Zhe Han

The effect of broader, directed antimicrobial prophylaxis including fungal coverage on perioperative infectious complications after radical cystectomy.

OBJECTIVES Radical cystectomy (RC) with urinary diversion has a significant risk of infection. In an effort to decrease the rate of infectious complications, we instituted a broader, culture-based preoperative antimicrobial regimen, including fungal coverage, and studied its effect on infectious complications after RC. MATERIALS AND METHODS In May 2013, antimicrobial prophylaxis for RC was changed at our institution after review of previous positive cultures. Ampicillin-sulbactam 3g, gentamicin 4mg/kg, and fluconazole 400mg replaced cefoxitin. Patients undergoing RC from May 2011 to May 2014 were included. Before and after implementation of the new regimen, 30-day infectious complications (positive blood culture, urinary tract infection, wound infection, abscess, and pneumonia) and adverse events (Clostridium difficile, readmission, and mortality) were compared. Multivariate logistic regression was used to identify independent risk factors for infection while controlling for covariates. RESULTS In total, 386 patients were studied (258 before the change and 128 after). The overall infection rate decreased with the new regimen (41% vs. 30%, P = 0.043) with improvements in wound (14% vs. 6%, P = 0.025) and fungal (10% vs. 3%, P = 0.021) infections. Median length of stay decreased from 8 (interquartile range [IQR]: 7-12) to 7 (IQR: 7-10) days (P = 0.008). On multivariate analysis, the new regimen decreased the risk of infections (odds ratio [OR] = 0.58, 95% CI [0.35-0.99], P = 0.044) whereas body mass index, operating room time, smoking, and total parenteral nutrition increased the risk (all P< 0.05). CONCLUSIONS Risk factors for infection after RC include body mass index, operating room time, smoking, and total parenteral nutrition use. Changing from cefoxitin to broader, culture-directed antimicrobial prophylaxis, based on institutional data to include antifungal coverage, decreased postoperative infections.

Cobicistat Significantly Increases Tacrolimus Serum Concentrations in a Renal Transplant Recipient with Human Immunodeficiency Virus Infection

Cobicistat is a pharmacokinetic booster in several fixed‐dose combination products for treatment of human immunodeficiency virus (HIV) infection. As a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, significant drug‐drug interactions are expected between cobicistat and medications that are metabolized primarily through the CYP3A pathway, including calcineurin inhibitors (e.g., tacrolimus and cyclosporine). We describe a case of tacrolimus toxicity due to supratherapeutic tacrolimus concentrations when Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) was initiated for newly diagnosed HIV infection in a 50‐year‐old renal transplant recipient who was previously receiving a stable tacrolimus regimen. Drug‐drug interaction via CYP3A inhibition was acknowledged, and weekly labs were ordered to allow for close monitoring of renal function and tacrolimus serum concentrations as recommended by Stribild prescribing information. The patient reported headache, insomnia, stomachache, and decreased urine output within 1 week of starting Stribild and was found to have acute kidney injury (serum creatinine [Scr]concentration increasing from 1.5–2.3 mg/dl) and a serum tacrolimus concentration of 111.2 ng/ml at 1 week follow‐up (goal trough level 4–6 ng/ml). Both tacrolimus and Stribild were withheld. In 15 days, the patients tacrolimus serum concentration returned to goal. In the interim, he required twice/week clinic visits for laboratory assessments and an emergency department visit for management of hyperkalemia (potassium 6.5 mEq/L). Triumeq (abacavir, dolutegravir, and lamivudine) was started about 4 weeks later after Scr returned to baseline, and his tacrolimus serum trough concentrations subsequently remained stable. To our knowledge, this is the first case report describing the extent, significance, and onset of cobicistat and tacrolimus drug‐drug interaction in clinical practice. As more fixed‐dose combination products including cobicistat as a pharmacokinetic booster come to market, clinicians should be reminded of its multitude of clinically significant drug‐drug interactions.

Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

Objectives The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. Methods This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. Results One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P  <   0.001), ALT ( P  <   0.001), alkaline phosphatase (ALK) ( P  <   0.001), total bilirubin (TBILI) ( P  <   0.001) and QTc ( P  =   0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = -0.33 (2.2), P  =   0.88], log ALT [β (SE) = -0.02 (0.03), P  =   0.63], ALK [β (SE) = 2.2 (2.9), P  =   0.46] and TBILI [β (SE) = -0.01 (0.04), P  =   0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P  =   0.02) and ALK of 7.1 U/L ( P  =   0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. Conclusions We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Guideline compliance and clinical outcomes among patients with Staphylococcus aureus bacteremia with infectious diseases consultation in addition to antimicrobial stewardship-directed review

HIGHLIGHTSASP review of patients with SAB were effective in ensuring appropriate therapy.Addition of IDC improved obtaining echocardiography and repeat blood cultures.IDC was also associated with significant reduction in all‐cause inpatient mortality.These findings establish the addition of IDC to ASP review of patients with SAB can further improve management and clinical outcomes. Objective: Previous studies have shown infectious diseases consultation (IDC) for Staphylococcus aureus bacteremia (SAB) improves management and outcomes. The influence of IDC on outcomes for SAB in addition to an antimicrobial stewardship program (ASP) review for adult inpatients with SAB has not been evaluated. The purpose of this study was to investigate the effect of IDC on SAB management with concomitant ASP review and resulting outcomes. Methods: Adult inpatients with SAB admitted December 2012‐October 2014 were included. The primary end point compared adherence to Infectious Disease Society of America guideline recommendations between patients receiving an IDC versus those not receiving an IDC. We also evaluated adherence to the individual components of the primary end point and clinical outcomes, including time to microbiologic clearance, recurrence of bacteremia, mortality, and length of stay. Results: This study included 154 patients (115 IDC and 39 non‐IDC). Guideline adherence was significantly greater in the IDC group 78% versus 46% in the non‐IDC group (P < .001). Significantly more patients in the IDC group had echocardiography (91% vs 67%; P < .001) and follow‐up blood cultures (92% vs 64%; P > .001). Mortality was also greater in the non‐IDC group (23%) versus 5% for the IDC group (P = .001). Conclusions: Patients with SAB receiving an IDC were more likely to receive guideline‐congruent management and had significantly reduced mortality. No improvements in antibiotic choice or dosing were observed, likely a result of ASP review.

Safety and Efficacy of Corticosteroid Use in Neurologic Trauma

Neurologic trauma, which consists of acute spinal cord injury and traumatic brain injury, is a leading cause of death and disability. In recent years, there have been improvements in the early recognition and prompt resuscitation of patients with neurologic trauma. However, there remain few pharmacologic treatments to reduce its secondary complications. Corticosteroids have been used in patients with neurologic trauma for more than 5 decades. Traditionally, their use has been to improve motor and sensory recovery. However, recently their utility to prevent and manage trauma-related pneumonia has been investigated. Given these new investigations, the purpose of this review article is to provide a comprehensive overview of the history and available scientific evidence surrounding the use of corticosteroids in neurologic trauma and caution against the use of these agents to prevent hospital-acquired pneumonia in this patient population.

Improved rates of antimicrobial stewardship interventions following implementation of the Epic antimicrobial stewardship module

We evaluated the impact of the Epic antimicrobial stewardship module (EAM) on the number of interventions, antimicrobial usage, and clinical outcomes. Use of the EAM allowed us to significantly increase the number of ASP antimicrobial reviews and interventions while maintaining a sustained impact on antimicrobial utilization.

Cefepime-Induced Encephalopathy, Single-Center Incidence, Complexities in Diagnosis

To the Editor—We read with interest the recent review from Appa et al. titled “Characterizing Cefepime Neurotoxicity: A Systematic Review” [1]. As a result of increasing concern for cefepime as a possible etiology for cases of encephalopathy, we investigated the overall incidence of this toxicity at our medical center from January 2016 to May 2017. Similar to the published study, we summarized patient characteristics of those with suspected cefepime-induced encephalopathy (CIE). Unique to our analysis, we included an assessment of other potential etiologies of encephalopathy at the time of symptom onset and the consequences of antibiotic therapy change. Out of 4446 patients receiving cefepime, there were 18 (0.4%) requests to change cefepime to an alternative antipseudomonal agent as a result of concern for CIE. This represents an incidence of 1 in 250 courses of cefepime. Upon review of these 18 cases, in only 3 (0.07%), or 1 in 1429 courses, was it evident that following cessation of cefepime (as the primary intervention) symptoms resolved. The remaining patients had other identified causes (n = 7) or symptoms did not improve following cefepime discontinuation alone (n = 8). Similar to Appa et al. and other studies reporting cases of CIE, the 3 patients with likely CIE in our study were older (range, 64–80 years) and had some degree of renal insufficiency (creatinine clearance range, 17–59 mg/dL) [1–4]. However, all patients were receiving appropriate doses for their renal function at the time of symptom onset. Patients developed symptoms consistent with CIE within 4–5 days of cefepime initiation, and symptoms resolved within 3–4 days of cefepime discontinuation. Additionally, all 3 patients had electroencephalogram (EEG) patterns with triphasic waveforms (TWFs). Among the 18 patients with suspected CIE, the average number of additional potential etiologies for encephalopathy was 4.8 (range, 3–9). Specifically, among the 3 patients with likely CIE, the number of additional etiologies ranged from 3 to 6. Other potential etiologies included baseline neurologic abnormalities, microvascular ischemic disease, other medications known to cause symptoms consistent with encephalopathy, uremia, sepsis/severe infection. Of interest, 6 (33%) patients with suspected CIE were changed to inferior and/or more toxic antibiotic regimens. Five patients received a more toxic antibiotic (eg, patient with baseline prolonged QTc interval who was started on ciprofloxacin or who required the addition of vancomycin). Three patients required an additional agent be added (eg, changed to aztreonam and vancomycin combination), and 1 patient was changed to piperacillin-tazobactam, which was not active against their Enterobacter infection. Similar to other studies, the primary limitation of our analysis is the difficulty of diagnosing CIE. While EEG findings are helpful in making this diagnosis, TWFs are not specific to cefepime. Rather, it is a consistent finding among patients with toxic or metabolic encephalopathy and structural encephalopathy, with the 3 most common causes being hepatic encephalopathy, renal failure, and anoxic brain injury [5]. Additionally, we observed a high number of other potential causes of encephalopathy among our index patients. Pinpointing cefepime as the primary cause of encephalopathy is a clinical challenge. What is possibly evident from this observation is that while cefepime alone may not be a definitive cause, perhaps it is the combination of cefepime among high-risk patients that may result in encephalopathy. Our data are consistent with the data provided by Appa et al., suggesting that encephalopathy is a possible, but uncommon reported toxicity with cefepime use. This toxicity is noted to occur primarily among elderly patients with reduced renal function. However, our analysis highlights the high potential for confounders when making a CIE diagnosis, as multiple etiologies for encephalopathy are often present among inpatients requiring broad-spectrum antibiotics. Additionally, given the limited amount of antipseudomonal agents available, patients with suspected CIE may be at increased risk for suboptimal antibiotic therapy. Consequently, prior to cefepime discontinuation due to suspected CIE, clinicians should carefully consider the risks of potentially selecting an inferior or more toxic antibiotic regimen.

Efficacy and Safety of a Vancomycin (VAN) Dosing Protocol Developed for Morbidly Obese (MO) Patients

Abstract Background An optional VAN loading dose (LD) of 25–30 mg/kg (total body weight), followed by maintenance dose (MD) of 15–20 mg/kg intravenously (IV) Q8–12H is recommended for patients with normal renal function. Studies suggest MO patients may require lower mg/kg doses to achieve therapeutic trough concentrations (TTCs). Our institutional VAN dosing protocol for MO patients (BMI ≥ 40 kg/m2) was revised in 2015 to recommend: LD 25–30 mg/kg (max 3000 mg), MD 12.5–15 mg/kg (max 2000 mg) IV Q8–12H. We evaluated initial TTC attainment, clinical and safety endpoints post protocol revision. Methods MO adult patients who received IV VAN between June 1, 2012–May 31, 2013 (pre-protocol revision) and August 1, 2015–July 31, 2016 (post-protocol revision) were included. Perioperative VAN, one-time doses, pregnancy, cystic fibrosis, hemodialysis and patients receiving VAN prior to admission were excluded. Results A total of 615 patients were screened, with 200 included for analysis (100 per group). Baseline demographics and VAN dosing are shown in Table 1. Initial TCs were drawn for 86 patients in the pre-revision group, and for 69 patients in the post-revision group. Initial VAN TCs are displayed in Table 2. Duration of VAN therapy was significantly shorter post-revision (5 days vs. 2 days, p ≤ 0.01). Mortality (14% vs. 10%, P = 0.38) and hospital length of stay (8.5 days vs. 7 days, p=0.09) were comparable between groups. There was no difference in the incidence of VAN-associated nephrotoxicity (16% vs. 10%, P = 0.20).Table 1 Baseline Demographics Pre-Revision 
(n = 100) Post-Revision 
(n = 100) P Value Age, years 53.7 ± 13.7 48.8 ± 15.6 0.06 Gender, male 21% 17% 0.47 BMI, kg/m2 44.5 (41.0–49.0) 45.5 (41.5–50.8) 0.33 Frequency of LD 30% 68% < 0.01 Initial MD, mg/kg 15.0 (12.8–17.0) 14.0 (12.9–15.0) < 0.01Table 2. Initial VAN TCs Pre-Revision 
(n = 86) Post-Revision 
(n = 69) P Value Therapeutic 35% 51% 0.05 TC, μg/mL 17.1 (12.9 – 22.6) 17.4 (13.4 – 24.0) 0.57 Subtherapeutic 34% 19% 0.04 Supratherapeutic 31% 30% 0.90 Conclusion The revised VAN dosing protocol for MO patients improved initial TTC attainment and decreased incidence of subtherapeutic TCs compared with current standard of care recommendations with no difference in clinical or safety outcomes. Disclosures All authors: No reported disclosures.

MP65-13 BROADER SPECTRUM ANTIMICROBIAL PROPHYLAXIS INCLUDING FUNGAL COVERAGE SIGNIFICANTLY REDUCES INFECTIOUS COMPLICATIONS AFTER RADICAL CYSTECTOMY

INTRODUCTION AND OBJECTIVES: Practices including reresection of the tumor site, induction course of Bacille CalmetteGuerin (BCG), and use of early cystectomy, have been recommended for patients with Stage T1 urothelial cancer of the bladder. We examined a population-based database to investigate current patterns of care among Stage T1 bladder cancer patients and factors that influence decisions and survival. METHODS: We interrogated the SEER-Medicare database to identify all patients with an initial diagnosis of stage T1 bladder cancer; those with mixed T1 and CIS were excluded. The number of patients undergoing reresection within 3 months of the initial resection were identified. Subsequent treatment after initial biopsy was identified (intravesical BCG or chemotherapy, cystectomy, or none). Patients were characterized for age, race, gender, education, and income. Time to cystectomy, cancer-specific survival and overall survival were determined. RESULTS: Among the 14,302 patients with stage T1 tumors, only 15% overall underwent reresection increasing from 8% in the first 5 years to 18% in the last 5 years. A minority of patients (13.5%) received adjuvant therapy after initial diagnosis including intravesical BCG in 6% (though this has increased to 9.5% in the last five years) and intravesical mitomycin in 7.5%. Patients receiving BCG were more likely to live in the West or Midwest. Among patients undergoing cystectomy, 2.0% occurred early (within 6 months) after initial resection and 4.3% after 6 months (mean time 21 months) though these rates have increased to 6% and 7.5%, respectively, in the past 5 years. Patients undergoing cystectomy were younger, more likely to be white and a lower comorbidity rate though wealth and education had no impact on these rates. Patients receiving BCG had a better cancer-specific and overall survival compared to mose who received mitomycin and no adjuvant therapy. Patients who underwent an early cystectomy had a modestly improved survival over those who underwent a late cystectomy. CONCLUSIONS: While reresecting tumor sites is now recommended in patients with T1 bladder tumors, this approach is still under utilized. BCG Intravesical therapy, especially after reresection, is minimally used though it appears to be associated with improved survival. Early cystectomy may need to be strongly considered for T1 bladder cancer especially in light of the ongoing shortage of BCG.

474Ceftaroline Salvage Therapy for MRSA Bacteremia Following Vancomycin Failure

Background. Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) is associated with significant morbidity and mortality. Vancomycin (VAN) is the drug of choice for MRSAB, optimization of VAN dosing is challenging in the setting of an elevated MIC (>1-2mcg/ml). Daptomycin (DAP) is an alternative for MRSAB, however DAP MICs tend to be elevated among patients with elevated VAN MICs or that failed VAN, increasing the risk for DAP failure. Ceftaroline (CFT) is active against MRSA and may be considered in the management of MRSAB as well. We summarize our experience with CFT as salvage therapy (ST) for MRSAB and the correlation observed between elevated VANMIC and/or VAN failure and DAP MIC. Methods. All adult patients that received CFT ST for MRSAB following VAN failure and/or in the setting of elevated VAN MIC (>1-2 mcg/ml) between August 31, 2012 to April 30, 2014 were included. Patients were evaluated for clearance and duration of positive blood cultures, MIC data, ST regimen, and VAN duration. MIC methodology included: VAN (Vitek-2); DAP (Etest); CFT (agar dilution). Results. Six MRSAB patients initially treated with VAN received CFT ST. All patients received prior or concomitant DAP with CFT. Five of 6 patients received an additional anti-MRSA antibiotic. Median VAN duration was 9 days and median total duration of positive blood cultures was 8.5 days. 83.3% (N = 5) of patients grew MRSA isolates with a VAN MIC of 1-2 mcg/ml, 3 of these isolates were DAP non-susceptible (NS). An additional MRSA isolate found to be DAP NS occurred in a patient that received 25 days VAN, and was reported to have had an elevated VAN MIC based on outside hospital cultures that could not be confirmed. All isolates were susceptible to CFT (MIC of 0.5-1 mcg/ml). One patient died prior to documented clearance of blood cultures, the remaining 5 survived and cleared blood cultures within 2-3 days following CFT. Conclusion. CFT in combination with an additional agent is effective as ST for MRSAB, resulting in blood culture clearance within 2-3 days. MRSA isolates with elevated VAN MIC values and patients with prolonged courses of VAN exhibited elevated DAP MIC values. CFT may be preferred over DAP for MRSAB following VAN failure and/or an elevated VAN MIC given the prevalence of elevated DAP MICs. Disclosures. J. Pisano, Pfizer: Grant Investigator, Research grant