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

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

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

4. 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

5. 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.

6. 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.

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

8. 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 ;26:1320–1332

9. 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.

10. 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.

11. Outcomes 2g Q8H (n=75) 1g Q6H (n=75) p value Primary Outcome
Time to Defervescence, h*
69 ( )
n=72
65.3 ( )
n=74
0.47
Secondary Outcomes
Duration of Cefepime, h*
88.0 ( )
80.8 ( )
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 ( )
89.8 ( )
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.

12. 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.

13. 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.

14. 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.

15. 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):
Baden LR et al. NCCN Guideline Version
Ann Oncol. 2016;27(suppl 5):v111-v118.
Haematologica. 2013;98(12):

16. 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

17. 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

18. 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;:JCO
Clin Infect Dis. 2018;67(11):

19. 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…

20. 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

21. 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

22. 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

23. 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

24. Questions?

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

26. 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