Clinical and Pharmacological Considerations for Concomitant Administration of Posaconazole and Isavuconazole with Letermovir.

We sought in this case-control retrospective study to compare posaconazole and isavuconazole (PCZ and IVC, respectively) plasma trough concentration (Ctrough) levels in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC Ctrough levels were not found to be significantly different between cases and controls, as they were 1.31 mg/liter (median) (interquartile range [IQR], 0.90) versus 1.36 mg/liter (IQR, 1.16) (P = 0.31) and 3.20 mg/liter (IQR, 2.40) versus 2.35 mg/liter (IQR, 1.50) (P = 0.17), respectively. In conclusion, we observed PCZ/IVC Ctrough levels within the expected range and no significant effect of LET coadministration.

Determination of antiretroviral drugs for buyers' club in Switzerland using capillary electrophoresis methods.

Human immunodeficiency virus-acquired immunodeficiency syndrome continues to be a major global public health issue, having claimed almost 33 million lives to date. Due to the high cost of antiretroviral treatment, access to these drugs remains difficult for vulnerable populations, such as migrants and people living in prisons, who often do not have health insurance. These factors lead to poorer health outcomes and higher transmission rates. The personal importation scheme for unapproved generics from foreign countries is one option to access affordable human immunodeficiency virus treatment. However, the risk of importing falsified medicine remains high, and the quality control of unapproved drugs is lacking. In this context, three CE methods for the analysis of nine antiviral drugs found in commercial pharmaceutical formulations were evaluated. The selected compounds were emtricitabine, tenofovir disoproxil, tenofovir alafenamide, rilpivirine, efavirenz, raltegravir, dolutegravir, abacavir, and lamivudine. The developed methods were successfully applied to determine the active pharmaceutical ingredients of commercial formulations and unapproved generics. The quality control of unapproved generics by CE is an attractive approach due to its good standard of quality, low cost, ecofriendliness, and ease of implementation.

Clinical considerations on posaconazole administration and therapeutic drug monitoring in allogeneic hematopoietic cell transplant recipients.

There is a paucity of data on posaconazole (PCZ) dosing and therapeutic-drug-monitoring (TDM) in allogeneic hematopoietic cell transplant recipients (allogeneic-HCTr). This was a 3-year retrospective multicenter study (January 1, 2016 to December 31, 2018) in adult allogeneic-HCTr who received PCZ (intravenously, IV and/or as delayed-release tablet, DRT) as prophylaxis or treatment for ≥7 consecutive days (D) with at least 1-PCZ-level available using data of the Swiss Transplant Cohort Study. The primary objective was to describe the distribution of PCZ-level and identify predictors of therapeutic PCZ-level and associations between PCZ-dosing and PCZ-level. A total of 288 patients were included: 194 (67.4%) and 94 (32.6%) received PCZ as prophylaxis and treatment, respectively, for a median of 90 days (interquartile range, IQR: 42-188.5). There were 1944 PCZ-level measurements performed, with a median PCZ level of 1.3 mg/L (IQR: 0.8-1.96). PCZ-level was <0.7 mg/L in 383/1944 (19.7%) and <1.0 mg/L in 656/1944 (33.7%) samples. PCZ-level was <0.7 mg/L in 260/1317 (19.7%) and <1.0 mg/L in 197/627 (31.4%) in patients who received PCZ-prophylaxis versus treatment, respectively. There were no significant differences in liver function tests between baseline and end-of-treatment. There were nine (3.1%) breakthrough invasive fungal infections (bIFI), with no difference in PCZ levels between patients with or without bIFI. Despite a very intensive PCZ-TDM, PCZ-levels remain below target levels in up to one-third of allogeneic-HCTr. Considering the low incidence of bIFI observed among patients with PCZ levels in the targeted range, our data challenge the clinical utility of routine universal PCZ-TDM.

Vulnerable patients forgo health care during the first wave of the Covid-19 pandemic.

During the first wave of the Covid-19 pandemic, access to health care was limited, and patients encountered important delays for scheduled appointments and care. Empirical data relying on patients' reports of forgoing health care are scarce. This study investigated Covid-19-related self-reports of forgoing health care in a sample of vulnerable outpatients in Geneva, Switzerland. We collected data from 1167 adult outpatients, including clinically vulnerable patients (with chronic diseases), geriatric patients (involved in a health care network for people aged 60 or older), and socially vulnerable patients (involved in a migrant health program or a mobile outpatient community care center) in June 2020. Data on sociodemographic factors, forgoing health care, and anti-SARS-CoV-2 antibodies were collected. Of the patients, 38.5% reported forgoing health care. Forgoing health care was more frequent for younger patients, women, patients with a low level of education, and patients with a chronic disease (p < .001). There was no significant association between the presence of anti-SARS-CoV-2 antibodies and forgoing health care (p = .983). As the decrease in routine management of patients might have important and unpredictable adverse health consequences, avoiding delayed health care is crucial.

Scientific publications in internal medicine and family medicine: a comparative cross-sectional study in Swiss university hospitals.

BACKGROUND: Family medicine is a relatively new academic medical discipline. We aimed to compare the main bibliometric indices of hospital-based senior physicians practicing internal medicine versus family medicine in Switzerland. METHODS: We conducted this cross-sectional study in March 2020. We selected all hospital-based senior physicians practicing internal medicine or family medicine in the six Swiss university hospitals. Using Web of Science, after removing from both groups of physicians the 5% with the highest number of publications, we extracted the number of publications, the number of publications per year, the number of citations, the number of citations per year, the number of citations per publication and the h-index. We compared the data between the two groups using negative binomial regressions and the proportion of physicians having at least one publication using chi-square tests. RESULTS: We included 349 physicians in the study (internal medicine: 51%, men: 51%). The median number of publications was three [interquartile range (IQR) = 18], the median number of citations was nine (IQR = 158) and the median h-index was one (IQR = 5). All bibliometric indices were similar in both groups, as was the proportion of physicians having at least one publication (family medicine: 87% versus 82%, P = 0.15). CONCLUSIONS: We found no association between the bibliometric indices and the medical specialty. Further studies are needed to explore other important indicators of academic output, such as those more specifically assessing its quality and scientific importance.

Clinical Considerations of Isavuconazole Administration in High-Risk Hematological Patients: A Single-Center 5-Year Experience.

BACKGROUND: There are limited real-life data on isavuconazole prophylaxis and treatment of invasive mold infections (IMI) in hematological patients and allogeneic hematopoietic cell transplant (HCT) recipients. OBJECTIVES: Primary objective was to describe the indications of real-life isavuconazole administration at a university hospital. Secondary objectives included the description of liver function tests and QTc interval between baseline and end of treatment (EOT), clinical outcomes and breakthrough IMI by the EOT. PATIENTS/METHODS: This was a 5-year single-center retrospective study of all adult patients with acute myeloid leukemia and/or allogeneic HCT recipients who received isavuconazole as prophylaxis and/or treatment between June 1, 2016, and July 31, 2020. RESULTS: Among 30 identified patients, the indications for isavuconazole administration were adverse events associated with prior antifungal treatment (N: 18, 60%: hepatotoxicity, renal insufficiency, long QTc interval, neurotoxicity, and potential drug-drug interactions in 6, 4, 3, 1 and 4 patients, respectively), clinical efficacy (N: 5, 16.6%), and other reasons (N: 10, 33.3%; 5/10 patients treated with isavuconazole to facilitate hospital discharge with orally administered appropriate treatment). Alanine aminotransferase significantly decreased from baseline (mean: 129 IU/L, range: 73, 202) to a mean of 48 IU/L (range: 20, 80) by day 14 (P-value: 0.02), 23.5 IU/L (range: 20, 27) by day 28 (P-value: 0.03) and 16.5 IU/L (range: 16, 17) by day 42 (P-value: 0.009). The QTc interval decreased from baseline (mean: 456.8 ms, range: 390, 533) to EOT (mean: 433.8 ms, range: 400, 472; P-value: 0.03). The mean isavuconazole plasma concentration was 2.9 mg/L (range: 0.9, 6.7). There was no breakthrough IMI observed. CONCLUSION: Isavuconazole is a safe and reliable antifungal agent in complex hematological patients, with relatively low hepatotoxicity and QTc interval shortening properties.

[Buyers' club†: an alternative for access to treatment†?] / Buyers' club†: une alternative pour l'accès au traitement†?

Rapid medication management for patients infected with HIV, HCV or HBV is key in optimizing a more favourable clinical response, in terms of morbidity, mortality, quality-of-life and reduced risk of transmission. If a drug is expensive, access to treatment for an uninsured patient with limited resources can be a hurdle that leads to forgoing healthcare for economic reasons. The buyers' club's objective is to provide logistics and/or financial assistance to a patient aiming to import qualitative generics for his personal use at an affordable price oversea. The drug is purchased on the internet.

La prise en charge médicamenteuse rapide pour les patients infectés par le VIH, le VHC ou le VHB est un élément clé pour obtenir une réponse clinique favorable en termes de morbidité, mortalité, et qualité de vie, et elle permet de diminuer les risques de transmission. Lorsqu'un médicament est cher, l'accès aux traitements pour un·e patient·e sans assurance avec des ressources limitées est une barrière qui peut conduire à renoncer aux soins pour des raisons économiques. Un buyers' club est une structure dont l'objectif est d'apporter une aide logistique et/ou financière à un·e patient·e qui souhaite importer à titre personnel un médicament de qualité et efficace à des conditions économiquement plus favorables. L'achat du médicament se fait par internet.

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Prioritization methodology for the monitoring of active pharmaceutical ingredients in hospital effluents.

The important number of active pharmaceutical ingredients (API) available on the market along with their potential adverse effects in the aquatic ecosystems, lead to the development of prioritization methods, which allow choosing priority molecules to monitor based on a set of selected criteria. Due to the large volumes of API used in hospitals, an increasing attention has been recently paid to their effluents as a source of environmental pollution. Based on the consumption data of a Swiss university hospital, about hundred of API has been prioritized following an OPBT approach (Occurrence, Persistence, Bioaccumulation and Toxicity). In addition, an Environmental Risk Assessment (ERA) allowed prioritizing API based on predicted concentrations and environmental toxicity data found in the literature for 71 compounds. Both prioritization approaches were compared. OPBT prioritization results highlight the high concern of some non steroidal anti-inflammatory drugs and antiviral drugs, whereas antibiotics are revealed by ERA as potentially problematic to the aquatic ecosystems. Nevertheless, according to the predicted risk quotient, only the hospital fraction of ciprofloxacin represents a risk to the aquatic organisms. Some compounds were highlighted as high-priority with both methods: ibuprofen, trimethoprim, sulfamethoxazole, ritonavir, gabapentin, amoxicillin, ciprofloxacin, raltegravir, propofol, etc. Analyzing consumption data and building prioritization lists helped choosing about 15 API to be monitored in hospital wastewaters. The API ranking approach adopted in this study can be easily transposed to any other hospitals, which have the will to look at the contamination of their effluents.

Protocol of a monocentric, double-blind, randomized, superiority, controlled trial evaluating the effect of in-prison OROS-methylphenidate vs. placebo treatment in detained people with attention-deficit hyperactivity disorder (BATIR).

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is characterized by difficulty paying attention, poor impulse control, and hyperactive behavior. It is associated with several adverse health and social outcomes and leads to an increased risk of criminality and recidivism. Worldwide, ADHD is thus highly prevalent in prisons. However, ADHD treatment has been neglected in such environments. Stimulant medications such as osmotic-release oral system methylphenidate (OROS-MPH) are first-line treatments in the general population, but they are under-prescribed in prisons due to concerns about abuse, even though such claims are not empirically supported. This project aims to compare the efficacy of a 3-month in-prison OROS-MPH vs. placebo treatment on the severity of core ADHD symptoms and relevant in- and post-prison outcomes. METHODS: This study is a phase III, double-blinded, randomized, superiority, controlled trial of OROS-MPH vs. placebo. After randomization, the participants will receive 3 months of treatment with OROS-MPH or placebo (1:1 ratio) while incarcerated. Upon release, all participants will be offered the treatment (OROS-MPH) for 1 year but will remain blinded to their initial study group. The study will be conducted at the Division of Prison Health, Geneva, Switzerland, among incarcerated men (n = 150). Measures will include (1) investigator-rated ADHD symptoms, (2) acute events collected by the medical and prison teams, (3) assessment of the risk of recidivism, (4) medication side effects, (5) medication adherence, (6) study retention, (7) health care/prison costs, and (8) 1-year recidivism. Analyses will include bivariable and multivariable modeling (e.g., regression models, mixed-effects models, survival analyses) and an economic evaluation (cost-benefit analysis). DISCUSSION: We expect that early identification and treatment of ADHD in prison will be an important public health opportunity and a cost-effective approach that is likely to reduce the vulnerability of incarcerated individuals and promote pathways out of criminal involvement. The study will also promote standards of care for people with ADHD in prison and provide recommendations for continuity of care after release. TRIAL REGISTRATION: ClinicalTrials.gov NCT05842330 . Registered on June 5, 2023. Kofam.ch SNCTP000005388. Registered on July 17, 2023.

Patented drug extension strategies on healthcare spending: a cost-evaluation analysis.

BACKGROUND: Drug manufacturers have developed "evergreening" strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole ("spillover effect"). METHODS AND FINDINGS: We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. "Extra costs" were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community. Estimated "extra costs" over the study period were €15.9 (95% CI 15.5; 16.2) million for scenario 1, €14.4 (95% CI 14.1; 14.7) million for scenario 2, and €30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover "extra cost" of €330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of €7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in "extra costs" of €503,600 (95% CI 444,500; 563,100). CONCLUSIONS: Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies.

The impact of antibiotic use on the incidence and resistance pattern of extended-spectrum beta-lactamase-producing bacteria in primary and secondary healthcare settings.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The emergence and spread of bacteria producing extended-spectrum beta-lactamases (ESBLs) has important therapeutic and epidemiologic implications. • A key target for the establishment of hospital antibiotic stewardship is reducing the occurrence of additional antibiotic resistance. • Further research is needed to accumulate supporting evidence that reducing antibiotic use will result in a parallel reduction in antibiotic resistance. WHAT THIS STUDY ADDS: • Fluoroquinolone restriction reversed ciprofloxacin resistance in primary and secondary healthcare settings. • Fluoroquinolone restriction reduced ESBL-producing bacteria incidence rates in both the primary and secondary healthcare settings. • This study highlights the value of time-series analysis in designing efficient antibiotic stewardship. AIMS: The objective of the present study was to study the relationship between hospital antibiotic use, community antibiotic use and the incidence of extended-spectrum beta-lactamase (ESBL)-producing bacteria in hospitals, while assessing the impact of a fluoroquinolone restriction policy on ESBL-producing bacteria incidence rates. METHODS: The study was retrospective and ecological in design. A multivariate autoregressive integrated moving average (ARIMA) model was built to relate antibiotic use to ESB-producing bacteria incidence rates and resistance patterns over a 5 year period (January 2005-December 2009). RESULTS: Analysis showed that the hospital incidence of ESBLs had a positive relationship with the use of fluoroquinolones in the hospital (coefficient = 0.174, P= 0.02), amoxicillin-clavulanic acid in the community (coefficient = 1.03, P= 0.03) and mean co-morbidity scores for hospitalized patients (coefficient = 2.15, P= 0.03) with various time lags. The fluoroquinolone restriction policy was implemented successfully with the mean use of fluoroquinolones (mainly ciprofloxacin) being reduced from 133 to 17 defined daily doses (DDDs)/1000 bed days (P < 0.001) and from 0.65 to 0.54 DDDs/1000 inhabitants/day (P= 0.0007), in both the hospital and its surrounding community, respectively. This was associated with an improved ciprofloxacin susceptibility in both settings [ciprofloxacin susceptibility being improved from 16% to 28% in the community (P < 0.001)] and with a statistically significant reduction in ESBL-producing bacteria incidence rates. DISCUSSION: This study supports the value of restricting the use of certain antimicrobial classes to control ESBL, and demonstrates the feasibility of reversing resistance patterns post successful antibiotic restriction. The study also highlights the potential value of the time-series analysis in designing efficient antibiotic stewardship.

A Cellular Assay for Spike/ACE2 Fusion: Quantification of Fusion-Inhibitory Antibodies after COVID-19 and Vaccination.

Not all antibodies against SARS-CoV-2 inhibit viral entry, and hence, infection. Neutralizing antibodies are more likely to reflect real immunity; however, certain tests investigate protein/protein interaction rather than the fusion event. Viral and pseudoviral entry assays detect functionally active antibodies but are limited by biosafety and standardization issues. We have developed a Spike/ACE2-dependent fusion assay, based on a split luciferase. Hela cells stably transduced with Spike and a large fragment of luciferase were co-cultured with Hela cells transduced with ACE2 and the complementary small fragment of luciferase. Cell fusion occurred rapidly allowing the measurement of luminescence. Light emission was abolished in the absence of Spike and reduced in the presence of proteases. Sera from COVID-19-negative, non-vaccinated individuals or from patients at the moment of first symptoms did not lead to a significant reduction of fusion. Sera from COVID-19-positive patients as well as from vaccinated individuals reduced the fusion. This assay was more correlated to pseudotyped-based entry assay rather than serology or competitive ELISA. In conclusion, we report a new method measuring fusion-inhibitory antibodies in serum, combining the advantage of a complete Spike/ACE2 interaction active on entry with a high degree of standardization, easily allowing automation in a standard bio-safety environment.

Decreased Levels of SARS-CoV-2 Fusion-Inhibitory Antibodies in the Serum of Aged COVID-19 Patients.

Background: The SARS-CoV-2 pandemic was particularly devastating for elderly people, and the underlying mechanisms of the disease are still poorly understood. In this study, we investigated fusion inhibitory antibodies (fiAbs) in elderly and younger COVID-19 patients and analyzed predictive factors for their occurrence. Methods: Data and samples were collected in two cohorts of hospitalized patients. A fusion assay of SARS-CoV-2 spike-expressing cells with ACE2-expressing cells was used to quantify fiAbs in the serum of patients. Results: A total of 108 patients (52 elderly (mean age 85 ± 7 years); 56 young (mean age 52 ± 10 years)) were studied. The concentrations of fiAbs were lower in geriatric patients, as evidenced at high serum dilutions (1/512). The association between fiAbs and anti-Spike Ig levels was weak (correlation coefficient < 0.3), but statistically significant. Variables associated with fusion were the delay between the onset of symptoms and testing (HR = −2.69; p < 0.001), clinical frailty scale (HR = 4.71; p = 0.035), and WHO severity score (HR = −6.01, p = 0.048). Conclusions: Elderly patients had lower fiAbs levels after COVID-19 infection. The decreased fiAbs levels were associated with frailty.

Impact of interactive computerised decision support for hospital antibiotic use (COMPASS): an open-label, cluster-randomised trial in three Swiss hospitals.

BACKGROUND: Computerised decision-support systems (CDSSs) for antibiotic stewardship could help to assist physicians in the appropriate prescribing of antibiotics. However, high-quality evidence for their effect on the quantity and quality of antibiotic use remains scarce. The aim of our study was to assess whether a computerised decision support for antimicrobial stewardship combined with feedback on prescribing indicators can reduce antimicrobial prescriptions for adults admitted to hospital. METHODS: The Computerised Antibiotic Stewardship Study (COMPASS) was a multicentre, cluster-randomised, parallel-group, open-label superiority trial that aimed to assess whether a multimodal computerised antibiotic-stewardship intervention is effective in reducing antibiotic use for adults admitted to hospital. After pairwise matching, 24 wards in three Swiss tertiary-care and secondary-care hospitals were randomised (1:1) to the CDSS intervention or to standard antibiotic stewardship measures using an online random sequence generator. The multimodal intervention consisted of a CDSS providing support for choice, duration, and re-evaluation of antimicrobial therapy, and feedback on antimicrobial prescribing quality. The primary outcome was overall systemic antibiotic use measured in days of therapy per admission, using adjusted-hurdle negative-binomial mixed-effects models. The analysis was done by intention to treat and per protocol. The study was registered with ClinicalTrials.gov (identifier NCT03120975). FINDINGS: 24 clusters (16 at Geneva University Hospitals and eight at Ticino Regional Hospitals) were eligible and randomly assigned to control or intervention between Oct 1, 2018, and Dec 31, 2019. Overall, 4578 (40·2%) of 11 384 admissions received antibiotic therapy in the intervention group and 4142 (42·8%) of 9673 in the control group. The unadjusted overall mean days of therapy per admission was slightly lower in the intervention group than in the control group (3·2 days of therapy per admission, SD 6·2, vs 3·5 days of therapy per admission, SD 6·8; p<0·0001), and was similar among patients receiving antibiotics (7·9 days of therapy per admission, SD 7·6, vs 8·1 days of therapy per admission, SD 8·4; p=0·50). After adjusting for confounders, there was no statistically significant difference between groups for the odds of an admission receiving antibiotics (odds ratio [OR] for intervention vs control 1·12, 95% CI 0·94-1·33). For admissions with antibiotic exposure, days of therapy per admission were also similar (incidence rate ratio 0·98, 95% CI 0·90-1·07). Overall, the CDSS was used at least once in 3466 (75·7%) of 4578 admissions with any antibiotic prescription, but from the first day of antibiotic treatment for only 1602 (58·9%) of 2721 admissions in Geneva. For those for whom the CDSS was not used from the first day, mean time to use of CDSS was 8·9 days. Based on the manual review of 1195 randomly selected charts, transition from intravenous to oral therapy was significantly more frequent in the intervention group after adjusting for confounders (154 [76·6%] of 201 vs 187 [87%] of 215, +10·4%; OR 1·9, 95% CI 1·1-3·3). Consultations by infectious disease specialists were less frequent in the intervention group (388 [13·4%] of 2889) versus the control group (405 [16·9%] of 2390; OR 0·84, 95% CI 0·59-1·25). INTERPRETATION: An integrated multimodal computerised antibiotic stewardship intervention did not significantly reduce overall antibiotic use, the primary outcome of the study. Contributing factors were probably insufficient uptake, a setting with relatively low antibiotic use at baseline, and delays between ward admission and first CDSS use. FUNDING: Swiss National Science Foundation. TRANSLATIONS: For the French and Italian translations of the abstract see Supplementary Materials section.

Impact of combined low-level mupirocin and genotypic chlorhexidine resistance on persistent methicillin-resistant Staphylococcus aureus carriage after decolonization therapy: a case-control study.

BACKGROUND: The clinical importance of low-level mupirocin resistance and genotypic chlorhexidine resistance remains unclear. We aimed to determine whether resistance to these agents increases the risk of persistent methicillin-resistant Staphylococcus aureus (MRSA) carriage after their use for topical decolonization therapy. METHODS: A nested case-control study was conducted of MRSA carriers who received decolonization therapy from 2001 through 2008. Cases, patients who remained colonized, were matched by year to controls, those in whom MRSA was eradicated (follow-up, 2 years). Baseline MRSA isolates were tested for mupirocin resistance by Etest and chlorhexidine resistance by qacA/B polymerase chain reaction. MRSA carriers with high-level mupirocin resistance were excluded. The effect of the primary exposure of interest, low-level mupirocin and genotypic chlorhexidine resistance, was evaluated with multivariate conditional logistic regression analysis. RESULTS: The 75 case patients and 75 control patients were similar except that those persistently colonized were older (P = .007) with longer lengths of hospital stay (P = .001). After multivariate analysis, carriage of combined low-level mupirocin and genotypic chlorhexidine resistance before decolonization independently predicted persistent MRSA carriage (odds ratio [OR], 3.4 [95% confidence interval {CI}, 1.5-7.8]). Other risk factors were older age (OR, 1.04 [95% CI, 1.02-1.1]), previous hospitalization (OR, 2.4 [95% CI, 1.1-5.7]), presence of a skin wound (OR, 5.7 [95% CI, 1.8-17.6]), recent antibiotic use (OR, 3.1 [95% CI, 1.3-7.2]), and central venous catheterization (OR, 5.7 [95% CI, 1.4-23.9]). CONCLUSIONS: Combined low-level mupirocin and genotypic chlorhexidine resistance significantly increases the risk of persistent MRSA carriage after decolonization therapy. Institutions with widespread use of these agents should monitor for resistance and loss of clinical effectiveness.

Modelling the impact of antibiotic use on antibiotic-resistant Escherichia coli using population-based data from a large hospital and its surrounding community.

OBJECTIVES: To determine the temporal relationship between antibiotic use and incidence of antibiotic-resistant Escherichia coli in both the inpatient and outpatient setting of a large urban area. METHODS: A retrospective observational time-series analysis was performed to evaluate the incidence of non-duplicate clinical isolates of E. coli resistant to ciprofloxacin, trimethoprim/sulfamethoxazole and cefepime from January 2000 through December 2007, combined with a transfer function model of aggregated data on antibiotic use in both settings obtained from the hospital's pharmacy and outpatient billing offices. RESULTS: Ciprofloxacin resistance increased from 6.0% (2000) to 15.4% (2007; P<0.0001) and cefepime resistance from 0.9% (2002) to 3.2% (2007; P=0.01). Trimethoprim/sulfamethoxazole resistance remained stable (23.7%-25.8%). Total antibiotic use increased in both settings, while fluoroquinolone use increased significantly only among outpatients. A temporal effect between fluoroquinolone resistance in community E. coli isolates and outpatient use of ciprofloxacin (immediate effect and time lag 1 month) and moxifloxacin (time lag 4 months) was observed, explaining 51% of the variance over time. The incidence of cefepime resistance in E. coli was correlated with ciprofloxacin use in the inpatient (lag 1 month) and outpatient (lag 4 months) settings and with the use of ceftriaxone (lag 0 month), piperacillin/tazobactam (3 months) and cefepime (3 months) in the hospital (R2=51%). CONCLUSIONS: These results support efforts to reduce prescribing of fluoroquinolones for control of resistant E. coli including extended-spectrum ß-lactamase producers and show the added value of time-series analysis to better understand the interaction between community and hospital antibiotic prescribing and its spill-over effect on antibiotic resistance.

Hepatitis C prevalences in the psychiatric setting: Cost-effectiveness of scaling-up screening and direct-acting antiviral therapy.

BACKGROUND & AIMS: Patients hospitalised because of mental illness often have risk factors for contracting HCV. Scaling-up HCV screening for all psychiatric inpatients as a case-detection strategy for viral elimination is underexplored. This study aimed to evaluate the cost-effectiveness of scaling-up HCV screening and treatment for psychiatry hospital admissions in Switzerland vs. the current standard-of-care risk-based approach, where only those with a history of substance misuse disorder are offered testing. METHODS: HCV prevalence by history of substance misuse disorder was analysed in medical records from inpatient admissions to a Swiss psychiatry department. Cost-effectiveness was analysed from a healthcare provider perspective through a decision-tree screening model, using these HCV prevalence data. Model and parameter uncertainty were assessed using deterministic and probabilistic sensitivity analyses. RESULTS: Prevalence of HCV in psychiatry inpatients with a history of substance misuse disorder (n = 1,013) was 25.7%, compared with 3.5% among the remaining inpatients (n = 3,535). Scaling up HCV screening and treatment for all psychiatry admissions was cost-effective vs. the risk-based approach, with an incremental cost-effectiveness ratio of US$9,188 per quality-adjusted life-year gained. The incremental cost-effectiveness ratio remained cost-effective considering a HCV prevalence as low as 0.07%. The population-level net monetary benefit of the generalised screening approach was US$435,156,348, with 917 additional patients per year detected and treated at a cost of US$3,294 per person (vs. US$2,122 under risk-based screening). CONCLUSIONS: Scaling up HCV screening and treatment at diagnosis with all-oral, interferon-free regimens as a generalised approach for psychiatric admissions was cost-effective and could support reaching World Health Organization targets for HCV elimination by 2030. LAY SUMMARY: Patients hospitalised because of mental illness often have risk factors for HCV. We found that testing all psychiatry patients in hospital for HCV was cost-effective compared with testing only patients who have a history of substance misuse. Scaling up HCV testing and treatment could help to wipe out HCV.

Impact of restricting procalcitonin measurements in a Swiss tertiary-care hospital on antibiotic use, clinical outcomes, and costs: An interrupted time-series analysis.

We evaluated the impact of a restriction of procalcitonin measurements on antibiotic use, length of stay, mortality, and cost in a Swiss tertiary-care hospital using interrupted time-series analysis. There was no significant change in level or slope for rates of antibiotic consumption, and costs decreased considerably, by ~54,488 CHF (US$55,714) per month.

Letermovir Primary Prophylaxis in High-Risk Hematopoietic Cell Transplant Recipients: A Matched Cohort Study.

BACKGROUND: Real-life data on the administration of letermovir as cytomegalovirus (CMV) primary prophylaxis after allogeneic hematopoietic cell transplantation (HCT) remain limited. METHODS: We conducted a retrospective single-center matched cohort study, comparing consecutive high-risk allogeneic HCT recipients (cases) receiving primary prophylaxis with letermovir and untreated matched historical controls, during a study period of 180 days. The primary outcome was the incidence of clinically significant (cs) CMV infection. Secondary outcomes included duration and costs of CMV-antiviral treatments, hospital resource utilization, hematology and laboratory parameters. RESULTS: Letermovir prophylaxis decreased csCMV infection incidence from 82.7% (controls) to 34.5% (cases; p-value < 0.0001). Controls were more likely to have >1 episode of csCMV infection (59.6%) compared to cases (11.5%; p-value < 0.0001). Letermovir was associated with: shorter overall CMV-associated treatment duration (49 days vs. 77.8 days; p-value: 0.02) and a trend for lower costs of CMV-associated treatments ($4096 vs. $9736; p-value: 0.07) and reduced length of stay (44.8 days vs. 59.8 days; p-value: 0.16). Letermovir administration was associated with significantly shorter duration (27.3 days vs. 57.1 days; p-value: 0.008) and lower costs ($1089 vs. $2281; p-value: 0.008) of valganciclovir treatment. Compared to controls, higher platelet counts were observed in cases (138 G/L vs. 92 G/L; p-value: 0.03) and renal function was improved (94 mL/min/1.73 m2 vs. 74 mL/min/1.73 m2; p-value: 0.006). CONCLUSIONS: Primary anti-CMV letermovir prophylaxis decreased the incidence of csCMV infection and the administration of CMV-associated treatments and costs, particularly those associated with valganciclovir. An effect of letermovir on platelet reconstitution and renal function of csCMV post-HCT was observed and needs further investigation.