Prevalence of colistin heteroresistance in carbapenem-resistant <i>Pseudomonas aeruginosa</i> and association with clinical outcomes in patients: an observational study

Howard‐Anderson, Jessica; Davis, Michelle H; Page, Alexander; Bower, Chris; Smith, Gillian; Jacob, Jesse T; Andersson, Dan I.; Weiss, David S.; Satola, Sarah W.

doi:10.1093/jac/dkab461

Cited by 13 publications

(9 citation statements)

References 21 publications

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“…This pathogen has a large genome (>6 Mb) with diverse regulatory genes, facilitating ecological diversity 13,14,15 and expression of genetic and phenotypic heterogeneity. Indeed, previous work identified carbapenem and colistin HR in different P. aeruginosa isolates 16,17,18,19,20 . However, to date, the distribution of HR against diverse clinically relevant antimicrobials has not been systematically assessed for this bacterium.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: How antimicrobial heteroresistance promotes bacterial adaptation to antimicrobial therapy – or not

Liao,

Nyhoegen,

Uecker

et al. 2023

Preprint

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Antimicrobial heteroresistance describes the phenomenon of antimicrobial resistance in only a subpopulation of a bacterial culture. It is usually believed to represent a selectively advantageous strategy promoting bacterial adaptation. Heteroresistance is common in human pathogens, yet often missed during diagnosis, potentially leading to treatment failures. To date, the exact characteristics and evolutionary benefits of heteroresistance are unexplored for most pathogens, including the high-risk pathogenPseudomonas aeruginosa. Here, we systematically studied heteroresistance for a representativeP. aeruginosastrain panel, including genomically distinct clinical and non-clinical isolates. We combined heteroresistance tests, over 2,500 evolution experiments, whole genome sequencing, and mathematical modelling and discovered: (i) an unexpected diversity of heteroresistance profiles across the strain panel, (ii) a high prevalence of beta-lactam, especially carbapenem heteroresistance, (iii) a clear fitness benefit of heteroresistance in treatments with continuously high antimicrobial concentrations, but (iv) no evolutionary advantages of heteroresistance in alternative regimens with initially below-MIC drug doses. We further demonstrate that fast switches between antimicrobials (i.e., fast sequential therapy) can constrain heteroresistance-promoted adaptation. We conclude that heteroresistance is not universally beneficial but only provides an evolutionary advantage under specific conditions, thereby pointing to treatment strategies that remain effective in the face of phenotypic resistance variation.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: How antimicrobial heteroresistance promotes bacterial adaptation to antimicrobial therapy – or not

Liao,

Nyhoegen,

Uecker

et al. 2023

Preprint

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“…A strength of this study was its large sample size compared to previous studies on CHR using the PAP assay [ 22 , 23 , 24 , 25 ]. Within this study, two different classification schemes for CHR were used.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Colistin Heteroresistance among Multidrug-Resistant Klebsiella pneumoniae Isolated from Intensive Care Patients in Europe

Braspenning,

Rajakani,

Sey

et al. 2024

Antibiotics

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Heteroresistance (HR) to colistin is especially concerning in settings where multi-drug-resistant (MDR) K. pneumoniae are prevalent and empiric use of colistin might lead to treatment failures. This study aimed to assess the frequency of occurrence of colistin HR (CHR) among (MDR) K. pneumoniae (n = 676) isolated from patients hospitalized in 13 intensive care units (ICUs) in six European countries in a clinical trial assessing the impact of decolonization strategies. All isolates were whole-genome-sequenced and studied for in vitro colistin susceptibility. The majority were colistin-susceptible (CS) (n = 597, MIC ≤ 2 µg/mL), and 79 were fully colistin-resistant (CR) (MIC > 2 µg/mL). A total of 288 CS isolates were randomly selected for population analysis profiling (PAP) to assess CHR prevalence. CHR was detected in 108/288 CS K. pneumoniae. No significant association was found between the occurrence of CHR and country, MIC-value, K-antigen type, and O-antigen type. Overall, 92% (617/671) of the K. pneumoniae were MDR with high prevalence among CS (91%, 539/592) and CR (98.7%, 78/79) isolates. In contrast, the proportion of carbapenemase-producing K. pneumoniae (CP-Kpn) was higher among CR (72.2%, 57/79) than CS isolates (29.3%, 174/594). The proportions of MDR and CP-Kpn were similar among CHR (MDR: 85%, 91/107; CP-Kpn: 29.9%, 32/107) and selected CS isolates (MDR: 84.7%, 244/288; CP-Kpn: 28.1%, 80/285). WGS analysis of PAP isolates showed diverse insertion elements in mgrB or even among technical replicates underscoring the stochasticity of the CHR phenotype. CHR isolates showed high sequence type (ST) diversity (Simpson’s diversity index, SDI: 0.97, in 52 of the 85 STs tested). CR (SDI: 0.85) isolates were highly associated with specific STs (ST101, ST147, ST258/ST512, p ≤ 0.003). The widespread nature of CHR among MDR K. pneumoniae in our study urge the development of rapid HR detection methods to inform on the need for combination regimens.

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“…It has been postulated that the detection of heteroresistance using the PAP method could be linked to treatment failure and/or mortality. However, two small studies have failed to prove the association between heteroresistance in A. baumannii and treatment failure, and between heteroresistance in P. aeruginosa and mortality ( 39 , 40 ). As a result of the poor predictive power of the PAP methodology, routine screening for heteroresistance by clinical microbiology laboratories is not recommended ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis

Longshaw,

Santerre Henriksen,

Dressel

et al. 2023

Microbiol Spectr

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This study aimed to determine the proportion of heteroresistance in carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex (CRAB) isolates in the cefiderocol arm of the randomized, Phase 3 CREDIBLE-CR study by population analysis profiling (PAP) and to determine whether there is any correlation between heteroresistance and clinical outcomes. PAP phenotypes [PAP-susceptible (PAP-S), PAP-heteroresistant (PAP-HR), or PAP-resistant (PAP-R)] were determined for baseline CRAB isolates after growing for 72 hours on agar plates containing twofold dilutions of cefiderocol (0.5–64 µg/mL). Clinical cure, microbiological eradication, and all-cause mortality (ACM) were analyzed by PAP phenotype. Only descriptive statistics were performed. Of the 38 CRAB isolates, 36 were susceptible and 2 were non-susceptible by broth microdilution (reference method), while 18 (47.4%) isolates were PAP-HR, 7 (18.4%) were PAP-S, and 13 (34.2%) were PAP-R. ACM by the end of study (end of treatment + 28 days) was 22.2% (4/18) for patients with PAP-HR isolates, 100% (7/7) with PAP-S isolates, and 61.5% (8/13) with PAP-R isolates. Among patients with PAP-HR isolates, 77.8% (14/18) had clinical cure and 38.9% (7/18) had microbiological eradication at test of cure. Among patients with PAP-S isolates, none had clinical cure or microbiological eradication. For patients with PAP-R isolates, clinical cure [23.1% (3/13)] and microbiological eradication [15.4% (2/13)] rates were low at test of cure. Using the PAP method, heteroresistance was detected in CRAB isolates in the cefiderocol arm in the CREDIBLE-CR study. However, heteroresistance was not associated with increased mortality or worse clinical and microbiological outcomes compared with patients with non-heteroresistant isolates. IMPORTANCE The population analysis profiling (PAP) test is considered the “gold standard” method to detect heteroresistance. It exposes bacteria to increasing concentrations of antibiotics at high cell densities to detect any minority resistant subpopulations that might be missed by the low inoculums used for reference susceptibility tests. However, its clinical relevance has not been well established. In the CREDIBLE-CR study, a numerically increased all-cause mortality was observed in the cefiderocol arm relative to the best available therapy arm for patients with Acinetobacter spp. infections. Heteroresistance has independently been proposed by another research group as a potential explanation of the mortality difference. An analysis of the baseline carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from patients treated with cefiderocol in the CREDIBLE-CR study showed the highest clinical cure rate and the lowest mortality for patients with PAP-heteroresistant isolates compared with PAP-susceptible or PAP-resistant isolates. These findings contradict the abovementioned hypothesis that heteroresistance contributed to the increased mortality.

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Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study

Cited by 13 publications

References 21 publications

WITHDRAWN: How antimicrobial heteroresistance promotes bacterial adaptation to antimicrobial therapy – or not

WITHDRAWN: How antimicrobial heteroresistance promotes bacterial adaptation to antimicrobial therapy – or not

Assessment of Colistin Heteroresistance among Multidrug-Resistant Klebsiella pneumoniae Isolated from Intensive Care Patients in Europe

Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis

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