Kimberly K. Scarsi

Impact of inactive empiric antimicrobial therapy on inpatient mortality and length of stay.

ABSTRACT The consequences of inactive empiric antimicrobial therapy are not well-described and may cause prolonged hospitalization or infection-related mortality. In vitro susceptibility results for 884 patients hospitalized at an academic medical center with gram-negative bloodstream infections (GNBI) from 2001 to 2003 were matched to antimicrobial orders within 24 h of culture. Clinical characteristics, organism, inpatient mortality, and length of stay after culture for patients with GNBI were compared between patients receiving active versus inactive empiric antimicrobial therapy. A total of 14.1% of patients with GNBI received inactive empiric therapy, defined as no antimicrobial therapy within 24 h of the culture active against the identified organism based on in vitro microbiology reports. Patients who received inactive therapy were more likely to be younger, to be infected with Pseudomonas aeruginosa, to have a nosocomial infection, and to receive antimicrobial monotherapy but less likely to be bacteremic with Escherichia coli or to have sepsis (P < 0.05). There were no significant differences in mortality between patients receiving active versus inactive empiric therapy (16.1% versus 13.6%, respectively) or in length of stay after positive culture (11.5 days versus 12.6 days, respectively). Only 45 patients had greater than 2 days of exposure to inactive therapy; however, 8/30 patients (26.7%) who never received active antimicrobial therapy died while in the hospital. Inactive empiric therapy was more common in healthier patients. Inactive antimicrobial therapy in the first 24 h did not significantly impact average outcomes for GNBI among hospitalized patients but may have caused harm to specific individuals.

Hepatotoxicity associated with long- versus short-course HIV-prophylactic nevirapine use: A systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project

Background and objective: The antiretroviral nevirapine can cause severe hepatotoxicity when used ‘off-label’ for preventing mother-to-child HIV transmission (PMTCT), newborn post-exposure prophylaxis and for pre- and post-exposure prophylaxis among non-HIV-infected individuals. We describe the incidence of hepatotoxicity with short-versus long-course nevirapine-containing regimens in these groups.Methods: We reviewed hepatotoxicity cases among non-HIV-infected individuals and HIV-infected pregnant women and their offspring receiving short- (≤4 days) versus long-course (≥5 days) nevirapine prophylaxis. Sources included adverse event reports from pharmaceutical manufacturers and the US FDA, reports from peer-reviewed journals/scientific meetings and the Research on Adverse Drug events And Reports (RADAR) project. Hepatotoxicity was scored using the AIDS Clinical Trial Group criteria.Results: Toxicity data for 8216 patients treated with nevirapine-containing regimens were reviewed. Among 402 non-HIV-infected individuals receiving short- (n = 251) or long-course (n = 151) nevirapine, rates of grade 1–2 hepatotoxicity were 1.99% versus 5.30%, respectively, and rates of grade 3–4 hepatotoxicity were 0.00% versus 13.25%, respectively (p < 0.001 for both comparisons). Among 4740 HIV-infected pregnant women receiving short- (n = 3031) versus long-course (n=1709) nevirapine, rates of grade 1–2 hepatotoxicity were 0.62% and 7.04%, respectively, and rates of grade 3–4 hepatotoxicity were 0.23% versus 4.39%, respectively (p< 0.001 for both comparisons). The rates of grade 3–4 hepatotoxicity among 3074 neonates of nevirapine-exposed HIV-infected pregnant women were 0.8% for those receiving short-course (n = 2801) versus 1.1 % for those receiving long-course (n=273) therapy (p < 0.72).Conclusions: Therapy duration appears to significantly predict nevirapine hepatotoxicity. Short-course nevirapine for HIV prophylaxis is associated with fewer hepatotoxic reactions for non-HIV-infected individuals or pregnant HIV-infected women and their offspring, but administration of prophylactic nevirapine for ≥2 weeks appears to be associated with high rates of hepatotoxicity among non-HIV-infected individuals and HIV-infected pregnant mothers. When full highly active antiretroviral therapy (HAART) regimens are not available, single-dose nevirapine plus short-course nucleoside reverse transcriptase inhibitors to decrease the development of HIV viral resistance is an essential therapeutic option for PMTCT and these data support the safety of single-dose nevirapine in this setting.

Point-of-care testing for infectious diseases: Opportunities, barriers, and considerations in community pharmacy

OBJECTIVES To identify opportunities to perform point-of-care (POC) testing and/or screening for infectious diseases in community pharmacies, provide an overview of such tests and how they are used in current practice, discuss how the Clinical Laboratory Improvement Amendments of 1988 (CLIA) affect pharmacists performing POC testing, and identify and discuss barriers and provide recommendations for those wanting to establish POC testing for infectious diseases services in community pharmacies. DATA SOURCES PubMed and Google Scholar were searched from November 2012 through May 2013 and encompassed the years 2000 and beyond for the narrative review section of this article using the search terms rapid diagnostic tests, POC testing and infectious diseases, pharmacy services, CLIA waiver, and collaborative drug therapy management. All state boards of pharmacy in the United States were contacted and their regulatory and legislative websites accessed in 2012 and January 2013 to review relevant pharmacy practice laws. DATA SYNTHESIS POC testing for infectious diseases represents a significant opportunity to expand services in community pharmacies. Pharmacist education and training are addressing knowledge deficits in good laboratory practices and test performance and interpretation. Federal regulations do not define the qualifications for those who perform CLIA-waived tests, yet few pharmacists perform such services. Fewer than 20% of states address POC testing in their statutes and regulations governing pharmacy. CONCLUSION POC testing for infectious diseases could benefit patients and society and represents an opportunity to expand pharmacy services in community pharmacies. Existing barriers to the implementation of such services in community pharmacies, including deficits in pharmacist training and education along with state regulatory and legislative variance and vagueness in statutes governing pharmacy, are not insurmountable.

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks

Women receiving efavirenz-based antiretroviral therapy plus a contraceptive implant had significantly lower levonorgestrel pharmacokinetics than women not receiving antiretroviral therapy. An unexpected high pregnancy rate (3/20, 15%) occurred in the efavirenz group, highlighting the clinical significance of this interaction.

Pharmacist-provided rapid HIV testing in two community pharmacies

OBJECTIVE To evaluate the acceptability and feasibility of pharmacist-provided rapid testing for human immunodeficiency virus (HIV) infection in community pharmacies. PRACTICE DESCRIPTION A pharmacist-provided HIV testing model-including rapid HIV testing, counseling, and linkage to confirmatory HIV testing services-was developed and implemented. SETTING Two independent pharmacies located in Michigan cities of different size and with different prevalence of HIV infection. MAIN OUTCOME MEASURES Number of HIV tests performed, time required for HIV testing services, description of participants who received an HIV test, and pharmacist and participant perception of the HIV testing experience. RESULTS From October 2011 to March 2013, pharmacists provided HIV tests to 69 participants. One (1.5%) participant had a reactive HIV test and was immediately referred to an appropriate health care provider for confirmatory testing. HIV testing services required a median time of 30 (range, 20-90) minutes. Participants had a median age of 23 (range, 18-61) years and were diverse by gender (59.4% women) and race (46.4% black; 39.1% white). This was the first HIV test for 42% of participants, many of whom reported high-risk behaviors in the prior 6 months. Participants and pharmacists reported favorable perceptions of the HIV testing experience. CONCLUSIONS This project demonstrates the acceptability and feasibility of pharmacist-provided rapid HIV testing in two community pharmacies with distinct characteristics. Further development of HIV testing services in this practice setting is warranted.

Effect of Differences in MIC Values on Clinical Outcomes in Patients with Bloodstream Infections Caused by Gram-Negative Organisms Treated with Levofloxacin

ABSTRACT Emerging evidence suggests that current fluoroquinolone dosing strategies may be inadequate to treat bloodstream infections caused by organisms classified as sensitive. This study sought to determine if differences in MICs for levofloxacin-susceptible gram-negative organisms correlate with differences in patient outcomes. A retrospective cohort study evaluated patients treated with levofloxacin for bloodstream infections caused by susceptible gram-negative organisms. Patients infected with gram-negative organisms for which MICs indicated susceptibility were categorized into three groups: those with organisms for which MICs were low (≤0.25 mg/liter), intermediate (0.5 mg/liter), and high (1 or 2 mg/liter). Patients were evaluated for baseline similarity, all-cause mortality, and measurements of morbidity. A total of 404 patients with bloodstream infections caused by gram-negative organisms were identified. Of these patients, 312 were treated with levofloxacin and included in the analysis. No significant difference in all-cause mortality among the three groups was observed. The high-MIC group had a significantly longer average hospital stay postculture than the low- and intermediate-MIC groups (16.4 days versus 7.3 and 7.9 days; P < 0.01) and a significantly longer duration of infection (2.1 days versus 1.0 and 1.2 days; P < 0.001). Multivariate analysis adjusting for covariates revealed that a high MIC was associated with an increase of 5.67 days (95% confidence interval, 0.77 to 10.62 days; P = 0.02) in the mean length of stay postculture compared to the mean length of stay for the low-MIC group. Patients treated with levofloxacin for bloodstream infections caused by gram-negative organisms for which MICs were elevated, yet still in the susceptible category, had worse outcomes than similar patients infected with organisms for which MICs were lower. In vitro susceptibility classifications of fluoroquinolones for the treatment of bloodstream infections caused by gram-negative organisms require further study.

The Use of ACE Inhibitors as Renoprotective Agents in Medicaid Patients with Diabetes

OBJECTIVE: To establish a relationship between angiotensin-converting enzyme (ACE) inhibitor therapy and renal outcomes in Medicaid patients with diabetes, and compare the use of ACE inhibitors between 1994 and 1998. METHODS: One thousand patients with either type 1 or type 2 diabetes were randomly selected from the Iowa Medicaid database and followed retrospectively from 1994 through 1998. Data on medication use (insulin, oral antidiabetic agents, or both) and medical services were collected from prescription claims and diagnostic codes. Differences were evaluated with nonparametric statistics. RESULTS: Overall, 402 patients (40.2%) were prescribed an ACE inhibitor during the study period before any adverse renal outcomes occurred; 25 of the patients in this group (6.2%) had a subsequent adverse renal outcome. One hundred patients (16.7%) not receiving an ACE inhibitor had an adverse renal outcome (p = 0.006). We evaluated four subgroups and found that patients with hypertension had fewer adverse renal outcomes if they were receiving ACE inhibitors whether they were taking (p = 0.0006) or not taking insulin (p = 0.047). There was no difference in adverse renal outcomes and ACE inhibitor use in normotensive patients who were taking (p = 0.15) or not taking insulin (p = 0.96). The pattern of use of ACE inhibitors in this population increased more than twofold between 1994 and 1998 (38.1% vs. 80.1%; p < 0.001). Of those patients who had adverse renal outcomes, almost one-half (43.2%) were not taking an ACE inhibitor in 1998. CONCLUSIONS: ACE inhibitors were renoprotective in patients with diabetes in the Iowa Medicaid population. All patients with diabetes who had hypertension had fewer renal outcomes when taking an ACE inhibitor. ACE inhibitors were used more frequently in 1998 than in 1994. The use of ACE inhibitors in this population is improving, but remains less than optimal.

Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: Implications for treatment guidelines

Objective:To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. Design:Prospective longitudinal PK study. Methods:HIV-infected pregnant antiretroviral therapy–naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20–24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). Results:Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18–35) years and baseline BMI was 32 (19–41) kg/m2. During pregnancy, total area under the time concentration (AUC0–12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0–12h remained unchanged during pregnancy [PK1: 1.6 (1.3–1.9) vs. PK2: 1.6 (1.3–1.9) &mgr;g·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3–2.1) &mgr;g·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08–0.15) vs. PK3: 0.12 (0.10–0.15) &mgr;g/mL, P = 0.09]. Albumin and LPV AUC0–12h fraction unbound were correlated (rs = 0.3, P = 0.03). Conclusions:Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.

Suboptimal Nevirapine Steady-state Pharmacokinetics During Intrapartum Compared With Postpartum in Hiv-1-seropositive Ugandan Women

Background: Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. Methods: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. Results: The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipants C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. Conclusions: Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.

Low incidence of renal impairment observed in tenofovir-treated patients

OBJECTIVES To compare the incidence of renal impairment in HIV-infected patients exposed versus unexposed to tenofovir and to characterize risk factors associated with renal impairment. METHODS We undertook a retrospective cohort and nested case-control study of 514 Northwestern University HIV Outpatient Study participants who received antiretroviral therapy (ART) between 1 August 2001 and 31 July 2007. Renal impairment was defined as meeting at least one of two validated criteria based on serum creatinine, calculated glomerular filtration rate and creatinine clearance. Multivariable analysis was performed to identify risk factors for renal impairment. RESULTS Renal impairment occurred in 14% (n = 72) of the cohort and was not correlated with exposure to tenofovir in univariate analyses. In multivariable analysis, more advanced age [odds ratio (OR) = 1.04, P = 0.02], diabetes (OR = 3.6, P < 0.01), decreased weight (OR = 0.97, P = 0.02) and endpoint CD4 ≤200 cells/mm(3) (OR = 2.5, P = 0.03) were positive predictors of renal impairment; tenofovir exposure (OR = 0.41, P = 0.01) was negatively correlated with renal impairment. CONCLUSIONS Tenofovir-containing ART was associated with less renal impairment than ART without tenofovir in a patient cohort with a high incidence of renal impairment. Chronic co-morbid conditions known to be associated with renal impairment should be excluded prior to attributing renal impairment to tenofovir.