Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-11

AUTHORS

Bruno François, Emmanuelle Mercier, Céline Gonzalez, Karim Asehnoune, Saad Nseir, Maud Fiancette, Arnaud Desachy, Gaëtan Plantefève, Ferhat Meziani, Paul-André de Lame, Pierre-François Laterre, for the MASTER 1 study group

ABSTRACT

PURPOSE: Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics. METHODS: Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement. RESULTS: Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days. CONCLUSIONS: Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy. More... »

PAGES

1-10

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00134-018-5229-2

DOI

http://dx.doi.org/10.1007/s00134-018-5229-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1104998024

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30343314


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31 schema:description PURPOSE: Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics. METHODS: Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement. RESULTS: Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days. CONCLUSIONS: Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.
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