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Semi-mechanistic PK/PD modelling of meropenem and sulbactam combination against carbapenem-resistant strains of Acinetobacter baumannii

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Abstract

Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC90 of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log10 kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.

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Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations

CR-AB:

carbapenem-resistant Acinetobacter baumannii

MEM/SUL:

meropenem and sulbactam combination

PTA:

probability of target attainment

PK/PD:

pharmacokinetic/pharmacodynamic

MIC:

minimum inhibitory concentration

MIC50 :

MIC required to inhibit the growth of 50% of isolates

MIC90 :

MIC required to inhibit the growth of 90% of isolates

%fT>MIC:

percentage of unbound drug concentration remaining above the MIC during a dosing interval

PBP:

penicillin-binding protein

CI:

confidence interval

OR:

odds ratio

RR:

risk ratio

UQCCR:

the University of Queensland Centre for Clinical Research

CA-MH:

cation-adjusted Mueller-Hinton

CLSI:

Clinical and Laboratory Standards Institute

FICI:

fractional inhibitory concentration index

CLCR :

creatinine clearance

BMI:

body mass index

q8h:

every 8 h

CFUs and CFUr :

bacterial burden for the sensitive and resistant bacterial subpopulations, respectively

Kgs and Kgr :

growth rate constant for the sensitive and resistant bacterial subpopulations, respectively

Bmax:

maximal bacterial burden

EmaxM and EmaxS :

the maximum rate of meropenem- and sulbactam-mediated bacterial killing, respectively

C M and C S :

concentration of meropenem and sulbactam, respectively

H M and H S :

power parameter for meropenem and sulbactam effect on both subpopulations, respectively

EC50Ms and EC50Ss :

meropenem and sulbactam concentration for which effect is 50% on the sensitive subpopulation, respectively

EC50Mr and EC50Sr :

meropenem and sulbactam concentration for which effect is 50% on the resistant subpopulation, respectively

INTSM :

maximum fractional change of the EC50Ss and EC50Sr caused by meropenem

HISM :

power parameter for meropenem potentiation of sulbactam effect

EC50INTsm :

meropenem concentration needed to achieve 50% of INTSM

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Funding

This work was supported by the Australian National Health and Medical Research Council for a Centre of Research Excellence fund (APP1099452). JAR is funded in part by a Practitioner Fellowship (APP1117065) from the National Health and Medical Research Council of Australia. SMSL received funding from the University of Queensland Research Training Scholarship. HMZ was kindly supported by the Marchant Foundation Fellowship. AJH received funding from a Griffith School of Medicine Research Higher degree scholarship.

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Authors and Affiliations

  1. Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia

    Sazlyna Mohd Sazlly Lim, Aaron J. Heffernan, Jason A. Roberts & Fekade B. Sime

  2. Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia

    Sazlyna Mohd Sazlly Lim

  3. School of Medicine, Griffith University, Southport, Australia

    Aaron J. Heffernan

  4. UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia

    Hosam M. Zowawi, Jason A. Roberts & Fekade B. Sime

  5. College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Hosam M. Zowawi

  6. King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia

    Hosam M. Zowawi

  7. Royal Brisbane and Women’s Hospital, Brisbane, Australia

    Jason A. Roberts

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  1. Sazlyna Mohd Sazlly Lim
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Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by SMSL. Data analysis was performed by SMSL and AJH. The first draft of the manuscript was written by SMSL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fekade B. Sime.

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Mohd Sazlly Lim, S., Heffernan, A.J., Zowawi, H.M. et al. Semi-mechanistic PK/PD modelling of meropenem and sulbactam combination against carbapenem-resistant strains of Acinetobacter baumannii. Eur J Clin Microbiol Infect Dis 40, 1943–1952 (2021). https://doi.org/10.1007/s10096-021-04252-z

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