Contact Information: Tigecycline (TG) Salvage Therapy for Legionnaires’ disease (LD) in Severely Ill Patients Deepika Slawek, MD, MPH NYU Langone Medical Center 550 First Avenue New York, NY 10016 Deepika Slawek, MD, MPH, Diana Altshuler, PharmD, Yanina Dubrovskaya, PharmD, Eddie Louie, MD Email: [email protected] # 1222 NYU Langone Medical Center, New York, NY ABSTRACT (REVISED) OBJECTIVE RESULTS § To describe, retrospectively, the use of TG in hospitalized patients with LD with Background: Mortality due to severe LD remains high with 20-25% of patients Table 1 (cont’d). Patient demographics and clinical presentation (n=12) high severity-of-illness scores or a high degree of immunosuppression who are requiring mechanical ventilation. TG, a minocycline derivative, is active against L. Figure 1. LD Treatment Prior to Starting TG unresponsive to standard monotherapy Required ICU admission 9/12 (75) pneumophila in animal and cell models, achieves high concentrations intracellularly 14 Septic shock 5/12 (42) and demonstrated minimal in vitro synergy with levofloxacin (LVX). Clinical data on TG METHODS for LD are limited to two case reports in immunocompromised hosts. We describe our Duration of ICU stay , days median (range) 12 (1-18) days 12 experience with TG as salvage therapy in severely ill patients with LD. Study Design Required mechanical ventilation 5/12 (42) § IRB approved single center retrospective case series (7/2008-2/2016) Methods: Patient demographics, clinical data and treatment details were collected Duration of mechanical ventilation , days 10 (1-22) 10 Inclusion Criteria Exclusion Criteria retrospectively. Clinical failure was defined based on vital signs (temperature ≥37.2 C, median (range) 12 heart rate ≥100 beats/min, respiratory rate ≥24 breath/min, systolic ≤100 mm Hg, § Hospitalized patients >18 years of age § Received initial treatment for LD for <24h Concomitant infections treated Pneumonia (n=2) 8 oxygen saturation on room air <90%) and/or physician-documented deterioration in § Positive Legionella urinary antigen, or 4x § Received TG for <24 h Clostridium difficile colitis (n=2) clinical parameters or death. elevated L. pneumophila antibody Endocarditis (n=1) 6 9 § Treated with TG after clinical deterioration on Results: At our University Medical Center 12 patients with severe LD (positive initial therapy (AZ, LVX, or AZ + LVX) Length of hospital stay, median (range) 15 (8-27) 4 Legionella urinary antigen n=8, elevated L. pneumophilia antibody n=4) Endpoints

Data are n (%) unless otherwise indicated. ICU - intensive care unit No. of pts on each prior to TG received TG salvage therapy after failure of initial treatment with azithromycin (AZ) § Clinical response- improved hemodynamics, improved oxygenation, decrease in 2 n=6 or LVX and AZ n=6 between 1/2008 and 2/2016. Median age of these patients leukocytosis Table 2. LD treatment course was 81 (37-90) years. More than half had ≥2 comorbidities, with cardiovascular and 0 1 pulmonary being more common. Two patients were immunocompromised due to RESULTS Days of therapy prior to TG, median (range) 4 (2-8) AZ LVX AZ + LVX active chemotherapy. PSI score on admission was 130 (97-223); at the time of switch Treated for another infection concomitantly 6/12 (50) Table 1. Patient demographics and clinical presentation (n=12) Antibiotics to TG, SOFA score was 6 (1-9) with respiratory worsening present in 11/12 patients Antibiotics given concomitantly after median of 4 (2-8) days of initial therapy. Seventy percent of patients required Males 8/12 (67) Vancomycin 8 intensive care unit stay for 12 (1-18) days, 42% (5/12) had septic shock and were Age, years median (range) 81 (37-90) intubated for 10 (1-22) days. Piperacillin tazobactam 4 Figure 2. LD Regimen after TG Started Race These patients received salvage therapy with TG 100 mg x 1 dose, followed by 50 mg Ceftriaxone 3 6 IV q12h in addition to LVX n=5, AZ n=3, LVX and AZ n=3, or as monotherapy n=1 for White 8 Cefepime 1 median of 8 (4-17) days. After TG salvage therapy, clinical improvement was seen in Asian 1 5 67% (8/12). Two patients died and 2 were made comfort care. No patients Meropenem 1 Other 3 experienced adverse events attributable to TG salvage therapy. Total duration of Reason for TG switch therapy was 18 (9-24) days. ≥2 comorbidities 7/12 (58) 4 Respiratory worsening 11/12 (91.7) Significant Comorbidities Conclusion: This small cohort of patients provides evidence that TG can be Clostridium difficile colitis 1/12 Arrythmia 5 3 considered for salvage therapy in patients failing macrolide and/or fluoroquinolone SOFA score at TG initiation, median (range) 6 (1-9) 5 therapy. Congestive heart failure 4 Selected end points after TG start No. of patients 2 Hypertension 4 Time to defervescence if febrile n=?, 13 (1-60) 3 3 Cancer 3 hours median (range) 1 BACKGROUND Hypothyroidism 3 Time to WBC decrease , days median 8/12 (75) 1 § Mortality from Legionnaires’ disease (LD) has declined from 34% in 1980 to 3.1% Asthma 2 (range) 0 in 2010. Twenty to 25% Chronic renal disease 1 TG used in combination with other agents to 11/12 (92) TG + AZ TG + LVX TG + AZ + LVX TG of LD patients still require mechanical ventilation, with 35% hospital mortality in treat LD these patients HIV/AIDS 1 COPD 1 TG treatment duration, median (range) 8 (4-17) CONCLUSION Data are n (%) unless otherwise indicated § Treatment of LD patients with high severity-of-illness scores (PSI, SOFA) Immunosuppressed due to medication effect 2/12 (17) § Eight patients out of the 12 reviewed showed improvement in clinical markers, such as fevers unresponsive to standard therapy with AZ or LVX is a clinical challenge Diagnosed with Legionella urinary Ag 8 and leukocytosis after initiation of TG Table 3. Treatment Outcomes § Tigecycline (TG) is a minocycline derivative that achieves high intracellular Diagnosed with L. pneumophila Ab 4 § This cohort had a high burden of comorbidities prior to infection with LD, both infectious and Early Case Fatality 2/12 (17) concentrations, and has been shown to be effective against L pneumophila in Multilobar pneumonia 9/12 (75) otherwise animal and cell models Overall case fatality 4/12 (33) PSI score on admission, median (range) 130 (97-223) § Data on regimens for patients failing standard therapy for LD is limited, and further Data are n (%) unless otherwise indicated. Ag - antigen, Ab - antibody, PSI - pneumonia severity index, SOFA - Sequential Clinical Response 8/12 (67) investigations into the use of TG in patients who are severely ill with LD should be pursued Organ failure Assessment, COPD - Chronic Obstructive Pulmonary Disease, HIV/AIDS - Human Immunodeficiency Data are n (%) unless otherwise indicated Virus/Acquired Immunodeficiency Syndrome