Risk Factors Associated with Mupirocin Resistance in Methicillin-Resistant Staphylococcus aureus

Implementation of meticillin-resistant Staphylococcus aureus (MRSA) decolonisation programmes has been increasing and the emergence of mupirocin resistance has been reported. However, the patient-level risk factors associated with mupirocin resistance are not clear. In this study, independent predictors of mupirocin resistance in MRSA among Providence Veterans Affairs Medical Center patients with MRSA-positive culture dates between 1 July 2004 and 30 June 2008 were identified using a frequency-matched case–control study. Forty cases (mupirocin-resistant) were matched on culture date quarter and year to 270 controls (mupirocin-susceptible). The adjusted conditional logistic regression model identified three significant independent predictors associated with mupirocin resistance in MRSA: (1) exposure to mupirocin in the year prior to the culture date [odds ratio (OR): 9.84; 95% confidence interval (CI): 2.93–33.09]; (2) Pseudomonas aeruginosa infection in the year before the culture-related admission (4.85; 1.20–19.61); and (3) cefepime use in the year prior to culture (2.80; 1.03–7.58). In sensitivity analyses, previous mupirocin exposure was associated with low-level [minimum inhibitory concentration (MIC) 8–128 mg/L; 23 cases, 202 controls; OR: 6.32; 95% CI: 1.58–25.33] and high-level (MIC ≥256 mg/L; 17 cases, 151 controls; OR: 11.18; 95% CI: 1.89–66.30) mupirocin resistance. To our knowledge, this is the first case–control study to reveal a strong association between previous mupirocin exposure and subsequent mupirocin resistance in MRSA, with demonstrated robustness in low- and high-level mupirocin resistance. Mupirocin susceptibility monitoring is critical for facilities instituting decolonisation with mupirocin as increased use may reduce effectiveness through resistance

Cost and Utilization of Behavioral Health Medications Associated with Rescission of an Exemption for Prior Authorization for Severe and Persistent Mental Illness in the Vermont Medicaid Program

BACKGROUND: In recent years, many state Medicaid programs have implemented preferred drug lists (PDL) to control pharmaceutical costs by generating supplemental rebate revenues and directing providers to the most cost-effective treatments. Two states, Michigan and Vermont, sought approval from the Centers for Medicare and Medicaid Services for supplemental rebates for their Medicaid fee-for-service programs in 2002. Behavioral health medications were largely excluded from PDLs and other managed care initiatives implemented by state Medicaid programs because of significant opposition to any impact on this vulnerable population. In November 2001, the Vermont Medicaid program implemented the Vermont Health Access Pharmacy Benefit Management Program, a PDL designed to promote cost-effective use of medications. Despite the potential cost savings resulting from implementation of a PDL, behavioral health providers and advocates in the state of Vermont opposed the implementation of the managed care initiative for beneficiaries with severe mental illness, and after January of 2002, Vermont\u27s program was changed to exempt beneficiaries meeting the severe and persistent mental illness (SPMI) criteria from prior authorization (PA) for behavioral health medications not on the Medicaid PDL. The SPMI exemption was phased out by June 30, 2006. OBJECTIVES: To determine the effects of the rescission of the PA exemption on utilization and costs of 3 classes of behavioral health medications (antidepressants, antipsychotics, and anxiolytics/sedatives). Secondary analyses were conducted to assess the association between rescission of the PA exemption and 2 quality measures that might be associated with pharmacy management policy: (a) behavioral health hospitalizations and (b) high-dose prescribing of antipsychotics, defined as dosing that exceeded the manufacturer-recommended maximum dose by 25%. METHODS: This was a retrospective analysis of pharmacy claims for beneficiaries of the Office of Vermont Health Access Medicaid Program for dates of service from July 1, 2005, through December 31, 2007. The 12-month PA exemption period for 3 categories of drugs (antidepressants, antipsychotics, and anxiolytics/sedatives) was July 1, 2005, through June 30, 2006; and the post-PA exemption period was the 12 months from January 1, 2007, through December 31, 2007, following rescission of the SPMI exemption. Costs in this analysis were defined as the amount paid by Medicaid, excluding federal drug rebates paid by drug manufacturers and supplemental rebates associated with the PDL program. Costs were adjusted for inflation using the Consumer Price Index for medical costs. Frequencies were used to identify trends between medication classes and time periods. Medical claims from the 2 time periods were used to assess inpatient hospitalization trends. Descriptive statistics, Pearson chi-square tests (for categorical data), and t-tests (for continuous data) were used to assess the 2 study cohorts. RESULTS: 17.8% (n=22,130) of 124,169 eligible beneficiaries in the PA exemption period had 1 or more pharmacy claims in the 3 classes of medications exempt from PA versus 19.2% (n=23,717) of 123,499 eligible beneficiaries in the post-PA exemption period. Utilization of behavioral medications per member per month (PMPM) increased by 14.3% from 0.14 claims PMPM in the PA exemption period to 0.16 claims PMPM in the post-PA exemption period, similar to the 14.1% increase in the utilization of nonbehavioral medications (from 0.64 to 0.73 claims PMPM). Utilization changed little between the PA exemption period and the post-PA exemption period for the 3 individual classes of behavioral health drugs, 0.08 claims PMPM versus 0.09 claims PMPM for antidepressants and 0.03 for both study periods for both antipsychotics and anxiolytics/sedative hypnotics. PMPM costs for the 3 drug classes exempt from PA increased by 2.1% from $12.76 to$13.03, compared with a 12.2% increase from $42.58 PMPM to$47.79 PMPM for nonbehavioral health medications. The small 2.1% increase in PMPM costs for the 3 formerly PA-exempt drug classes was attributable in part to a 12.9% reduction in average cost per pharmacy claim, from $94.05 to$81.92, including a 24.8% reduction in the average cost per antidepressant claim, from $65.59 to$49.33. For the subgroup of beneficiaries taking atypical antipsychotic medications, the percentage with high-dose prescriptions decreased from 3.1% to 2.2%. Mental health inpatient hospitalizations also decreased from 0.6% of beneficiaries in the PA exemption period to 0.4% in the post-PA exemption period. CONCLUSIONS: In a Medicaid population excluding Medicare dual-eligible beneficiaries, the rescission of a PA exemption for 3 major classes of behavioral health medications in a PDL was not associated with decreased utilization of formerly PA-exempt behavioral health medications. The increase in PMPM spending for the formerly PA-exempt behavioral health medications was small compared with the increase in PMPM cost for nonbehavioral health medications, and there were fewer beneficiaries with hospitalization for mental health reasons in the period after rescission of the PA exemption

Evaluation of a Program to Improve Diabetes Care Through Intensified Care Management Activities and Diabetes Medication Copayment Reduction

BACKGROUND: Medication copayment reduction can be integrated with disease management programs to incentivize patient engagement in chroniccare management. While disease management programs in diabetes havebeen evaluated across a range of settings and designs, less is knownregarding the effectiveness of copayment reduction as a component ofdisease management. OBJECTIVE: To evaluate the short-term results of a diabetes-focused disease management program that included copayment reduction, care coordination, and patient goal setting, focusing on rates of evidence-based care processes and all-cause pharmacy and health care costs. METHODS: Blue Cross & Blue Shield of Rhode Island offered large employer groups the opportunity to participate in a diabetes disease management initiative that featured reduced copayments (from $7/$25/$40 for generic, tier 2, and tier 3 drugs, respectively, to$ 0 for generic and $0-$2 for brand drugs) for diabetes-related medications. In return for the copayment reduction, participants agreed to the following: (a) participate in care coordination with a case manager, (b) have an annual physical examination, (c) have a hemoglobin A1c blood test at least twice annually, and (d) have a low-density lipoprotein cholesterol (LDL-C) test at least once annually. Patients received personalized support provided by a registered nurse and dietician, disease-related education provided by nurses, and intensified case management services, including working with a health coach to establish healthy behavioral change goals. All study subjects were aged 18 years or older and had at least 1 ICD-9-CM code for diabetes and at least 1 claim for an antidiabetic drug during a 12-month measurement period, which was each subject’s most recent 12-month period of continuous enrollment from January 1, 2008, through May 31, 2010. Administrative claims data were used to determine the percentage of intervention (participating) and nonintervention (nonparticipating) subjects from among all of the plan’s employer groups who received at least once-yearly monitoring of A1c, high-density lipoprotein cholesterol (HDL-C), and LDL-C; medical attention (or drug therapy) for nephropathy; and an eye examination. We conducted multivariate logistic regression analyses to assess the effect of the intervention and other patient characteristics and comorbidities on rates of performance of these care processes, aggregating the 5 processes of care into an “all or none” single composite outcome. We also developed a propensity score-weighted model to attempt to adjust for differences between the intervention and nonintervention groups resulting from the nonrandomized study design. Additionally, we quantified average plan payments to providers less patient copayments (i.e., net plan cost) per patient per year (PPPY) for the 12-month follow-up period and compared these costs for the intervention versus nonintervention groups. RESULTS: The study sample consisted of 9,698 patients with diabetes; 649 (6.7%) of whom participated in the intervention. 9,049 (93.3%) patients were identified by the insurer as patients with diabetes receiving usual care. Patients in the intervention and nonintervention groups were similarly likely to have all 5 recommended processes of care performed (40.1% vs. 38.9%, respectively, P = 0.543). Younger patients received all 5 recommended care processes less frequently than older patients (30.5%, 38.0%, and 47.0% for ages 18-48 years, 49-59 years, and 60 years or older, respectively, P \u3c 0.001); in adjusted analyses, patients aged 60 years or older were approximately twice as likely to receive all 5 care processes compared with patients aged 18-48 years (odds ratio [OR] = 1.97, 95% CI = 1.75-2.21). Users of oral antidiabetic monotherapy were least likely to have these processes of care performed compared with users of multiple oral therapies (OR = 1.23, 95% CI = 1.11-1.36) and insulin (OR = 1.59, 95% CI = 1.41-1.78). PPPY prescription drug costs incurred by the plan were greater for intervention than comparison patients (means [SDs] of $3,139 [$3,426] vs. $2,854 [$3,938], respectively, P \u3c 0.001); and the generic-dispensing ratio was slightly lower (means [SDs] of 62.1% [22.4%] and 65.4% [23.0%], respectively, P \u3c 0.001). There were no significant differences between the intervention and comparison groups in mean [SD] PPPY all-cause medical care costs ($7,475 [$17,601] vs. $8,577 [$22,972], respectively, P = 0.213) or total all-cause costs ($10,613 [$18,590] vs. $11,431 [$24,060], P = 0.666). CONCLUSIONS: Patients participating in this incentive program featuring diabetes medication copayment reduction and disease management components did not receive recommended care any more or less frequently than other enrolled members with diabetes. Younger patients and those utilizing oral antidiabetic monotherapy as their drug regimens were less likely to have the recommended processes of care performed. While prescription drug expenditures incurred by the plan were greater for intervention patients, between-group differences in total costs for medications and all-cause medical care were not statistically significant. Further follow-up is required to determine the success of this program over the longer term in promoting quality of care and achieving cost reductions and improved health outcomes

Alternatives to potentially inappropriate medications for use in e-prescribing software: triggers and treatment algorithms

Objective: To describe the development of evidence-based electronic prescribing (e-prescribing) triggers and treatment algorithms for potentially inappropriate medications (PIMs) for older adults. Design: Literature review, expert panel and focus group. Setting: Primary care with access to e-prescribing systems. Participants: Primary care physicians using e-prescribing systems receiving medication history. Interventions: Standardised treatment algorithms for clinicians attempting to prescribe PIMs for older patients. Main outcome measure: Development of 15 treatment algorithms suggesting alternative therapies. Results: Evidence-based treatment algorithms were well received by primary care physicians. Providing alternatives to PIMs would make it easier for physicians to change decisions at the point of prescribing. Conclusion: Prospectively identifying older persons receiving PIMs or with adherence issues and providing feasible interventions may prevent adverse drug events

Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Children

Introduction: Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. Objective: The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. Methods: This retrospective study included pregnant women aged 12–55 years and their live-birth infants born from 2010 to 2012 present in Optum’s deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. Results: Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92–1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05–2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01–1.54). Conclusion and Relevance: In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy

The Risk of Hepatotoxicity with Fluoroquinolones: A National Case-Control Safety Study

Purpose. Fluoroquinolones are generally considered safe and well-tolerated. However, suspected fluoroquinolone induced hepatotoxicity has been increasingly reported, but data are lacking. Thus, the objective of this study was to assess the risk of hepatotoxicity in patients using fluoroquinolones compared to non-users. Methods. National Veterans Affairs (VA) hospital admissions were assessed between January 1, 2002 and December 31, 2008. Our case-control study matched patients with a primary diagnosis of hepatotoxicity (cases) to those with myocardial infarction (controls) on admission date (matched up to 1:6). Conditional logistic regression was used to compute adjusted odds ratios (OR) and 95% confidence intervals (CI) of hepatotoxicity associated with fluoroquinolone exposure. Results. Our study included 7,862 cases and 45,512 matched controls. The majority of study patients were white (63.4%), males (97.7%), with a mean age of 61 years. After adjusting for confounders, fluoroquinolone use was significantly associated with a 20% increased risk of hepatotoxicity development (OR 1.20, 95% CI 1.04-1.38) compared to non-users. A statistically significant increased risk of hepatotoxicity was associated with ciprofloxacin use individually (OR 1.29, 95% CI 1.05-1.58), but not with levofloxacin or moxifloxacin use. Conclusion. The use of fluoroquinolones was associated with an increased risk of hepatotoxicity relative to non-users in our national VA study population

Comparative Safety Analysis of Opioid Agonist Treatment in Pregnant Women with Opioid Use Disorder: A Population-Based Study

Introduction and Objective: Receipt of opioid agonist treatment during early and late pregnancy for opioid use disorder may relate to varying perinatal risks. We aimed to assess the effect of time-varying prenatal exposure to opioid agonist treatment using buprenorphine or methadone on adverse neonatal and pregnancy outcomes. Methods: We conducted a retrospective cohort study of pregnant women with opioid use disorder using Rhode Island Medicaid claims data and vital statistics during 2008–16. Time-varying exposure was evaluated in early (0–20 weeks) and late (≥ 21 weeks) pregnancy. Marginal structural models with inverse probability of treatment weighting were applied. Results: Of 400 eligible pregnancies, 85 and 137 individuals received buprenorphine and methadone, respectively, during early pregnancy. Compared with 152 untreated pregnancies with opioid use disorders, methadone exposure in both periods was associated with an increased risk of preterm birth (adjusted odds ratio [aOR]: 2.52; 95% confidence interval [CI] 1.07–5.95), low birth weight (aOR: 2.99; 95% CI 1.34–6.66), neonatal intensive care unit admission (aOR, 5.04; 95% CI 2.49–10.21), neonatal abstinence syndrome (aOR: 11.36; 95% CI 5.65–22.82), respiratory symptoms (aOR, 2.71; 95% CI 1.17–6.24), and maternal hospital stay \u3e 7 days (aOR, 14.51; 95% CI 7.23–29.12). Similar patterns emerged for buprenorphine regarding neonatal abstinence syndrome (aOR: 10.27; 95% CI 4.91–21.47) and extended maternal hospital stay (aOR: 3.84; 95% CI 1.83–8.07). However, differences were found favoring the use of buprenorphine for preterm birth versus untreated pregnancies (aOR: 0.17; 95% CI 0.04–0.77), and for several outcomes versus methadone. Conclusions: Methadone and buprenorphine prescribed for the treatment of opioid use disorder during pregnancy are associated with varying perinatal risks. However, buprenorphine may be preferred in the setting of pregnancy opioid agonist treatment. Further research is necessary to confirm our findings and minimize residual confounding

Identification and characterization of Src SH3 ligands from phage-displayed random peptide libraries.

We have used the Src homology 3 (SH3) domain to screen two phage-displayed random peptide libraries, each containing 2 x 10(8) unique members, and have identified a series of high affinity peptide ligands. The peptides possess similar proline-rich regions, which yield a consensus Src SH3-binding motif of RPLPPLP. We have confirmed this motif by screening a phage-displayed peptide library biased for SH3 ligands and identifying the same consensus sequence. Binding studies using synthetic peptides suggest that the RPLPPLP motif is important for SH3 binding and confers specificity for the Src SH3 domain, and that residues which flank the motif may also contribute to binding. Peptides that contain the RPLPPLP motif compete Src, but not Abl or phospholipase C gamma, SH3 interactions with SH3-binding proteins from cell lysates (IC50 = 1-5 microM). Furthermore, RPLPPLP-related peptides are able to accelerate progesterone-induced maturation of Xenopus laevis oocytes. A similar acceleration has been observed in oocytes treated with activated, but not normal, Xenopus Src, suggesting the possibility that the peptides are able to antagonize the negative regulation of Src activity by Src SH3 in vivo

Isolation of a NCK-associated Kinase, PRK2, an SH3-binding Protein and Potential Effector of Rho Protein Signaling

The NCK adapter protein is comprised of three consecutive Src homology 3 (SH3) protein-protein interaction domains and a C-terminal SH2 domain. Although the association of NCK with activated receptor protein-tyrosine kinases, via its SH2 domain, implicates NCK as a mediator of growth factor-induced signal transduction, little is known about the pathway(s) downstream of NCK recruitment. To identify potential downstream effectors of NCK we screened a bacterial expression library to isolate proteins that bind its SH3 domains. Two molecules were isolated, the Wiskott-Aldrich syndrome protein (WASP, a putative CDC42 effector) and a serine/threonine protein kinase (PRK2, closely related to the putative Rho effector PKN). Using interspecific backcross analysis the Prk2 gene was mapped to mouse chromosome 3. Unlike WASP, which bound the SH3 domains of several signaling proteins, PRK2 specifically bound to the middle SH3 domain of NCK and (weakly) that of phospholipase Cgamma. PRK2 also specifically bound to Rho in a GTP-dependent manner and cooperated with Rho family proteins to induce transcriptional activation via the serum response factor. These data suggest that PRK2 may coordinately mediate signal transduction from activated receptor protein-tyrosine kinases and Rho and that NCK may function as an adapter to connect receptor-mediated events to Rho protein signaling

Enhanced biodegradation of PAHs in historically contaminated soil by M. gilvum inoculated biochar

The inoculation of rice straw biochar with PAH-degrading Mycobacterium gilvum (1.27 × 1011 ± 1.24 × 1010 cell g−1), and the subsequent amendment of this composite material to PAHs contaminated (677 mg kg−1) coke plant soil, was conducted in order to investigate if would enhance PAHs biodegradation in soils. The microbe-biochar composite showed superior degradation capacity for phenanthrene, fluoranthene and pyrene. Phenanthrene loss in the microbe-biochar composite, free cell alone and biochar alone treatments was, respectively, 62.6 ± 3.2%, 47.3 ± 4.1% and non-significant (P > 0.05); whereas for fluoranthene loss it was 52.1 ± 2.3%; non-significant (P > 0.05) and non-significant (P > 0.05); and for pyrene loss it was 62.1 ± 0.9%; 19.7 ± 6.5% and 13.5 ± 2.8%. It was hypothesized that the improved remediation was underpinned by i) biochar enhanced mass transfer of PAHs from the soil to the carbonaceous biochar “sink”, and ii) the subsequent degradation of the PAHs by the immobilized M. gilvum. To test this mechanism, a surfactant (Brij 30; 20 mg g−1 soil), was added to impede PAHs mass transfer to biochar and sorption. The surfactant increased solution phase PAH concentrations and significantly (P < 0.05) reduced PAH degradation in the biochar immobilized M. gilvum treatments; indicating the enhanced degradation occurred between the immobilized M. gilvum and biochar sorbed PAHs