Bacteraemia with an MBL-producing <i>Klebsiella pneumoniae</i>: treatment and the potential role of cefiderocol heteroresistance

Witt, Lucy S; Steed, Danielle Barrios; Burd, Eileen M.; Ozturk, Tugba; Davis, Michelle H; Satola, Sarah W.; Weiss, David S.; Jacob, Jesse T

doi:10.1093/jac/dkac197

Cited by 7 publications

(10 citation statements)

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“…It is noteworthy, that rapid acquisition of CFD resistance in E. cloacae through mutations of the CirA siderophore receptor during CFD therapy have been recently reported in the literature ( Klein et al., 2022 ; Nurjadi et al., 2022 ). It has also been suggested that acquisition of CFD resistance during treatment could be related to overproduction of NDM enzymes ( Johnston et al., 2020 ), mutations affecting porins and efflux pumps, mutations in penicillin-binding-protein 3, and heteroresistance mechanisms ( Karakonstantis et al., 2022 ; Witt et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study

Larcher

Laffont-Lozes

Roger

et al. 2022

Front. Cell. Infect. Microbiol.

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IntroductionNovel last resort beta-lactam antibiotics are now available for management of infections due to New-Delhi Metallo-Beta-Lactamase (NDM) producing Enterobacterales and non-fermenters with Difficult-to-Treat Resistance. However, data regarding the use of imipenem-cilastatin-relebactam (IMI-REL), cefiderocol (CFD) and ceftazidime-avibactam plus aztreonam (CAZ-AVI-ATM) are scarce in real-life settings. This study aimed to describe the use of last resort beta-lactam antibiotics, the microbiology and the outcome, in patients hospitalized in a tertiary hospital.MethodsWe conducted a monocentric observational cohort study from 2020/01/01, to 2022/08/31. We screened all patients admitted to Nimes University Hospital who have received ≥ 1 dose of last resort beta-lactam antibiotics during the study period, using the Pharmacy database. We included patients treated with IMI-REL, CFD and CAZ-AVI-ATM. The primary endpoint was the infection-free survival rate. We also calculated rates of microbiological and clinical cure, recurrent infection, death and adverse events.ResultsTwenty-seven patients were included in the study and 30 treatment courses were analyzed: CFD (N=24; 80%), CAZ-AVI-ATM (N=3; 10%) and IMI-REL (N=3; 10%). Antibiotics were used in 21 males (70%) and 9 females (30%) with a median age at 65-year-old [50-73.5] and a median Charlson index at 1 [0-2]. Almost all the patients had ≥ 1 risk factor for carbapenem resistant bacteria, a half of them was hospitalized for severe COVID-19, and most of antibiotic courses (N=26; 87%) were associated with ICU admission. In the study population, the probability of infection-free survival at day-90 after last resort beta-lactam therapy initiation was 48.4% CI95% [33.2-70.5]. Clinical failure rate was at 30%, microbiological failure rate at 33% and mortality rate at 23%. Adverse events were documented in 5 antibiotic courses (17%). In details, P. aeruginosa were mainly treated with CFD and IMI-REL, S. maltophilia with CFD and CAZ-AVI-ATM, A. baumannii with CFD, and NDM producing-K. pneumoniae with CAZ-AVI-ATM and CFD. After a treatment course with CFD, CAZ-AVI-ATM and IMI-REL, the probability of infection-free survival was 48% CI95% [10.4-73.5], 33.3% CI95% [6.7-100], 66.7% CI95% [30-100], respectively.Discussion/conclusionUse of last resort beta-lactam antimicrobials in real-life settings was a safe and efficient therapeutic option for severe infections related to Gram-negative bacteria with Difficult-to-Treat Resistance.

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Section: Discussionmentioning

confidence: 99%

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study

Larcher

Laffont-Lozes

Roger

et al. 2022

Front. Cell. Infect. Microbiol.

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“…We have demonstrated that beta-lactamase amplification is a common phenomenon leading to cefiderocol HR, that amplification occurs in vivo following cefiderocol treatment (Figure 1K), and that cefiderocol HR correlates with and may lead to treatment failure in clinical trials 21,22 . We recently described a metallo-beta-lactamase producing K. pneumoniae strain isolated from a patient who failed cefiderocol therapy 29 (Figure 5A). Although classified susceptible to cefiderocol by clinical testing, our analyses revealed that this strain is cefiderocol HR (Figure 5B).…”

Section: Beta-lactamase Amplification In An Isolate Causing Clinical ...mentioning

confidence: 99%

Copy number flexibility facilitates heteroresistance to increasing antibiotic pressure and threatens the beta-lactam pipeline

Choby

Ozturk

Abbott

et al. 2022

Preprint

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Novel antibiotics are threatened by rapid emergence of resistance. Heteroresistance (HR) is a form of resistance where a phenotypically unstable and often undetected minority resistant subpopulation co-exists with a susceptible population. We observed HR to cefiderocol, a novel beta-lactam developed to resist beta-lactamases including ESBLs. The resistant subpopulation was a continuum; increasing gene amplification of otherwise ineffective ESBLs mediated increased resistance in decreasing numbers of cells. Surprisingly, ESBL amplification further increased when mutations or beta-lactamase inhibitors (BLI) were employed to inhibit activity, demonstrating that amplification overcomes inefficient activity. After one exposure to sub-breakpoint concentrations of cefiderocol/BLI, this enhanced amplification mediated resistance in an isolate collected before clinical introduction of the drugs. Therefore, amplification allows HR isolates to employ pre-existing, otherwise ineffective beta-lactamases to overcome novel beta-lactam/BLIs without new, stable evolution. This phenotypic flexibility is undetected during drug development and reveals an unappreciated threat to beta-lactam/BLIs that dominate the antibiotic pipeline.

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“…We read with interest the Research Letter from Witt et al , 1 describing a case report of Klebsiella pneumoniae NDM-5 bacteraemia with a subsequent recurrence in which the authors postulate a link to cefiderocol heteroresistance.…”

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confidence: 99%

“…According to the Supplementary data provided, 1 heteroresistance was recorded where there was a 6 log reduction in cfu observed on the 32 mg/L plate (in the case of cefiderocol corresponding to 2-fold the CLSI resistance breakpoint of 16 mg/L) compared with the drug-free control. However, as cefiderocol MICs by agar dilution are typically at least 1 dilution higher than broth microdilution, it is not valid to apply the broth dilution breakpoint of 16 mg/L for this purpose as the equivalent agar dilution breakpoint is likely in the region of 32 mg/L, meaning heteroresistance should be assessed on plates containing cefiderocol 64–128 mg/L.…”

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confidence: 99%

“…Therefore, it is our opinion that the results of the PAP analysis interpreted by Witt et al . 1 as evidence of cefiderocol-heteroresistant subpopulations are most likely a combination of methodological artefacts from the agar dilution-based method in non-iron-depleted medium plus the higher inoculum used. Future investigations of heteroresistance to cefiderocol or other antibiotics should be careful to ensure appropriate methods are used to minimize potential misinterpretation of in vitro observations, especially when seeking to postulate correlations to clinical outcomes.…”

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confidence: 99%

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Comment on: Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance

Longshaw¹,

Henriksen

Slover

et al. 2022

Journal of Antimicrobial Chemotherapy

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Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance

Cited by 7 publications

References 8 publications

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study

Copy number flexibility facilitates heteroresistance to increasing antibiotic pressure and threatens the beta-lactam pipeline

Comment on: Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance

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