Impact of PhORCAS references on overall application score for postgraduate year 1 pharmacy residency candidates.

PURPOSE: The disparity between the number of applicants for postgraduate year 1 (PGY1) pharmacy residency positions and the number of available residency positions increases the need to optimize how applicants are evaluated. The purpose of the study described here was to evaluate the correlation of ratings of residency candidate characteristics by academic and professional references listed on residency applications with overall application score, applicant ranking, and the likelihood of candidates receiving an invitation to interview. METHODS: A multicenter, retrospective study was conducted to evaluate the correlation of reference writers' ratings of 13 candidate characteristics and their overall recommendations with program-determined outcomes (eg, final application score, applicant ranking, and invitation to interview) through analysis of PGY1 applications submitted through the Pharmacy Online Residency Centralized Application System (PhORCAS) from 2015 through 2018. Keywords and themes within the open-ended section of letters of reference were also analyzed for correlation with overall application score. RESULTS: A total of 5,923 references listed on 1,867 applications to 4 PGY1 pharmacy residency programs processed by PhORCAS were included in the analysis. For the majority of applicant characteristic ratings (ie, 74% of 56,872 ratings overall), reference writers rated candidates as exceeding expectations, and applicants were "highly recommended" by these evaluators in 91% of cases. References' average characteristic ratings and overall recommendations were poorly correlated with final application score (R2 = 0.12 [P < 0.0001] and R2 = 0.08 [P < 0.0001], respectively), final ranking (R2 = 0.02 [P < 0.0001] and R2 = 0.03 [P < 0.0001], respectively), and invitation to interview (R2 = 0.07 [P < 0.0001] and R2 = 0.04 [P < 0.0001], respectively). For the themes evaluated, references' use of teaching words best correlated with normalized final application score, although the correlation was poor (R2 = 0.007, P = 0.0001). CONCLUSION: Reference writers' ratings of PGY1 residency candidate characteristics in PhORCAS are poorly correlated with application score, applicant ranking, and invitation to interview. The results of this study suggest that the existing PhORCAS standardized form for submitting references is of limited utility in its current state.

Influence of ß-Lactam Infusion Strategy on Acute Kidney Injury.

Limited literature is available assessing nephrotoxicity with prolonged ß-lactam infusions. This study compared the incidence of acute kidney injury (AKI) associated with a prolonged ß-lactam infusion or an intermittent infusion. This was a retrospective, matched-cohort study at an academic medical center from July 2006 to September 2015. Adult patients who received piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) for at least 48 h were evaluated. Patients were excluded for preexisting renal dysfunction or pregnancy. The primary outcome was difference in incidence of AKI evaluated using the RIFLE (risk, injury, failure, loss, and end-stage) criteria. Patients in the intermittent group were matched 3:1 to patients in the prolonged-infusion group based on the following: ß-lactam agent, age, gender, Charlson comorbidity index, baseline creatinine clearance, hypotension, receipt of vancomycin, and treatment in an intensive care unit. A total of 2,390 patients were included in the matched analysis, with 1,700 receiving intermittent infusions and 690 receiving prolonged infusion. The incidence of AKI was similar in the prolonged-infusion group to that in the intermittent-infusion group (21.6% versus 18.6%; P = 0.1). After multivariate regression, prolonged infusion was not associated with increased odds of AKI (odds ratio [OR], 1.07; 95% confidence interval [95% CI], 0.83 to 1.39). Independent predictors of AKI included TZP therapy, concomitant nephrotoxins, hypotension, and heart failure. Although AKIs were numerically more common in patients receiving prolonged ß-lactam infusions than those receiving intermittent infusions, prolonged infusion was not an independent risk factor for AKI.

Nephrotoxicity in Patients with or without Cystic Fibrosis Treated with Polymyxin B Compared to Colistin.

Nephrotoxicity is the primary adverse effect of the polymyxins. The relative rates of toxicity of polymyxin B and colistin have not been fully elucidated, especially in patients with cystic fibrosis (CF). A retrospective cohort study of adults treated with polymyxin B or colistin for at least 48 h was conducted. The primary endpoint was the incidence of kidney injury assessed by RIFLE (i.e., risk, injury, failure, loss, end-stage renal disease) criteria. Risk factors for kidney injury were evaluated using multivariate Cox regression. A total of 414 patients were evaluated, 220 of whom had CF. In patients without CF, there was no difference in kidney injury with polymyxin B and colistin (42.9% versus 50.3%, P = 0.46). Loop diuretic exposure was a risk factor for kidney injury (adjusted hazard ratio [aHR], 1.82; 95% confidence interval [CI], 1.16 to 2.83) in this population. In patients with CF, polymyxin B and colistin were associated with similar rates of kidney injury (34.5% versus 29.8%, P = 0.77). Diabetes (aHR, 2.68; 95% CI, 1.01 to 7.11), loop diuretics (aHR, 3.02; 95% CI, 1.36 to 6.73), and progressive care unit admission (aHR, 8.21; 95% CI, 2.55 to 26.46) were risk factors for kidney injury, while higher baseline serum creatinine levels (per 1 mg/dl) were protective (aHR, 0.08; 95% CI, 0.01 to 0.48). Total unadjusted kidney injury in polymyxin-treated patients was less frequent in those who had CF (30.5% versus 48.5%, P < 0.001). Polymyxin B and colistin are associated with a high incidence of kidney injury; cystic fibrosis may be protective against polymyxin nephrotoxicity, but further investigation is needed to confirm this conjecture.

Comparison of ß-lactam plus aminoglycoside versus ß-lactam plus fluoroquinolone empirical therapy in serious nosocomial infections due to Gram-negative bacilli.

We sought to compare clinical cure on day 7 and a 28-day all-cause mortality in patients who received an anti-pseudomonal ß-lactam with a fluoroquinolone or an aminoglycoside for treatment of nosocomial bacteremia or pneumonia due to Gram-negative bacilli while in the ICU. This retrospective cohort study was conducted in critically ill patients at an academic medical centre from January 2005 to August 2011. A total of 129 patients (83 receiving aminoglycoside and 46 receiving fluoroquinolone combinations) were included. Seven-day clinical cure rates were 74% and 72% for fluoroquinolone and aminoglycoside groups, respectively (p = 0.84). There was no significant difference in the odds of clinical cure with a fluoroquinolone as compared to an aminoglycoside combination (adjusted odds ratio 2.4, 95% confidence interval [CI] 0.7-9.0). There was no significant difference in 28-day mortality in patients who received a fluoroquinolone or an aminoglycoside combination (22% vs. 18%, adjusted hazard ratio 0.82, 95% CI 0.29-2.28).

Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime.

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in the AKI incidence between the TZP-VAN and FEP-VAN groups, evaluated using the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Patients in the two groups were matched on the basis of age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and intravenous contrast exposure. In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN, whereas it was 12.6% in patients receiving FEP-VAN (P < 0.001). After the patients were matched, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN than in those receiving FEP-VAN (21.4% versus 12.5%, P < 0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI than FEP-VAN therapy (95% confidence interval, 1.64 to 2.94 times) in logistic regression. AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than in those receiving vancomycin in combination with cefepime. This finding reinforces the need for the judicious use of combination empirical antimicrobial therapy.

Optimizing beta-lactam pharmacodynamics against Pseudomonas aeruginosa in adult cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis (CF) exhibit increased clearance of beta-lactams. The purpose of this study was to predict the probability of beta-lactam target attainment (PTA) against Pseudomonas aeruginosa in adult CF patients based on local microbiological data. METHODS: CF-specific pharmacokinetic parameters were obtained from published data for aztreonam, cefepime, ceftazidime, meropenem and piperacillin-tazobactam. Pharmacodynamic modeling was used to determine the PTA for bolus, prolonged infusion, and continuous infusion regimens. RESULTS: Prolonged infusion of meropenem 2g every 8h performed the best among all regimens tested, with a PTA of 83%. The PTA was increased with both prolonged and continuous infusion; however, no regimen reached the target PTA of >90% against P. aeruginosa in CF patients at our institution. CONCLUSIONS: Prolonged and continuous infusion provided higher PTA than bolus for all regimens. Further investigation of novel regimens in CF patients is needed.

Utilizing Monte Carlo Simulations to Optimize Institutional Empiric Antipseudomonal Therapy.

Pseudomonas aeruginosa is a common pathogen implicated in nosocomial infections with increasing resistance to a limited arsenal of antibiotics. Monte Carlo simulation provides antimicrobial stewardship teams with an additional tool to guide empiric therapy. We modeled empiric therapies with antipseudomonal ß-lactam antibiotic regimens to determine which were most likely to achieve probability of target attainment (PTA) of ≥90%. Microbiological data for P. aeruginosa was reviewed for 2012. Antibiotics modeled for intermittent and prolonged infusion were aztreonam, cefepime, meropenem, and piperacillin/tazobactam. Using minimum inhibitory concentrations (MICs) from institution-specific isolates, and pharmacokinetic and pharmacodynamic parameters from previously published studies, a 10,000-subject Monte Carlo simulation was performed for each regimen to determine PTA. MICs from 272 isolates were included in this analysis. No intermittent infusion regimens achieved PTA ≥90%. Prolonged infusions of cefepime 2000 mg Q8 h, meropenem 1000 mg Q8 h, and meropenem 2000 mg Q8 h demonstrated PTA of 93%, 92%, and 100%, respectively. Prolonged infusions of piperacillin/tazobactam 4.5 g Q6 h and aztreonam 2 g Q8 h failed to achieved PTA ≥90% but demonstrated PTA of 81% and 73%, respectively. Standard doses of ß-lactam antibiotics as intermittent infusion did not achieve 90% PTA against P. aeruginosa isolated at our institution; however, some prolonged infusions were able to achieve these targets.

Early experience with tedizolid: clinical efficacy, pharmacodynamics, and resistance.

Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.

Fulminant Invasive Pulmonary Aspergillosis After a Near-Drowning Accident in an Immunocompetent Patient.

OBJECTIVE: To report on invasive aspergillosis infection in an immunocompetent adult after a near-drowning event, which allowed this pathogen to easily gain access to the human respiratory system and result in rapid, severe infection. CASE SUMMARY: A 51-year-old female developed severe pneumonia after a near-drowning accident. Two days after admission, a bronchial alveolar lavage (BAL) was performed and was positive for Aspergillus fumigatus. After a 30-day hospital course, multiple antifungals, and various routes of administration, the patient expired. DISCUSSION:: Pneumonia is particularly common because of the aspiration of contaminated water. Whereas pneumococci, staphylococci, and Gram-negative bacteria are all common pathogens for this type of infection, fungi such as Aspergillus spp can also be involved and may be life threatening. Typically, these cases are reported in individuals with an immunodeficiency such as from receipt of myelosuppressive chemotherapy, bone marrow transplants, or lung transplants. Despite initiation of an appropriate empirical antifungal regimen, the rapid recovery of A fumigatus from pulmonary alveolar lavage and BAL samples as well as extremely elevated levels of galactomannan and (1→3)-ß-D glucan may have indicated an invasive fungal infection (IFI). CONCLUSION:: IFIs are uncommon in immunocompetent adults, but in the event of a near-drowning accident, environmental fungi can gain access to the human respiratory system and result in rapid, severe infection. Based on this case and the others described, it appears that near-drowning patients need an early initial evaluation for IFI.

Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness.

Platelet activation results in the release and upregulation of mediators responsible for immune cell activation and recruitment, suggesting that platelets play an active role in immunity. Animal models and retrospective data have demonstrated benefit of antiplatelet therapy on inflammatory mediator expression and clinical outcomes. This study sought to characterize effects of clopidogrel on the incidence and severity of community-acquired pneumonia (CAP). A retrospective cohort study was conducted of Kentucky Medicaid patients (2001-2005). The exposed cohort consisted of patients receiving at least six consecutive clopidogrel prescriptions; the non-exposed cohort was comprised of patients not prescribed clopidogrel. Primary endpoints included incidence of CAP and inpatient treatment. Secondary severity endpoints included mortality, intensive care unit admission, mechanical ventilation, sepsis, and acute respiratory distress syndrome/acute lung injury. CAP incidence was significantly greater in the exposed cohort (OR 3.39, 95% CI 3.27-3.51, p < 0.0001) that remained after adjustment (OR 1.48, 95% CI 1.41-1.55, p < 0.0001). Inpatient treatment was more common in the exposed cohort (OR 1.96, 95% CI 1.85-2.07, p < 0.0001), but no significant difference remained after adjustment. Trends favoring the exposed cohort were found for the secondary severity endpoints of mechanical ventilation (p = 0.07) and mortality (p = 0.10). Pooled analysis of published studies supports these findings. While clopidogrel use may be associated with increased CAP incidence, clopidogrel does not appear to increase--and may reduce--its severity among inpatients. Because this study was retrospective and could not quantify all variables (e.g., aspirin use), these findings should be explored prospectively.

Fungal infection in heart-lung transplant recipients receiving single-agent prophylaxis with itraconazole.

OBJECTIVES: Heart and lung transplant recipients are at risk for invasive fungal infections. This study evaluated the affect of single-agent antifungal prophylaxis with itraconazole on the rate of fungal infections after heart or lung transplant. MATERIALS AND METHODS: An observational, retrospective study was performed to evaluate the rate of fungal infections in heart and lung transplant recipients at the University of Kentucky Medical Center over 4.5 years who received itraconazole as a single therapy prophylaxis. RESULTS: Eighty-three recipients (42 heart, 41 lung) had an overall fungal infection incidence of 16.9% (14/83), while the incidence was 11.9% for heart recipients (5/42), and 22.0% for lung recipients (9/41). CONCLUSIONS: Single-agent use with itraconazole in heart or lung transplant recipients did not affect the rate of fungal infection as compared with previous reports. The incidence of fungal infection increased significantly within 3 months after escalation of immunosuppressant for treatment of acute rejection.

Candidemia incidence in recipients of parenteral nutrition.

BACKGROUND: The purpose of this study was to assess the incidence of candidemia in recipients of parenteral nutrition (PN) in a tertiary medical center with disease-specific guidelines for appropriate PN use. METHODS: A retrospective, medical record/database review was conducted for adult patients who received PN in a 473-bed medical center from January 2006 to October 2008. Patients receiving PN >72 hours with no recent history of fungemia or concomitant antifungal therapy were evaluated for candidemia incidence with special interest in intensive care unit (ICU) patients. Epidemiological and clinical factors promoting candidemia development, pattern of systemic antifungal therapy use, and patient outcomes were investigated. RESULTS: Of 286 PN recipients, 14 (4.9%) patients were diagnosed with new-onset candidemia, with an incidence rate of 1.6 episodes per 1000 hospital-days. In the subgroup of 177 ICU patients, 11 (6.2%) patients developed candidemia, with an incidence rate of 2.4 episodes per 1000 ICU-days. PN duration was significantly longer in the candidemia group, with a median of 17 (4-53) days compared with 8 (4-124) days in the noncandidemia group (P = .013). Severity of illness was defined as major to extreme in 83.5% of patients. Hospital mortality in the candidemia group was greater than in the noncandidemia group (35.7% vs 16.2%, P = .058). CONCLUSIONS: Guidelines for PN therapy appropriately limit unnecessary use of PN but also select out severely ill patients who are at high risk for the development of candidemia. This study generates questions for future studies, including the benefits of empirical antifungal therapy in high-risk PN recipients.

Effects of a pharmacist-to-dose computerized request on promptness of antimicrobial therapy.

OBJECTIVES: To examine the effects of computerized requests for pharmacist-to-dose (PTD), an advanced clinical decision support tool for dosing guidance, on antimicrobial therapy with vancomycin and aminoglycosides, describe PTD request utilization, and identify factors that may prolong this process. DESIGN: A retrospective review was conducted of patients hospitalized from Jan 2004 to Jun 2006 with suspected pneumonia who received vancomycin, tobramycin, or gentamicin via PTD (study) or routine provider order entry (control). MEASUREMENTS: The primary endpoint was time to pharmacist completion of PTD request. Secondary data points included medication turn-around times for first doses of vancomycin or aminoglycosides and for first doses of any antibiotic, dose adjustment for renal dysfunction, medication errors, and time of order entry. Multivariate analysis was conducted to identify predictors of total time to pharmacist verification and time to administration of first doses of vancomycin or aminoglycosides. RESULTS: Median time for pharmacist completion of PTD requests was 29 minutes. Delays were noted in the study group (n = 49) by comparison with the control group (n = 48) for median time to first dose of vancomycin or aminoglycoside (185 vs. 138 min, p = 0.45) and for any antibiotic (134 vs. 118 min, p = 0.42), respectively. Fewer medication errors were reported in the study group (5 vs. 18 errors, p = 0.002). In a multivariate model, PTD was not significantly predictive of time to pharmacy verification or medication turn-around time. CONCLUSIONS: Pharmacists completed pharmacist-to-dose consultations for dosing guidance of vancomycin and aminoglycosides within a median of 30 minutes. Implementation of a computerized request for clinical pharmacists to provide medication-related clinical decision support increased medication turn-around time of vancomycin and aminoglycosides and reduced medication errors. Consultation of clinical pharmacists by computerized request for initial antibiotic dosing of medications with narrow therapeutic windows is an option for medication-related clinical decision support but providers should be aware that consultation may delay medication turn-around time.

Which hydroxy? Evidence for species differences in the regioselectivity of glucuronidation in rat, dog, and human in vitro systems and dog in vivo.

The glucuronidation of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-[7-{[(1R,2S)-2-phenylcyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2-diol (AZ11939714) was studied in UDP-glucuronic acid (UDPGA)-supplemented hepatic microsomes from rat, dog, and human liver. The major biliary metabolite of this compound after intraduodenal administration to a beagle dog was also studied. The techniques of HPLC, HPLC-MS and HPLC-NMR were used to characterize the glucuronides. An analysis of the proton NMR chemical shift differences between parent and metabolites was sufficient to deduce the sites of glucuronidation, although these were confirmed by 2D ROESY experiments. In dog microsomes, AZ11939714 was O-glucuronidated exclusively at the 1-position of the cyclopentanediol. This glucuronide was also the major metabolite in dog bile. In human microsomes, AZ11939714 was O-glucuronidated almost exclusively at the 3-hydroxymethyl position. Rat microsomes produced a mixture of glucuronides at the 2-position of the cyclopentanediol (major) and at the 3-hydroxymethyl position (minor). A clear qualitative species difference in the glucuronidation of AZ11939714 has been demonstrated in vitro. This may have implications for the choice of laboratory species to study the pharmacokinetics and safety of this compound.