Faculty Bibliography

BACKGROUND:Parameters within reconstitution, storage, stability, and administration may be optimized according to the unique pharmacokinetics of each antibiotic to ensure a successful desensitization. OBJECTIVE:The study aims to evaluate the successfulness and safety of antibiotic desensitization protocols developed by the pharmacy department at our institution. METHODS:A retrospective study was conducted at an 800-bed, urban, tertiary care, academic medical center. A total of 36 patients 18 years of age or older, admitted to our intensive care units between March 2013 and July 2017, who underwent antibiotic desensitization utilizing our pharmacy developed protocols were included. RESULTS:In 36 patients, 61 desensitization cases were identified and included; 17 (47%) were male, 27 (75%) were Caucasian, and the median age was 55 years (range 19-94). In all, 15 different antibiotics were administered for desensitization, with meropenem (n = 12, 20%), ampicillin (n = 7, 11%), piperacillin/tazobactam (n = 7, 11%), and penicillin (n = 7, 11%) being the most common; 59 (97%) of 61 desensitizations were completed successfully with or without experiencing reactions, and 53 (89%) of the successful desensitization cases were completed without reactions. Two cases were categorized as anaphylaxis, which was severe enough to terminate the desensitization process. Of the 59 cases successfully completed, the 6 (10%) cases that experienced reactions were managed successfully during desensitization with completion of the process. Conclusion and Relevance: The findings suggest that our pharmacy-developed antibiotic desensitization protocols are successful and safe and may be adapted by other institutions.

Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggests that once daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI).In a multicenter, retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) ≥30 mL/min who received ≥48h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once and twice daily PMB dosing. Secondary endpoints included time to AKI and recovery of renal function.Of 273 eligible patients, 100 from each group were matched based on propensity scores. In the matched groups, nephrotoxicity, defined according to RIFLE criteria, was more frequent with once versus twice daily dosing (47% vs. 17% P=0.0005). After adjusting for residual differences by multivariate conditional logistic regression, once daily dosing was more likely to result in nephrotoxicity (adjusted odds ratio 2.5, 95% CI 1.413-4.541, P=0.002). Among 64 patients who developed AKI, the median onset was similar between groups (7 days with once vs. 6 days with twice daily dosing, P=0.095). Of 37 patients who had their serum creatinine evaluated subsequently, 29/37 (78%) had recovery of renal function. No patient required renal replacement therapy.Our findings suggest that AKI is significantly more common with PMB once daily as compared to twice daily dosing with no difference in time to AKI. Prospective randomized study is warranted to validate these results.

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

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

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.

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.

We describe a case of a 72-year-old man with early-stage chronic lymphocytic leukemia (CLL) who presented with invasive nontyphoidal Salmonella (iNTS) infection, necrotizing pneumonia, and chronic infection of a hilar lymph node. Infection is a major cause of death in patients with CLL. Though few cases of iNTS infection associated with CLL have been described in the literature, to our knowledge this is the first reported case of iNTS-associated necrotizing pneumonia. Immunocompromised state in patients, even with early-stage CLL, likely predisposes them to invasive infection with intracellular organisms, such as Salmonella spp. In this case, successful treatment was achieved with prolonged course of intravenous followed by oral antibiotics without any surgical removal of infected focus.

Treatment of Legionnaires' disease in severely ill or immunosuppressed patients presents a clinical challenge. Tigecycline (TG) achieves high concentrations intracellularly and has been shown to be effective against L. pneumophila in animal and cell models. We report our experience using TG as second-line therapy. Clinical response was seen in most patients after switching to TG alone or as a combination therapy.

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.