Comparative-Effectiveness of Oral Beta-Lactams and Fluoroquinolones for Stepdown Therapy in Patients with Enterobacterales Bloodstream Infections: A Retrospective Cohort Study.

Background: This study compares treatment failure for patients who received oral beta-lactams (BLs) and fluoroquinolones (FQs) for stepdown treatment of Enterobacterales bloodstream infections (BSIs). Methods: We conducted a single-center, retrospective, age- and sex-matched, cohort study, at a Veterans Affairs (VA) hospital in South Texas. Eligible patients were at least 18 years of age with a monomicrobial BSI treated with a single oral BL or FQ antibiotic. Treatment failure was defined as recurrence or all-cause mortality within 90 days of documented BSI. Bivariate (chi-square, Fisher's Exact, and Wilcoxon Rank Sum) and multivariate (logistic regression) statistical tests were used to compare groups. Results: A total of 130 patients were included in this study, with 65 patients per group. Groups were well balanced with respect to exact age, sex assigned at birth, Caucasian race, source control, intensive care unit admission, and Charlson Comorbidity Index. Importantly, 60% of patients in the BL group had cultures that were resistant to FQs and 71% were prescribed cefpodoxime. Patients in the BL group had higher median (interquartile range [IQR]) Pitt bacteremia scores than those in the FQ group: 2 (1-4) vs. 1 (1-2), p=0.04. Patients in the BL group also had a higher median (IQR) duration of intravenous (IV) antibiotics than those in the FQ group: 5 (3-7) vs. 4 (3-5), p=0.02. Treatment failure was statistically comparable for patients in the BL and FQ groups: 15% vs. 12%, p=0.61. This finding was consistent in a multivariate logistic regression model with group (BL vs. FQ) as the independent variable, treatment failure as the dependent variable, and Pitt bacteremia score and duration of IV antibiotics as covariates (OR: 0.76, 95% CI: 0.27-2.18). One patient in the FQ group experienced Clostridioides difficile infection. Conclusion: This study suggests that BLs may be as effective as FQs for oral stepdown treatment of Enterobacterales BSI without the potential associated risks. Furthermore, in the setting of FQ-resistant Enterobacterales BSI secondary to urinary source, third generation oral cephalosporins (i.e., cefpodoxime) may be reasonable alternatives.

The Risk and Clinical Implications of Antibiotic-Associated Acute Kidney Injury: A Review of the Clinical Data for Agents with Signals from the Food and Drug Administration's Adverse Event Reporting System (FAERS) Database.

Antibiotic-associated acute kidney injury (AA-AKI) is quite common, especially among hospitalized patients; however, little is known about risk factors or mechanisms of why AA-AKI occurs. In this review, the authors have reviewed all available literature prior to 1 June 2022, with a large number of AKI reports. Information regarding risk factors of AA-AKI, mechanisms behind AA-AKI, and treatment/management principles to decrease AA-AKI risk were collected and reviewed. Patients treated in the inpatient setting are at increased risk of AA-AKI due to common risk factors: hypovolemia, concomitant use of other nephrotoxic medications, and exacerbation of comorbid conditions. Clinicians should attempt to correct risk factors for AA-AKI, choose antibiotic therapies with decreased association of AA-AKI to protect their high-risk patients, and narrow, when clinically possible, the use of antibiotics which have decreased incidence of AKI. To treat AKI, it is still recommended to discontinue all offending nephrotoxic agents and to renally adjust all medications according to package insert recommendations to decrease patient harm.

From Start to Finish: Examining Factors Associated With Higher Likelihood of Publication Among Abstracts Presented at an International Infectious Diseases Scientific Meeting.

Background: The landscape of infectious diseases research by interprofessional teams continues to change in both scope and engagement. Limited information exists regarding publication metrics and factors associated with publication of abstracts presented at professional infectious diseases meetings. Methods: This was a retrospective, observational study evaluating abstracts presented at IDWeek in 2017 and 2018. The primary endpoint was the proportion of abstracts that were subsequently published in peer-reviewed journals. Factors associated with publication were evaluated, and a description of publication metrics was reported. Results: Of the 887 abstracts analyzed from the IDWeek meetings, 236 (26.6%) were published. Significantly more abstracts were published if they were presented as a platform presentation versus poster presentation (35% vs 21%, P < .001). Inclusion of a PhD author significantly increased the likelihood of publication (P = .0014). Prospective studies, greater number of authors, and greater number of study subjects were more common among published abstracts. Median time to publication was 10.9 months, and the majority were published in infectious diseases journals, with an overall average impact factor of 7.7 across all journals. Conclusions: Abstracts from IDWeek presented as oral platforms and those including a PhD author were more likely to be published. Large, diverse authorship teams were common among published abstracts. The high quality of resulting manuscripts is evident by the destination journals and their respective impact factors. These data may be used to inform and motivate clinicians and trainees engaging in infectious diseases-related research.

Retrospective Cohort Evaluating the Comparative Effectiveness of Ceftaroline and Daptomycin as First-Line Therapies for Inpatient Treatment of Diabetic Foot Infection in the United States Veterans Health Care System.

BACKGROUND: Both ceftaroline and daptomycin are possible therapeutic options for diabetic foot infection (DFI) and both are active against methicillin-resistant Staphylococcus aureus (MRSA) infection; however, no previous studies have evaluated their effectiveness head-to-head. OBJECTIVE: This study compared hospital readmission and mortality proportions among patients receiving ceftaroline fosamil or daptomycin for DFI. PATIENTS AND METHODS: This was a retrospective cohort, comparative effectiveness study of adults (aged ≥ 18 years) admitted to United States Veterans Health Care System hospitals with a diagnosis code for DFI between 1 October 2010 and 30 September 2014 with an electronic order for ceftaroline or daptomycin as first-line therapy within 14 days of admission. Baseline characteristics were compared using Chi-square, Fisher's exact, and Wilcoxon rank-sum tests. Hospital readmission and patient mortality proportions were compared through multivariable logistic regression models with Hispanic ethnicity, prior hospitalization, dyslipidemia, and Charlson comorbidity score as covariates. RESULTS: In total, 223 patients were included (ceftaroline, n = 71; daptomycin n = 152). At baseline, ceftaroline patients were more likely to be Hispanic (18 vs. 6%, p < 0.01) and have been hospitalized in the past 90 days (34 vs. 19%, p = 0.02). Unadjusted 90-day hospital readmission proportions for ceftaroline versus daptomycin were 34 vs. 49%, and unadjusted 90-day mortality proportions were 1% vs. 8%. In multivariable models, ceftaroline patients were less likely to experience 90-day hospital readmission (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25-0.85) and 90-day mortality (OR 0.14, 95% CI 0.01-0.77). CONCLUSIONS: In this population, ceftaroline was associated with lower 90-day hospital readmission and 90-day mortality compared with daptomycin when used as first-line therapy for DFI.

Comparative Safety Signal Assessment of Hospitalization Associated With the Use of Atypical Antipsychotics.

Background: Persons with symptoms of psychosis receiving treatment with atypical antipsychotics (AAPs) can experience serious adverse events (AEs) requiring admission to the hospital. The comparative likelihood of AE-related hospitalization following the use of all AAPs has not been fully characterized. Therefore, we evaluated the safety signals of hospitalizations associated with the use of AAPs. Methods: We conducted a cross-sectional analysis using the FDA Adverse Event Reporting System (FAERS) database (from January 1, 2004, to December 31, 2021) to examine disproportionality in reporting hospitalizations suspected to be associated with 12 AAPs (aripiprazole, asenapine, brexpiprazole, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, and pimavanserin, quetiapine, risperidone, and ziprasidone). Hospitalization in the FAERs database is an outcome that is recorded as a result of an AE occurring at any drug dose. We estimated reporting odds ratios (RORs) by comparing the odds of hospitalization occurring with a particular AAP to the odds of its occurrence with other drugs. In addition, we considered the presence of a significant safety signal when the lower limit of the 95% confidence interval (CI) of the ROR is >1. Results: A total of 204,287 cases of hospitalizations were reported to the FDA for individuals treated with AAPs. There were significant safety signals of hospitalization associated with using clozapine (ROR, 2.88; 95% CI, 2.84-2.92), olanzapine (ROR, 2.61; 95% CI, 2.57-2.64), quetiapine (ROR, 1.87; 95% CI, 1.85-1.89), risperidone (ROR, 1.41; 95% CI, 1.39-1.43), aripiprazole (ROR, 1.34; 95% CI, 1.32-1.35), and ziprasidone (ROR, 1.14; 95% CI, 1.10-1.18). However, no hospitalization-related safety signals were observed with the use of paliperidone, pimavanserin, iloperidone, asenapine, lurasidone, and brexpiprazole. The ROR estimates were numerically higher among older adults than younger adults. Conclusions: This cross-sectional assessment of data from FAERs (2004-2021) suggested that users of clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone were more likely to report being hospitalized than users of other AAPs. Given that the FAERs database only contains spontaneous reports of AEs experienced by persons exposed to a drug but without information on exposed persons who did not have an event, a cohort study comparing hospitalizations among new users of individual AAPs against each other is needed to delineate these safety signals further.

Delirium Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime are known to be associated with delirium. Other antibiotics may also lead to delirium, but no study has systemically compared delirium associations for many available antibiotics. OBJECTIVE: The objective of this study was to evaluate the association between delirium and antibiotics using the FDA Adverse Event Reporting System (FAERS). METHODS: FAERS reports from January 1, 2004 to December 31, 2018 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (95% CI) for the association between antibiotics and delirium were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was greater than 1.0. RESULTS: A total of 10,015,622 reports (including 16,982 delirium reports) were considered, after inclusion criteria were applied. Statistically significant delirium RORs (95% CI) for antibiotics were: ertapenem 21.07 (16.38-27.10), cefepime 9.8 (6.37-15.09), imipenem 9.68 (6.75-13.89), ofloxacin 7.73 (4.00-14.92), ceftazidime 6.09 (2.73-13.62), clarithromycin 5.34 (4.37-6.53), cefaclor 5.32 (1.71-16.58), ampicillin-sulbactam 4.49 (2.13-9.45), levofloxacin 4.47 (3.88-5.16), linezolid 4.33 (3.28-5.72), moxifloxacin 3.51 (2.81-4.38), azithromycin 2.76 (2.09-3.64), piperacillin-tazobactam 2.41 (1.47-3.93), trimethoprim-sulfamethoxazole 2.36 (1.61-3.47), metronidazole 1.85 (1.31-2.60), ciprofloxacin 1.83 (1.44-2.33), and cefuroxime 1.81 (1.03-3.20). CONCLUSION: This study found statistically significant increased risk of reporting delirium with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin-sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime.

In vitro activity of non-antibiotic drugs against Staphylococcus aureus clinical strains.

OBJECTIVES: We hypothesised that one or more of the non-antibiotic candidates selected for this study would demonstrate antibiotic activity against Staphylococcus aureus. METHODS: We determined minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for non-antibiotic drugs (amlodipine, azelastine, ebselen and sertraline) against five clinical S. aureus isolates and one quality control strain using the Microplate Alamar Blue Assay (MABA). Our research group selected clinical isolates obtained from nasal and wound swab cultures of patients with skin and soft-tissue infections who were seen at primary care clinics in the South Texas Ambulatory Research Network (STARNet). RESULTS: Three of the non-antibiotic drugs had identical MICs for all isolates: amlodipine, 64 µg/mL; azelastine, 200 µg/mL; and sertraline, 20 µg/mL. MICs for ebselen were 0.25 µg/mL (SA-29213, A1019 and J1019), 0.5 µg/mL (A32 and B60) and 1 µg/mL (B72). MBCs for amlodipine, azelastine and sertraline were within one dilution of their MICs, indicating bactericidal activity for all test isolates. Ebselen MBCs were one to two dilutions higher in most isolates, also indicating bactericidal activity for all test isolates. CONCLUSION: In summary, all four non-antibiotics demonstrated in vitro activity to varying degrees against S. aureus clinical isolates. Ebselen was the most potent of the four non-antibiotics tested.

Brief Overview of Approaches and Challenges in New Antibiotic Development: A Focus On Drug Repurposing.

Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non-antibiotic indications may possess antibiotic properties, and therefore may have repurposing potential, either alone or in combination with an antibiotic. They might also serve as "antibiotic adjuvants" to enhance the activity of certain antibiotics.

Outcomes in chronic lymphocytic leukemia patients on novel agents in the US Veterans Health Administration System.

The US veteran population has a high proportion of chronic lymphocytic leukemia (CLL) risk factors. Using the Veterans Health Administration (VHA) population, we conducted a retrospective chart review of 1205 CLL patients who initiated treatment with a novel oral agent. For 1L ibrutinib, 33% (n = 107) discontinued therapy during the study, of which 64% discontinued due to adverse events (AEs). For relapsed/refractory (R/R) ibrutinib, 35% (n = 262) discontinued therapy, of which 63% discontinued due to AEs. For R/R venetoclax, 31% (n = 27) discontinued therapy, of which 41% were due to AEs. For idelalisib, 84% (n = 41) discontinued therapy, of which 54% were due to AEs. This real-world study suggests that AEs play an important role in dose reductions and discontinuations; however, physician inexperience in using these drugs when they were first introduced could be part of what is leading to these negative outcomes.

Correction to: Comparing Acute Kidney Injury Reports Among Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

In the original publication of the article, the second sentence in the figure 2 caption should read as below.

Comparing Acute Kidney Injury Reports Among Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: A study using the US FDA Adverse Event Reporting System (FAERS) found significant acute kidney injury (AKI) reporting associations with vancomycin, fluoroquinolones, penicillin combinations, and trimethoprim-sulfamethoxazole. Other antibiotics may also lead to AKI, but no study has systemically compared AKI reporting associations for many available antibiotics. OBJECTIVE: The objective of this study was to evaluate the reporting associations between AKI and many available antibiotics using FAERS. METHODS: FAERS reports from 1 January 2015 to 31 December 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify AKI cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations between antibiotics and AKI were calculated. A reporting association was considered statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS: A total of 2,042,801 reports (including 20,138 AKI reports) were considered. Colistin had the greatest proportion of AKI reports, representing 25% of all colistin reports. AKI RORs (95% CI) for antibiotics were, in descending order: colistin 33.10 (21.24-51.56), aminoglycosides 17.41 (14.49-20.90), vancomycin 15.28 (13.82-16.90), trimethoprim-sulfamethoxazole 13.72 (11.94-15.76), penicillin combinations 7.95 (7.09-8.91), clindamycin 6.46 (5.18-8.04), cephalosporins 6.07 (5.23-7.05), daptomycin 6.07 (4.61-7.99), macrolides 3.60 (3.04-4.26), linezolid 3.48 (2.54-4.77), carbapenems 3.31 (2.58-4.25), metronidazole 2.55 (1.94-3.36), tetracyclines 1.73 (1.26-2.36), and fluoroquinolones 1.71 (1.49-1.97). CONCLUSION: This study found 14 classes of antibiotics having significant reporting associations with AKI. Among the antibiotics evaluated in this study, colistin had the highest AKI ROR and moxifloxacin had the lowest.

Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS).

INTRODUCTION: Fluoroquinolones, clarithromycin, linezolid, tigecycline, cefditoren, doxycycline, and trimethoprim-sulfamethoxazole are known to be associated with hypoglycemia, but few studies have considered concomitant glucose-lowering medications. OBJECTIVE: The objective of this study was to evaluate the association between hypoglycemia and antibiotics using the US Food and Drug Administration Adverse Event Reporting System (FAERS), while accounting for concomitant glucose-lowering medications including sulfonylureas and meglitinides. METHODS: FAERS reports from 1 January 2004 to 31 December 2017 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the association between antibiotics and hypoglycemia were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS: A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93-22.03), tigecycline 3.32 (1.95-5.65), clarithromycin 2.41 (1.89-3.08), ertapenem 2.07 (1.14-3.75), moxifloxacin 2.06 (1.59-2.65), levofloxacin 1.66 (1.37-2.01), and linezolid 1.54 (1.07-2.20). After adjusting for concomitant sulfonylureas and meglitinides, the following antibiotics were still significantly associated with hypoglycemia: cefditoren 14.25 (9.08-22.39), tigecycline 3.34 (1.96-5.68), ertapenem 1.93 (1.03-3.60), and clarithromycin 1.56 (1.15-2.11). CONCLUSION: In many patients, antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if not taken with sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported.

Rhabdomyolysis Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

Introduction: Daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir are known to be associated with rhabdomyolysis. Other antibiotics may also lead to rhabdomyolysis, but no study has systemically compared rhabdomyolysis associations for many available antibiotics. Objectives: The objective of this study was to evaluate the association between rhabdomyolysis and many available antibiotics using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2004 to December 31, 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify rhabdomyolysis cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and rhabdomyolysis were calculated. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1.0. Results: A total of 2,334,959 reports (including 7,685 rhabdomyolysis reports) were considered, after inclusion criteria were applied. Daptomycin had the greatest proportion of rhabdomyolysis reports, representing 5.5% of all daptomycin reports. Statistically significant rhabdomyolysis RORs (95% CI) for antibiotics were (in descending order): daptomycin 17.94 (14.08-22.85), cefditoren 8.61 (3.54-20.94), cefaclor 7.16 (2.28-22.49), erythromycin 5.93 (3.17-11.10), norfloxacin 4.50 (1.44-14.07), clarithromycin 3.95 (2.77-5.64), meropenem 3.19 (1.51-6.72), azithromycin 2.94 (1.96-4.39), cefdinir 2.84 (1.06-7.62), piperacillin-tazobactam 2.61 (1.48-4.61), trimethoprim-sulfamethoxazole 2.53 (1.52-4.21), linezolid 2.49 (1.47-4.21), ciprofloxacin 2.10 (1.51-2.92). Conclusions: This study confirms prior evidence for rhabdomyolysis associations with daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir. This study also identifies previously unknown rhabdomyolysis associations with meropenem, cefditoren, cefaclor, and piperacillin-tazobactam.

Comparative-effectiveness of ceftaroline and daptomycin as first-line MRSA therapy for patients with sepsis admitted to hospitals in the United States Veterans Health Care System.

Objectives: This study compared hospital readmission and mortality for patients with sepsis who received ceftaroline or daptomycin as first-line MRSA therapy.Methods: This retrospective comparative-effectiveness study included adults ≥18 years old hospitalized in the United States Veterans Health Care System with sepsis between 10/1/2010-9/30/2014, who received ceftaroline or daptomycin within 14 days of hospital admission as the first antibiotic effective against methicillin resistant Staphylococcus aureus (MRSA). Patients with pneumonia, and those who received both study drugs, were excluded. Baseline characteristics were compared using Chi-square, Fischer's exact, Student's t, and Wilcoxon Rank Sum tests. Patient outcomes were compared with multivariable logistic regression models.Results: 409 patients were included (ceftaroline = 67, daptomycin = 342). Ceftaroline patients were older, less likely to be Black, more likely to have diabetes with complications, and had higher Charlson comorbidity scores. Median (interquartile range) time from admission to drug initiation was 1 (0-1) day for ceftaroline and 1 (1-3) day for daptomycin (p = 0.01). Unadjusted hospital readmission rates for ceftaroline and daptomycin, respectively, were: 30-day (25%/37%, p = 0.06), 60-day (27%/44%, p = 0.008), and 90-day (28%/46%, p = 0.01). Unadjusted mortality rates were: in-hospital (7%/12%, p = 0.4), 30-day (3%/9%, p = 0.1), 60-day (6%/12%, p = 0.2), and 90-day (7%/15%, p = 0.1). In multivariable models with all divergent baseline characteristics included as covariates, patients treated with ceftaroline were less likely to experience (OR, 95% CI): 30/60/90-day hospital readmission (0.54, 0.29-0.98; 0.42, 0.23-0.76; 0.42, 0.23-0.75) and 30/60/90-day mortality (0.23, 0.04-0.82; 0.34, 0.10-0.93; 0.34, 0.11-0.86).Conclusion: In patients with sepsis, ceftaroline was associated with fewer hospital readmissions and lower mortality as compared to daptomycin. Prospective investigations in larger, more generalized cohorts are needed to examine outcomes with specific MRSA therapies.

Torsades de pointes and QT prolongation Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System.

Introduction: Macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone are known to be associated with Torsades de pointes/QT prolongation (TdP/QTP). Other antibiotics may also lead to TdP/QTP, but no study has systemically compared TdP/QTP associations for many available antibiotics. Objectives: The objective of this study was to evaluate the association between TdP/QTP and many available antibiotics using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify TdP/QTP cases. We calculated the Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and TdP/QTP. An association was considered to be statistically significant when the lower limit of the 95%CI was greater than 1.0. Results: A total of 2,042,801 reports (including 3,960 TdP/QTP reports) were considered, after inclusion criteria were applied. Macrolides had the greatest proportion of TdP/QTP reports. Of the 4,092 reports associated with macrolides, 108 reports (2.6%) were associated with TdP/QTP. Significant TdP/QTP RORs (95%CI) for the antibiotics were (in descending order): macrolides 14.32 (11.80-17.38), linezolid 12.41 (8.52-18.08), amikacin 11.80 (5.57-24.97), imipenem-cilastatin 6.61 (3.13-13.94), fluoroquinolones 5.68 (4.78-6.76), penicillin combinations 3.42 (2.35-4.96), and ceftriaxone 2.55 (1.41-4.62). Conclusion: This study confirms prior evidence for TdP/QTP associations with macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone. This study also identifies a new association between amikacin and TdP/QTP.

Clostridium difficile Infection Risk with Important Antibiotic Classes: An Analysis of the FDA Adverse Event Reporting System.

Introduction: Antibiotic use is an important risk factor for Clostridium difficile infection (CDI). Prior meta-analyses have identified antibiotics and antibiotic classes that pose the greatest risk for CDI; however, CDI epidemiology is constantly changing and contemporary analyses are needed. Objectives: The objective of this study was to evaluate the association between CDI and important antibiotic classes in recent years using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CDI cases. We computed the Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and CDI. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1. Results: A total of 2,042,801 reports (including 5,187 CDI reports) were considered, after inclusion criteria were applied. Lincosamides (e.g., clindamycin) had the greatest proportion of CDI reports, representing 10.4% of all lincosamide reports. CDI RORs (95%CI) for the antibiotic classes were (in descending order): lincosamides 46.95 (39.49-55.82), monobactams 29.97 (14.60-61.54), penicillin combinations 20.05 (17.39-23.12), carbapenems 19.16 (15.52-23.67), cephalosporins/ monobactams/carbapenems 17.28 (14.95-19.97), cephalosporins 15.33 (12.60-18.65), tetracyclines 7.54 (5.42-10.50), macrolides 5.80 (4.48-7.51), fluoroquinolones 4.94 (4.20-5.81), and trimethoprim-sulfonamides 3.32 (2.03-5.43). Conclusion: All antibiotic classes included in the study were significantly associated with CDI. Lincosamides (e.g., clindamycin) had the highest CDI ROR among the antibiotics evaluated in this study.

Comparison of Quetiapine Abuse and Misuse Reports to the FDA Adverse Event Reporting System With Other Second-Generation Antipsychotics.

BACKGROUND: Second-generation antipsychotics (SGAs) are assumed to have little abuse potential. However, reports of quetiapine abuse have emerged as prescribing has increased in recent years. The US Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) provides postmarketing information regarding adverse drug events (ADEs). This is the first study to analyze quetiapine abuse-related ADEs reported to FAERS to determine whether a disproportionate rate of such events have been reported when compared with other commonly used SGAs. METHODS: A cross-sectional analysis of FAERS data from January 1, 2015, to December 31, 2017, was performed. The total number of all-cause and abuse-related ADEs reported to FAERS regarding quetiapine, olanzapine, aripiprazole, and risperidone were identified, along with demographic and mortality data. The proportional reporting ratio (PRR) was calculated to assess disproportionate reporting of abuse-related adverse drug reactions between quetiapine and each of three alternative SGA medications. RESULTS: Abuse-related ADEs represented 11% (3144/27 962) of total ADEs reported for quetiapine, 8% for olanzapine (1548/19 228), 5% (1380/29 699) for aripiprazole, and 3% (1168/45 518) for risperidone. The PRRs (95% confidence interval) for quetiapine versus olanzapine, aripiprazole, and risperidone were 1.40 (1.32-1.48), 2.42 (2.28-2.57), and 4.38 (4.10-4.68), respectively, indicating that abuse-related events were significantly more likely to be reported with quetiapine than each comparator drug. In addition, more deaths were reported among the abuse-related events regarding quetiapine (673) than olanzapine (200), aripiprazole (88), and risperidone (143). CONCLUSION: This study corroborates recent evidence indicating that quetiapine might possess a significantly higher abuse potential than other commonly used SGAs. Although prospective studies are needed to better understand the abuse potential of quetiapine, increased vigilance in monitoring for signs of substance abuse might be warranted when prescribing quetiapine.

Antipseudomonal monotherapy or combination therapy for older adults with community-onset pneumonia and multidrug-resistant risk factors: a retrospective cohort study.

BACKGROUND: Infectious Diseases Society of America guidelines recommend empiric antipseudomonal combination therapy when Pseudomonas is suspected. However, combination antipseudomonal therapy is controversial. This study compares all-cause 30-day mortality in older patients who received antipseudomonal monotherapy (PMT) or antipseudomonal combination therapy (PCT) for the treatment of community-onset pneumonia. METHODS: This population-based, retrospective cohort study used data from over 150 Veterans Health Administration hospitals. Patients were classified as being at low, medium, or high risk of drug-resistant pathogens. In total, 31,027 patients were assigned to PCT or PMT treatment arms based on antibiotics received in the first 48 hours of hospital admission. RESULTS: The unadjusted 30-day mortality difference between PCT and PMT was most pronounced in the low-risk group (18% vs 8%), followed by the medium-risk group (24% vs 18%) and then the high-risk group (39% vs 33%). PCT was associated with higher 30-day mortality than PMT overall (adjusted odds ratio [aOR], 1.54; 95% confidence interval [CI], 1.43-1.66) in all 3 risk groups: low (aOR, 1.69; 95% CI, 1.50-1.89), medium (aOR, 1.30; 95% CI, 1.14-1.48), and high (aOR, 1.21; 95% CI, 1.04-1.40). CONCLUSIONS: Older adults who received combination antipseudomonal therapy for community-onset pneumonia fared worse than those who received monotherapy. Empiric combination antipseudomonal therapy should not be routinely offered to all patients suspected of having pseudomonal pneumonia.

Ubiquitin Receptor RPN13 Mediates the Inhibitory Interaction of Diphenyldihaloketones CLEFMA and EF24 With the 26S Proteasome.

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome. We employed standard fluorogenic peptide-based proteasome activity assay for trypsin-like, chymotrypsin-like, and caspase-like activities of human purified 26S proteasome in cell-free conditions. GFPu-1 and HUVEC cells were used as proteasome reporter cells. Direct binding studies used purified 19S, 20S, 26S, and recombinant RPN13-Pru for interaction with biotinylated analogs of CLEFMA and EF24. The reaction mixtures were subjected to horizontal gel electrophoresis, streptavidin-blotting, pull-down assays, and immunoblotting. The identity of the interacting protein was determined by 2D gel electrophoresis and LC-MS/MS. Drug affinity responsive target stability technique was utilized to examine if CLEFMA binding confers protection to RPN13 against thermolysin-catalyzed proteolysis. We found that trypsin-and chymotrypsin-like activities of the 26S proteasome were reduced significantly by both compounds. The compounds also reduced the proteolytic activity in GFPu-1 and HUVEC cells, resulting in accumulation of ubiquitinated proteins without affecting the autophagy process. From direct binding assays a 43 kDa protein in the 26S proteasome was found to be the interacting partner. This protein was identified by tandem mass spectroscopy as regulatory particle subunit 13 (RPN13), a ubiquitin receptor in the 19S regulatory particle. Furthermore, binding of CLEFMA to RPN13 did not protect latter from thermolysin-mediated proteolysis. Together, this study showed diphenyldihaloketones as potential proteasome inhibitors for treatment of diseases with perturbed proteasome function. The results also unraveled RPN13 as a unique target of CLEFMA and EF24. As a result, these compounds inhibit both trypsin-like and chymotrypsin-like proteasome activities.

Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24.

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits ß type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.