Penetration of Gentamicin Into the Alveolar Lining Fluid of Critically Ill Patients With Ventilator-Associated Pneumonia

doi:10.1378/chest.128.2.545

Chest

Volume 128, Issue 2, August 2005, Pages 545-552

https://doi.org/10.1378/chest.128.2.545 Get rights and content

Study objectives

To estimate the penetration of gentamicin into lung tissue by measuring its concentrations in alveolar lining fluid (ALF) and blood in critically ill patients with ventilator-associated pneumonia (VAP)

Patients and interventions

The study population consisted of 24 patients who were admitted to an ICU for respiratory failure and developed VAP. Patients were scheduled to undergo bronchoscopy with BAL after IV administration of a once-daily, 240-mg schedule of gentamicin for the treatment of VAP. Patients were assigned at random to one of four groups of six patients each according to the scheduled time for bronchoscopy (1, 2, 4, or 6 h, respectively). A serum sample was obtained at 0.5 h (n = 24), and both serum and ALF samples (n = 6) were collected at each of the above specified times for measurement of antibiotic concentrations

Measurements and results

Mean ± SEM gentamicin concentrations in the ALF were 2.95 ± 0.37, 4.24 ± 0.42, 3.10 ± 0.39, and 2.65 ± 0.35 μg/mL at 1, 2, 4, and 6 h, respectively, after the start of antibiotic infusion. Maximum gentamicin concentrations in serum (13.39 ± 0.91 μg/mL, n = 24) and ALF (4.24 ± 0.42 μg/mL, n = 6) were achieved at 0.5 h and 2 h, respectively, giving a penetration ratio of 0.32. The mean ratios of ALF/serum concentrations between 1 h and 6 h ranged from 0.30 to 1.14. After completion of the distribution phase, a significant positive correlation (p = 0.02) was found between gentamicin concentrations in the serum and ALF

Conclusions

Once-daily IV administration of 240-mg gentamicin achieved average peak antibiotic concentrations of 4.24 μg/mL in the ALF 2 h after administration, and an ALF/serum penetration ratio of 32%. Higher gentamicin doses to produce higher peak blood levels than those found with the study dose are necessary to obtain active alveolar concentrations against less sensitive microorganisms in the treatment of VAP in ICU patients

Section snippets

Patients

This open-labeled uncontrolled study took place at the University Intensive Care Unit of the “KAT” Hospital (Athens, Greece) after the study protocol was approved by the hospital scientific and ethics committee. Twenty-four, white, adult, intubated, critically ill patients receiving MV who were scheduled to undergo diagnostic fiberoptic bronchoscopy while receiving gentamicin for the treatment of VAP were selected for this study. All patients were admitted to the ICU for acute respiratory

Results

Twenty-four ICU patients (16 men and 8 women) were successfully enrolled in the study. However, three patients were dropped and replaced due to BAL sampling duration violations. All patients underwent a scheduled fiberoptic bronchoscopy the first day of treatment with gentamicin administered as an IV infusion of 240 mg (mean administered dose, 3.5 ± 0.1 mg/kg). All patients successfully completed the bronchoscopy and BAL procedures. No major adverse effects were noted except for a transient

Discussion

In the present study, gentamicin penetration of ALF was assessed by comparing concentrations of the antibiotic achieved in the ALF and serum following the IV administration of a once-daily dosing schedule in 24 critically ill patients with VAP. As far as we are aware from the literature (MEDLINE search, key words “gentamicin,” “BAL,” “bronchoalveolar lavage,” “alveolar lining fluid”), this is the first human study in which gentamicin concentrations have been compared in these two compartments.

Conclusions

Once-daily, IV administration of gentamicin, 240 mg, achieved average peak antibiotic concentrations of 4.24 μg/mL in the ALF 2 h after administration and an adequate ALF/serum penetration ratio of 32%. However, a gentamicin dose higher than the study dose is necessary to obtain active alveolar concentrations against less-sensitive microorganisms in the treatment of VAP in ICU patients.

Acknowledgments

We thank Dr. Evangelia Kouskouni, Head of the Microbiology Department, Aretaieion Hospital (Athens, Greece) for her kind assistance in the laboratory.

References (41)

YJ Valcke et al.
Penetration of netilmicin in the lower respiratory tract after once-daily dosing
Chest
(1992)
RD Moore et al.
Association of aminoglycoside plasma levels with therapeutic outcome Gram-negative pneumonia
Am J Med
(1984)
H Yoshioka et al.
Placental transfer of gentamicin
J Pediatr
(1972)
MJ Richards et al.
Nosocomial infections in medical intensive care units in the United States: National Nosocomial Infections Surveillance System
Crit Care Med
(1999)
JL Vincent et al.
The prevalence of nosocomial infection in intensive care units in Europe: Results of the European Prevalence of Infection in Intensive Care (EPIC) Study; EPIC International Advisory Committee
JAMA
(1995)
J Chastre et al.
Ventilator associated pneumonia
Am J Respir Crit Care Med
(2002)
Bergogne-Berezin E. Pharmacokinetics of antibiotics in respiratory secretions. In: Pennigton JE, ed. Respiratory...
DR Baldwin et al.
Pulmonary disposition of antimicrobial agents:in vivoobservations and clinical relevance
Antimicrob Agents Chemother
(1992)
E Bergogne-Berezin
Predicting the efficacy of antimicrobial agents in respiratory infections: is tissue concentration a valid measure?
J Antimicrob Chemother
(1995)
Y Valcke et al.
Pharmacokinetics of antibiotics in the lungs
Eur Respir J
(1990)

GL Drusano

Role of pharmacokinetics in the oucome of infections

Antimicrob Agents Chemother

(1988)

JF Murray et al.

An expanded definition of the adult respiratory distress syndrome

Am Rev Respir Dis

(1988)

Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups

Am Rev Respir Dis

(1990)

DR Baldwin et al.

Pulmonary disposition of antimicrobial agents: methodological considerations

Antimicrob Agents Chemother

(1992)

SI Rennard et al.

Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution

J Appl Physiol

(1986)

AE Taylor et al.

Permeability of the alveolar membrane to solutes

Circ Res

(1965)

J Theodore et al.

Transalveolar transport of large polar solutes (sucrose, inulin, and dextran)

Am J Physiol

(1975)

C Govantes et al.

Measurement of tobramycin in bronchoalveolar lavage fluid by a modified fluorescence polarization immunoassay

J Antimicrob Chemother

(1995)

AJ Carcas et al.

Tobramycin penetration into epithelial lining fluid of patients with pneumonia

Clin Pharmacol Ther

(1999)

WA Knaus et al.

APACHE II: a severity of disease classification system

Crit Care Med

(1985)

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This study was funded entirely by the School of Pharmacy, University of Athens

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml)

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Chest

Clinical Investigations in Critical CarePenetration of Gentamicin Into the Alveolar Lining Fluid of Critically Ill Patients With Ventilator-Associated Pneumonia

Study objectives

Patients and interventions

Measurements and results

Conclusions

Section snippets

Patients

Results

Discussion

Conclusions

Acknowledgments

Chest

Am J Med

J Pediatr

Nosocomial infections in medical intensive care units in the United States: National Nosocomial Infections Surveillance System

Crit Care Med

The prevalence of nosocomial infection in intensive care units in Europe: Results of the European Prevalence of Infection in Intensive Care (EPIC) Study; EPIC International Advisory Committee

JAMA

Ventilator associated pneumonia

Am J Respir Crit Care Med

Pulmonary disposition of antimicrobial agents:in vivoobservations and clinical relevance

Antimicrob Agents Chemother

Predicting the efficacy of antimicrobial agents in respiratory infections: is tissue concentration a valid measure?

J Antimicrob Chemother

Pharmacokinetics of antibiotics in the lungs

Eur Respir J

Role of pharmacokinetics in the oucome of infections

Antimicrob Agents Chemother

An expanded definition of the adult respiratory distress syndrome

Am Rev Respir Dis

Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups

Am Rev Respir Dis

Pulmonary disposition of antimicrobial agents: methodological considerations

Antimicrob Agents Chemother

Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution

J Appl Physiol

Permeability of the alveolar membrane to solutes

Circ Res

Transalveolar transport of large polar solutes (sucrose, inulin, and dextran)

Am J Physiol

Measurement of tobramycin in bronchoalveolar lavage fluid by a modified fluorescence polarization immunoassay

J Antimicrob Chemother

Tobramycin penetration into epithelial lining fluid of patients with pneumonia

Clin Pharmacol Ther

APACHE II: a severity of disease classification system

Crit Care Med

Clinical Investigations in Critical Care
Penetration of Gentamicin Into the Alveolar Lining Fluid of Critically Ill Patients With Ventilator-Associated Pneumonia