Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii

Zhu, Shijiang; Song, Chu; Zhang, Jiayuan; Diao, Shuo; Heinrichs, Tobias M.; Martins, Frederico Severino; Lv, Zhihua; Zhu, Yue; Yu, Mingming; Sy, Sherwin K. B.

doi:10.3389/fmicb.2022.1013939

Cited by 13 publications

(14 citation statements)

References 72 publications

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“…The demographical characteristics of the virtual patient population were simulated as previously described ( Sy et al, 2014 ; Zhu et al, 2022a ). Albumin was assumed to be normally distributed, 2.0 ± 0.5 g/dl (mean ± SD).…”

Section: Methodsmentioning

confidence: 99%

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

et al. 2022

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The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

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Section: Methodsmentioning

confidence: 99%

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

et al. 2022

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“…Even though polymyxins are emerging as the antibiotics of last resort to treat MDR infections including HAP/VAP, this class of drug is associated with toxicity and poor therapeutic outcomes, including a rapid rise of heteroresistance in monotherapy [ 4 ]. The combination of polymyxins with other antibiotics in the treatment of MDR infections has exhibited in vitro synergies [ 5 , 6 , 7 , 8 ], but there is no convincing clinical evidence that a combination regimen of polymyxins is superior to monotherapy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae

Zhang

Diao

et al. 2023

Pharmaceutics

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This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

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“…Acinetobacter baumannii also has an extraordinary ability to acquire or upregulate resistance determinants representing it as one of the organisms that pose threats to present antibiotics [ 3 , 4 ]. Acinetobacter baumannii is a Gram-negative, nonmotile, obligate aerobic, oxidase-negative, catalase-positive, and nonfermentative coccobacillus that harbors a number of successful virulence factors which enable its multidrug resistance phenomenon [ 5 ]. Species A. baumannii , which predominantly causes nosocomial infections, belongs to the Moraxellaceae family [ 6 ] and is responsible for other health issues such as hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), septicaemias, endocarditis, secondary meningitis, and various infections of skins, soft tissues, and urinary tracts [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds

Shil

Akter

Sultana

et al. 2023

Journal of Tropical Medicine

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Acinetobacter baumannii (A. baumannii) is an opportunistic bacterium that has developed multidrug resistance (MDR) to most of today’s antibiotics, posing a significant risk to human health. Considering the fact that developing novel drugs is a time-consuming and expensive procedure, this research focuses on utilizing computational resources for repurposing antibacterial agents for A. baumannii. We targeted shikimate kinase, an essential enzyme in A. baumannii, that plays a significant role in the metabolic process. The basis for generating new therapeutic compounds is to inhibit the shikimate kinase and thereby targeting the shikimate pathway. Herein, 1941 drug-like compounds were investigated in different in silico techniques for assessing drug-likeness properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, binding affinity, and conformation analysis utilizing Autodock-vina and SwissDock. CHEMBL1237, CHEMBL1237119, CHEMBL2018096, and CHEMBL39167178 were determined as potential drug candidates for suppressing shikimate kinase protein. Molecular Dynamics Simulation (MDS) results for root mean square deviation, root mean square fluctuation, hydrogen bond, and gyration radius confirm the drug candidates’ molecular stability with the target protein. According to this study, CHEMBL1237 (Lisinopril) could be the most suitable candidate for A. baumannii. Our investigation suggests that the inhibitors of shikimate kinase could represent promising treatment options for A. baumannii. However, further in vitro and in vivo studies are necessary to validate the therapeutic potential of the suggested drug candidates.

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Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii

Cited by 13 publications

References 72 publications

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae

Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds

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