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Abstract: Background: Solid organ transplant recipients are especially vulnerable to Clostridium difficile infection (CDI) due to cumulative risk factors including increased exposure to healthcare settings, persistent immunosuppression, and higher rates of antimicrobial exposure. We aimed to identify risk factors associated with CDI development in kidney transplant recipients including implications of immunosuppressive therapies and acid‐suppressing agents. Methods: This was a single‐center, non‐interventional, retrospective case‐control study of adult subjects between June 1, 2009 and June 30, 2013. During this time, 728 patients underwent kidney transplantation. Overall, 22 developed CDI (cases) and were matched 1:3 with 66 controls. Cases and controls were also matched for induction agent, kidney allograft type (living or deceased), and time from transplant to CDI result (±60 days). Results: The majority of subjects received a deceased donor kidney (77.3%) and basiliximab induction therapy (86.4%). The overall CDI incidence was 3%. Factors independently associated with CDI were average tacrolimus trough (AOR = 1.25, 95% CI = 1.00‐1.56, P = .048) and antibiotic exposure for urinary tract infections (UTI) (AOR = 4.17, 95% CI = 1.12‐15.54, P = .034). Proton pump inhibitor use was not associated with CDI (OR = 0.81, 95% CI = 0.29‐2.29, P = .691). Conclusion: Maintaining a clinically appropriate tacrolimus trough and judicious antibiotic use and selection for UTI treatment could potentially reduce CDI in the kidney transplant population. [ABSTRACT FROM AUTHOR]

Background: Evidence is limited about the comparative safety of antibiotic regimens for treatment of community-acquired pneumonia (CAP). We compared the risk of adverse drug events (ADEs) associated with antibiotic regimens for CAP treatment among otherwise healthy, non-elderly adults., Methods: We conducted an active comparator new-user cohort study (2007-2019) of commercially-insured adults 18-64 years diagnosed with outpatient CAP, evaluated via chest x-ray, and dispensed a same-day CAP-related oral antibiotic regimen. ADE follow-up duration ranged from 2-90 days (e.g., renal failure [14 days]). We estimated risk differences [RD] per 100 treatment episodes and risk ratios using propensity score weighted Kaplan-Meier functions. Ankle/knee sprain and influenza vaccination were considered as negative control outcomes., Results: Of 145 137 otherwise healthy CAP patients without comorbidities, 52% received narrow-spectrum regimens (44% macrolide, 8% doxycycline) and 48% received broad-spectrum regimens (39% fluoroquinolone, 7% β-lactam, 3% β-lactam + macrolide). Compared with macrolide monotherapy, each broad-spectrum antibiotic regimen was associated with increased risk of several ADEs (eg, β-lactam: nausea/vomiting/abdominal pain [RD per 1000, 3.20; 95% CI, 0.99–5.73]; non–Clostridioides difficile diarrhea [RD per 1000, 4.61; 95% CI, 2.47–6.82]; vulvovaginal candidiasis/vaginitis [RD per 1000, 3.57; 95% CI, 0.87, 6.88]). Narrow-spectrum antibiotic regimens largely conferred similar risk of ADEs. We generally observed similar risks of each negative control outcome, indicating minimal confounding., Conclusions: Broad-spectrum antibiotics were associated with increased risk of ADEs among otherwise healthy adults treated for CAP in the outpatient setting. Antimicrobial stewardship is needed to promote judicious use of broad-spectrum antibiotics and ultimately decrease antibiotic-related ADEs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To characterize antibiotic utilization for outpatient community-acquired pneumonia (CAP) in the United States., Methods: We conducted a cohort study among adults 18-64 years diagnosed with outpatient CAP and a same-day guideline-recommended oral antibiotic fill in the MarketScan® Commercial Database (2008-2019). We excluded patients coded for chronic lung disease or immunosuppressive disease; recent hospitalization or frequent healthcare exposure (e.g., home wound care, patients with cancer); recent antibiotics; or recent infection. We characterized utilization of broad-spectrum antibiotics (respiratory fluoroquinolone, β-lactam + macrolide, β-lactam + doxycycline) versus narrow-spectrum antibiotics (macrolide, doxycycline) overall and by patient- and provider-level characteristics. Per 2007 IDSA/ATS guidelines, we stratified analyses by otherwise healthy patients and patients with comorbidities (coded for diabetes; chronic heart, liver, or renal disease; etc.)., Results: Among 263 914 otherwise healthy CAP patients, 35% received broad-spectrum antibiotics (not recommended); among 37 161 CAP patients with comorbidities, 44% received broad-spectrum antibiotics (recommended). Ten-day antibiotic treatment durations were the most common for all antibiotic classes except macrolides. From 2008 to 2019, broad-spectrum antibiotic use substantially decreased from 45% to 19% in otherwise healthy patients (average annual percentage change [AAPC], -7.5% [95% CI -9.2%, -5.9%]), and from 55% to 29% in patients with comorbidities (AAPC, -5.8% [95% CI -8.8%, -2.6%]). In subgroup analyses, broad-spectrum antibiotic use varied by age, geographic region, provider specialty, and provider location., Conclusions: Real-world use of broad-spectrum antibiotics for outpatient CAP declined over time but remained common, irrespective of comorbidity status. Prolonged duration of therapy was common. Antimicrobial stewardship is needed to aid selection according to comorbidity status and to promote shorter courses., (© 2024 John Wiley & Sons Ltd.)

Background: The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients., Methods: This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/μL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course., Results: Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous., Conclusion: Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings., (© 2023 Wiley Periodicals LLC.)

The three-dimensional organization of the genome supports regulated gene expression, recombination, DNA repair, and chromosome segregation during mitosis. Chromosome conformation capture (Hi-C) 1,2 analysis has revealed a complex genomic landscape of internal chromosomal structures in vertebrate cells 3-7 , but the identical sequence of sister chromatids has made it difficult to determine how they topologically interact in replicated chromosomes. Here we describe sister-chromatid-sensitive Hi-C (scsHi-C), which is based on labelling of nascent DNA with 4-thio-thymidine and nucleoside conversion chemistry. Genome-wide conformation maps of human chromosomes reveal that sister-chromatid pairs interact most frequently at the boundaries of topologically associating domains (TADs). Continuous loading of a dynamic cohesin pool separates sister-chromatid pairs inside TADs and is required to focus sister-chromatid contacts at TAD boundaries. We identified a subset of TADs that are overall highly paired and are characterized by facultative heterochromatin and insulated topological domains that form separately within individual sister chromatids. The rich pattern of sister-chromatid topologies and our scsHi-C technology will make it possible to investigate how physical interactions between identical DNA molecules contribute to DNA repair, gene expression, chromosome segregation, and potentially other biological processes.

Temporal information about cellular RNA populations is essential to understand the functional roles of RNA. We have developed the hydrazine/NH 4 Cl/OsO 4 -based conversion of 6-thioguanosine (6sG) into A', where A' constitutes a 6-hydrazino purine derivative. A' retains the Watson-Crick base-pair mode and is efficiently decoded as adenosine in primer extension assays and in RNA sequencing. Because 6sG is applicable to metabolic labeling of freshly synthesized RNA and because the conversion chemistry is fully compatible with the conversion of the frequently used metabolic label 4-thiouridine (4sU) into C, the combination of both modified nucleosides in dual-labeling setups enables high accuracy measurements of RNA decay. This approach, termed TUC-seq DUAL, uses the two modified nucleosides in subsequent pulses and their simultaneous detection, enabling mRNA-lifetime evaluation with unprecedented precision., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Background: There is a growing need for robust antimicrobial stewardship interventions in both ambulatory and solid organ transplant (SOT) populations., Methods: A retrospective quasi-experiment was conducted to evaluate the impact of a pharmacist-driven antimicrobial stewardship intervention targeting cytomegalovirus (CMV) viremia in ambulatory SOT recipients. The intervention consisted of (a) real-time CMV DNA surveillance and result notification conducted by the pharmacist and (b) recommendations for the optimization of drug therapy provided at the time of result notification. The intervention period was compared to a pre-intervention period of usual care. Of 431 adult SOT recipients who had an initial quantifiable CMV viral load in the ambulatory setting, 185 received antiviral induction therapy and were included for analysis., Results: Significantly fewer patients in the intervention period reached a CMV viral load >10 000 IU/mL immediately prior to treatment (10.6% vs 27.3%; P = 0.004), and a significantly greater proportion of patients in the intervention period achieved CMV eradication at 21 days (84.5% vs 71.7%; P = 0.038). Additional differences favoring the intervention period were antiviral initiation within 5 days of the first quantifiable CMV DNA (62.4% vs 55.0%; P = 0.02) and time-to-CMV eradication (25.5 vs 28.9 days; P = 0.003). Although not significant, there were also numerical reductions in CMV-related hospital admissions (11.9% vs 19.0%; P = 0.188) and CMV disease (5.9% vs 12.0%; P = 0.151) during the intervention period, as well as fewer episodes of CMV resistance at 1-year (2.3% vs 4.0%; P = 0.689)., Conclusion: Together, these findings suggest a potential role for pharmacist involvement in CMV surveillance and treatment optimization in ambulatory SOT recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

For this study, we utilized class-I and class-II preQ 1 -sensing riboswitches as model systems to decipher the structure-activity relationship of rationally designed ligand derivatives in vitro and in vivo. We found that synthetic preQ 1 ligands with amino-modified side chains that protrude from the ligand-encapsulating binding pocket, and thereby potentially interact with the phosphate backbone in their protonated form, retain or even increase binding affinity for the riboswitches in vitro. They, however, led to significantly lower riboswitch activities in a reporter system in vivo in E. coli. Importantly, when we substituted the amino- by azido-modified side chains, the cellular activities of the ligands were restored for the class-I conditional gene expression system and even improved for the class-II counterpart. Kinetic analysis of ligand binding in vitro revealed enhanced on-rates for amino-modified derivatives while they were attenuated for azido-modified variants. This shows that neither high affinities nor fast on-rates are necessarily translated into efficient cellular activities. Taken together, our comprehensive study interconnects in vitro kinetics and in vitro thermodynamics of RNA-ligand binding with the ligands' in vivo performance and thereby encourages azido- rather than amino-functionalized design for enhanced cellular activity.

It is unclear if the prophylaxis dose of 300 mg/day is sufficient for achieving serum concentrations targeting the treatment of invasive fungal infections. To evaluate differences between PCZ serum concentrations in patients receiving the DRT vs the OS and in patients receiving higher doses than 300 mg/day of the DRT, a retrospective review was conducted on inpatients who received PCZ for either treatment or prophylaxis. Baseline demographics including comorbid conditions, indication and dose of therapy were collected. Serum trough concentrations were collected at steady state. Fifty-seven patients received PCZ during the study period. A total of 35 levels were collected (DRT n = 18, OS n = 17). Patients receiving the DRT had levels >0.7 mcg/mL 100% of the time compared to 58.8% in those receiving the OS. No significant difference was seen in serum concentrations at 300 mg/day (n = 14) vs 400 mg/day (n = 8) of the DRT (1.55 mcg/mL (1.08-2.50) vs 2.5 mcg/mL (1.85-2.70), P = .19). The DRT leads to more consistent levels in the therapeutic range than the OS. Standard dosing of 300 mg/day with DRT achieves adequate concentrations for prophylaxis and treatment of IFIs, although further data are needed to determine optimal serum concentrations for treatment., (© 2016 Blackwell Verlag GmbH.)

Limited data are available on intraventricular vancomycin dosing for meningitis. This study explored clinical characteristics that correlated with cerebrospinal fluid (CSF) concentrations. Over a nine-year period, 13 patients with 34 CSF vancomycin concentrations were evaluated. CSF output and time from dose correlated with CSF vancomycin concentration. No relationship was seen with regards to CSF protein, white blood cell count or glucose., (Copyright © 2015. Published by Elsevier Ltd.)

Ceftaroline is a broad-spectrum cephalosporin used to treat infections caused by a variety of microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae. However, it is not active against Pseudomonas aeruginosa, Bacteroides fragilis, and carbapenem-resistant Enterobacteriaceae. Its approved indications include community-acquired bacterial pneumonia and bacterial infections of skin and skin structures. It has also been used off-label to treat osteomyelitis, endocarditis, and meningitis caused by ceftaroline-susceptible organisms., (Copyright © 2015 Cleveland Clinic.)

Objectives: Vancomycin and daptomycin are the two most frequently prescribed parenteral antimicrobials for resistant Gram-positive bacterial infections. The purpose of this study was to compare antimicrobial adverse event rates and associated healthcare interventions and healthcare utilization in patients treated with the two antimicrobials., Methods: All patients aged ≥18 years, discharged home from Cleveland Clinic on outpatient parenteral antimicrobial therapy (OPAT) with daptomycin or vancomycin between 1 July 2007 and 30 June 2010 were screened. Logistic regression models were built to calculate propensity to be treated with daptomycin for each patient. Propensity score-matched vancomycin-treated controls were identified for each daptomycin-treated patient. Adverse event, healthcare intervention and healthcare utilization rates during OPAT were compared in the matched cohort using negative binomial regression models., Results: One thousand, two hundred and eighty-eight patients were identified. Three-to-one matching provided the best matching characteristics and identified 119 daptomycin-treated subjects (2518 OPAT days) and 357 vancomycin-treated controls (6649 OPAT days). The mean patient age was 56 years and the mean OPAT duration was 19 days. Antimicrobial adverse event rates for the daptomycin and vancomycin groups were 3.2 and 7.7 per 1000 OPAT days, respectively [relative risk (RR) 0.38; 95% CI 0.15-0.86; P = 0.02]. Antimicrobial intervention rates were 5.6 and 27.1 per 1000 OPAT days, respectively (RR 0.21; 95% CI 0.11-0.36; P < 0.001). Readmissions for worsening infection or treatment complication were not significantly different between daptomycin (5%) and vancomycin (7%)., Conclusions: Patients receiving daptomycin at home have 60% fewer antimicrobial adverse events and require 80% fewer antimicrobial interventions than similar patients receiving vancomycin.

Objective: Evaluate antimicrobial stewardship interventions targeted to reduce highly active antiretroviral therapy (HAART)- or opportunistic infection (OI)-related medication errors and increase error resolution., Design: Retrospective before-after study., Setting: Academic medical center., Patients: Inpatients who were prescribed antiretroviral therapy before the intervention (January 1, 2011, to October 31, 2011) and after the intervention (July 1, 2012, to December 31, 2012). Patients treated with lamivudine or tenofovir monotherapy for hepatitis B were excluded., Methods: Antimicrobial stewardship interventions included education, modification of electronic medication records, collaboration with the infectious diseases (ID) department, and prospective audit and review of HAART and OI regimens by an ID clinical pharmacist., Results: Data for 162 admissions from the preintervention period and 110 admissions from the postintervention period were included. The number of admissions with a medication error was significantly reduced after the intervention (81 [50%] of 162 admissions vs 37 (34%) of 110 admissions; P < .00)1. A total of 124 errors occurred in the preintervention group (mean no. of errors, 1.5 per admission), and 43 errors occurred in the postintervention group (mean no. of errors, 1.2 per admission). The most common error types were major drug interactions and dosing in the preintervention group and renal adjustment and OI-related errors in the postintervention group. A significantly higher error resolution rate was observed in the postintervention group (36% vs 74%; P < .001). After adjustment for potential confounders with logistic regression, admission in the postintervention group was independently associated with fewer medication errors (odds ratio, 0.4 [95% confidence interval, 0.24-0.77]; P = .005). Overall, presence of an ID consultant demonstrated a higher error resolution rate (32% without a consultation vs 68% with a consultation; P = .002)., Conclusions: Multifaceted, multidisciplinary stewardship efforts reduced the rate and increased the overall resolution of HAART-related medication errors.

Background: The recommended treatment for severe Clostridium difficile infection (CDI) is oral vancomycin alone. Combination therapy with metronidazole is only recommended in cases complicated by shock, ileus, or toxic megacolon. However, patients with severe infection are often treated with combination therapy despite a lack of data supporting this practice., Aim: To evaluate differences in outcomes for patients with severe CDI treated with oral vancomycin alone versus combination therapy., Methods: Medical records of 78 patients with severe CDI receiving either oral vancomycin alone or combination therapy for ≥ 72h were retrospectively reviewed. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥ 48h without development of a complication. Other endpoints included cure rates, complication rates, and recurrence rates., Findings: There was no difference in the incidence of clinical cure between monotherapy and combination therapy (57.1% vs 65.1%, P = 0.49). Median time to clinical cure was 7.0 days for the monotherapy group and 8.0 days for combination therapy (P = 0.19). After adjustment for potential confounders, the hazard ratio of the time to clinical cure for combination therapy compared with monotherapy was 0.58 (P = 0.10). There was no difference in recurrence rate or rates of individual complications between groups; however, there was a significantly higher composite complication rate in the combination therapy group., Conclusion: These data suggest that there is no difference in treatment outcomes between monotherapy and combination therapy for severe CDI., (© 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Because a significant proportion of Staphylococcus aureus strains as well as most coagulase-negative staphylococci are resistant to penicillin and semisynthetic beta-lactam drugs, the need for vancomycin and related antibiotics has never been greater. Effective use of vancomycin requires knowledge of dosing parameters and selection of target trough levels appropriate to the specific infection and to the pathogen being treated. For clinicians, it is vital to remain up-to-date with evolving definitions for vancomycin susceptibility, with new interpretations of efficacy, and with information on toxicity.

Any assistance an author receives with writing a scientific article that is not acknowledged in the article is described as ghost-writing. Articles ghost-written by medical writers engaged by pharmaceutical companies who have a vested interest in the content have caused concern after scandals revealed misleading content in some articles. A key criterion of authorship in medical journals is final approval of the article submitted for publication. Authors are responsible for the content of their articles and for acknowledging any assistance they receive. Action taken by some journals and medical writer associations to encourage acknowledgement is an uphill task in the light of disinterest from the pharmaceutical industry and ignorance or similar lack of interest by those who agree to be named authors. However, acknowledgment alone is not sufficient to resolve medical ghost-writing; issues of how the acknowledgement is formulated, permission to acknowledge and access to raw data also need to be tackled.

Objective: Using a Delphi Consultation process, a group of medical writers established by the European Medical Writers Association (EMWA) set out to determine the current thinking on the problems of ghostwriting in medical publications and what should be done about them. In this context, ghostwriting is where a professional medical writer prepares a manuscript on behalf of a named author, but the writer is not listed as an author., Methods: A 4-round Delphi consultation process was conducted via email to generate statements about the main issues in ghostwriting. Participants rated their agreement with the statements on a scale of 0-10., Results and Conclusions: Members of the task force strongly believed that professional medical writers can improve the quality of scientific papers, but that fact is often not recognised outside the medical writing profession. At least in part, this is because of a perception that ghostwritten papers may have been inappropriately influenced by pharmaceutical companies. One theme that emerged strongly from the discussions was transparency. Members thought it very important that the existence of a ghostwriter should always be made clear to the reader. Another strong theme was the importance of defining in detail what practices relating to ghostwriting are ethical, and what practices are not. This definition of ethical ghostwriting should be widely known, and unethical ghostwriting should be strongly condemned. Use of the term 'ghostwriting' itself was questioned. Members of the task force felt that use of a more neutral term should be encouraged. The task force suggested various activities for ensuring that above the objectives could be met, including discussions with other interested parties, such as journal editors and pharmaceutical companies, educating medical writers about ethical practices, further research into ghostwriting, and developing guidelines for ethical medical writing.

Long-term culture of canine marrow cells allows in vitro studies of the hematopoietic system of the dog and characterization of early progenitor cells. Colonies of fresh marrow cells grew equally good in both agar or methylcellulose supplemented with fetal calf serum, while colonies of long-term cultures required agar-based medium containing human serum. Optimum colony growth was obtained when stem cell factor (SCF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) were used as growth stimuli of colony forming units (CFU). Similar results were achieved with several cell culture media. Addition of hydrocortisone to long-term cultures improved clonogenic growth of cultured cells. Addition of 2-mercaptoethanol had no effect. Strong differences were observed in long-term culture with different horse serum lots and the addition of fetal calf serum to long-term culture suppressed CFU growth of cultured cells. Recharging of cultures with fresh marrow cells on day 7 of culture improved CFU growth only in the following week but had little effect on the outcome. Adding SCF to long-term cultures led to differentiation of more primitive cells and destruction of the stromal layer. Investigation of purified and cultured cell populations was possible when preestablished long-term cultures as stromal layers were used. Loss of long-term culture-initiating ability could be demonstrated in this system with lineage negative marrow cells expanded ex vivo with SCF and GM-CSF.