Publications

BACKGROUND: Ceftazidime/avibactam (C/A), ceftolozane/tazobactam (C/T), imipenem/relebactam (I/R), and meropenem/vaborbactam (M/V) combine either a cephalosporin (C/T and C/A) or a carbapenem antibiotic (M/V and I/R) with a β-lactamase inhibitor. They are used to treat carbapenem-resistant Enterobacterales (CRE) and/or multidrug-resistant Pseudomonas aeruginosa (MDRPA).

OBJECTIVE: We compared the pooled clinical success of these medications to older therapies.

METHODS: PubMed and EMBASE were searched from January 1, 2012, through September 2, 2020, for C/A, C/T, I/R, and M/V studies. The main outcome was clinical success, which was assessed using random-effects models. Stratified analyses were conducted for study drug, sample size, quality, infection source, study design, and multidrug-resistant gram-negative organism (MDRGNO) population. Microbiological success and 28- and 30-day mortality were assessed as secondary outcomes. Heterogeneity was determined using I2 values.

RESULTS: Overall, 25 articles met the inclusion criteria; 8 observational studies and 17 randomized control trials. We detected no difference in clinical success comparing new combination antibiotics with standard therapies for all included organisms (pooled OR, 1.21; 95% CI, 0.96-1.51). We detected a moderate level of heterogeneity among the included studies I2 = 56%. Studies that focused on patients with CRE or MDRPA infections demonstrated a strong association between treatment with new combination antibiotics and clinical success (pooled OR, 2.20; 95% CI, 1.60-3.57).

CONCLUSIONS: C/T, C/A, I/R, and M/V are not inferior to standard therapies for treating various complicated infections, but they may have greater clinical success for treating MDRPA and CRE infections. More studies that evaluate the use of these antibiotics for drug-resistant infections are needed to determine their effectiveness.

INTRODUCTION: Antibiotics and opioids are targeted by public health and stewardship communities for reductions in prescribing across the country. This study evaluates trends and factors associated with outpatient prescribing by dental and medical providers in a large integrated health system.

METHODS: This was a cross-sectional study of national dental and medical outpatient visits from Department of Veterans Affairs facilities in 2015-2017; analyzed in 2019-2020. Antibiotic and opioid prescribing rates were assessed by provider and facility characteristics. Multivariable Poisson regression adjusted for repeated measures by the provider was used to assess the independent association between facility and provider characteristics and rate of prescribing.

RESULTS: Over the study period, 4,625,840 antibiotic and 10,380,809 opioid prescriptions were identified for 115,625,890 visits. Physicians prescribed most antibiotics (67%). Dentists prescribed 6% of the antibiotics but had the highest per-visit antibiotic prescribing rate compared to medical providers (6.75 vs 3.90 prescriptions per 100 visits, p<0.0001), which was largely driven by dental specialists. By contrast, dentists had lower opioid prescribing than medical providers (3.02 vs 9.20 prescriptions per 100 visits, p<0.0001). Overall, antibiotic and opioid prescribing decreased over time, with opioids having the greatest decreases (-28.0%). In multivariable analyses, U.S. geographic region, rurality, and complexity were associated with prescribing for both drug classes. Opioid and antibiotic prescribing were positively correlated.

CONCLUSIONS: Although antibiotic and opioid prescribing has decreased, there are still important target areas for improvement. Interventions need to be tailored to community characteristics such as rurality and provider type.

OBJECTIVE: To assess the effectiveness and acceptability of antimicrobial stewardship-focused implementation strategies on inpatient fluoroquinolones.

METHODS: Stewardship champions at 15 hospitals were surveyed regarding the use and acceptability of strategies to improve fluoroquinolone prescribing. Antibiotic days of therapy (DOT) per 1,000 days present (DP) for sites with and without prospective audit and feedback (PAF) and/or prior approval were compared.

RESULTS: Among all of the sites, 60% had PAF or prior approval implemented for fluoroquinolones. Compared to sites using neither strategy (64.2 ± 34.4 DOT/DP), fluoroquinolone prescribing rates were lower for sites that employed PAF and/or prior approval (35.5 ± 9.8; P = .03) and decreased from 2017 to 2018 (P < .001). This decrease occurred without an increase in advanced-generation cephalosporins. Total antibiotic rates were 13% lower for sites with PAF and/or prior approval, but this difference did not reach statistical significance (P = .20). Sites reporting that PAF and/or prior approval were "completely" accepted had lower fluoroquinolone rates than sites where it was "moderately" accepted (34.2 ± 5.7 vs 48.7 ± 4.5; P < .01). Sites reported that clinical pathways and/or local guidelines (93%), prior approval (93%), and order forms (80%) "would" or "may" be effective in improving fluoroquinolone use. Although most sites (73%) indicated that requiring infectious disease consults would or may be effective in improving fluoroquinolones, 87% perceived implementation to be difficult.

CONCLUSIONS: PAF and prior approval implementation strategies focused on fluoroquinolones were associated with significantly lower fluoroquinolone prescribing rates and nonsignificant decreases in total antibiotic use, suggesting limited evidence for class substitution. The association of acceptability of strategies with lower rates highlights the importance of culture. These results may indicate increased acceptability of implementation strategies and/or sensitivity to FDA warnings.

BACKGROUND: In a cohort of Veterans dually enrolled in the Department of Veterans Affairs (VA) and Medicare Part D, we sought to describe high-dose daily opioid use among Veterans with unexplained gastrointestinal (GI) symptoms and structural GI diagnoses and examine factors associated with high-dose use.

METHODS: We used linked national patient-level data from the VA and Centers for Medicare and Medicaid Services (CMS). We grouped patients into 3 subsets: those with unexplained GI symptoms (e.g., chronic abdominal pain); structural GI diagnoses (e.g., chronic pancreatitis); and those with a concurrent unexplained GI symptom and structural GI diagnosis. High-dose daily opioid use levels were examined as a binary variable [≥ 100 morphine milligram equivalents (MME)/day] and as an ordinal variable (50-99 MME/day, 100-119 MME/day, or ≥ 120 MME/day).

RESULTS: We identified 141,805 chronic GI patients dually enrolled in VA and Part D. High-dose opioid use was present in 11% of Veterans with unexplained GI symptoms, 10% of Veterans with structural GI diagnoses, and 15% of Veterans in the concurrent GI group. Compared to Veterans with only an unexplained GI symptom or structural diagnosis, concurrent GI patients were more likely to have higher daily opioid doses, more opioid days ≥ 100 MME, and higher risk of chronic use. Factors associated with high-dose use included opioid receipt from both VA and Part D, younger age, and benzodiazepine use.

CONCLUSIONS: A significant subset of chronic GI patients in the VA are high-dose opioid users. Efforts are needed to reduce high-dose use among Veterans with concurrent GI symptoms and diagnoses.

BACKGROUND: Drug supply disruptions have increased during the COVID-19 pandemic, especially for medicines used in the ICU. Despite reported shortages in wealthy countries, global analyses of ICU drug purchasing during COVID-19 are limited.

RESEARCH QUESTION: Has COVID-19 impacted global drug purchases of first-, second-, and third-choice agents used in intensive care?

STUDY DESIGN AND METHODS: We conducted a cross-sectional time series study in a global pharmacy sales dataset comprising approximately 60% of the world's population. We analyzed pandemic-related changes in units purchased per 1,000 population for 69 ICU agents. Interventional autoregressive integrated moving average models tested for significant changes when the pandemic was declared (March 2020) and during its first stage from April through August 2020, globally and by development status.

RESULTS: Relative to 2019, ICU drug purchases increased by 23.6% (95% CI, 7.9%-37.9%) in March 2020 (P < .001) and then decreased by 10.3% (95% CI, -16.9% to -3.5%) from April through August (P = .006). Purchases for second-choice medicines changed the most, especially in developing countries (eg, 29.3% increase in March 2020). Despite similar relative changes (P = .88), absolute purchasing rates in developing nations remained low. The observed decrease from April through August 2020 was significant only in developed countries (-13.1%; 95% CI, -17.4% to -4.4%; P < .001). Country-level variation seemed unrelated to expected demand and health care infrastructure.

INTERPRETATION: Purchases for intensive care medicines increased globally in the month of the COVID-19 pandemic declaration, but before peak infection rates. These changes were most pronounced for second-choice agents, suggesting that inexpensive, generic medicines may be purchased more easily in anticipation of pandemic-related ICU surges. Nevertheless, disparities in access persisted. Trends seemed unrelated to expected demand, and decreased purchasing from April through August 2020 may suggest overbuying. National and international policies are needed to ensure equitable drug purchasing during future pandemics.

OBJECTIVE: United States dentists prescribe 10% of all outpatient antibiotics. Assessing appropriateness of antibiotic prescribing has been challenging due to a lack of guidelines for oral infections. In 2019, the American Dental Association (ADA) published clinical practice guidelines (CPG) on the management of acute oral infections. Our objective was to describe baseline national antibiotic prescribing for acute oral infections prior to the release of the ADA CPG and to identify patient-level variables associated with an antibiotic prescription.

DESIGN: Cross-sectional analysis.

METHODS: We performed an analysis of national VA data from January 1, 2017, to December 31, 2017. We identified cases of acute oral infections using International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Antibiotics prescribed by a dentist within ±7 days of a visit were included. Multivariable logistic regression identified patient-level variables associated with an antibiotic prescription.

RESULTS: Of the 470,039 VA dental visits with oral infections coded, 12% of patient visits with irreversible pulpitis, 17% with apical periodontitis, and 28% with acute apical abscess received antibiotics. Although the median days' supply was 7, prolonged use of antibiotics was frequent (≥8 days, 42%-49%). Patients with high-risk cardiac conditions, prosthetic joints, and endodontic, implant, and oral and maxillofacial surgery dental procedures were more likely to receive antibiotics.

CONCLUSIONS: Most treatments of irreversible pulpitis and apical periodontitis cases were concordant with new ADA guidelines. However, in cases where antibiotics were prescribed, prolonged antibiotic courses >7 days were frequent. These findings demonstrate opportunities for the new ADA guidelines to standardize and improve dental prescribing practices.

OBJECTIVE: To characterize postextraction antibiotic prescribing patterns, predictors for antibiotic prescribing and the incidence of and risk factors for postextraction oral infection.

DESIGN: Retrospective analysis of a random sample of veterans who received tooth extractions from January 1, 2017 through December 31, 2017.

SETTING: VA dental clinics.

PATIENTS: Overall, 69,610 patients met inclusion criteria, of whom 404 were randomly selected for inclusion. Adjunctive antibiotics were prescribed to 154 patients (38.1%).

INTERVENTION: Patients who received or did not receive an antibiotic were compared for the occurrence of postextraction infection as documented in the electronic health record. Multivariable logistic regression was performed to identify factors associated with antibiotic receipt.

RESULTS: There was no difference in the frequency of postextraction oral infection identified among patients who did and did not receive antibiotics (4.5% vs 3.2%; P = .59). Risk factors for postextraction infection could not be identified due to the low frequency of this outcome. Patients who received antibiotics were more likely to have a greater number of teeth extracted (aOR, 1.10; 95% CI, 1.03-1.18), documentation of acute infection at time of extraction (aOR, 3.02; 95% CI, 1.57-5.82), molar extraction (aOR, 1.78; 95% CI, 1.10-2.86) and extraction performed by an oral maxillofacial surgeon (aOR, 2.29; 95% CI, 1.44-3.58) or specialty dentist (aOR, 5.77; 95% CI, 2.05-16.19).

CONCLUSION: Infectious complications occurred at a low incidence among veterans undergoing tooth extraction who did and did not receive postextraction antibiotics. These results suggest that antibiotics have a limited role in preventing postprocedural infection; however, future studies are necessary to more clearly define the role of antibiotics for this indication.

Background Adherence to oral anticoagulation (OAC) is critical for stroke prevention in atrial fibrillation. However, the COVID-19 pandemic may have disrupted access to such therapy. We hypothesized that our analysis of a US nationally representative pharmacy claims database would identify increased incidence of lapses in OAC refills during the COVID-19 pandemic. Methods and Results We identified individuals with atrial fibrillation prescribed OAC in 2018. We used pharmacy dispensing records to determine the incidence of 7-day OAC gaps and 15-day excess supply for each 30-day interval from January 1, 2019 to July 8, 2020. We constructed interrupted time series analyses to test changes in gaps and supply around the pandemic declaration by the World Health Organization (March 11, 2020), and whether such changes differed by medication (warfarin or direct OAC), prescription payment type, or prescriber specialty. We identified 1 301 074 individuals (47.5% women; 54% age ≥75 years). Immediately following the COVID-19 pandemic declaration, we observed a 14% decrease in 7-day OAC gaps and 56% increase in 15-day excess supply (both P<0.001). The increase in 15-day excess supply was more marked for direct OAC (69% increase) than warfarin users (35%; P<0.001); Medicare beneficiaries (62%) than those with commercial insurance (43%; P<0.001); and those prescribed OAC by a cardiologist (64%) rather than a primary care provider (48%; P<0.001). Conclusions Our analysis of nationwide claims data demonstrated increased OAC possession after the onset of the COVID-19 pandemic. Our findings may have been driven by waivers of early refill limits and patients' tendency to stockpile medications in the first weeks of the pandemic.

BACKGROUND: While the COVID-19 pandemic may have substantially hindered the provision of routine immunisation services worldwide, we have little data on the impact of the pandemic on vaccine supply chains.

METHODS: We used time-series analysis to examine global trends in vaccine sales for a total of 34 vaccines and combination vaccines using data from the IQVIA MIDAS Database between August 2014 and August 2020 across 84 countries. We grouped countries into three income-level categories, and we modelled the changes in vaccine sales from April to August 2020 versus April to August 2019 using autoregressive integrated moving average models.

RESULTS: In March 2020, global sales of vaccines dropped from 1211.1 per 100 000 to 806.2 per 100 000 population in April 2020, an overall decrease of 33.4%; however, the vaccine sales interruptions recovered disproportionately across economies. Between April 2020 and August 2020, we found a significant decrease of 20.6% (p<0.001) in vaccine sales across high-income countries (HICs), in contrast with a significant increase of 10.7% (p<0.001) across lower middle-income countries (LMICs), relative to the same period in 2019. From August 2014 through August 2020, monthly per capita vaccine sales across HICs remained, on average, at least four times higher than in LMICs and nearly three times higher than in upper middle-income countries.

CONCLUSION: Our study revealed the heterogeneous impact of COVID-19 on vaccine sales across economies while underlining the substantial consistent disparities in per capita vaccine sales before and during the first wave of the COVID-19 pandemic. Action to ensure equitable distribution of vaccines is needed.