Antimicrobial Stewardship Strategies in Patients with Hematologic Malignancies Carley Buchanan, PharmD Infectious Diseases Clinical Pharmacist Western Pennsylvania Hospital March 9, 2019

Disclosure I have no actual or potential conflict of interest in relation to this presentation.

Objective Discuss strategies to manage antimicrobial treatment and prophylaxis in patients with hematologic malignancies.

Patients with Hematologic Malignancies Often severely immunocompromised Chemotherapy, HSCT Neutropenic for extended duration of time Frequent inpatient admissions Exposed to a multitude of antimicrobials Prophylaxis, treatment of infections This unique patient population commonly presents us with several challenges: HSCT: hematopoietic stem cell transplant

IDSA Recommendations “We suggest ASPs develop facility-specific guidelines for fever and neutropenia (F&N) management in hematology-oncology patients over no such approach.” “We suggest implementation of ASP interventions to improve the appropriate prescribing of antifungal treatment in immunocompromised patients.” Implementation of stewardship intervention should be done in collaboration with the hematology-oncology team The infectious disease society of America provides a few recommendations to stewarship programs regarding these patients. ASPs: antibiotic stewardship programs Clin Infect Dis. 2016;62(10):e51-77.

Febrile Neutropenia (FN) Fever occurs in >80% of hematology patients who are neutropenic following chemotherapy Where can ASPs impact patient care? Empiric treatment choice and dosing Role of antifungals De-escalation Duration of therapy Allergy assessment Perhaps one of the most common things these patients present with is febrile neutropenia - Clin Infect Dis. 2004;39 Suppl 1:S32-7.

Empiric Treatment of FN Empiric treatment choice Anti-pseudomonal beta-lactam +/- anti-MRSA agent Algorithm based approach Febrile Neutropenia Algorithm Antimicrobial dosing strategies Extended infusion Site-specific microbiology data, education Other alternatives Recommended empiric treatment regimens for febrile neutropenia include… High mortality rates with pseudomonas infections in FN Anti-MRSA agents typically reserved for suspected catheter-related infections, SSTI, PNA, hemodynamic instability

Alternative Cefepime Dosing Recommended 2g q8h Alternative 1g q6h FDA approved dosing for cefepime in febrile neutropenia is… Similar target attainment between 1g q6h and 2g q8h Less drug per day – less exposure for patient Lodise TP et al. Pharmacotherapy. 2006;26:1320–1332

Alternative Cefepime Dosing Retrospective chart review of 150 patients at WPH June 2015 – September 2017 Control: cefepime 2g q8h Intervention: cefepime 1g q6h Inclusion criteria Patients >18 years of age hospitalized with FN Absolute neutrophil count <500 cells/uL Documented temperature of >38.3 °C or 38.0 °C sustained over 1 hour Primary outcome Time to defervescence After this change took place we conducted a… WPH: West Penn Hospital Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Baseline Characteristics 2g q8h (n=75) 1g q6h (n=75) p value Age, years* 61 (51-65) 63 (55-67) 0.38 Male, n (%) 48 (64) 1.00 Hematologic Malignancy, n (%) 70 (93.3) 74 (98.7) Stem Cell Transplant, n (%) 4 (5.3) 6 (8.0) Non-Hematologic Malignancy n (%) 5 (6.7) 1 (1.3) SAPS II Score 40 (35-47) 40 (36-47) 0.89 Admitted to ICU, n (%) 9 (12) Time to ANC Recovery, days* 9.0 (4-17) n=55 9.0 (5-15) n=53 0.93 Time to 1st Dose, minutes* 162 153 0.95 Positive Blood Culture, n (%) 16 (21.3) 12 (16.0) Gram Negative Bacteremia, n (%) 7 (9.3) Baseline characteristics are listed for your review Point out heme patient population *Variables presented as median (interquartile range) SAPS II: simplified acute physiology score ANC: absolute neutrophil count Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Outcomes 2g Q8H (n=75) 1g Q6H (n=75) p value Primary Outcome Time to Defervescence, h* 69 (52.4-115.3) n=72 65.3 (51.8-100.1) n=74 0.47 Secondary Outcomes Duration of Cefepime, h* 88.0 (63.7-115) 80.8 (48.1-125.5) 0.34 Length of Hospital Stay, days* 7 (4-26) 9 (4-30) 0.50 All-Cause 30-day Mortality, n (%) 8 (10.7) 7 (9.3) 0.79 30-day Mortality Due to Infection, n (%) 2 (2.7) 1.00 30-day Mortality Due to GNR Infection, n (%) 1 (1.3) Time to Defervescence with Isolated GNR, h* n = 7 for 2g q8h n = 5 for 1g q6h 59.0 (54.1-86.5) 89.8 (61.0-204.5) There was no difference in the primary outcome of time to defervesence *Variables presented as median (interquartile range) Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Displayed here is the kaplan meier curve plotting cumulative survival according to time to defervescence; As you can see the curves closely mimic each other with no statistical difference Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Conclusion No significant difference in time to defervescence or mortality at 30 days between patients who received cefepime 2g q8h compared to 1g q6h for the treatment of FN This alternative dosing strategy results in less cefepime drug exposure and less potential risk for drug toxicities Limitations: Small number of patients with gram negative infection Cefepime related toxicity not evaluated Power From this retrospective review we concluded… Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Median time to first dose: Additional Findings Time to anti-pseudomonal beta-lactam administration Increased mortality with Pseudomonas aeruginosa infections Anti-pseudmonal beta-lactam administration within 60 mins Median time to first dose: ~2.5h Cefepime added to ADC ~50min From this review we came across an important finding that our time to first-dose administration of cefepime was suboptimal… ADC: automated dispensing cabinet Moffa, M et al. Poster #1594. Presented at ID Week Oct 2018.

Febrile Neutropenia Treatment Duration Variety of recommendations Organization Duration Comments IDSA (2010) ANC >500 cells/mm3 “continue for at least the duration of neutropenia or longer if clinically necessary” NCCN (2018) Until neutropenia resolves “may be appropriate in some cases to de-escalate to a fluoroquinolone” ESMO (2016) Afebrile 5-7 days Exception: acute leukemia Continue antibiotics 10d or until ANC recovery ECIL (2011) >72h IV antibiotics Afebrile >48h Hemodynamically stable Recommendation irrespective of neutrophil count or expected duration of neutropenia Moving on to the next area for ASP intervention: duration of therapy for febrile neutropenia IDSA: Infectious Diseases Society of America NCCN: National Comprehensive Cancer Network ESMO: European Society for Medical Oncology ECIL: European Conference on Infections in Leukemia Clin Infect Dis. 2011;52(4):427-31. Baden LR et al. NCCN Guideline Version 1.2018. Ann Oncol. 2016;27(suppl 5):v111-v118. Haematologica. 2013;98(12):1826-35.

How Long Study Aguilar-Guisado et al. Open label, randomized, controlled phase 4 trial Inclusion criteria: >18 years of age, admitted to hematology ward, receiving treatment for hematologic malignancy or undergoing HSCT, with high-risk for FN, with no microbiological diagnosis Experimental Group (n=78) Control Group (n=79) Empiric antimicrobial therapy withdrawn >72h apyrexia plus clinical recovery Empiric antimicrobial therapy withdrawn after >72h apyrexia, clinical recovery, and ANC >500 cells/uL I’d like to highlight a study performed by Aguilar-Guisado and colleagues which was an… Lancet Haematol. 2017 Dec;4(12):e573-e583

How Long Study Aguilar-Guisado et al. Experimental (n=78) Control (n=79) p value Primary Endpoint EAT-free days 16.1 (6.3) 13.6 (7.2) 0.026 Secondary Endpoints Crude Mortality 1 (1.3) 3 (3.8) 0.62 Days of fever 5.7 (5.0) 6.3 (5.9) 0.53 Data expressed as mean (SD) EAT: empirical antimicrobial therapy Conclusion “In high-risk patients with hematologic malignancies and febrile neutropenia empiric therapy can be discontinued after 72h of apyrexia and clinical recovery irrespective of neutrophil count.” The authors found that… EAT-free days = difference between number of follow-up days (28d) and number of days EAT received Lancet Haematol. 2017 Dec;4(12):e573-e583

Fluoroquinolone (FQ) Prophylaxis Recommended for use in high-risk patients Reductions in mortality and febrile episodes Risks of fluoroquinolones Increased resistance Clostridium difficile infection Adverse reactions Extensive warnings Tendon rupture, CNS effects, aortic ruptures/tears Levofloxacin prophylaxis and ESBL bacteremia The final topic for today’s discussion revolves around the use of fluoroquinolone prophylaxis in our neutropenic patients FQ resistance increased from <1% in 1990 to ~30% in some areas on 2009 Satlin and colleagues J Clin Oncol. 2018;:JCO1800374. Clin Infect Dis. 2018;67(11):1720-1728.

Fluoroquinolone Prophylaxis Alternatives Withhold FQ and replace with conditional order for anti-pseudomonal beta-lactam while admitted PRN order entered in place of FQ prophylaxis for neutropenic patients undergoing acute myeloid leukemia (AML) induction Cefepime stocked in automated dispensing cabinet FQ prophylaxis algorithm Through this initiative we withheld…

Fluoroquinolone Prophylaxis Alternatives   Pre-intervention (n=35) Post-intervention (n=26) Primary Outcome, n (%) 90-day mortality 7 (20.0) 4 (15.4) Secondary Outcomes, n (%)  30-day mortality 2 (5.7) 2 (7.7) Total bacteremic episodes* 18 (51.4) 17 (65.4) Bacteremic episodes with GNR [mono- or polymicrobial] 6 (17.1) 12 (46.2) Clostridium difficile 3 (11.5) Febrile neutropenia 35 (100) 25 (96.2) ICU admission 9 (25.7) 6 (23.1) Rate of FQ resistance, n (%) Pre-intervention (n=6) Post-intervention (n=13) Ciprofloxacin non-susceptible 6 (100) 4 (30.7) Our initial results show – include column for total bacteremia Infection related mortality Pre-intervention 5/7 (71.4%) Post-intervention 2/4 (50%) *Patients may have experienced more than one episode of bacteremia GNR: gram negative rod

Preliminary Conclusions Similar rates of: Mortality ICU admission Febrile neutropenia Improved resistance patterns Increased GNR bacteremia Preliminary conclusions from early assessment of this initiative show

Summary Multiple roles for ASPs in hematologic malignancies Areas for intervention Algorithms Febrile neutropenia, anti-fungal Alternative dosing strategies Duration Limiting empiric therapy when no source identified Decreasing exposure to fluoroquinolone prophylaxis In summary

Assessment Question During the empiric treatment of febrile neutropenia which class of medication should be administered first? a. Anti-MRSA agent b. Antifungal c. Anti-pseudomonal beta-lactam d. Antiviral

Questions?

Antimicrobial Stewardship Strategies in Patients with Hematologic Malignancies Carley Buchanan, PharmD Infectious Diseases Clinical Pharmacist Western Pennsylvania Hospital March 9, 2019

Alternative Cefepime Dosing: Exclusion Criteria Age < 18 or > 89 years of age CrCl < 30 mL/min or on dialysis Subjective fevers only Admission from outside hospital Received other empiric antimicrobial prior to cefepime Change in dosing scheme after initial 36 hours therapy Change in antibiotic due to allergy, adverse drug event, or targeted therapy based on cultures/susceptibilities Pregnancy Residence at correctional facility