2018 BMT Pharmacists Conference Infection Prophylaxis in the HCT patient Melissa D. Johnson, PharmD, AAHIVP Associate Professor of Medicine Duke University Medical Center Liaison Clinical Pharmacist Duke Antimicrobial Stewardship Outreach Network Durham, North Carolina [email protected] @idpharmacist Disclosures • Research grants: Merck, Charles River Laboratories Objectives • Assess the factors influencing risk of infection in hematopoietic cell transplant recipients • Compare and contrast current, recently approved and emerging antimicrobials for prophylaxis in hematopoietic cell transplant recipients • Discuss recent studies evaluating antimicrobials for prophylaxis in hematopoietic cell transplant recipients • Identify important monitoring parameters and supportive strategies for prophylaxis in hematopoietic cell transplant recipients Hematopoietic Cell Transplantation Transplant Variables and Infection Risk • Underlying disease Pre-Tx Stem cells • Type of transplant Therapy +/- GVHD Autologous, Allogeneic • HLA matching Conditioning • Conditioning regimen Engraftment • Source of stem cells • Graft manipulation • Graft versus host disease • Donor & recipient age Bacterial Viruses Fungal INFECTIOUS PATHOGENS Respiratory Pneumocystis Viruses Other Case Question 1 • 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) Treatment plan: Standard induction followed by allogeneic hematopoietic peripheral blood stem-cell transplant • Which of the following pathogens is he at greatest risk of infection from during the post-transplant, pre-engraftment period? a. Mucorales spp. b. Pneumocystis jirovecii c. E. coli d. Varicella zoster virus Allogeneic HCT Pre Post Late Phase Engraftment Engraftment PERIODS OF RISK Bacterial Viral Fungal Figure adapted from: Tomblyn M. et al. Biol Blood Marrow Transplant. 2009;15(10):1143–1238. Risks for bacterial infection in HCT • Pre-engraftment & early post-engraftment Neutropenia Gram Positive Mucosal breakdown Gram Negative Indwelling CVCs Bloodstream, Lungs, GI tract • Late phase GVHD Hypoglobulinemia Encapsulated bacteria CVCs Bacterial Percent of HCT Recipients Experiencing Infection 6 collaborating transplant centers Infections 2006-2011 in HCT 0 10 20 30 40 50 60 BSI 444 HCT patients C. diff Matched, unrelated 55% Matched, related 40% Mismatched 6% Pneumonia Peripheral blood cells 87% BMT 12% UCT 1% T cell depleted <1% UTI Myeloablative 72% Sinusitis 93% of patients experienced an infection Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. 231 Bacteremias in HCT Recipients in 6 collaborating transplant centers Bacterial 2006-2011 Infections 55% 21% in HCT Gram Positive Gram Negative 140 120 100 444 HCT patients Matched, unrelated 55% 80 Matched, related 40% Mismatched 6% 60 Peripheral blood cells 87% BMT 12% 40 UCT 1% T cell depleted <1% Episodes of Number 20 MyeloablatiVe 72% 0 VRE CoNS MSSA MRSA E. coli other GP E faecium E faecalis beta strep C. freundiiE. cloacae B. cepaciaOther GN A. baumanii P. aeruginosaK. pneumoniaS. maltophilia Polymicrobial Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. 231 Bacteremias in HCT Recipients in 6 collaborating transplant centers Bacterial 2006-2011 Infections 55% 21% in HCT Gram Positive Gram Negative 140 120 Mortality within 7 days of bacteremia: 100 444 HCT patients 13% vs 45% (p=0.02) Matched, unrelated 55% 80 Matched, related 40% Mismatched 6% 60 Peripheral blood cells 87% BMT 12% 40 UCT 1% T cell depleted <1% Episodes of Number 20 MyeloablatiVe 72% 0 VRE CoNS MSSA MRSA E. coli other GP E faecium E faecalis beta strep C. freundiiE. cloacae B. cepaciaOther GN A. baumanii P. aeruginosaK. pneumoniaS. maltophilia Polymicrobial Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. Bacterial 146 Bacterial Infection Episodes in 104 haplo-HCT with post-transplant Cyclophosphamide & PBSC Infections June 2009-June 2015 in HCT 43% 39% Gram Positive Gram Negative 40 104 T-cell replete 35 haploidentical peripheral 30 blood HCT 25 Myeloablative 41% Nonmyeloablative 59% 20 15 No FQ prophylaxis used 10 5 0 62% of patients VRE MRSA CoNS Strep C. diff experienced a bacterial GP Rod S. aureus infection Enterococcus P.aeruginosa S. maltophilia S. pneumoniae Anaerobic GNR C. diff: 13% Enterbacteriaceae Slade M et al. Transpl Infect Dis 2017; 19:e12629. Pros/Cons of Prophylaxis Pros Cons • Reduction of infection • C. difficile infection Fewer documented • Change in microbiota, yeast infections overgrowth Fewer bacteremias • Antibiotic exposure à development of resistant • Reduction of fever pathogens • Mortality benefit Up to 30% multi-drug All-cause & infection- resistant isolates in those receiving fluoroquinolone related prophylaxis Febrile episode NNT= 5 (leukemia/HCT) • Side effects Bacterial infection NNT= 6 (leukemia/HCT) • Drug interactions Mortality NNT=43 (leukemia/HCT) Leibovici L et al. Cancer 2006. 107(8): 1743-1751. Ideal Bacterial Prophylaxis in HCT • Broad spectrum of activity Includes P. aeruginosa, Enterobacteriaceae Low propensity to induce resistance • Good safety profile • Available IV/PO • Few drug interactions Prophylaxis: Bacterial Pathogens • Fluoroquinolones high-risk, expected durations of Example Protocol for Bacterial Prophylaxis* prolonged and profound neutropenia Type Recommendation Auto Ciprofloxacin 500 mg PO BID with conditioning through 3 (ANC ≤100 cells/mm for >7 days) duration of neutropenia or until IV antibiotics started for febrile neutropenia; start on first day of conditioning • B-I recommendation from IDSA, 2-A regimen NMA Allo Ciprofloxacin 500 mg PO BID with conditioning through recommendation from NCCN duration of neutropenia or until IV antibiotics started for febrile neutropenia; start on first day of conditioning Intermediate risk: autologous HCT regimen; continue/resume until 6 months post-transplant MA Allo Ciprofloxacin 500 mg PO BID with conditioning through (matched duration of neutropenia or until IV antibiotics started for sibling and febrile neutropenia; start on first day of conditioning MUD) regimen Bulk of data with levofloxacin and MA Cord Ciprofloxacin 500 mg PO BID with conditioning through duration of neutropenia or until IV antibiotics started for ciprofloxacin febrile neutropenia; start on first day of conditioning regimen; continue/resume until 6 months post-transplant GVHD Penicillin VK 500 mg PO BID (if chronic GVHD on any immunosuppression) for coverage against Streptococcus Timing of discontinuation not pneumoniae systematically studied Freifeld AG et al. Clin Inf Dis 2011;52:e56-e93; NCCN Practice Guidelines in Oncology v.1.2018. *Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Case Question 2 • 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) Treatment plan: Standard induction followed by allogeneic hematopoietic peripheral blood stem-cell transplant • Which of the following agents has the most data to support its use as bacterial prophylaxis during the pre- engraftment period for allogeneic HCT? a. Cefiderocol b. Amoxicillin/clavulanate c. Penicillin d. Ciprofloxacin Newer antibiotics in development Phase III/recently approved Activity vs Resistant Pathogens Novel Features Name Route(s) CRAB CRPA CRE OPP Class Target Mechanism No X-R Meropenem + IV + - - +/- vaborbactam Delafloxacin IV + PO - - - - Cefiderocol IV - - - +/- Eravacycline IV + PO - - - - Imipenem - IV - - - - relebactam Omadacycline IV + PO - - - - Plazomicin IV - - - - Aztreonam- IV - - - - Avibactam Finafloxacin IV - - - - Murepavidin IV + + + + CRAB= Carbapanem Resistant Acinetobacter baumanii CRPA= Carbapenem Resistant Pseudomonas aeruginosa CRE= Carbapenem Resistant Enterobacter spp. OPP= Other important pathogen Adapted from: World Health Organization; 2017 (WHO/EMP/IAU/2017.11). Licence: CC BY-NC-SA 3.0 IGO X-R= Cross resistance Fungal Infections 100 in HCT 90 80 70 60 50 40 30 20 10 0 Medicine Heme-Malig HCT SOT Solid Tumor HIV Surgery Invasive Candidiasis Invasive Aspergillosis Mucormycosis Cryptococcosis Azie et al. Diag Micro Infect Dis. 2012;73:293-300 Proven/Probable Invasive Fungal Infections in HCT (N=444) Type of Infection Site of Infection 20 30 18 16 25 14 20 12 10 15 8 6 10 4 5 2 0 Number of infections of Number 0 CNS Mixed Candida Sinusitis Exophiala Aspergillus Mucorales Alternaria Pneumonia Bloodstream Disseminated Pneumocystis jiroveci Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. Fungal Infections in HCT Timeline Early IFI Late IFI Very Late IFI Fusarium Mucormycosis Aspergillus Candida 0 60 120 180 240 300 360 Days following transplantation Horan J., Perfect J and Alexander B. Invasive Fungal Disease in the Transplant Population: Overview. In: Principles and Practices of Transplant Infectious Diseases. Eds: Safdar A. Risks for IFI in HCT : Pre-Engraftment Risk Factor Details Transplant Related Donor HLA similarity Autologous < Allogeneic (MRD < MMRD/URD) Stem cell source Peripheral blood < bone marrow < cord blood; increased risk with T-cell depleted and CD34 selected cells Conditioning regimen NMA < MA in early infections, NMA ≥ MA in late infections Post-Transplant Related Neutropenia Especially in early risk period Viral illness CMV (most commonly associated), RSV, parainfluenza, +/- influenza GVHD Both acute (particularly grade III-IV) and chronic GVHD Horan J, Perfect J and Alexander B. Invasive Fungal Disease in the Transplant Population: Overview. In: Principles and Practices of Transplant Infectious Diseases. Eds: Safdar