Background: This clinical trial evaluated the pharmacokinetics and safety/tolerability of amikacin/fosfomycin solution using a vibrating plate nebulizer, in mechanically ventilated patients with ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP). Methods: Nine adult patients were consented to receive three escalating doses of a combination of 50 mg/mL amikacin and 20 mg/mL fosfomycin; doses were separated by 24 -2 hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2 hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow Ò Inline Nebulizer System; PARI Pharma GmbH, positioned in the inspiratory limb tubing between the ventilator and the patient. The nebulizer remained in-line until all treatments had been delivered. Concentrations of amikacin and fosfomycin were measured in tracheal aspirate and plasma samples obtained during the 24 hr after each dose. Results: Fifteen minutes after dosing with the 300/120 mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations -SD were 12,390 -3,986 lg/g, and fosfomycin concentrations were 6,174 -2,548 lg/g (n¼6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4 lg/mL, and the highest observed fosfomycin plasma concentration was 0.8 lg/mL. Administration time was approximately 2 min/mL. No adverse effects on respiratory rate, peak airway pressures, or oxygenation were observed during or following drug or placebo administration. Conclusions: High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration with an inline nebulizer system. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration.
The incidence of acute mountain sickness was determined by questionnaire in 454 individuals who attended week-long continuing medical education programs at ski resorts in the Rocky Mountains with base elevations of about 2000 m. As a control group, 96 individuals who attended continuing medical education programs at sea level in San Francisco completed similar questionnaires. Study subjects were classified as having acute mountain sickness when they reported three or more of the five possible cardinal symptoms: headache, insomnia, dyspnea, anorexia, and fatigue. Only symptoms with an intensity of at least grade 2 (moderate) out of 5 were analyzed. Acute mountain sickness-like symptoms occurred in 25% of subjects at 2000 m compared with 5% of subjects at sea level. The incidence of acute mountain sickness at 2000 m was greatest among subjects who had come from lower altitudes. Half of the subjects with symptoms took medication. The duration of symptoms was short, with 90% of all symptoms that were reported occurring in the first 72 hours. Acute mountain sickness is common at intermediate altitudes, and it is frequently severe enough to prompt self-medication.
In 8 patients with diffuse infiltrates on chest radiograph undergoing fiberoptic bronchoscopy for suspected Pneumocystis carinii pneumonia, bronchoalveolar lavage sediment and supernatant concentrations of pentamidine were compared 18 to 24 h after administration of 4 mg/kg intravenous (n = 3) and aerosolized (n = 5) pentamidine isethionate. Aerosol was inhaled for 35 to 40 min with 300 mg of pentamidine isethionate in a jet nebulizer, baffled to decrease the particle size to 1.42 micron +/- 1.88 (mass median aerodynamic diameter +/- geometric standard deviation). Bronchoalveolar pentamidine concentrations were: In sediment, 9.34 +/- 1.74 postintravenous versus 705 +/- 242 ng/ml postaerosol (mean +/- SEM, p less than 0.05); supernatant, 2.64 +/- 0.73 postintravenous versus 23.2 +/- 7.75 ng/ml postaerosol (mean +/- SEM, p less than 0.05). Serum pentamidine levels were low or undetectable after aerosolization. Aerosol administration delivers significantly higher concentrations of pentamidine to the air spaces than does intravenous delivery in patients with diffuse alveolar infiltrates.
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