Validation of a Model Predicting Anti-infective Lung Penetration in the Epithelial Lining Fluid of Humans

Aulin, Linda B. S.; Välitalo, Pyry A. J.; Rizk, Matthew L.; Visser, Sandra A.G.; Rao, Gauri G.; Graaf, Piet H. van der; Hasselt, J. G. Coen van

doi:10.1007/s11095-017-2336-7

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…This log ratio for PhX1 (0.65) was higher than that for ciprofloxacin ( 58 – 60 ) at a ratio of −0.2 and similar to isoniazid ( 61 ) at a ratio of 1, linezolid ( 62 – 64 ) at 0.7, and rifampin ( 65 , 66 ) at 0.7, while ethionamide ( 67 ) at 2.8, moxifloxacin ( 68 ) at 1.5, and pyrazinamide ( 69 ) at 3.2 showed significantly higher ratios, indicative of their superior intrapulmonary penetration. However, recent literature points to several flaws associated with determining an epithelial lining fluid/plasma concentration using single-point values such as the C max ( 57 , 70 , 71 ). The systemic hysteresis associated with both epithelial lining fluid and plasma compound concentrations requires a more stable pharmacokinetic (PK) parameter to be determined, such as an AUC measurement.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

et al. 2021

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“…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. We expect that such factors will not affect the specific subpopulations studied in different ways and therefore will not have a great impact on the general findings derived in this analysis.…”

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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“…Despite its limitations, BAL remains the standard method for obtaining samples to assess drug concentrations in ELF. 20,26,27 Antibiotics PK/PD Optimization…”

Section: Factors Affecting Drug Penetration Into the Pulmonary Systemmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Optimization of Hospital-Acquired and Ventilator-Associated Pneumonia: Challenges and Strategies

Abouelhassan

Nicolau

2022

Semin Respir Crit Care Med

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Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are correlated with high mortality rates worldwide. Thus, the administration of antibiotic therapy with appropriate dosing regimen is critical. An efficient antibiotic is needed to maintain an adequate concentration at the infection site, for a sufficient period of time, to achieve the best therapeutic outcome. It can, however, be challenging for antibiotics to penetrate the pulmonary system due to the complexity of its structure. Crossing the blood alveolar barrier is a difficult process determined by multiple factors that are either drug related or infection related. Thus, the understanding of pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics identifies the optimum dosing regimens to achieve drug penetration into the epithelial lining fluid at adequate therapeutic concentrations. Critically ill patients in the ICU can express augmented renal clearance (ARC), characterized by enhanced renal function, or may have renal dysfunction necessitating supportive care such as continuous renal replacement therapy (CRRT). Both ARC and CRRT can alter drug elimination, thus affecting drug concentrations. PK of critically ill patients is less clear due to the multiple variabilities associated with their condition. Therefore, conventional dosing regimens often lead to therapeutic failure. Another major hurdle faced in optimizing treatment for HAP/VAP is the reduction of the in vitro potency. Therapeutic drug monitoring (TDM), if available, may allow health care providers to personalize treatment to maximize efficacy of the drug exposures while minimizing toxicity. TDM can be of significant importance in populations whom PK are less defined and for resistant infections to achieve the best therapeutic outcome.

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Validation of a Model Predicting Anti-infective Lung Penetration in the Epithelial Lining Fluid of Humans

Cited by 7 publications

References 20 publications

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

Design principles of collateral sensitivity-based dosing strategies

Pharmacokinetic/Pharmacodynamic Optimization of Hospital-Acquired and Ventilator-Associated Pneumonia: Challenges and Strategies

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