Faculty Bibliography

Extended infusion (EI) administration of β-lactams can improve target attainment in critically ill patients with altered pharmacokinetics/pharmacodynamics. To optimize meropenem dosing in patients with severe sepsis/septic shock, our Antimicrobial Stewardship Program implemented a EI meropenem (EIM) protocol in an 18-bed Medical Intensive Care Unit in March 2014. In this retrospective study, we compared intensive care unit (ICU) mortality and clinical response in patients who received meropenem for ≥72 hours administered per EIM protocol of 1 g over 3 hours every 8 hours versus intermittent infusion (IIM) protocol of 500 mg over 30 minutes every 6 hours. Age, weight, comorbidities, severity of illness, and vasopressor use were comparable between groups (EIM protocol n = 52, IIM protocol n = 96). The IIM protocol group had higher rates of renal dose adjustment at meropenem initiation. Among 56 identified gram-negative (GN) pathogens, 94% had meropenem minimal inhibitory concentration ≤0.25 mg/L. The ICU mortality was lower (19 vs 37%; P = .032) and clinical response was higher (83% vs 46%; P < .01) in the EIM protocol versus IIM protocol group. Total vasopressor days were shorter (2 vs 3 days; P = .038), and white blood cell normalization rate was higher (87% vs 51%; P < .01) in the EIM protocol versus IIM protocol group. There was no difference in days of mechanical ventilation, duration of therapy, and ICU stay. The IIM protocol was also identified as an independent risk factor associated with ICU mortality (hazard ratio: 3.653, 95% confidence interval: 1.689-7.981; P = .001) after adjusting for Sequential Organ Failure Assessment score. In this cohort of patients with severe sepsis/septic shock and highly susceptible GN pathogens, there was improved mortality and clinical response in the EIM protocol group.

Purpose: Leveraging pharmacy personnel resources for the purpose of antimicrobial stewardship program (ASP) operations presents a challenging task. We describe our experience integrating all pharmacists into an ASP, and evaluate the impact on ASP interventions, antimicrobial utilization, rate of selected hospital-onset infections and readmission. Summary: During a study period (January 1 to December 31, 2015), a total of 14 552 ASP-related pharmacy interventions were performed (ASP clinical pharmacotherapy specialists [CPS] n = 4025; non-ASP CPS n = 4888; hospital pharmacists n = 5639). Sixty percent of interventions by ASP CPS were initiated utilizing the dedicated ASP phone, and 40% through prospective audit and feedback. Non-ASP CPS performed interventions during bedside rounds (dose adjustment 23%, initiate new or alternative anti-infective 21%, discontinue antibiotic(s) 12%, therapeutic drug monitoring 11%, de-escalation 4%), whereas hospital pharmacists participated at the point of verification (dose adjustment 75%, restricted antibiotic verification 15%, and reporting major drug-drug interactions 4%). The acceptance rate of interventions by providers and clinicians was >90% for all groups. Annual aggregate antimicrobial use decreased by 6.4 days of therapy/1000 patient-days (DOT/1000 PD; P = 1.0). Ceftriaxone use increased by 8.4 DOT/1000 PD (P = .029) without a significant compensatory increase in the use of antipseudomonal agents. Sustained low rates of hospital-onset Clostridium difficile (CDI) and carbapenem-resistant Enterobacteriaceae (CRE) infections were observed in 2015 compared with the prior year (1.1 and 1.2 cases/1000 PD, 0.2 and 0.1 cases/1000 PD, respectively). Thirty-day readmission rate decreased by 0.6% (P = .019). Conclusions: Integration of all pharmacists into ASP activities based on the level of patient care and responsibilities is an effective strategy to expand clinical services provided by ASP.

BACKGROUND: Pediatric antimicrobial stewardship programs (ASPs) within larger institutions have unique opportunities to develop programs specialized to the needs of the pediatric program. In January 2013, our institution established a formalized pediatric ASP utilizing the prospective audit and feedback process. In an effort to standardize therapy and improve quality of care, members of the ASP developed evidence-based guidelines for management of common inpatient pediatric infections. ASP members met periodically with faculty and house staff to discuss guidelines and ways to improve prescribing. METHODS: Provider adherence with clinical inpatient practice guidelines, frequency of interventions suggested by ASP, and acceptance of interventions by providers were elements used to measure process change. We measured outcome data by analyzing antimicrobial utilization (defined as days of therapy) and length of therapy. RESULTS: Over a period of 2 years, institutional ASP guidelines were applicable to nearly half (44%) of all antimicrobial orders. Interventions were performed on 30% of all antimicrobial orders, of which 89% were accepted. Total antimicrobial days of therapy and length of therapy decreased significantly when comparing pre- and post-ASP. Overall, the susceptibility profiles of common bacterial pathogens to antibiotics remained stable. CONCLUSIONS: Pediatric ASPs within larger institutions have opportunities to create programs specific to the needs of the population they serve. We observed high rates of adherence by providers and a subsequent reduction in antibiotic utilization when implementing an audit feedback-based process.

Background. Due to altered pharmacokinetics/pharmacodynamics in critically ill patients, administration of beta-lactams as EI provides better target attainment in therapeutic drug monitoring studies. To optimize meropenem (MER) dosing in patients with severe sepsis or septic shock, our antimicrobial stewardship program implemented a MER EI protocol in an 18-bed medical intensive care unit (MICU) in March 2014. Methods. We conducted a retrospective evaluation to compare outcomes in MICU patients with severe sepsis and septic shock who received MER for >=72h administered as EI 1 g over 3 h Q8H with a total daily dose (TDD) 3g (1/2015-1/2017) vs. SI 500 mg over 30 minutes Q6H with TDD 2 g (1/2012-1/2014). ICU mortality and clinical response (CR) were evaluated as endpoints. CR was defined by improvement in signs and symptoms of infection. Results. Of 667 patients who received MER, 148 were included (EI n = 52, SI n = 96). Age, weight, comorbidities (malignancy 31 vs. 33%, P = 0.8; chronic liver disease [CLD] 15 vs. 23%, P = 0.4), severity of illness (median mAPACHE II 18 vs. 19, P = 0.6; SOFA 5 vs. 6, P = 0.5) and vasopressors' use (75 vs. 79%, P = 0.5) were comparable between EI and SI groups. Serum creatinine (SCr) was lower in EI group (median 1.1 vs. 1.4 SI, P = 0.05). Gram-negative (GN) pathogens (MIC<=0.25 mg/mL, 94%) were identified in 44% of patients in EI vs. 38% in SI group, P = 0.5. MER TDD was higher in EI group (3 vs. 1.5g SI, P < 0.01) with no difference in use of combination therapy (64 vs. 46%, P = 0.06). ICU mortality (median time to death 9 days) was lower (19 vs. 37%, P = 0.047) and CR was higher (83 vs. 46%, P = 0.038) in EI vs. SI group. Total pressor days on MER were shorter (2 vs. 3 days, P < 0.01) and white blood cell normalization rate was higher (87% vs. 51%, P < 0.01) in EI vs. SI group, whereas there was no difference in days of mechanical ventilation, duration of MER therapy and ICU stay. After adjusting for SCr, severity of illness scores, combination therapy and SI group in a multivariate model, CLD (OR 3.3, 95% CI 1.36-7.77, P = 0.008) and lower MER TDD (OR 1.8, 95% CI 1.09-2.98, P = 0.02) were independent predictors of ICU mortality. Conclusion. In this cohort of MICU patients with severe sepsis or septic shock and low MIC of GN pathogens, there was improved mortality and CR in MER EI group. Our finding of potential benefit of higher MER TDD in these patients warrants further exploration in a prospective study

Background. It is still unclear whether prolonged duration of therapy (DOT) for VAT might be protective against progression to pneumonia. From a stewardship view, shortening DOT may help to contain emergence of multidrug-resistant organisms (MDRO) in PICU. To this effect, we sought to compare clinical characteristics and outcomes in PICU patients with NLFGNR VAT treated with >7 days (prolonged course group, PCG) vs. <=7 days (short course group, SCG). Methods. This retrospective stewardship evaluation between January 2009 and July 2016 was conducted in a 12-bed PICU. Antibiotic choice and DOT were at the physicians' discretion. VAT was defined by signs and symptoms and positive sputum (>=moderate polymorphonuclear cells and >=moderate NLFGNR growth) without radiographic findings. Primary outcomes were rate of microbiologically documented or clinically suspected (CS) pulmonary infection recurrence and emergence of resistance (>=4 increase in minimal inhibitory concentration) or MDRO within 30 days of VAT treatment. Thirty-day readmission and in-hospital mortality were also assessed. Results. Fifty patients were included (PCG n = 27, SCG n = 23). Median age was 1.6 years (0-18.8), PIM2 score was 1 (0.1-82.8), 62% of patients had a tracheostomy at baseline, 70% had P. aeruginosa, and these were comparable between groups. More patients in PCG vs. SCG (44% vs. 13%, P = 0.03) had an admission diagnosis of respiratory failure. Mechanical ventilation (12.5 vs. 5 days, P < 0.01) and PICU stay (16 vs. 6 days, P < 0.01) were longer in PCG vs. SCG. Median DOT was 10 (8-30) in PCG vs. 6 days (3-7) in SCG, with beta-lactams as the common agents and no difference in combination therapy (33% vs. 13%, P = 0.1). Clinical response at the end of treatment was 89% in PCG and 100% in SCG, P = 0.2. Recurrence was 26% in PCG and 9% (all CS) in SCG, P = 0.2 at 17 days (1-29) and 9.5 days (4-15) P = 0.5, respectively. Emergence of resistance or MDRO occurred in 15% in PCG vs. 0% in SCG, P = 0.1. Readmission and in-hospital mortality were 7% vs. 9%, P = 0.9 and 7% vs. 0%, P = 0.5 in PCG and SCG, respectively. Conclusion. In this small cohort of PICU patients with NLFGNR VAT, there was no microbiologically documented recurrence and emergence of resistance or MDRO in SCG compared with PCG. Our findings suggest that short DOT may be considered for children who are less sick including those with a tracheostomy at baseline

Background. Antibiotic (ABX) use and outcome measures (rate of HO-CDI, local antimicrobial resistance) are recommended ASP metrics. These metrics can be used for internal benchmarking to assess ASP performance within an institution over time. Methods. An adult ASP at our 750-bed academic medical center was implemented in 2008. ASP interventions include prospective audit and feedback, prior authorization with fuoroquinolone (FLQ) restriction as an ASP target and implementation of facility-specifc guidelines for common infections. Newer ASP initiatives were Cepheid/Xpert for blood cultures with Gram-positive cocci in pairs and clusters with daily real-time ASP interventions (11/2014), oral vancomycin secondary prophylaxis for patients with prior CDI (4/2014) and optimization of beta-lactam (BL) dosing (pip-eracillin-tazobactam [PTZ] extended infusion hospital-wide 4/2013; cefepime [CEF] 4/2015 and meropenem 7/2015 protocols). ABX use is measured in days of therapy per 1000 patient-days (DOT/1000 PD) and length of therapy/admission when ABX were administered (LOT/ADM). NHSN defnition is used for HO-CDI. For resistance trends the first unique isolate/patient/year regardless of source or susceptibility profle was included. Statistical analysis of trends during 8-years period 2009-2016 was performed by Poisson (SAS). Results. Major shifs in ABX use include decrease in FLQ use (-17%, P < 0.01) with compensatory increase in cefriaxone (CTX, +12%, P < 0.01), antipseudomonal BL (+3%, P < 0.01) and no change in carbapenem (+0.6%, P=0.5) as well as an increase in nafcillin and oxacillin (+7%, P < 0.01) use. There was a decrease in aggregate LOT/ADM (-4%, P < 0.01) with no change in DOT/1000 PD. We observed a decrease in HO-CDI rate (-17%, P < 0.01). Major resistance trends include reduction in Enterobacteriaceae spp. and Pseudomonas aeruginosa isolates nonsusceptible (NS) to FLQ (-4%, P < 0.01;-10%, P < 0.01, respectively) with increase in Enterobacteriaceae spp. NS to cefriaxone, (+3%, P < 0.01). A decrease in P. aeruginosa NS to PTZ (-11%, P < 0.01) and no change for CEF was reported. There was no Difference in Enterobacteriaceae spp. NS to PTZ or CEF. Conclusion. Overall, reported trends aligned with ASP initiatives. Increased CTX NS is of concern and warrants an ASP-led strategy to decrease CTX use

PURPOSE: The integration of pharmacy residents into an antimicrobial stewardship program (ASP) is described, and data on the residents' ASP interventions and outcomes are reported. SUMMARY: ASP coverage of nighttime, holiday, and weekend shifts is often provided by infectious diseases (ID) medical fellows and staff pharmacists, potentially leading to inconsistent stewardship practices. As part of an initiative by a large urban hospital to provide around-the-clock, comprehensive ASP services 7 days a week, postgraduate year 2 (PGY2) pharmacy residents in ID or critical care were assigned to provide ASP coverage on weekends. Over a 12-month period, residents providing ASP weekend coverage documented a total of 1,443 interventions, of which 1,000 (69%) were pursuant to 72-hour prospective audit and feedback review and 443 (31%) occurred during ASP phone coverage. A comparison of overall antimicrobial utilization (mean +/- S.D. days of therapy [DOT] per 1,000 patient-days [PD]) before and after implementation of resident ASP coverage on weekends showed a decrease in aggregate antimicrobial use from 799.3 +/- 46.8 to 740.7 +/- 17.3 DOT/1,000 PD (a difference of 58.6 DOT/1,000 PD, p = 0.08), with a corresponding decline in the incidence of hospital-onset Clostridium difficile infection (from 1.18 cases to 0.9 case per 1,000 PD). CONCLUSION: By expanding the hospital's ASP services by assigning PGY2 pharmacy residents to weekend coverage, the institution was able to provide high-level clinical care 7 days per week, which benefited both patients and PGY2 pharmacy residents while meeting national ASP regulatory requirements.

STUDY OBJECTIVE: Despite recent reports of relatively high rates (16-37%) of acute kidney injury (AKI) in patients receiving the combination of intravenous piperacillin-tazobactam (PTZ) and vancomycin, data are limited evaluating the impact of PTZ infusion strategy on the occurrence of nephrotoxicity. The objective of this study was to compare the rates of nephrotoxicity in patients receiving vancomycin in combination with PTZ administered as an extended infusion (EI) versus a standard infusion (SI). DESIGN: Single-center, retrospective, matched-cohort study. SETTING: Large academic tertiary care hospital. PATIENTS: Two hundred eighty adults with a creatinine clearance (CrCl) of 40 ml/minute or higher who received at least 96 hours of vancomycin plus PTZ EI (140 patients) or vancomycin plus PTZ SI (140 patients) between January 1, 2009, and December 31, 2011, and between January 1, 2013, and December 31, 2014 (year 2012 was skipped due the closure of inpatient units following Superstorm Sandy); 48 patients in each group were admitted to the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The median age of all patients was 67 (interquartile range [IQR] 54-77) years, and CrCl was 75 (IQR 55-107) ml/minute. Nephrotoxicity was assessed by the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) criteria. Rates of AKI, according to these criteria, were similar between groups: 17.9% versus 17.1% (p=1) and 32.9% versus 29.3% (p=0.596) for the PTZ EI and PTZ SI groups, respectively. When controlling for residual differences between groups in a conditional logistic regression analysis, no association was observed between receipt of PTZ EI and RIFLE-defined AKI (odds ratio 0.522, 95% confidence interval 0.043-6.295, p=0.609). Time to onset of nephrotoxicity was 4 (IQR 3-6) days, with no significant difference noted between groups (p=0.887). CONCLUSION: Our findings suggest a similar rate of nephrotoxicity between patients who received vancomycin in combination with PTZ EI versus PTZ SI. These results need to be further validated in a prospective randomized controlled study.

BACKGROUND: Cefepime and meropenem are used frequently in hospitalized patients for broad-spectrum empiric coverage, however, practitioners are often reluctant to prescribe these antibiotics for patients with a self-reported nonsevere, nontype I allergic reaction to penicillin. METHODS: Retrospective review of electronic medical records of adults with a self-reported allergy to penicillin who received at least 1 dose of cefepime, ceftriaxone, cefoxitin, cephalexin, or meropenem to assess incidence and type of allergic reactions. RESULTS: Of 175 patients included, 10 (6%) patients experienced an allergic reaction. The incidence for individual study drugs were cefepime 6% (6 of 96), meropenem 5% (3 of 56), cefoxitin 8% (1 of 13), ceftriaxone 0% (0 of 69), and cephalexin 0% (0 of 8). The majority of patients experienced a rash with or without pruritus and fever. Patients with a concomitant "sulfa" allergy (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.4-21, P = .02) or >/=3 other drug allergies (OR 6.4, 95% CI 1.3-32, P = .025) were more likely to have an allergic reaction. CONCLUSIONS: In one of the largest retrospective reviews of hospitalized patients who received full dose therapy with cefepime, ceftriaxone, and meropenem, the incidence of allergic reactions was low and reactions were mild. Cefepime, ceftriaxone, and meropenem can be considered for use in patients with a self-reported nontype I penicillin allergy.

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL_CR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL_CR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.