Prevention is the Best Medicine: Antimicrobial Prophylaxis in the Hematology & Oncology Population

Transcription

1 Prevention is the Best Medicine: Antimicrobial Prophylaxis in the Hematology & Oncology Population Hilary Teaford, Pharm.D. Pharmacy Grand Rounds 9/25/ MFMER slide-1

2 Objectives Describe considerations for the appropriate selection of antimicrobial prophylaxis in cancer patients Review appropriate dosing, side effects, and duration of antimicrobial agents for antifungal, antibacterial, and antiviral prophylaxis Identify some select agents in hematology which require unique antimicrobial prophylaxis considerations 2018 MFMER slide-2

3 Infection Risk in Cancer Patients Impaired Immunity Chemotherapy INFECTION

4 Type of Infection Risk by Immune Deficit Innate Immunity Neutrophils Bacterial, fungal and some viral 1 Natural Killer Cells Viral Acquired Immunity Antibody-Mediated (B cell) Viral reactivation Cell-Mediated (T cell) CD4 + helper T cells Pneumocystis jirovecii (PJP) Complement Encapsulated bacteria 1. Galani. J. Leukoc. Biol (4) MFMER slide-4

5 Hematopoiesis Lymphoid Line = ACQURIED IMMUNITY ALL CLL Lymphoma MM B B Naive Lymphoid Progenitor T T Plasma Cells Stem cell Myeloid Line = INNATE IMMUNITY AML,MDS, AA Neutrophils Myeloid Progenitor Eosinophils, Basophils, Monocytes ALL= Acute Lymphocytic Leukemia AML=Acute Myeloid Leukemia CLL= Chronic Lymphocytic Leukemia MM= Multiple Myeloma MDS=myelodysplastic syndrome AA: Aplastic Anemia

6 PJP Bacterial Viral Fungal 2018 MFMER slide-6

7 PJP Bacterial Viral Fungal 2018 MFMER slide-7

8 Common Bacterial Pathogens Escherichia coli Enterococcus species Staphylococcus coag. Neg Staphylococcus aureus Pseudomonas aeruginosa Klebsiella/Raoultella Viridans Group Streptococcus Enterbacter Cloacae Complex Number of Isolates Most Common Isolates in Hem./Onc. Patients at Mayo Clinic Hospital Rochester

9 Common Bacterial Pathogens Escherichia coli Enterococcus species Staphylococcus coag. Neg Staphylococcus aureus Pseudomonas aeruginosa Klebsiella/Raoultella Viridans Group Streptococcus Enterbacter Cloacae Complex Infection Sources: Chemotherapy- Induced Mucosal Damage Catheter Sites Number of Isolates Most Common Isolates in Hem./Onc. Patients at Mayo Clinic Hospital Rochester

10 Bacterial Fungal Viral Pneumocystis Unique Agents Optimal Antimicrobial Prophylaxis: Meta-Analysis Relative Risk of Death Compared to Placebo Relative All-Cause Mortality Reduction vs. Placebo in Afebrile Neutropenic Patients SMZ-TMP mg PO BID Any Quinolone SMZ-TMP Other Systemic Gafter-gvili. Cochrane Database Syst Rev SMZ-TMP= sulfamethoxazoletrimethoprim SMZ-TMP: sulfamethoxazole-trimethoprim

11 Bacterial Fungal Viral Pneumocystis Unique Agents Agents Used in Antibacterial Prophylaxis Line Drug Considerations in Hem./Onc. Patients Preferred Levofloxacin 1 Reported QTc prolongation (possibly less with Ciprofloxacin 2 ) Next Ciprofloxacin Levofloxacin= more strep. viridans coverage preferred Alternate 3 rd generation cephalosporin 3 : Cefdinir Cefpodoxime Sulfamethoxazoletrimethoprim (SMZ-TMP) Lacks pseudomonal coverage Lacks pseudomonal coverage Drug interaction: methotrexate Myelosuppression Caution in renal dysfunction 1. Prevention and Treatment of Cancer-Related Infections. NCCN. Version Briasoulis. Cardiology (2) Yemm. J. Antimicrob. Chemother (1)

12 Bacterial Fungal Viral Pneumocystis Unique Agents Defining Neutropenia Neutropenia Defined by NCCN: Absolute Neutrophil Count (ANC) less then 500 neutrophils/mcl OR ANC less than 1000 neutrophils/mcl with expected drop to <500 neutrophils/mcl within 48 hours Profound Neutropenia: <100 neutrophils/mcl Prolonged Neutropenia: >7 days Prevention and Treatment of Cancer-Related Infections. NCCN. Version NCCN= National Comprehensive Cancer Network 2018 MFMER slide-12

13 Bacterial Fungal Viral Pneumocystis Unique Agents Risk of Bacterial Infections in Cancer Patients NCCN Guidelines: Consider fluoroquinolone prophylaxis throughout course of neutropenia if expected ANC <1000 for >7 days Solid Tumors Multiple Myeloma CLL Lymphoma Low: less myelosuppressive chemotherapy Intermediate: regimen specific VDT-PACE CODOX-M/IVAC R-CHOP14 Acute Leukemia AML ALL High: myelosuppression needed for treatment efficacy Prevention and Treatment of Cancer-Related Infections. NCCN. Version

14 Bacterial Fungal Viral Pneumocystis Unique Agents Emerging Controversy: Multiple Myeloma Fluoroquinolone Prophylaxis 977 Newly Diagnosed Multiple Myeloma Patients >21 years old Placebo x 12 weeks Levofloxacin 500 mg PO qd x 12 weeks composite of fever/all-cause mortality with levofloxacin after 12 weeks gram negative infections with levofloxacin Same amount of C.diff, MRSA or ESBLs Weaknesses: composite outcome, neutropenia grouping Drayson Blood Dec 2017, 130 (Suppl 1) 903; C.diff= clostridium difficile MRSA= Methicillin-resistant Staphylococcus aureus ESBL=Extended spectrum beta-lactamases 2018 MFMER slide-14

15 PJP Fungal Viral Bacterial 2018 MFMER slide-15

16 Bacterial Fungal Viral Pneumocystis Unique Agents Primary Fungal Organisms of Concern Organism Mortality in Invasive Infection Candida (most common) 30% 1 Aspergillus 40-90% 2 Mucor 54% 3 1.Cleveland (10) Dagenais. Clin. Microbiol. Rev (3) Roden. Clin. Infect. Dis (5) MFMER slide-16

17 Bacterial Fungal Viral Pneumocystis Unique Agents Agents Used in Fungal Prophylaxis Azole class effects: LFT elevations, most prolong QTc, CYP inhibition Drug Spectrum: most candida Fluconazole Spectrum: candida, aspergillus Voriconazole Safety and Convenience Considerations Among azoles less potent CYP 3A4 inhibition Hallucinations, vision changes Itraconzole Echinocandins Inconsistent bioavailability, heart failure exacerbations Anidulafungin not hepatically or renally cleared Spectrum: candida, aspergillus, mucor Isavuconazonium/ Isavuconazole Shortens QT interval Seemingly fewer drug interactions Posaconazole Amphotericin B Suspension requires high fat meal, strong CYP3A4 inhibition Tablet has significantly improved bioavailability Infusion reactions, electrolyte abnormalities, nephrotoxicity Prevention and Treatment of Cancer-Related Infections. NCCN. Version

18 Bacterial Fungal Viral Pneumocystis Unique Agents Recommendations for Select Patient Groups Population Low Risk Solid Tumors Antifungal Prophylaxis None in most cases Medium Risk Lymphoma Multiple Myeloma CLL High-Risk AML ALL Preferred: fluconazole or an echinocandin during prolonged neutropenia Preferred: posacaonzole during prolonged neutropenia Alternate: voriconazole, an echinocandin, or amphotericin B during prolonged neutropenia Preferred: fluconazole or an echinocandin during prolonged neutropenia Alternate: amphotericin B during prolonged neutropenia Prevention and Treatment of Cancer-Related Infections. NCCN. Version MFMER slide-18

19 Bacterial Fungal Viral Pneumocystis Unique Agents Isavuconazole as Prophylaxis for Invasive Fungal Infections (IFI) Author Number of Patients Design and Population Results Cornely Phase 2 Dose Escalation study in AML primary ppx Rausch Retrospective study in primary ppx leukemia patients No major ADEs, 10% patients had breakthrough IFI 18% of primary ppx pts had breakthrough IFI Fung Case Series 5 cases of breakthrough IFI, 3/5 primary ppx Cornely et. al. Antimicrob Agents Chemother. 2015;59(4). Rausch. Clin. Infect. Dis Fung et al. Clin Infect Dis Ppx: Prophylaxis ISA= Isavuconazole ADE= Adverse Drug Event 2018 MFMER slide-19

20 Bacterial Viral Fungal PJP 2018 MFMER slide-20

21 Bacterial Fungal Viral Pneumocystis Unique Agents Viral Pathogens of Concern Virus Pathology HSV- Herpes Simplex Virus Skin lesions, meningitis, blindness, encephalitis VZV- Varicella Zoster Virus Rash, neuritis, aseptic meningitis, neuropathy, encephalitis, pneumonitis, hepatitis, pancreatitis HBV- Hepatitis B Virus CMV- Cytomegalovirus Acute hepatitis, chronic liver disease, cirrhosis, and hepatocellular carcinoma Colitis, hepatitis, encephalitis, myocarditis, retinitis, Guillen-Barre syndrome Prevention and Treatment of Cancer-Related Infections. NCCN. Version MFMER slide-21

22 Bacterial Fungal Viral Pneumocystis Unique Agents Antiviral Agents Agent Prophylactic Dosing Comments HSV/VZV Acyclovir mg PO BID OR 5 mg/kg IV qd Valacyclovir 500 mg PO BID or TID Renally dosed Need hydration to avoid crystal nephropathy, renally dosed CMV (also covers HSV/VZV) Ganciclovir 5 mg/kg IV q12h x 7-14 days Marrow suppression, renally dosed Valganciclovir HBV Entecavir: *Preferred* Tenofovir: *Preferred* Lamivudine 900 mg PO qd 0.5 mg PO qd Renally dosed TDF: 300 mg PO qd TAF: 25 mg PO qd 100 mg PO qd Black box warning: lactic acidosis, hepatomegaly with steatosis Prevention and Treatment of Cancer-Related Infections. NCCN. Version MFMER slide-22

23 Type of Infection Risk by Immune Deficit Innate Immunity Neutrophils Bacterial, fungal and some viral 1 Natural Killer Cells Viral Acquired Immunity Antibody-Mediated (B cell) Viral reactivation Cell-Mediated (T cell) CD4 + helper T cells Pneumocystis jirovecii (PJP) 1. Galani. J. Leukoc. Biol (4) MFMER slide-23

24 Bacterial Fungal Viral Pneumocystis Unique Agents Bacterial Fungal Viral Pneumocystis Unique Agents Populations Needing Antiviral Prophylaxis Population Type of Prophylaxis Prolonged Neutropenia (ALL/AML most likely) Multiple Myeloma on proteasome inhibitor (bortezomib or carfilzomib) Chronic Lymphocytic Leukemia (CLL) on alemtuzumab Lymphoma on CD-20 antibody (rituximab) Any patient with previous episode HSV during neutropenia or longer VZV throughout therapy HSV throughout therapy HBV (if HBsAg+) throughout therapy CMV surveillance throughout therapy HBV (if HBsAg+) throughout therapy HSV throughout therapy Prevention and Treatment of Cancer-Related Infections. NCCN. Version MFMER slide-24

25 Summary of Antiviral, Antifungal and Antibacterial Prophylaxis AML During neutropenia: levofloxacin, posaconazole & acyclovir* ALL During neutropenia: levofloxacin, fluconazole(or an echinocandin), acyclovir* CML/MM/Lymphoma: Same as ALL during prolonged neutropenia Refer to concomitant medications for antivirals to continue throughout therapy Any patient Acyclovir throughout therapy if past episode of HSV *Acyclovir may be continued throughout therapy 2018 MFMER slide-25

26 Case for Assessment Question 1 A patient with AML, recently discharged following count recovery is admitted due to pneumonia. She is started on cefepime. She is on levofloxacin, posaconazole and acyclovir prior to admission. Her ANC>2000 neutrophils/mcl MFMER slide-26

27 What should you do with the levofloxacin & posaconazole? A) Keep both B) Keep the levofloxacin, discontinue the posaconazole C) Discontinue both D) Discontinue the posaconzole, keep the levofloxacin 2018 MFMER slide-27

28 What should you do with the levofloxacin & posaconazole? A) Keep both B) Keep the levofloxacin, discontinue the posaconazole C) Discontinue both D) Discontinue the posaconzole, keep the levofloxacin 2018 MFMER slide-28

29 Viral PJP Bacterial Fungal 2018 MFMER slide-29

30 Bacterial Fungal Viral Pneumocystis Unique Agents Pneumocystis jirovecii (PJP) Caused by fungus Pneumocystis jirovecii Overall mortality in non-hiv patients= 30.6% 1 Prophylaxis leads to 85% reduction in PJP 2 Line of Drug Dose Reasons to not use Therapy 3 Preferred SMZ-TMP Bactrim SS : mg PO qd Bactrim DS : mg PO 3x weekly Methotrexate use May cause myelosuppression Alternate Pentamidine 300 mg inhaled through nebulizer every 4 weeks following albuterol neb Breakthrough PJP in upper lobe Dapsone 100 mg PO daily G6PD deficiency Atovaquone 1500 mg daily of oral-suspension with high-fat meal Bad taste Must take with food 1. Liu Y et al. Oncotarget. 2017;8(35) 2. Stern. Cochrane Database Syst. Rev (10). 3. Prevention and Treatment of Cancer-Related Infections. NCCN. Version SMZ-TMP: sulfamethoxazole-trimethoprim 2018 MFMER slide-30

31 Type of Infection Risk by Immune Deficit Innate Immunity Neutrophils Bacterial, fungal and some viral 1 Natural Killer Cells Viral Acquired Immunity Antibody-Mediated (B cell) Viral reactivation Cell-Mediated (T cell) CD4 + helper T cells Pneumocystis jirovecii (PJP) 1. Galani. J. Leukoc. Biol (4) MFMER slide-31

32 Bacterial Fungal Viral Pneumocystis Unique Agents PJP Prophylaxis: Patient Populations PJP ppx is recommended per NCCN Associated Conditions High-dose steroids Temozolomide+ radiation Idelalisib Alemtuzumab T-Cell depleting agents: purine analogs (fludarabine, cladribine) Other PJP risk factors Gemcitabine 1 Bendamustine 2 Rituximab 3 ALL, lymphoma, multiple myeloma, CNS disease Glioblastoma CLL, lymphoma CLL CLL (FCR), AML (CLAG-M, FLAG-M) Associated Conditions Lymphoma, solid tumors Lymphoma, CLL Lymphoma (R-CHOP14), CLL 1.Lingaratnam. Leuk. Lymphoma (1) Abkur. Clin. Case Reports (4) Martin-Garrido. Chest (1)

33 Bacterial Fungal Viral Pneumocystis Unique Agents Risk of PJP in Intermittent Steroid Use Intermittent Courses of Corticosteroids Also Present a Risk for Pneumocystis Pneumonia in Non-HIV Patients: Calero-Bernal et. al Design Descriptive review of 128 cases of PJP, most without PJP ppx Results 50% of patients had hematological disease ~20% patients used steroids intermittently with chemotherapy (equiv. 70 mg of prednisone per day) Rituximab, methotrexate and everolimus most common other immunosuppressive agents in cases Takeaway: intermittent steroids with chemotherapy may also be risk factor for PJP 2018 MFMER slide-33

34 Bacterial Fungal Viral Pneumocystis Unique Agents Duration of Therapy for PJP Prophylaxis Group Alemtuzumab Other T-cell depleting therapies (purine analogs) Corticosteroids Duration For 2 months and until CD4 + count is greater than 200 cells/mcl Until CD4 + count is greater than 200 cells/mcl Throughout active therapy, including taper and for at least 6 weeks after cessation 1 : 79 out of 113 patients (70%) with PJP were diagnosed with PJP during steroid taper period 2 1. Cooley. Intern. Med. J (12b) Sepkowitz. J. Am. Med. Assoc (6) MFMER slide-34

35 Case for Assessment Question #2 A Multiple Myeloma patient being treated with weekly CyBorD (Cyclophosphamide-Bortezomib- Dexamethasone) is admitted for pneumonia. Dexamethasone is given 40 mg (267 mg prednisone equivalent) weekly. He has SMZ-TMP and acyclovir as home meds. His ANC is >2000 neutrophils/mcl 2018 MFMER slide-35

36 What should you do with his SMZ- TMP and acyclovir? A.Discontinue both agents B.Keep SMZ-TMP, stop acyclovir C.Keep both D.Keep both and add fluconazole 2018 MFMER slide-36

37 What should you do with his SMZ- TMP and acyclovir? A.Discontinue both agents B.Keep SMZ-TMP, stop acyclovir C.Keep both D.Keep both and add fluconazole 2018 MFMER slide-37

38 Agents With Unique Considerations 2018 MFMER slide-38

39 Bacterial Fungal Viral Pneumocystis Unique Agents Type of Infection Risk by Immune Deficit Innate Immunity Neutrophils Bacterial, fungal and some viral 1 Natural Killer Cells Viral Acquired Immunity Antibody-Mediated (B cell) Viral reactivation Cell-Mediated (T cell) CD4 + helper T cells Pneumocystis jirovecii (PJP) Complement Encapsulated bacteria 1. Galani. J. Leukoc. Biol (4) MFMER slide-39

40 Bacterial Fungal Viral Pneumocystis Unique Agents Eculizumab (Soliris ) Mechanism of action: high affinity to compliment protein C5 Black box warning: meningococcal infections fold increase in meningococcal infection risk Manufacturer Recommendation: Provide meningococcal vaccines (MenACWY, MenB) 2 weeks prior to starting therapy If unable to wait two weeks: Administer vaccines ASAP and provide 2 weeks of antibacterial prophylaxis (ciprofloxacin or penicillin VK) Soliris(Eculizumab) Prescr. Inf MFMER slide-40

41 Bacterial Fungal Viral Pneumocystis Unique Agents Need for Antibacterial Prophylaxis Throughout Eculizumab Therapy 80% of eculizumab-treated meningococcal cases had non-groupable N.meningitidis strains 1 Strains possibly not covered by vaccines 1 Cases reports of fully vaccinated pts with serogroup B meningitis 2 Consider prophylaxis with penicillin while on treatment 2 1. Reher. Vaccine (19) McNamara. Am. J. Transplant (9) MFMER slide-41

42 Bacterial Fungal Viral Pneumocystis Unique Agents Alemtuzumab (Campath ) Mechanism: binds to CD52 on surface of B and T lymphocytes, monocytes, macrophages and natural killer cells 18% of patients in approval study had fatal infections (on prophylaxis) Category Recommendation Duration Viral PJP HSV: Yes CMV: weekly surveillance HBV: if positive Yes >2 months after completion & CD4 + >200 cells/mcl Bacterial Fungal No recommendation Campath(Alemtuzumab). Prescr. Inf MFMER slide-42

43 True or False: there is some evidence that SMZ-TMP may have value throughout eculizumab therapy 2018 MFMER slide-43

44 True or False: there is some evidence that SMZ-TMP may have value throughout eculizumab therapy 2018 MFMER slide-44

45 Summary Prolonged neutropenia generally necessitates antibacterial, antifungal and antiviral prophylaxis and is most common in acute leukemia patients Steroids and T-cell depleting agents, such as alemtuzumab, increase risk of PJP Assessment of oncology drug interactions, hepatic/renal function, and risk of myelosuppression is key to regimen selection Alemtuzumab and eculizumab are two agents with unique antimicrobial prophylaxis considerations 2018 MFMER slide-45

46 Bacterial Fungal Pneumocystis Viral Fungal Spectrum vs Cost Drug Cost Per Day ($) Fluconazole Voriconazole Itraconzole Isavuconazonium sulfate/ isavuconazole Posaconazole Echinocandins (micafungin & caspofungin & anidulafungin) Caspo: Mica: Ani: 216 Amphotericin B weekly (466 daily) 2018 MFMER slide-46

47 Bacterial Fungal Pneumocystis Viral Common Viral Pathogens of Concern HSV- Herpes Simplex Virus Percent of Patients Seropositive HSV-1: 53.9% in year olds HSV-2: 15.7% in year olds Pathology Skin lesions, meningitis, blindness, encephalitis VZV- Varicella Zoster Virus 98% in year olds Rash, neuritis, aseptic meningitis, neuropathy, encephalitis, pneumonitis, hepatitis, pancreatitis HBV- Hepatitis B Virus CMV- Cytomegalovirus 0.27% HBsAg+ Acute hepatitis, chronic liver disease, cirrhosis, and hepatocellular carcinoma 58.9% of patients > 6 years Colitis, hepatitis, encephalitis, peri/myocarditis, >90% of patients > 90 years retinitis, Guillen-Barre syndrome 2018 MFMER slide-47