Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial

Abstract

Background: Staphylococcus aureus remains a common cause of ventilatorassociated pneumonia, with little change in infection rates over the past 15 years. This phase 2 study evaluated suvratoxumab, an anti-alpha-toxin monoclonal antibody, in reducing incidence of S. aureus pneumonia in intensive care unit (ICU) subjects on mechanical ventilation (MV). Methods:We did a multicenter, single-dose, randomized, placebo-controlled, doubleblind, phase 2 pilot trial in 9 countries. Eligible subjects were patients in an ICU ≥18 years of age, currently intubated and on MV, positive for S. aureus lower respiratory tract (LRT) colonization as assessed by polymerase chain reaction (PCR) of endotracheal aspirate, and with no diagnosis of new-onset pneumonia. Subjects were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received anti-S. aureus antibiotics for >48 hours; had a CPIS ≥6, APACHE-II score ≥25, a SOFA score ≥9; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Subjects were screened for S. aureus lower respiratory tract (LRT) colonization using real-time polymerase chain reaction (PCR).Colonized subjects were randomly assigned 1:1:1 to a single intravenous infusion of suvratoxumab 2000 mg, 5000 mg or placebo. Randomization was stratified by country and by whether subjects received anti-S. aureus systemic antibiotic therapy. Based on pre-defined PK criteria, the 2000 mg arm was discontinued upon the recommendation of the data monitoring committee at an interim analysis. Primary efficacy endpoint was incidence of S. aureus pneumonia, adjudicated by a blinded independent panel, through 30 days post dose in the modified intent-to-treat study population. Primary safety endpoints were Francois et al. Suvratoxumab Ph2 (NCT02296320) D3 5 treatment-emergent AEs assessed through 30 and 90 days, treatment-emergent SAEs, adverse events of special interest, and new onset chronic disease, all assessed through 190 days. Findings: PCR screening of 737 ICU subjects identified 213 with S. aureus colonization; of these, 96 were randomized to receive suvratoxumab 5000 mg and 100 to placebo. At 30 days, 17/96 (17•7%) suvratoxumab and 26/100 (26•0%) placebo subjects had developed S. aureus pneumonia (relative risk reduction, 31.9%; 90% confidence interval [CI], −7•5 to 56•8; P = 0•166). At 30 days, incidences of treatmentemergent adverse events (AEs) and serious AEs were similar in suvratoxumab and placebo groups (90•6% [87/96] vs. 90•0% [90/100] and 37•5% [36/96] vs 32•0% [32/100], respectively). At 90 and 190 days, incidence of treatment-emergent AEs was still similar in suvratoxumab and placebo groups (92.

α‐hemolysin of Staphylococcus aureus impairs thrombus formation

“…The antibody was not effective in preventing S . aureus –induced pneumonia in intensive care patients, 37 but its effects on thrombus stabilization has not been assessed before now.…”

“…Although the monoclonal antibody tested in this study had nearly no effect on Hla-induced lysis of platelets, a humanized Hla neutralizing antibody (MEDI4893*) 36 inhibited organ damage in S. aureus sepsis in animal models 11 and is well tolerated in humans. 35 The antibody was not effective in preventing S. aureus-induced pneumonia in intensive care patients, 37 but its effects on thrombus stabilization has not been assessed before now.…”

Ventilator-associated pneumonia prevention in the Intensive care unit using Postpyloric tube feeding in China (VIP study): study protocol for a randomized controlled trial

“…Subglottic secretion drainage may not shorten the duration of mechanical ventilation or ICU length-of-stay as is once thought [ 45 – 49 ]. Furthermore, two recent RCTs showed no significant difference in VAP development among ventilated ICU patients receiving probiotic or monoclonal antibody administration than placebo [ 50 , 51 ].…”

Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments

“…Surewaard et al recently revealed that α-hemolysin causes rapid platelet aggregation and liver injury, resulting in multi-organ failure during S. aureus sepsis, but these consequences could be avoided in mice treated with MEDI4893 [103]. MEDI4893 has passed Phase 2 clinical studies for the prevention of S. aureus pneumonia in high-risk critical care unit patients in 2020, and more recently, MEDI4893 showed efficacy and safety in preventing S. aureus ventilator-associated pneumonia [104,105]. In addition, AR-301 and ASN100 are two other neutralizing antibodies that have entered clinical trials.…”