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dc.contributor.authorMohd Sazlly Lim, S
dc.contributor.authorHeffernan, AJ
dc.contributor.authorRoberts, JA
dc.contributor.authorSime, FB
dc.date.accessioned2021-03-17T22:50:38Z
dc.date.available2021-03-17T22:50:38Z
dc.date.issued2021
dc.identifier.issn0066-4804
dc.identifier.doi10.1128/AAC.02472-20
dc.identifier.urihttp://hdl.handle.net/10072/403220
dc.description.abstractDue to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.Synergism of FOS/SUL against 50 clinical CR-AB isolates were screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill and 2-log kill after 24-hours with combination therapy.The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased four- to eight-fold, compared to the monotherapy MIC50 and MIC90 In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate, at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam 4 g every 8 hours, demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69-76%, as compared to ∼15-30% with monotherapy regimens at the highest doses.The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherAmerican Society for Microbiology
dc.relation.ispartofjournalAntimicrob Agents Chemother
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical Microbiology
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0605
dc.subject.fieldofresearchcode1108
dc.subject.fieldofresearchcode1115
dc.titleSemi-mechanistic PK/PD modelling of fosfomycin and sulbactam combination against carbapenem-resistant Acinetobacter baumannii.
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMohd Sazlly Lim, S; Heffernan, AJ; Roberts, JA; Sime, FB, Semi-mechanistic PK/PD modelling of fosfomycin and sulbactam combination against carbapenem-resistant Acinetobacter baumannii., Antimicrob Agents Chemother, 2021
dc.date.updated2021-03-16T22:58:16Z
dc.description.versionAccepted Manuscript (AM)
gro.description.notepublicThis publication has been entered as an advanced online version in Griffith Research Online.
gro.rights.copyright© 2021 American Society for Microbiology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorHeffernan, Aaron J.


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