A Longitudinal Integrative Course Series to Prepare Students for Advanced Pharmacy Practice Experiences.

Background: This paper describes a series of integrative courses intentionally designed to prepare students for Advanced Pharmacy Practice Experiences (APPEs) in a block system curriculum. Innovation: Three integration blocks are interspersed throughout the didactic curriculum to serve as checkpoints to ensure competency as students progress in the curriculum, rather than waiting until the end to determine competency. Complex patient case discussions and a series of high-stakes assessments are used to reinforce and evaluate cumulative retention of knowledge, skills, and attitudes. Findings: Class of 2022 exam results showed that in the cohort of students who failed the high-stakes comprehensive knowledge assessment (CKA) and pharmacy calculations exams during the first integration block (IB), failure rates decreased in subsequent IBs, indicating early detection of knowledge deficiencies and either exam performance improvement in each IB or failure to progress to the next IB. A survey of the same cohort indicated that the final integration block prior to advanced pharmacy practice experiences (APPEs) helped improve confidence in applying key knowledge and skills into practice. Conclusion: The series of integration blocks designed and implemented at WesternU provides opportunities to reinforce knowledge and skills while requiring students to demonstrate maintenance of core competency as they progress through the curriculum.

Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and ß-lactamase-inhibitor combination.

The management of infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, continues to be a significant challenge to clinicians. Ceftolozane/tazobactam is a novel antibacterial and ß-lactamase-inhibitor combination that has shown appreciable activity against wild-type Enterobacteriaceae and potent activity against P. aeruginosa. Moreover, ceftolozane/tazobactam has not demonstrated cross-resistance to other antimicrobial classes, particularly those affected by extended-spectrum ß-lactamases, AmpC ß-lactamase, a loss in porin channels, or the overexpression of efflux pumps in P. aeruginosa. Ceftolozane/tazobactam has completed two Phase II clinical trials in complicated intra-abdominal and complicated urinary tract infections. A Phase III, multicenter, prospective, randomized, open-label study has been initiated to evaluate the safety and efficacy of ceftolozane/tazobactam versus piperacillin/tazobactam for the treatment of ventilator-associated pneumonia. A Medline search of articles from inception to May 2013 and references for selected citations was conducted. Data from abstracts presented at conferences were also appraised. This article reviews the antimicrobial, pharmacokinetic, and pharmacodynamic profile of ceftolozane/tazobactam, and discusses its potential role in therapy.

Cost-effectiveness of linezolid in methicillin-resistant Staphylococcus aureus skin and skin structure infections.

Linezolid is a novel oxazolidinone antibacterial agent with a broad clinical application, especially in methicillin-resistant Staphylococcus aureus skin and soft-tissue infections and skin and skin-structure infections. Pharmacoeconomic advantages include decreased hospital duration, reduction in intravenous antibiotic use and early discharge opportunities that contribute to an overall reduction in healthcare resources. Linezolid's oral formulation has a pharmacokinetic profile that is similar to its intravenous formulation, which creates opportunities for early discharge not available to comparators like vancomycin and daptomycin. Both vancomycin and daptomycin require intravenous therapy, which compounds the resources required in treating methicillin-resistant S. aureus skin and soft tissue/skin and skin structure infections. Pharmacoeconomic studies have demonstrated an overall reduction in total direct costs to the payer in favor of linezolid over its comparators. Its overall reduction in healthcare utilization makes it an appropriate alternative to the standard therapy, vancomycin.

Cost-effectiveness analysis of linezolid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus: complicated skin and skin structure infection using Bayesian methods for evidence synthesis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and skin structure infection (cSSSI) is a prominent infection encountered in hospital and outpatient settings that is associated with high resource use for the health-care system. OBJECTIVE: A decision analytic (DA) model was developed to evaluate the cost-effectiveness analysis (CEA) of linezolid, daptomycin, and vancomycin in MRSA cSSSI. METHODS: Bayesian methods for evidence synthesis were used to generate efficacy and safety parameters for a DA model using published clinical trials. CEA was done from the US health-care perspective. Efficacy was defined as a successfully treated patient at the test of cure without any adverse reaction. Primary outcome was the incremental cost-effectiveness ratio between linezolid and vancomycin, daptomycin and vancomycin, and linezolid and daptomycin in MRSA cSSSI. Univariate and probabilistic sensitivity analyses were performed to test the robustness of the model. RESULTS: The total direct costs of linezolid, daptomycin, and vancomycin were $18,057, $20,698, and $23,671, respectively. The cost-effectiveness ratios for linezolid, daptomycin, and vancomycin were $37,604, $44,086, and $52,663 per successfully treated patient, respectively. Linezolid and daptomycin were dominant strategies compared to vancomycin. However, linezolid was dominant when compared to daptomycin. The model was sensitive to the duration of daptomycin and linezolid treatment. CONCLUSION: Linezolid and daptomycin are potentially cost-effective based on the assumptions of the DA model; however, linezolid appears to be more cost-effective compared to daptomycin and vancomycin for MRSA cSSSIs.

Assessment of patient communication skills during OSCE: examining effectiveness of a training program in minimizing inter-grader variability.

OBJECTIVE: To assess effectiveness of a training program in reducing inter-grader variability in grading communication skills during an objective structured clinical exam (OSCE). METHODS: Global communication (GC) skills are assessed by standardized participants (SP) and faculty during each OSCE using a 6 item rubric. Despite criteria delineated in the GC rubric, inter-grader variability was observed. During 2008-2009 academic year, a training program was implemented before each OSCE to achieve more consistent interpretation and grading in GC skills. GC grades between SP and faculty for 2nd and 3rd level student OSCEs during 2008-2009 (post-training) were compared to 2007-2008 (pre-training). Data was analyzed using repeated measures ANOVA. RESULTS: 274 and 281 students participated in OSCEs during 2007-2008 and 2008-2009 academic years, respectively. Training significantly (P<.001) decreased grader variability between SPs and faculty. There was a greater mean difference between faculty vs. SP before training (faculty 14.68, SP 15.87) compared to after training (faculty 13.51, SP 13.78). Mean GC scores for both faculty and SPs also decreased significantly after training. CONCLUSION AND PRACTICE IMPLICATIONS: A training program may be necessary to reduce inter-rater variability in assessment of OSCE communication skills if it is to be truly helpful to student pharmacists learning to counsel patients.

A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients.

OBJECTIVES: Candida non-albicans species cause an increasing proportion of invasive candidiasis (IC). Prompt initiation of effective antifungal therapy has been shown to positively impact the outcomes of IC. Caspofungin is often reserved as a second-line agent after suboptimal response to initial therapy. We determined the impact of the timing of caspofungin administration on outcomes of IC. METHODS: Medical records were reviewed on all hospitalized adults who received >or=72 h of caspofungin for IC (isolation of Candida species from blood, intra-abdominal or other sterile sites). Clinical data were extracted from medical charts and recorded. Patients were classified based on delayed initiation (DI; >3 days) versus early initiation (EI;

Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): a meta-analysis.

OBJECTIVE: To evaluate the clinical and microbiological outcomes of linezolid versus vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) using a meta-analysis. RESEARCH DESIGN AND METHODS: Clinical trials were identified using PubMed, the Cochrane Central Register of Controlled Trials, and the International Pharmaceutical Abstracts from inception to March 2009. Primary outcomes evaluated resolution of signs and symptoms of infection in clinically evaluable (CE) patients, and microbiological eradication in both the modified intent-to-treat (MITT) and MRSA evaluable (MRSA ME) patients. MITT patients had a culture-confirmed Gram-positive pathogen (S. aureus) at baseline. Secondary outcomes included mortality, adverse drug reactions (ADR), and discontinuation due to ADRs. The Mantel-Haenszel odds ratios (OR) with 95% confidence intervals (CI) were calculated using the fixed effects model based on the assumption that there was little to no heterogeneity between the studies in the primary analysis. Sensitivity analyses were performed for each outcome by removing the most weighted study. RESULTS: Five studies with a total of 2652 patients (1361/linezolid; 1291/vancomycin) were identified. Resolution of infection in CE patients (OR = 1.41; 95% CI: 1.03, 1.95) and MITT patients (OR = 1.91; 95% CI: 1.33, 2.76) favored the use of linezolid over vancomycin, but did not remain significant after sensitivity analyses (CE: OR = 1.29; 95% CI: 0.81, 2.05; MITT: OR = 1.73; 95% CI: 0.87, 3.41). Microbiological eradication in MRSA ME patients consistently favored the use of linezolid over vancomycin (OR = 2.90; 95% CI: 1.90, 4.41). No difference in mortality was observed between the two groups (OR = 1.17; 95% CI: 0.85, 1.62). Higher proportions of linezolid patients were found to have diarrhea (119/1361 vs. 52/1291), nausea (102/1361 vs. 46/1291) and thrombocytopenia (54/1121 vs. 8/1071), whereas a higher proportion of vancomycin patients were found to have renal insufficiency compared to linezolid (16/634 vs. 4/703). Inconsistent results were seen with the incidence of anemia and rash between the base-case (anemia: OR = 1.36; 95% CI: 0.90, 2.08; rash: OR = 0.26; 95% CI: 0.10, 0.68) and sensitivity analyses (anemia: OR = 2.33; 95% CI: 1.24, 4.37; rash: OR = 0.57; 95% CI: 0.12, 2.71). Discontinuation due to ADRs was not statistically different between linezolid and vancomycin (OR = 1.06; 95% CI: 0.75, 1.51). CONCLUSION: Resolution of infection in CE and MITT patients were inconsistent; however, a sub-analysis revealed that linezolid was more likely to consistently achieve microbiologic eradication in MRSA ME patients. Apparent risks of thrombocytopenia, nausea, diarrhea, and possibly anemia may limit linezolid use in treating MRSA cSSTI. This study was limited due to an inability to assess for the effects of hetero-resistance and appropriate vancomycin dosing on outcomes. Moreover, the small number of studies made controlling for heterogeneity challenging.

Comparison of method-specific vancomycin minimum inhibitory concentration values and their predictability for treatment outcome of meticillin-resistant Staphylococcus aureus (MRSA) infections.

The objectives of this study were to examine the predictive value of method-specific vancomycin (VAN) minimum inhibitory concentration (MIC) results on treatment outcomes of meticillin-resistant Staphylococcus aureus (MRSA) infections. VAN MIC values for MRSA strains were determined using Etest, VITEK-1, MicroScan (MScan) and broth microdilution (BMD), with additional screening for heterogeneous glycopeptide-intermediate S. aureus (hGISA) phenotype. Patients' charts were reviewed for outcome correlation. Performance characteristics of method-specific VAN MICs in predicting outcome were compared. Most (76%) of the 92 strains tested caused pneumonia or bacteraemia. The majority of strains tested (>70%) had a VAN MIC >1mg/L by Etest or MScan compared with 41% by Vitek and 7% by BMD. Agreement between test methods for high versus low MICs (>1mg/L vs. < or = 1mg/L) ranged from 36% to 71%. High versus low VAN MICs by Etest differentiated response of invasive strains to VAN. Performance characteristics (sensitivity/specificity/positive predictive value/negative predictive value) were: Etest, 55/81/89/38%; and Vitek, 56/62/81/32/%, respectively. Eight strains (9%) demonstrated a hGISA phenotype; more yielded high MICs by Etest, MScan and Vitek than BMD (87%, 87% and 75% vs. 50%). In conclusion, VAN MIC testing methods produce highly variable results. The Etest method appears to be relatively more reliable in predicting treatment response and yielded higher MICs for strains with a hGISA phenotype.

Reducing empirical use of fluoroquinolones for Pseudomonas aeruginosa infections improves outcome.

BACKGROUND: We previously reported ciprofloxacin resistance (CR) and empirical use of fluoroquinolones as predictors of mortality in patients infected with Pseudomonas aeruginosa in a case-control study. Here, we assessed the clinical impact of reducing empirical fluoroquinolone use for P. aeruginosa infections in hospitalized patients by performing a follow-up study in 2005-06 [period 2 (P2)] and comparing this with prior data from 2001-02 [period 1 (P1)]. METHODS: Medical charts of infected patients who received at least 72 h of antibiotic therapy were reviewed. Patients were subgrouped based on the susceptibility of infected strains into the CR or ciprofloxacin-susceptible group. Antibiograms, patient and treatment variables and outcome measures were compared between groups and between study periods. RESULTS: Study patients were elderly (median age, 76 years), had a median of three co-morbidities and a median APACHE II score of 13. Most (75%) had pneumonia or urosepsis. Empirical use of fluoroquinolones was reduced by 30% in P2 versus P1, with a corresponding 39% increase in piperacillin/tazobactam use. The resultant positive impact observed in the CR group during P2 includes shortened delay to receipt of effective therapy (1 versus 3.5 days, P < 0.0001), reduced length of stay (13 versus 16 days, P = 0.03) and 2-fold lower mortality (9% versus 22%, P = 0.05). Susceptibility of P. aeruginosa improved by 10% to all antipseudomonal agents tested. CONCLUSIONS: In settings where high rates of fluoroquinolone resistance exist, use of non-fluoroquinolone-based empirical regimens for P. aeruginosa infections improves patient outcomes and organism susceptibility over time.

High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.

BACKGROUND: Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 microg/mL. METHODS: A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC (>/=2 vs <2 microg/mL) for efficacy and high vs low trough (>/=15 vs <15 microg/mL) for nephrotoxicity analyses. RESULTS: Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents. CONCLUSIONS: High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 microg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 microg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.

Fluoroquinolone-resistant Pseudomonas aeruginosa: risk factors for acquisition and impact on outcomes.

OBJECTIVES: Resistance among Pseudomonas aeruginosa has risen dramatically and parallels the increase in fluoroquinolone (FQ) prescribing in recent years. Risk factors for FQ resistance in P. aeruginosa and its impact on outcomes need to be well characterized. METHODS: A case-control study was carried out on hospitalized adult patients from whom FQ-resistant (case) and FQ-susceptible (control) P. aeruginosa were isolated. RESULTS: A total of 177 patients with positive cultures (91 cases and 86 controls) and 119 with documented infections (65 cases, 54 controls) were included in risk factor and outcomes analysis, respectively. Independent risk factors for FQ resistance were: FQ exposure (OR 12.6, CI 4.95-32), nosocomial acquisition (OR 8.6, CI 3.5-20.7), and diabetes mellitus (OR 6.4, CI 2.1-19.3). An FQ agent was prescribed in 59% of patients receiving an 'antipseudomonal' empirical regimen. Compared with controls, FQ-resistant cases had a median delay to receiving effective therapy of 3.5 days versus 1 day and poorer outcomes: (i) lower complete response rate (45% versus 63%, P=0.04); (ii) longer time to achieve clinical stability (8 days versus 3 days, P=0.005); and (iii) higher infection-related mortality (21% versus 7%; OR = 2.9, 0.9-9.4). Empirical FQ use (OR 4.6, CI 1.5-14.3), FQ resistance (OR 3.6, CI 1.0-13.1), and high APACHE II score (OR 1.1, CI 1.0-1.2) were independent risk factors for increased mortality. CONCLUSIONS: FQ exposure from widespread prescribing is a modifiable risk factor for FQ resistance in P. aeruginosa. FQ empirical therapy for Pseudomonas infections may be associated with significant delays in administering effective therapy resulting in adverse outcomes.