Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals : A Retrospective Cohort Study.

BACKGROUND: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. OBJECTIVE: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). DESIGN: Retrospective cohort. SETTING: 619 U.S. hospitals. PARTICIPANTS: Adult inpatients. MEASUREMENTS: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. RESULTS: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. LIMITATION: Residual confounding. CONCLUSION: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration; NIH Intramural Research Program.

Patient factors associated with oral generic olanzapine initiation and substitution among Medicaid beneficiaries: a new user cohort study.

OBJECTIVE: Generic drugs typically are less expensive than branded products; however, several factors can limit generic drug utilization. This study assesses the associations of patient factors with generic olanzapine initiation and substitution. METHODS: A retrospective new user cohort study was conducted using the 2011-2012 Medicaid administrative claims data. Beneficiaries continuously enrolled during the 6 month washout period prior to their initial oral brand or generic olanzapine prescription were included and followed up to 12 months. Among brand olanzapine new users, time to generic substitution and competing risk outcomes was estimated using the Fine-Gray cumulative incidence function. Patient demographic and health service utilization factors were assessed in the multivariate cause-specific hazards model. RESULTS: Among olanzapine new users, 70.7% patients initiated generic treatment. Beneficiaries aged ≥21, and living in the Midwest and West regions were more likely to initiate generic olanzapine. Among brand new users, 28.2% switched to generic olanzapine, 23.6% switched to an alternative atypical antipsychotic treatment and 38.0% discontinued within 12 months. Beneficiaries who resided in urban areas (adjusted hazard ratio [AHR) = 0.53, 95% CI = 0.37-0.75) and had prior hospitalizations (AHR = 0.85, 95% CI = 0.75-0.96) had lower rates of generic substitution, whereas those with emergency department (ED) visits (AHR = 1.06, 95% CI = 1.02-1.10) had a higher rate of generic substitution. In addition, beneficiaries in different age subgroups also had different rates of generic substitution in different regions. CONCLUSION: Medicaid beneficiaries' age, geographic region, prior hospitalization and ED utilization were associated with generic olanzapine initiation and substitution. Tailored educational outreach targeting these patient subgroups might improve generic olanzapine utilization.

Oral generic tacrolimus initiation and substitution in the Medicaid population: a new user cohort study.

OBJECTIVE: Although existing studies have compared clinical efficacy and pharmacokinetics of generic with brand tacrolimus, little is known about generic tacrolimus utilization patterns or factors predicting generic substitution. This study examines associations between patient-level factors and generic tacrolimus initiation or substitution among new users of oral generic or brand-name tacrolimus. METHODS: This new user retrospective cohort study identified 374 beneficiaries who initiated generic or brand tacrolimus treatment, using 100% Medicaid administrative claims data from 11 states in 2011-2012. Outcomes were generic tacrolimus initiation and substitution within 12 months of treatment initiation. Multivariable logistic regression and Cox proportional hazards models were used to identify factors associated with generic tacrolimus initiation and substitution. RESULTS: Two-thirds of oral tacrolimus new users initiated generic tacrolimus. Patients who were older age and black were significantly more likely to initiate generic tacrolimus (adjusted odds ratio [AOR] = 1.02, 95% confidence interval [CI] = 1.001-1.03; AOR = 2.54, 95% CI = 1.40-4.62; respectively). Patients with more concomitant prescriptions, more comorbidities, or higher initial daily dosage had significantly lower likelihoods of initiating generic tacrolimus (AOR = 0.93, 95% CI = 0.87-0.99; AOR = 0.87, 95% CI = 0.77-0.99; AOR = 0.96, 95% CI = 0.93-0.993). Among brand tacrolimus new users, 23.6% substituted with generics within 12 months, and an addition of prior hospitalization or unit of initial daily dosage increment was associated with 35% (subdistribution hazard ratio [SHR] = 1.35, 95% CI = 1.02-1.76) or 2% (SHR = 1.02, 95% CI = 1.00-1.04) increase in likelihood of generic substitution, respectively. CONCLUSIONS: Understanding associations between patient-level factors with generic tacrolimus initiation and substitution could help practitioners and policymakers monitor treatment effect and facilitate generic tacrolimus utilization.

Safety of dietary supplements use among patients with cancer: A systematic review.

Dietary supplements (DS) are commonly taken by patients with cancer, but safety of DS use remains unclear. A systematic literature search was conducted using PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts and Alt HealthWatch databases from inception through October 12, 2018. Included studies were limited to clinical trials including patients with cancer, DS products as interventions, evaluation of safety endpoints of DS use, and published in English. Sixty-five studies were included to evaluate 20 different DS among patients with 12 types of cancer. Botanical DS (n = 13), vitamins (n = 8), and probiotics/synbiotics (n = 7) were the top 3 types of DS evaluated in these trials. Majority of studied DS appeared safe. Among 19 trials including patients with cancer undergoing chemotherapy, most (n = 18) of studied DS (e.g., vitamins, botanical, omega-3 fatty acid) were found to be safe. Evaluation of DS use and its safety should be regularly incorporated in clinical trials among patients with cancer.

Generic escitalopram initiation and substitution among Medicare beneficiaries: A new user cohort study.

OBJECTIVES: To examine patterns of generic escitalopram initiation and substitution among Medicare beneficiaries. METHODS: This retrospective new user cohort used a 5% random sample of 2013-2015 Medicare administrative claims data. Fee-for-service Medicare beneficiaries continuously enrolled in Parts A, B, and D during a 6-month washout period prior to their initial generic or brand oral escitalopram prescriptions were included (n = 12,351). The primary outcomes were generic escitalopram treatment initiation, and among brand escitalopram initiators, generic substitution within 12 months. Patient demographics, health service utilization, and prescription level factors were measured and assessed. RESULTS: Among all escitalopram initiators, about 88.2% Medicare beneficiaries initiated generic escitalopram. Beneficiaries who were younger age, male, residing in non-Northeast regions or urban area, in the Part D plan deductible benefit phase, and filling prescriptions at community/retail pharmacies were more likely to initiate generic treatment. Among brand escitalopram initiators (n = 1,464), about 20.7% switched to generic escitalopram, 31.2% switched to another alternative antidepressant, 25.1% discontinued treatment, and 8.7% were lost to follow up or passed away within 12 months after brand initiation. Factors associated with generic escitalopram substitution included region (Midwest vs. Northeast, adjusted hazard ratio (HR) = 1.46, 95% CI = 1.04-2.05), pre-index hospitalization (HR = 1.31; 95% CI = 1.16-1.48) and lower escitalopram average daily dosage (HR = 0.97; 95% CI = 0.95-0.99). CONCLUSIONS: In 2013-2015, almost 90% Medicare beneficiaries initiated generic escitalopram treatment. Among brand escitalopram initiators, about 1 in 5 patients switched to generic escitalopram within 1 year, as compared to 1 in 4 or 1 in 3 who discontinued current or switched to alternative treatment, respectively. Medicare beneficiary's geographic region was independently associated with generic escitalopram initiation and substitution. Findings from this study not only provide up-to-date evidence in generic escitalopram use patterns among Medicare population, but also can guide educational and practice interventions to further increase generic escitalopram use.

Generic levothyroxine initiation and substitution among Medicare and Medicaid populations: a new user cohort study.

PURPOSE: Generic levothyroxine has been approved and available since 2004 but its substitution remains controversial. Therefore, the objective was to examine patterns of and identify factors associated with initiation and substitution of generic levothyroxine treatment. METHODS: This was a retrospective observational study, including new users of brand and generic levothyroxine in 2013-2015 Medicare (n = 15,877) or 2011-2012 Medicaid (n = 9390) administrative claim databases. The primary outcomes included (1) generic levothyroxine initiation, and (2) among brand-new users, generic levothyroxine substitution in 12 months. The factors associated with generic levothyroxine initiation and substitution were measured. RESULTS: Among all levothyroxine new users, Medicare beneficiaries had a higher proportion of generic levothyroxine initiation than Medicaid beneficiaries (66.40% vs. 44.04%, respectively). Medicare beneficiaries' demographic factors, and health service utilizations were associated with generic levothyroxine initiation. Medicaid beneficiaries who were male and residing in the northeast region and rural areas were more likely to initiate generic levothyroxine. Among brand levothyroxine new users, the generic substitution rate was higher in the Medicare than the Medicaid cohort (18.26 vs. 3.88%). Medicare brand levothyroxine new users' demographic factors and health service utilizations were associated with generic levothyroxine substitution. Medicaid brand levothyroxine new users who were residing in the northeast region, with more prior hospitalization, and initiating a lower dosage of brand levothyroxine, had higher rates of generic substitution. CONCLUSION: Patient demographic factors and health service utilizations are associated with generic levothyroxine initiation and substitution. Educational outreach programs targeted to increase generic levothyroxine use and prescription savings should be tailored based on different patient populations.

National trends in prescription proton pump inhibitor use and expenditure in the United States in 2002-2017.

OBJECTIVES: In the United States, proton pump inhibitors (PPIs) are one of the most commonly prescribed classes of drugs, but contemporary data on national-level utilization patterns for PPI use are limited. This study examined the trends in prescription PPI use and expenditures, overall and by patient subgroups, and identified predictors of PPI use. METHODS: Prescription PPI use was identified from the 2002-2017 Medical Expenditure Panel Survey data using the brand and generic names. Trends in PPI use were examined overall and by patients' sociodemographic characteristics and disease status. Trends in brand and generic PPI users and total and average PPI expenditures were also examined. A multivariable model was used to identify patient factors associated with PPI use. RESULTS: The overall proportion of PPI users increased from 5.70% in 2002-2003 to 6.73% in 2016-2017 (P value = 0.011). Increased trends in PPI use were observed among U.S. adults aged 65 years and older, both males and females, non-Hispanic whites, non-Hispanic blacks, Hispanics, Asians, in all 4 geographic regions, with public health insurance, and those who were obese (all P value < 0.05). Whereas PPI use increased significantly, the average PPI expenditure per patient decreased significantly. Multivariable results found that participants who were aged 25 years or older, were female, were non-Hispanic whites, resided in the Northeast, had higher incomes, had public or private health insurance, were obese, were married had a higher likelihood of using PPIs. CONCLUSION: Increased PPI use was observed among most of the patient subgroups. Understanding the utilization patterns of PPIs could help practitioners identify potential treatment disparities and monitor the safety of PPI use.

Impact of U.S. federal and state generic drug policies on drug use, spending, and patient outcomes: A systematic review.

BACKGROUND: Prescription drugs contribute to increased healthcare expenditures in the United States (U.S.). Use of generic drugs has been recognized as an effective tool to control rising prescription drug costs. This study aimed to evaluate the impact of U.S. federal and state generic drug policies on drug use, spending, and patient outcomes. METHODS: A systematic search was performed in June 2017, using PubMed, Web of Science, PsycINFO, and Business Source Premier. Search was limited to published articles in English language, including human subjects in the U.S., and with at least one outcome measure related to health service utilization, spending, or patient outcomes. RESULTS: Thirty-four studies constituting seven key policy domains were included. Medicaid/Medicare Prior Authorization (PA) policies (n = 4) led to increased generic use, reduced patient and payer's spending on prescriptions without causing deterioration in patient's health-related quality of life. Medicare prescription plan's generic drug benefits (n = 4) had impact on increased generic use and generated savings, but the limited access to branded drugs may increase medication use gaps and risks of hospitalizations. State generic substitution laws (n = 3) caused increased generic use and cost savings for both consumers and states. Medicare/Medicaid coverage cap policies (n = 3) were associated with increased patient's out-of-pocket spending (OOP) and reduced prescription spending for payers. Policies lowering cost-sharing (n = 7) were associated with increased patient's medication use and adherence, but the impact varied by therapeutic classes. Existing evidence evaluating Medicare Part D (n = 12) suggested decreased prescription spending for beneficiaries and Medicare. Generic gap coverage reduced patient's OOP and Medicare spending. Finally, early evidence showed reduced consumers' OOP prescription spending after the ACA (n = 2). CONCLUSIONS: Federal and state policies regarding generic drugs have resulted in reduced spending for consumers and payers. However, the overall impact on patient outcomes remains unclear.

Adverse event reporting patterns of concomitant botanical dietary supplements with CYP3A4 interactive & CYP3A4 non-interactive anticancer drugs in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: To examine the adverse event (AE) reporting patterns for concomitant Botanical Dietary Supplements (BDS) and anticancer drugs. RESEARCH DESIGN AND METHODS: Using the 2004-2015 U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, AEs involving commonly used BDS and anticancer drugs (categorized into CYP3A4 interactive and CYP3A4 non-interactive) were examined. Disproportionality analyses using reporting odds ratios (RORs) assessed the relative reporting rates of 1) serious AEs (i.e., mortality and morbidity) with concomitant use of BDS (overall and by type) and anticancer drugs compared to anticancer drugs only; and 2) AEs by specific System Organ Classes (SOCs). RESULTS: A total of 3,264 AEs were reported involving concomitant BDS and CYP3A4 interactives, and 3,885 involving concomitant BDS and non-interactive anticancer drugs. ROR of serious AEs with concomitant all BDS and anticancer drugs compared to anticancer drugs alone showed a potential protective signal (ROR = 0.65, 95% CI = 0.62,0.68), but ROR for açaí and non-interactive anticancer drugs indicated potential risk (ROR = 1.70, 95% CI = 1.01,2.86). Heterogeneity of reporting patterns of AEs related to certain SOCs was observed for use of BDS along with anticancer drugs. CONCLUSION: This study identified potential protective and risk signals for AEs with concomitant use of BDS and anticancer drugs.

The Association Between Patient Sociodemographic Characteristics and Generic Drug Use: A Systematic Review and Meta-analysis.

BACKGROUND: Generic drugs are bioequivalent and cost-effective alternatives to brand drugs. In 2014, $254 billion was saved because of the use of generic drugs in the United States. OBJECTIVE: To critically assess evidence on the association between patient characteristics and generic drug use in order to inform the development of educational outreach for improving generic drug use among patients. METHODS: We systematically searched the literature between January 2005 and December 2016 using PubMed, Web of Science, Ovid MEDLINE, Google Scholar, and EBSCO IPA-MEDLINE for potentially relevant studies. The titles and abstracts of identified articles were assessed independently by 2 reviewers. Titles and abstracts that were not written in English, were published before 2005, were not empirical, did not contain sociodemographic data, or were not policy or methodologically relevant to generic drug use were excluded. Data were pooled in a meta-analysis using the RStudio software to assess the association of patient-related factors with generic drug use. RESULTS: Our searches resulted in 11 articles on patient-level factors, and 6 of these articles had sufficient information to conduct meta-analyses in the domains of patients' gender, age, race/ethnicity, and income. Quantitative analysis indicated that no differences in generic drug use existed between subgroups of patients defined by gender, age, or race/ethnicity. However, patients with lower income (i.e., < 200% federal poverty level [FPL]) were more likely to use generic drugs than those with higher income (≥ 200% FPL; pooled OR = 1.32, 95% CI = 1.15-1.52). Heterogeneity was high (I 2 > 75%) for all analyses but income. CONCLUSIONS: Patients with lower income were more likely to use generic drugs, whereas evidence was heterogeneous regarding an association between generic drug use and gender, age, or race/ethnicity. Educational outreach targeting patients with higher incomes to understand their perspectives in generic drugs may help improve generic drug use within that population. DISCLOSURES: Funding for this study was made possible, in part, by the U.S. Food and Drug Administration through grant U01FD005486. Hansen has provided expert testimony for Daiichi Sankyo. No other authors have declared a potential conflict of interest. Views expressed in written materials or publications and by speakers do not necessarily reflect the official policies of the U.S. Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. government. Study concept and design were contributed by Howard, Harris, Kiptanui, Hansen, and Qian. Frank, Mishuk, Howard, Harris, and Kiptanui collected the data, and data interpretation was performed by Mishuk and Hansen, along with Qian, Harris, and Kiptanui. The manuscript was written and revised primarily by Mishuk, along with Qian and Hansen.

Medicinal potential of Passiflora foetida L. plant extracts: biological and pharmacological activities.

OBJECTIVE: To investigate analgesic, antidiarrhoeal and cytotoxic activities of the ethanol extract of Passiflora foetida L. (Passifloraceae) by three experimental methods. METHODS: Analgesic activity of the ethanol extract of Passiflora foetida L. (EEPF) acetic acid-induced writhing inhibition in mice. The method of castor oil-induced diarrhoea in mice was utilized to evaluate antidiarrhoeal activity. The cytotoxic activity of EEPF was explored with a brine shrimp lethality bioassay. RESULTS: The extract showed 68.75% and 30.00% inhibition of writhe at the doses of 500 and 250 mg/kg body weight, respectively. The extract increased the mean latent period prior to diarrhoeal onset to about 1.55 h and 1.17 h, and decreased the mean number of stools to 4.4 and 5.6 at the doses of 500 and 250 mg/kg body weight. The extract also demonstrated cytotoxic activity in the brine shrimp lethality assay, and the median lethal concentration for brine shrimp nauplii was 80 µg/mL. CONCLUSION: The results suggest that the plant extract has analgesic and antidiarrhoeal activities, supporting its uses in traditional medicine. The results also demonstrate that the plant extract possesses cytotoxic activities.

Medicinal potential of Passiflora foetida L. plant extracts: biological and pharmacological activities / 中西医结合学报

To investigate analgesic, antidiarrhoeal and cytotoxic activities of the ethanol extract of Passiflora foetida L. (Passifloraceae) by three experimental methods.