Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient

Abstract

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In vivo adaptive antimicrobial resistance in Klebsiella pneumoniae during antibiotic therapy

“…A report from China revealed that following a 6-day course of ceftazidime/avibactam treatment, a ST11 K. pneumoniae strain developed ceftazidime/avibactam resistance, owing to the mutation of KPC-2 to KPC-33, with a substitution of D179Y within the Ω loop ( Li D. et al, 2021 ). The Ω loop is located at residues 164–179, which is an essential domain for class A β-lactamases, and the substitution of D179Y may be detrimental to the binding of avibactam ( Gaibani et al, 2021 ; Wang et al, 2021 ). Another study conducted in Italy showed that in vivo development of ceftazidime/avibactam resistance in K. pneumoniae was also linked to the D179Y substitution in KPC-3, which emerged after 17-day of ceftazidime/avibactam treatment ( Gaibani et al, 2018 ).…”

“…Of note, the low antibiotic pressure may have selected hybrid subpopulations of KPC-KP due to the high adaptability of KPC to ceftazidime/avibactam. For example, a study reported that KPC-KP strains isolated from bronchoalveolar lavage harbor bla KPC-3 and T243M mutations, while those isolated from the blood have D179Y mutation ( Gaibani et al, 2021 ). Except for KPC, the in vivo emerging P170S exchange in CTX-M-14 has also been associated with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but this substitution was not sufficient for full resistance ( Both et al, 2017 ).…”

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

“…Ceftazidime (CAZ) is a cephalosporin that is active against P. aeruginosa ; together with avibactam (AVI), a non-ß-lactam ß-lactamase-inhibitor inhibiting enzymes belonging to Ambler classes A and C and selected class D beta-lactamases [ 58 ], it extends the spectrum against Enterobacteriaceae and several multi-drug resistant (MDR) Pseudomonas isolates [ 59 , 60 , 61 ]. In the last five years, novel beta-lactamase inhibitors, such as taniborbactam combined with a cephalosporin [ 62 , 63 ], as well as reports on the resistance of ceftazidime-avibactam (CAZ-AVI), have emerged [ 64 , 65 ]; however, we would like to highlight how the PK/PD targets were determined for AVI alone and how target attainment was achieved for the combination using PK/PD modelling. CAZ-AVI has been studied extensively in preclinical in vitro and in vivo models, as summarized elsewhere [ 66 ].…”

A novel strategy of infusion of ceftazidime-avibactam plus aztreonam for the treatment of infections due to OXA48 & NDM producing carbapenem resistantKlebsiella pneumoniae: Time is of the essence

“…The PK/PD index for therapeutic e cacy of BL is often considered as T > MIC for 50% of the dosing interval [2]. However, the PK/PD index for resistance suppression is T > 4xMIC for more than 50% of the dosing interval [3]. AVI has a short half-life & so needs a prolonged infusion to maintain a level of 2.5 µg/ml which protects ATM from OXA48.…”