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      Open Access: True


Article Info

DATE

2018-10-21

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,

ABSTRACT

PurposeHospital-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.MethodsEligibility 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.ResultsThirteen 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.ConclusionsAdjunctive 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

1787-1796

References to SciGraph publications

  • 2010-04-10. Antibody responses in patients with invasive Staphylococcus aureus infections in EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES
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    http://scigraph.springernature.com/pub.10.1007/s00134-018-5229-2

    DOI

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

    DIMENSIONS

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    PUBMED

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    23 schema:description PurposeHospital-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.MethodsEligibility 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.ResultsThirteen 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.ConclusionsAdjunctive 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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    30 schema:keywords APACHE II score
    31 AR-301
    32 AR-301-treated patients
    33 Ae
    34 CaBP
    35 Committee
    36 ConclusionsAdjunctive treatment
    37 HABP
    38 ICU
    39 ICU patients
    40 ICUs
    41 II score
    42 IgG1 mAb
    43 MRSA
    44 MethodsEligibility
    45 PK profiles
    46 PurposeHospital
    47 ResultsThirteen ICUs
    48 Staphylococcus aureus
    49 VABP patients
    50 adjunctive treatment
    51 administration
    52 alpha
    53 analysis
    54 anti-infective monoclonal antibodies
    55 anti-staphylococcal mAbs
    56 antibiotics
    57 antibodies
    58 aureus
    59 aureus HABP
    60 aureus alpha
    61 aureus eradication
    62 aureus pneumonia
    63 bacterial pneumonia
    64 benefits
    65 blinded committee
    66 buffer
    67 care antibiotics
    68 clinical benefit
    69 clinical improvement
    70 clinical outcomes
    71 cohort
    72 common infections
    73 concern
    74 confirmation
    75 critical concern
    76 culture
    77 day 28
    78 days
    79 dose cohorts
    80 drugs
    81 duration
    82 efficacy
    83 eradication
    84 faster microbiologic eradication
    85 favorable safety profile
    86 follow
    87 group
    88 hospital
    89 human IgG1 mAb
    90 human monoclonal antibody
    91 human trials
    92 improvement
    93 infection
    94 investigators
    95 mAbs
    96 microbiologic confirmation
    97 microbiologic eradication
    98 microbiologic outcomes
    99 monoclonal antibodies
    100 negative follow
    101 onset
    102 options
    103 outcomes
    104 pathogens
    105 patients
    106 pharmacokinetics
    107 pharmacokinetics of AR-301
    108 placebo buffer
    109 placebo cohort
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    111 placebo-controlled study
    112 pneumonia
    113 presence
    114 profile
    115 safety
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    130 ventilator-associated bacterial pneumonia
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