Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 <i>Klebsiella pneumoniae</i>–Producing KPC-31, a D179Y Variant of KPC-3

Tiseo, Giusy; Falcone, Marco; Leonildi, Alessandro; Giordano, Cesira; Barnini, Simona; Arcari, Gabriele; Carattoli, Alessandra; Menichetti, Francesco

doi:10.1093/ofid/ofab141

Cited by 43 publications

(28 citation statements)

References 22 publications

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“…The strains also produced the following ESBLs: CTX-M-15, OXA-1, OXA-9, TEM-1. Among the 247 KPC-Kp strains we performed sequence typing on 41 isolates; all KPC-Kp tested belonged to the ST512 and carried the bla KPC-3 gene [22]; bla genes encoding OXA-9 and SHV-11 were also detected.…”

Section: Study Populationmentioning

confidence: 99%

Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study)

Falcone¹,

Tiseo²,

Galfo³

et al. 2022

Clinical Microbiology and Infection

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Section: Study Populationmentioning

confidence: 99%

Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study)

Falcone¹,

Tiseo²,

Galfo³

et al. 2022

Clinical Microbiology and Infection

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“…Shields et al found that pneumonia was an independent risk factor for CZA clinical failure, while the receipt of renal replacement therapy (RRT) predicted microbiological failure and CZA resistance development [ 39 ]. Recently, clinical and microbiological failures with CZA have combined to the development of decreased susceptibility/resistance to this agent, as described in a case of septic thrombosis, a high clinical complexity condition [ 43 ], and in a case of delayed source control [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, they revealed a strong impact of a high-inoculum effect on CFDC MICs, which is even more worrisome [ 65 ]. Tiseo et al described a case of recurrent KPC- Kp bacteremia successfully treated with MVB after in vivo, CZA-induced resistance development to CZA and CFDC [ 44 ]. Moreover, a case of a NDM producing E. col i intra-abdominal infection in a hematopoietic stem cell transplant recipient was reported where CFDC resistance evolved after 19 days of administration.…”

Section: Resultsmentioning

confidence: 99%

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

et al. 2021

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The worldwide propagation of antimicrobial resistance represents one of the biggest threats to global health and development. Multi-drug-resistant organisms (MDROs), including carbapenem-resistant non-fermenting Gram-negatives and Enterobacterales, present a heterogeneous and mutating spread. Infections by MDRO are often associated with an unfavorable outcome, especially among critically ill populations. The polymyxins represented the backbone of antibiotic regimens for Gram-negative MDROs in recent decades, but their use presents multiple pitfalls. Luckily, new agents with potent activity against MDROs have become available in recent times and more are yet to come. Now, we have the duty to make the best use of these new therapeutic tools in order not to prematurely compromise their effectiveness and at the same time improve patients’ outcomes. We reviewed the current literature on ceftazidime/avibactam, meropenem/vaborbactam and cefiderocol, focusing on antimicrobial spectrum, on the prevalence and mechanisms of resistance development and on the main in vitro and clinical experiences available so far. Subsequently, we performed a step-by-step construction of a speculative algorithm for a reasoned prescription of these new antibiotics, contemplating both empirical and targeted use. Attention was specifically posed on patients with life-risk conditions and in settings with elevated prevalence of MDRO.

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“…We observed the strongest trade-offs during cefiderocol resistance development of OXA-48 and KPC-2 against carbapenems and aztreonam (KPC-2). Such collateral sensitivity/functional trade-offs can open the path for alternative treatment strategies, and they have been successfully exploited in the clinical setting with a carbapenem-β-lactamase inhibitor combination against ceftazidime-avibactam and cefiderocol resistant K. pneumoniae harboring the natural KPC-31 [23]. However, the molecular causes of these collateral effects remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Evolution of β-lactamase mediated cefiderocol resistance

Fröhlich

Sørum

Tokuriki

et al. 2022

Preprint

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Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties of two clinically efficient cephalosporins, ceftazidime and cefepime. Consequently, cefiderocol represents a treatment alternative for infections caused by multi-drug resistant Gram-negatives. Using directed evolution on a wide variety of different β-lactamases, such as KPC-2 and CTX-M-15 (Ambler class A), NDM-1 (class B), CMY-2 (class C) and OXA-48 (class D), we studied the role of cefiderocol during β-lactamase-mediated resistance development. First, we investigated how the expression of different β-lactamases causes changes in cefiderocol susceptibility. In a low-copy number vector, we found that OXA-48 and KPC-2 conferred non or marginal decreases in cefiderocol susceptibility, respectively. On the contrary, CMY-2, CTX-M-15 and NDM-1 substantially decreased cefiderocol susceptibility by 16-, 8- and 32-fold, respectively. Second, we determined the evolutionary potential of these enzymes to adapt to increasing concentrations of cefiderocol. Our data show that with the acquisition of only 1 to 2 mutations, all β-lactamases were evolvable to further cefiderocol resistance by 2- (NDM-1, CTX-M-15), 4- (CMY-2), 8- (OXA-48) and 16-fold (KPC-2). Cefiderocol resistance development was often associated with collateral susceptibility changes including increased resistance to ceftazidime and ceftazidime-avibactam as well as functional trade-offs against different β-lactam drugs. Taken together, contemporary β-lactamases of all Ambler classes can potentially contribute to cefiderocol resistance development and can acquire mutations allowing them to adapt to increasing cefiderocol concentration. At the same time, resistance development caused clinically important cross-resistance, especially against ceftazidime combinations.

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Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 Klebsiella pneumoniae–Producing KPC-31, a D179Y Variant of KPC-3

Cited by 43 publications

References 22 publications

Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study)

Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study)

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

Evolution of β-lactamase mediated cefiderocol resistance

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