Evaluation of Epithelial Lining Fluid Concentration of Amikacin in Critically Ill Patients With Ventilator-Associated Pneumonia

Najmeddin, Farhad; Shahrami, Bita; Azadbakht, Sayna; Dianatkhah, Mehrnoush; Rouini, Mohammad Reza; Najafi, Atabak; Ahmadi, Arezoo; Sharifnia, Hamidreza; Mojtahedzadeh, Mojtaba

doi:10.1177/0885066618754784

Cited by 30 publications

(21 citation statements)

References 17 publications

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“…The ELF amikacin concentrations and resultant half-life in the HFIM apparatus were approximated using previous aminoglycoside ELF:serum ratios in conjunction with the established concentration-time curves for the blood amikacin exposure (14,37,38). In brief, the estimated unbound plasma concentration of amikacin was multiplied by the average ELF:serum penetration ratio (0.12, 0.3, 0.85, and 1.14) identified for other aminoglycosides (gentamicin and tobramycin) at the corresponding time points (0.5, 1, 2, and 4 h) (14,37,38). The ELF half-life (1.92 h) was derived from a noncompartmental analysis of the resultant concentration-time curve over the course of 24 h, which approximates that identified previously (39,40).…”

Section: Methodsmentioning

confidence: 99%

“…These factors may be particularly important in patients with Gramnegative bacillary pneumonia for two reasons. First, amikacin penetration into the epithelial lining fluid (ELF), the site of infection, is only approximately 10% of the plasma C max (14). Second, there may be limited treatment options available for multidrugresistant bacteria should aminoglycoside therapy fail.…”

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confidence: 99%

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Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Heffernan

Sime

Sarovich

et al. 2020

Antimicrob Agents Chemother

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Given that aminoglycosides, such as amikacin, may be used for multi-drug resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia and sepsis treatment choices. A hollow-fibre infection model with two P. aeruginosa isolates (MIC 2 and 8 mg/L) with an initial inoculum ∼108 colony-forming unit/mL was used to test different amikacin dosing regimens. Three regimens (15, 25 and 50 mg/kg) simulating a blood exposure and a 30 mg/kg regimen simulating the epithelial lining fluid (ELF) for potential respiratory tract infection were tested. Data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole genome sequencing was used to identify mutations associated with resistance emergence. While bacterial density was reduced by >6-logs within the first 12 h in simulated blood exposures, following this initial bacterial kill, there was amplification of a resistant sub-population with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5-log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggest that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections respectively. Our results suggest that amikacin efficacy may be improved with the use of high dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Heffernan

Sime

Sarovich

et al. 2020

Antimicrob Agents Chemother

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“…However, attaining target antibiotic exposures in the ELF is limited by the blood-alveolar barrier, which inhibits antibiotics diffusing into the site of infection [6]. The ELF penetration of anti-pseudomonal aminoglycosides, such as amikacin, is only about 8% of the concurrent plasma concentration [7]. As patient mortality is minimised when the aminoglycoside maximum concentration (C max ) relative to the pathogen minimum inhibitory concentration (MIC) exceeds eightfold, the impaired diffusion into the ELF following intravenous administration may be a key determinant of reduced clinical response rates for patients with VAP when receiving intravenous aminoglycosides [5,8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Inhaled delivery methods bypass the blood-alveolar barrier, leading to aminoglycoside concentrations within the ELF that are at least 35-fold greater than those achieved with intravenous administration. Such high antibiotic concentrations correspond to a C max /MIC > 8 for susceptible pathogens [7,[12][13][14]. Despite high amikacin concentrations in ELF following inhalation, no mortality benefit was demonstrated for adjunct inhaled amikacin in two recently published, randomised controlled clinical trials [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa

et al. 2021

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Background Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing. Objective The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing. Methods Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance. Results In the presence of broth alone, there was rapid and extensive (> 6 − log 10 ) bacterial killing, with emergence of resistance identified in amikacin concentrations < 976 mg/L. In contrast, the rate and extent of bacterial killing was reduced (≤ 5 − log 10 ) when exposed to an acidic pH and mucin. Surfactant did not appreciably impact the bacterial killing or resistance emergence when compared with broth alone for either isolate. The combination of mucin and an acidic pH further reduced the rate of bacterial killing, with the maximal bacterial killing occurring 24 h following initial exposure compared with approximately 4-8 h for either mucin or an acidic pH alone. Conclusions Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.

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“…[13][14][15] These changes may lead to sub-therapeutic drug level and poor control of infection. [16][17][18][19] Pathophysiological changes following abdominal involvement in sepsis may affect the pharmacokinetic profile of drugs different from other forms of sepsis. Also, fluid shifting from the intravascular compartment into the interstitial or large third spacing, administrating massive volume of resuscitation fluid, multiple laparotomies, and surgeries lead to significant local extravascular fluid accumulation in the abdominal cavity.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis

et al. 2019

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Purpose: Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intraabdominal sepsis compared to pneumosepsis. Methods: Adult septic patients received amikacin therapy were studied. Patients with intraabdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. Results: There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, P=0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, P=0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P=0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, P=0.015). Conclusion: Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis.

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Evaluation of Epithelial Lining Fluid Concentration of Amikacin in Critically Ill Patients With Ventilator-Associated Pneumonia

Cited by 30 publications

References 17 publications

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa

Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis

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