Distinct evolution of colistin resistance associated with experimental resistance evolution models in <i>Klebsiella pneumoniae</i>

Aulin, Linda B. S.; Koumans, Catharina I.M.; Haakman, Y; Os, Wisse van; Kraakman, M. E. M.; Gooskens, Jairo; Smits, Wiep Klaas; Liakopoulos, Apostolos; Hasselt, J. G. Coen van

doi:10.1093/jac/dkaa450

Cited by 8 publications

(7 citation statements)

References 5 publications

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“…There is in vivo evidence that this mutation is responsible for colistin resistance in clinical strains of K. pneumoniae (Kong et al, 2021). In the literature, only one study reported the frameshift mutation 104delT -F35fs (Aulin et al, 2021). The MIC90, the concentration that inhibited 90% of the strains in our study, was > 16 µg/ml, and more than half of the isolates (55%) had a MIC of 256 µg/ml.…”

Section: Discussionmentioning

confidence: 43%

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Prolonged Outbreak of Carbapenem and Colistin-Resistant Klebsiella pneumoniae at a Large Tertiary Hospital in Brazil

et al. 2022

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Multidrug-resistant gram-negative bacteria, such as carbapenem and colistin-resistant Klebsiella pneumoniae (ColR-CRKP), represent a major problem for health systems worldwide and have high lethality. This study investigated the genetic relationship, antimicrobial susceptibility profile, and resistance mechanisms to ColR-CRKP isolates from patients infected/colonized in a tertiary hospital in Salvador, Bahia/Brazil. From September 2016 to January 2018, 46 patients (56 ColR-CRKP positive cultures) were enrolled in the investigation but clinical and demographic data were obtained from 31 patients. Most of them were men (67.7%) and elderly (median age of 62 years old), and the median Charlson score was 3. The main comorbidities were systemic arterial hypertension (38.7%), diabetes (32.2%), and cerebrovascular disease (25.8%). The average hospitalization stay until ColR-CRKP identification in days were 35.12. A total of 90.6% used mechanical ventilation and 93.7% used a central venous catheter. Of the 31 patients who had the data evaluated, 12 had ColR-CRKP infection, and seven died (58.4%). Previous use of polymyxins was identified in 32.2% of the cases, and carbapenems were identified in 70.9%. The minimum inhibitory concentration (MIC) for colistin was > 16 μg/mL, with more than half of the isolates (55%) having a MIC of 256 μg/mL. The blaKPC gene was detected in 94.7% of the isolates, blaNDM in 16.0%, and blaGES in 1.7%. The blaOXA–48, blaVIM, and blaIMP genes were not detected. The mcr-1 test was negative in all 56 isolates. Alteration of the mgrB gene was detected in 87.5% (n = 49/56) of the isolates, and of these, 49.0% (24/49) had alteration in size probably due to IS903B, 22.4% (11/49) did not have the mgrB gene detected, 20.4% (10/49) presented the IS903B, 6.1% (3/49) had a premature stop codon (Q30*), and 2.1% (1/49) presented a thymine deletion at position 104 – 104delT (F35fs). The PFGE profile showed a monoclonal profile in 84.7% of the isolates in different hospital sectors, with ST11 (CC-258) being the most frequent sequence type. This study presents a prolonged outbreak of ColR-CRKP in which 83.9% of the isolates belonged to the same cluster, and 67.6% of the patients evaluated had not used polymyxin, suggesting the possibility of cross-transmission of ColR-CRKP isolates.

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Section: Discussionmentioning

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Prolonged Outbreak of Carbapenem and Colistin-Resistant Klebsiella pneumoniae at a Large Tertiary Hospital in Brazil

et al. 2022

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“…We thereby did not consider factors that could further contribute to treatment outcomes for specific pathogens or antibiotics. We did not consider that more complex evolutionary mutational trajectories can occur with associated complex patters of changes in antibiotic sensitivity and MIC 47 , which are not easily definable to apply to antibiotic treatment in general. Other factors not considered include local antibiotic tissue concentrations 48,49 , pharmacokinetic drug-drug interactions or the contribution of the immune system.…”

Section: Discussionmentioning

confidence: 99%

Design principles of collateral sensitivity-based dosing strategies

Aulin

Liakopoulos

Graaf

et al. 2021

Preprint

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Collateral sensitivity (CS)-based antibiotic treatments, where increased antibiotic resistance to one antibiotic leads to increased antibiotic sensitivity of second antibiotic, could constitute a strategy to limit emergence of antibiotic resistance. However, it is unclear how to design CS-based dosing schedules that effectively suppress resistance. Here, we use a mathematical modelling approach incorporating pharmacokinetic and pharmacodynamic features to simulate bacterial population dynamics for different combination treatment designs. We study how differences in pathogen- and drug-specific factors influence the probability of resistance at end of treatment for different dosing strategies. We show that drug administration sequence is critical, whilst surprisingly, reciprocal CS was not essential to suppress resistance. Overall, we find that one-day cycling or simultaneous treatment schedules were most effective to supress the probability of resistance. In conclusion, our analysis provides insight into key design principles that contribute to the success of CS-based treatment strategies in suppressing resistance.

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“…The lack of fresh media supply may result in nutrient depletion and (toxic) waste product accumulation, and the bacteria are exposed to non-dynamic and sometimes clinically irrelevant drug concentrations. These factors may impact bacterial response both phenotypically and genotypically [ 130 ]. Moreover, the duration of static time–kill experiments is usually restricted to 24 h, which may be too short to capture regrowth due to resistance development.…”

Section: Time–kill Curve Approachesmentioning

confidence: 99%

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

Zeitlinger

2021

Antibiotics

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Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.

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Distinct evolution of colistin resistance associated with experimental resistance evolution models in Klebsiella pneumoniae

Cited by 8 publications

References 5 publications

Prolonged Outbreak of Carbapenem and Colistin-Resistant Klebsiella pneumoniae at a Large Tertiary Hospital in Brazil

Prolonged Outbreak of Carbapenem and Colistin-Resistant Klebsiella pneumoniae at a Large Tertiary Hospital in Brazil

Design principles of collateral sensitivity-based dosing strategies

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

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