Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection: enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition

Thanyaluck Siriyong, Rachael M. Murray, Lucy E. Bidgood, Simon A. Young, Florence Wright, Benjamin J. Parcell, Supayang Piyawan Voravuthikunchai, Peter J. Coote (Lead / Corresponding author)

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    Abstract

    The aim of the study was to determine the efficacy of dual β-lactam combination treatments derived from eight approved drugs against Galleria mellonella larvae infected with MDR strains of P. aeruginosa. Carbapenem-resistant P. aeruginosa NCTC 13437 and an unrelated clinical isolate were used to infect G. mellonella larvae and the efficacy of twenty-eight dual β-lactam combination therapies were compared to their constituent monotherapies. For the most potent combinations identified, penicillin-binding protein (PBP) inhibition profiles were measured and compared with each constituent antibiotic. Five of the dual β-lactam combinations resulted in greater than 70% survival of infected G. mellonella. Two combinations showed potent, enhanced efficacy versus both strains − ceftazidime + meropenem and aztreonam + meropenem. Comparison of PBP inhibition profiles revealed that the enhanced efficacy of these two dual β-lactam combinations could not be explained by more potent inhibition of PBPs or inhibition of a broader range of PBPs. A possible contribution to the enhanced efficacy of the combinations could be stimulation of innate immunity via increased haemocyte numbers compared to their constituent monotherapies. Combinations of β-lactam antibiotics show promise in overcoming MDR P. aeruginosa and are worthy of additional study and development.

    Original languageEnglish
    Article number9098
    Pages (from-to)1-13
    Number of pages13
    JournalScientific Reports
    Volume9
    DOIs
    Publication statusPublished - 24 Jun 2019

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    Penicillin-Binding Proteins
    Pseudomonas Infections
    Lactams
    Combination Drug Therapy
    Pseudomonas aeruginosa
    meropenem
    Larva
    Anti-Bacterial Agents
    Aztreonam
    Hemocytes
    Carbapenems
    Ceftazidime
    Innate Immunity
    Therapeutics
    Pharmaceutical Preparations

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    Siriyong, Thanyaluck ; Murray, Rachael M. ; Bidgood, Lucy E. ; Young, Simon A. ; Wright, Florence ; Parcell, Benjamin J. ; Voravuthikunchai, Supayang Piyawan ; Coote, Peter J. / Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection : enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition. In: Scientific Reports. 2019 ; Vol. 9. pp. 1-13.
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    Dual β-lactam combination therapy for multi-drug resistant Pseudomonas aeruginosa infection : enhanced efficacy in vivo and comparison with monotherapies of penicillin-binding protein inhibition. / Siriyong, Thanyaluck; Murray, Rachael M.; Bidgood, Lucy E.; Young, Simon A.; Wright, Florence; Parcell, Benjamin J.; Voravuthikunchai, Supayang Piyawan; Coote, Peter J. (Lead / Corresponding author).

    In: Scientific Reports, Vol. 9, 9098, 24.06.2019, p. 1-13.

    Research output: Contribution to journalArticle

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