Aerosolized antibiotics in mechanically ventilated patients: delivery and response.
OBJECTIVE
To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents.


METHODS
Prospective serial study with cases as their own control.


METHODS
A 10-bed respiratory care unit for patients with chronic respiratory failure in a tertiary university hospital.


METHODS
Ventilator dependent patients who are otherwise medically stable. All subjects had a tracheostomy in place, were colonized with gram-negative organisms, and produced purulent secretions which could be sampled daily.


METHODS
Six patients received nine courses of nebulized therapy, which consisted of treatments every 8 hrs of gentamicin (80 mg) or amikacin (400 mg) for 14 to 21 days.


RESULTS
Doses to the lung were measured using radiolabeled aerosols and antibiotic concentrations in sputum. The response was assessed by a) changes in the volume of respiratory secretions; b) effect on bacterial cultures; and c) changes in the inflammatory cells and mediators of inflammation of the respiratory secretions (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], soluble intercellular adhesion molecule-1 [sICAM-1], and human leukocyte elastase). On average, patients inhaled 35.4 +/- 5.08% (SD) of the initial drug placed in the nebulizer (neb-charge). Of this neb-charge, 9.50 +/- 2.78% was found on the respirator tubing and tracheostomy tube and 21.9 +/- 7.15% was actually deposited in the lungs. The remainder of the neb-charge was sequestered in the nebulizer or exhaled. Trough sputum concentrations averaged 4.3 +/- 3.2 microg/mL/mg neb-charge (range 234 to 520 microg/mL) and increased to 16.6 +/- 8.1 microg/mL/mg neb-charge (range 1005 to 5839 microg/mL) immediately after therapy (p = .011). Serum concentrations were undetectable in most determinations except for a single patient who was in renal failure (8.7 microg/mL amikacin). Treatment caused a significant reduction in the volume of secretions (p = .002). Weekly cultures revealed eradication of Pseudomonas species, Serratia marcescens, and Enterobacter aerogenes in most of the trials. Before antibiotic treatment, concentrations of IL-1beta were higher than those reported in acute respiratory distress syndrome. Throughout the duration of the study, IL-1beta correlated significantly with the absolute number of macrophages, neutrophils, and lymphocytes, respectively (r2 = .55, p = .002; r2 = .50, p < .0004, r2 = .36, p = .005). TNF-alpha concentrations correlated with lymphocytes and neutrophils, respectively (r2 =.27, p = .013, r2 = .21, p = .033). sICAM-1 concentrations increased two-fold (p < .001) during treatment and then returned to baseline. The volume of secretions was related to neutrophil and IL-1beta concentrations, respectively (r2 = .25, p = .008, r2= .35, p = .006).


CONCLUSIONS
Nebulizer delivery of aerosolized aminoglycosides is efficient and predictable. In our clinical model, aerosolized antibiotics can make a significant impact on respiratory secretions. Their efficacy in treatment of critically ill patients remains to be determined.
Palmer
L B
LB
Department of Medicine, University Medical Center, Stony Brook, NY, USA.
Smaldone
G C
GC
Simon
S R
SR
O'Riordan
T G
TG
Cuccia
A
A
D000328:Adult; D000336:Aerosols; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000008:administration & dosage* / Q000009:adverse effects; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016022:Case-Control Studies; D002908:Chronic Disease; D015169:Colony Count, Microbial; D003428:Cross Infection / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D005839:Gentamicins / Q000008:administration & dosage* / Q000009:adverse effects; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D009330:Nebulizers and Vaporizers; D011446:Prospective Studies; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency / Q000628:therapy; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013183:Sputum / Q000378:metabolism / Q000382:microbiology; D014132:Trachea / Q000382:microbiology / Q000473:pathology; D014139:Tracheostomy
D000336:Aerosols; D000900:Anti-Bacterial Agents; D016207:Cytokines; D005839:Gentamicins; D018799:Intercellular Adhesion Molecule-1; D000583:Amikacin