Anti-Pseudomonas activity in bronchial secretions of patients receiving amikacin or tobramycin as a continuous infusion

Mombelli, G; Coppens, Luc; Thys, Jean-Pierre; Klastersky, Jean

doi:10.1128/aac.19.1.72

Cited by 28 publications

(15 citation statements)

References 9 publications

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“…When the results of the different dosage schedules are examined, higher maximum serum and bronchial amikacin concentrations can be detected with a once-daily i.v. drug administration regimen than with a twicedaily or continuous-infusion regimen (20). Based on the data retrieved, Valcke et al registered the highest peak aminoglycoside concentration in ELF (14.7 mg/liter) after i.v.…”

Section: Discussionmentioning

confidence: 99%

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Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Tayman

El-Attug

Adams

et al. 2011

Antimicrob Agents Chemother

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Aminoglycosides like amikacin are frequently administered in the treatment of suspected or proven Gram-negative infections in neonates, often in combination with penicillins. Due to a concentration-dependent killing combined with a postantibiotic effect, the bactericidal efficacy of amikacin relates to its peak serum concentration. Consequently, therapeutic peak levels at the infection site will define the effectiveness of antibiotic therapy. Renal side effects and ototoxicity relate to the trough serum amikacin concentration, based on the saturation of renal and cochlear cell-binding sites. The pharmacokinetics (PK) of amikacin displays extensive interindividual variability, which makes it difficult to achieve an effective and safe administration in the individual neonate (1).Based on maturational differences in body composition and renal immaturity in early life, differences in both distribution volume (V d , in liters/kg) and clearance (CL t , in ml/kg/min) of this hydrophilic drug have been observed. Because of the higher water content in preterm infants, and thus a higher distribution volume for hydrophilic drugs, a relatively higher amikacin dose is necessary in this population (3,25).Since pulmonary infections can be a major cause of neonatal morbidity and mortality, antibiotic levels in bronchial secretions and bronchial and alveolar epithelial lining fluid (ELF) are of specific interest. Measuring antibiotic concentrations in the lung is not easy and is usually represented by ELF concentrations. Keeping the anatomy of the blood-bronchial barrier in mind, one can imagine that to reach ELF, the antibiotic must pass through the epithelial lining cells linked by tight junctions (14). Consequently, biochemical characteristics like the degree of protein binding and the lipophilicity and diffusibility of the antibiotic will influence antibiotic concentrations in interstitial fluid and in ELF. In adults, we are aware of studies to assess the blood-alveolar barrier after parenteral administration of amikacin. Dull et al. showed that, after intramuscular (i.m.) administration, the highest amikacin serum concentration correlated significantly with the highest bronchial secretion concentration of that individual and that elimination of amikacin from serum and bronchial secretions occurred at approximately the same rate, with a peak concentration that is blunted in the alveolar compared to the blood compartment (12). Since data in neonates are lacking, the aim of this study is to describe amikacin concentration in the bronchial ELF of newborns.

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Section: Discussionmentioning

confidence: 99%

“…1). To compare our data with already published evidence, we performed a systematic literature search on aminoglycoside (amikacin [8,12,17,20,23], tobramycin [5,7,9,17,19,20], gentamicin [21,22], and netilmicin [26]) quantification in BAL fluid after parenteral (i.v. or i.m.)…”

Section: Discussionmentioning

confidence: 99%

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Tayman

El-Attug

Adams

et al. 2011

Antimicrob Agents Chemother

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“…In supplemental material published previously (158), it was reported that mean serum concentrations as low as 1.29 g/liter and mean sputum concentrations of 2,286 g/g were recorded following aerosolized administration of 560 mg (171).…”

Section: Serum and Sputum Pharmacokineticsmentioning

confidence: 99%

“…Although aminoglycosides are distributed almost freely in the extracellular space of most tissues because of their minimal protein binding and high water solubility, they cross biological membranes poorly, so drug concentrations in bronchial secretions are low, thus restricting their efficacy in the treatment of respiratory tract infections (158)(159)(160)(161)(162). Low concentrations of aminoglycosides in the respiratory tract upon intravenous dosing are due to their polycationic charge and their lipid insolubility (163).…”

Section: Serum and Sputum Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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“…Older papers use bioassays or agar disc diffusion assays, which are time consuming and interpretation is often complicated by the growth of bacteria present in sputum. [9][10][11][12][13] V C The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an LC tandem MS assay for the quantification of β-lactam antibiotics in the sputum of cystic fibrosis patients

Forier

Heck

Carlier

et al. 2017

Journal of Antimicrobial Chemotherapy

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Objectives: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data.Methods: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation. Results:The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations. Conclusions:The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler.

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Anti-Pseudomonas activity in bronchial secretions of patients receiving amikacin or tobramycin as a continuous infusion

Cited by 28 publications

References 9 publications

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Development and validation of an LC tandem MS assay for the quantification of β-lactam antibiotics in the sputum of cystic fibrosis patients

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