower Cmin (0.38 ± 2.98 vs. 3.62 ± 3.88, p < 0.001) and higher infratherapeutic Cmin values (16 vs. 1, p < 0.001) than the non-ECMO group. Multivariate analysis identified ECMO support (-0.668, CI95 -0.978--0.358) and plasma albumin levels (-0.023, CI95 -0.046--0.001) as risk factors for low Cmin values. When comparing pre- and post-therapeutic drug optimisation samples from the ECMO group, the dose required to achieve therapeutic Cmin was 6.44 mg/kg twice a day. Therapeutic drug optimisation is essential to improve target attainment.