In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral ß-lactam/ß-lactamase inhibitor combination.
J Antimicrob Chemother
; 78(1): 93-100, 2022 12 23.
Article
en En
| MEDLINE
| ID: mdl-36272135
ABSTRACT
OBJECTIVES:
Oral ß-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable ß-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model.METHODS:
Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae, five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2â mg/L (ledaborbactam fixed at 4â mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600â mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10â cfu/thigh change at 24â h relative to 0â h controls was plotted against ledaborbactam fAUC0-24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis.RESULTS:
The meanâ±âSD 0â h bacterial burden was 5.96â±â0.24â log10â cfu/thigh. Robust growth (3.12â±â0.93â log10â cfu/thigh) was achieved in untreated control mice. Growth of 2.51â±â1.09â log10â cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure-response relationships were strong (meanâ±âSD R2â=â0.82â±â0.15). The median ledaborbactam fAUC0-24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model.CONCLUSIONS:
Ledaborbactam fAUC0-24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against ß-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145).
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de beta-Lactamasas
/
Antibacterianos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Antimicrob Chemother
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM