Objectives Results Conclusions Despite failure or intolerance to prior azole treatment patients transitioned to either ISAV POSA or VORI for salvage therapy had significant reductions in ID: 844316
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1 Introduction Objectives Results Conclusi
Introduction Objectives Results Conclusions • Despite failure or intolerance to prior azole treatment, patients transitioned to either ISAV, POSA, or VORI for salvage therapy had significant reductions in MSG scores • Majority of patients obtained an overall improved outcome (Table 3). However, the study was not powered to detect differences in improvement rates between agents • In CNS patients, VORI significantly reduced CNS MSG scores ; however, ISAV and POSA were not powered to detect a difference specifically in CNS disease • Majority of improved outcomes were seen in lungs, skin and soft tissue, and bone infections. • More adverse drug reactions were reported with VORI than with POSA or ISAV • ISAV, POSA, and VORI are all potential options for salvage therapy ; however, prospective comparative trials with larger sample size are needed to define their role in treatment of cocci beyond salvage therapy References • Single center, retrospective, chart review • Limited sample size • Drug doses not assessed due to inconsistencies in provider notes • Unable to correlate drug levels with clinical outcomes given retrospective nature • Inter - provider variation in documentation • Limitations inherent to MSG scoring system Evaluate the efficacy and safety of ISAV, POSA, and VORI in the salvage treatment of cocci Methods Study Design: Retrospective, single center, chart review at Kern Medical in Bakersfield, CA Study Period: January 1, 2010 to April 18, 2018 Inclusion Criteria : • Age ≥18 years old • Cocci treatment (salvage therapy) ( tx ) with ISAV, POSA, or VORI after failure or intolerance to prior azole therapy • Minimum of 1 month of therapy Exclusion Criteria : • No follow up with infectious disease physician • Immunocompromised patient • Dual therapy with additional antifungal therapy (i.e. intrathecal/intravenous amphotericin) Primary Outcome : Overall change in Mycosis Study Group Score (MSG Score ) from start of salvage therapy (ISAV, POSA, or VORI) to final infectious disease clinic visit Secondary Outcome : Response to therapy defined by improved, stable, or unresponsive outcomes based on change in MSG score and clinician assessment at final clinic visit Safety: Adverse drug reactions Statistical Analysis: Wilcoxon Signed Rank Sum Test Limitations Janet Yoon, Pharm.D., 1 Jeff Jolliff, Pharm.D., 1 Brittany Andruszko, Pharm.D., 1 Arash Heidari, M.D., 2 Royce Johnson, M.D. 2 1 Department of Clinical Pharmacy Services, Kern Medical, Bakersfield, CA 2 David Geffen School of Medicine UCLA, Department of Medicine, Kern Medical, Bakersfield, CA Treatment of Coccidioidomycosis with 2 nd Generation Triazoles as Salvage Therapy Contact Information: 1700 Mt. Vernon Ave Bakersfield , CA 93306 Janet.Yoon@kernmedical.com Phone Number: (661) 326 - 2197 Fax Number: (661) 862 - 7684 391 Table 1: Characteristics ISAV n=15 POSA n=31 VORI n=21 Total n=67 Age, Years + 44 (38 - 51.5) 45 (36.5 - 59) 46 (40 - 55) 45 (36.5 - 55.5) Sex* Male 10 (66.6) 24 (77.4) 14 (66.6) 48 (71.6) Race/Ethnicity* Hispanic 12 (80) 16 (51.6) 15 (71.4) 43 (64.1) Non - Hispanic White 0 (0 ) 3 (9.6) 3 (14.2) 6 (9) African American 2 (13.3) 10 (32.2) 1 (4.8) 13 (19.4) Other 1 (6.6) 2 (6.4) 2 (9.5) 5 (7.5) Weight, Kg + 79 (64.5 - 86) 82 (70.5 - 88) 82.5 (67 - 87) 82 (67.5 - 87) Height, Inches + 65 (62.5 - 66) 67(63 - 69) 66 (65 - 68) 66 (63 - 68) Site of Infection* Lung Only 3 (20) 6 (19.3) 4 (19.1) 13 (19.4) Skin or Soft Tissue 2 (13.3) 6 (19.3) 0 (00) 8 (11.9) Bone or Joint 4 (26.6) 15 (48.3) 0 (00) 19 (28.3) Meningitis 6 (40) 4 (12.9) 17 (80.9) 27 (40.3) Immediately Preceding Tx * Fluconazole 1 (6.6) 19 (61.3) 20 (95.2) 40(59.7) Voriconazole 9 (60) 11 (35.4) --- 2 0 (29.9) Itraconazole --- 1 (3.2) 1 (4.8) 2 (2.9) Posaconazole 5 (33.3) --- 0 (0 ) 5 (7.5) Reason for Salvage Tx* Refractory Infection 8 (53.3 ) 23 (74.2) 16 (76.2) 47 (70.1) Medication I ntolerance 5 (33.3) 5 (16.1) 1 (4.8) 11 (16.4) Refractory and Intolerant 2 (13.3) 3 (9.6) 4 (19) 9 (13.4) Duration of Immediately Preceding Tx , month + 23 (8.5 - 20) 20 (4 - 47 ) 36 (19 - 62) 24 (6 - 48.5) Duration of Salvage Tx, month + 10 (4.5 - 14 ) 25 (15.5 - 43) 46 (26 - 63 ) 25 ( 12 - 44.5) # of Failed Tx + One 1 (6.6) 16 (51.6) 16 (76.2) 33 (49.3) Two 10 (66.7) 11 (35.5) 5(23.8) 26 (38.8) Three or More 4 (26.7) 4 (12.9) 0 (0 ) 8 (11.9) + (Median, IQR), * n(%) Table 2: Primary Outcome – Overall Δ in MSG Score n MSG Score – Pre + MSG Score – Post + Median P - value ISAV 15 5 (3.5 - 7.5) 2 (2 - 3) - 2 0.0032 POSA 31 5 ( 3.5 - 8 ) 2 ( 1 - 2) - 3 ≤ 0.001 VORI 21 6 (4 - 7) 2 (0 - 3) - 2 ≤ 0.001 + (Median, IQR) Table 3: Secondary Outcome Composite of MSG Score change and clinician assessment ISAV ( n=15) POSA (n=31) VORI ( n=21) Total ( n=67) Improved* 1 11 (73.3) 25 (80.6) 13 (61.9) 49 (73.1) Stable* 2 4 (26.6) 6 (20) 4 (19) 14 (20.9) Unresponsive* 3 0 (00) 0 (00) 4 (19) 4 (5.9) * n(%); 1 : �50% decrease in MSG score, unequivocal documentation of clinical improvement, or a 25 - 49% decrease in MSG score & physician’s impression of improvement; 2 : Unchanged score or a MSG score that declined by 3 : Reported relapsed or disease progression, MSG score increase Table 4: Overall Outcomes by Site of Infection MSG Score – Pre + MSG Score – Post + Median Overall Improved (%) Lungs (n=13) ISAV (3 ) 4 ( 4 - 7 ) 2 (1 - 2) 2 3 ( 100) POSA (6) 5.5 (3 - 7.5) 1.5 (1 - 2) 3.5 5 ( 83) VORI (4) 3 (2.5 - 4.75) 1.5(0.75 - 3.75 ) 1.5 2 ( 50) Skin or Soft Tissue (n=8) ISAV(2 ) 5 (4 - 6) 2 (2,2) 3 2 ( 100) POSA (6) 5.5 (4.25 - 8.25) 2.5 (2 - 3) 3.5 6 ( 100) Bone (n=19) ISAV (4 ) 6.5 (5.5 - 7.25) 2 (2 - 2) 4.5 4 ( 100) POSA (15 ) 5 (4 - 7.5) 1 ( 1 - 2) 3 12 ( 80) CNS (n=27) ISAV (6 ) 4.5(2.5 - 5) 3 (1.25 - 4.75) 1.5 2 ( 33.3) POSA (4) 2.5 (0.75 - 5) 0.5 (0 - 1.25) 2 2 ( 50) VORI (17) 6 (4 - 7) 2 (0 - 3) 4 11(64.7) + (Median, IQR) Table 2.2 MSG Score Changes in CNS Disease n MSG Score – Pre + MSG Score – Post + Median P - value ISAV 6 4.5 (2.5 - 5) 3 (1.25 - 4.75) 0 N/A POSA 4 2.5 (0.75 - 5) 0.5 (0 - 1.25) - 2 N/A VORI 17 6 (4 - 7) 2 (0 - 3) - 3 0.002 + (Median, IQR) Table 2.1 MSG Score Changes in Non - CNS Disease n MSG Score – Pre + MSG Score – Post + Median P - value ISAV 9 6 (4 - 7) 2 (2 - 2) - 2 ≤ 0.001 POSA 27 5 (4 - 8) 2 (1 - 3) - 3 ≤ 0.001 VORI 4 3 (2.5 - 4.75) 1.5 (0.75 - 3.75) - 1 N/A + (Median, IQR) 1. Galgiani , JN, Ampel , NM, Blair JE, et al. Coccidioidomycosis . Clin Infect Dis . 2005; 41:1217 - 23. 2. California Department of Public Health. Coccidioidomycosis in California Provisional Monthly Report. Center for Infectious Diseases, Division of Communicable Disease Control, Infectious Disease Branch, Surveillance and Statistics Section. 30 June 2018. Available at: https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Doc ument%20Library/CocciinCAProvisionalMonthlyReport.pdf. Accessed July 7, 2018. 3. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis . Clin Infect Dis . 2016;63(6). doi:10.1093/ cid /ciw360. 4. Thompson GR, Rendon A, Ribeiro dos Santos R, et al. Isavuconazole Treatment of Cryptococcosis and Dimorphic Mycoses. Clin Infect Dis . 2016;63(3):356 - 362. doi:10.1093/ cid /ciw305. 5. Galgiani JN, Cantanzaro A, Cloud GA, et al. Comparison of Oral Fluconazole and Itracconazole for Progressive, Nonmeningeal Coccidioidomycosis : a Randomized, Double - Blind Trial. Mycoses Study Group, Ann Intern Med, 2000, vol. 133 ( pge 676 - 86) 6. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist . 2013;6:163 - 174. doi:10.2147/IDR.S51340. 7. Kim MM, Vikram HR, Kusne S, et al. Treatment of refractory coccidioidomycosis with voriconazole or posaconazole . Clin Infect Dis. 2011;53(11):1060 - 6 8. Stevens DA, Rendon A, Gaona - Flores V, et al. Posaconazole Therapy for Chronic Refractory Coccidioidfomycosis . Chest . 2007;132(3):952 - 958. doi:10.1378/chest.07 - 0114. 9 ISAV 23 4 POSA 2 2 VORI 2 4 ISAV 2 2 POSA Improved Stable Unresponsive Figure 1: Secondary Outcome in Non - CNS and CNS Disease NON - CNS 11 4 2 VORI Typical Management : 3,5 • Triazole antifungals (typically fluconazole or itraconazole) or amphotericin B • May not be fully effective or tolerated in severe infections requiring salvage therapy with newer agents New Triazole Antifungals : 3,4,6,7,8 • Posaconazole (POSA)and voriconazole (VORI) have limited outcomes data, but demonstrate beneficial results in patients who have failed conventional therapy • Isavuconazonium, a prodrug of isavuconazole (ISAV), has a favorable side effect profile and efficacy in vitro . In vivo data is limited to 9 cases of primary pulmonary cocci Coccidioidomycosis (cocci) : 1 • Systemic fungal infection infecting 150,000/year • Endemic to southwestern United States • Most are self - limiting and confined to the lungs, but the disease can disseminate to the bone, soft tissue, and central nervous system in severe cases 1 California 8,203 cases In 2017 Kern County 2,827 cases Bakersfield CNS 1 13 3 1 1 1 0 4 8 12 16 ISAV POSA VORI Figure 2: Adverse Drug Reactions Photodermatitis Transaminitis Epigastric pain Emesis Chelitis