Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables.

A randomized open-label study was conducted to compare the pharmacokinetics and pharmacodynamics of grepafloxacin with those of clarithromycin in patients with chronic bronchitis whose sputa were colonized with potential bacterial pathogens. Patients received oral grepafloxacin 400 mg od for 10 days (n = 15) or oral clarithromycin 500 mg bd for 10 days (n = 10). Sputum samples were collected before the first dose, 1, 4 and 8 h after a dose on day 1 and then before a dose on days 2, 3, 5, 7 and 10 to determine the time to eradication (T(erad)) of the potential bacterial pathogens. Blood samples for measurement of grepafloxacin or clarithromycin and 14-hydroxyclarithromycin concentrations were obtained before a dose and 1, 2, 4, 8 and 12 h after doses on days 1 and 5. The area under the inhibitory serum concentration-time curve over 24 h (AUIC(24)), peak serum concentration:MIC ratio (C(max):MIC) and the percentage of the dosing interval during which the serum concentration exceeded the MIC (%tau >MIC) were calculated and serum inhibitory titres (SITs) were determined. Haemophilus spp. were the predominant potential bacterial pathogens and were recovered from the sputa of 24 patients. Strains of Streptococcus pneumoniae were isolated from two patients in the grepafloxacin group and a strain of Moraxella catarrhalis was isolated from one patient in the clarithromycin group. Haemophilus spp. isolates were eradicated from the sputa of 13 of 14 (93%) patients given grepafloxacin, but from only two of 10 (20%) patients given clarithromycin (P < 0.05). In the other eight (80%) patients who received clarithromycin, the sputum cultures remained positive throughout the 10 day course. Grepafloxacin eliminated potential bacterial pathogens more quickly than clarithromycin (median T(erad) 4 h versus 76 h). The S. pneumoniae strains were eradicated by grepafloxacin within 4 h and the single M. catarrhalis strain was eradicated by clarithromycin within 1 h. The greater efficacy of grepafloxacin, compared with that of clarithromycin, in terms of the incidence and speed of eradication of the Haemophilus spp. isolates, was associated with higher median values of AUIC(24) (169 SIT(-1)*h versus 8.1 SIT(-1)*h), C(max):MIC ratio (23.6 versus 0.7) and %tau >MIC (100% versus 0%). A Hill-type model adequately described the relationship between the percentage probability of eradicating potential bacterial pathogens from sputa and the plasma grepafloxacin concentration.

Lidocaine absorption and metabolism after oropharyngeal application in young and young-elderly adults.

The purpose of this study was to evaluate the effect of age on lidocaine absorption and metabolism after application to the oropharynx and vocal cords in a manner similar to preparation for flexible fiberoptic bronchoscopy. Five healthy volunteers were studied in each of two age groups: from 25 to 37 and 60 to 68 years of age. Each volunteer had a total of lidocaine 300 mg administered as a gargle, gel, or directly to the vocal cords. Blood samples and expectorant were collected to determine concentrations of lidocaine and its metabolites, monoethylglycinxylidide (MEGX) and glycinxylidide (GX). No differences in peak plasma lidocaine concentrations, 2.09 +/- 1.28 mumol/L (1 microgram/mL = 4.27 mumol/L) in young subjects, and 2.35 +/- 0.85 mumol/L in young-elderly subjects, or lidocaine AUC were seen between the two age groups. Lidocaine recovered in expectorant ranged from 96 to 168 mg. This study suggests that, over the age range studied, increased age does not impair lidocaine absorption from the oropharynx or lidocaine metabolism when topical lidocaine is used during flexible fiberoptic bronchoscopy.

Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication.

Fifty patients with gram-negative lower respiratory tract infections were treated with intravenous ciprofloxacin to evaluate efficacy and safety. Relationships between individual pharmacokinetics and clinical and bacteriologic outcome were studied. Ciprofloxacin concentrations in plasma were determined by high-performance liquid chromatography. Respiratory secretion cultures were obtained daily to determine the eradication day of the infecting organism. Susceptibility (minimum inhibitory concentration) to ciprofloxacin and other antimicrobials was determined using standard microdilution techniques. The mean age of the patients was 70 years. They had multiple underlying diseases, and two thirds of them were ventilator dependent at entry. Approximately 50% of the patients had failed previous treatment for the same infections. Patients infected with Enterobacteriaceae or Haemophilus influenzae with minimum inhibitory concentrations of less than 0.25 mg/L responded well to intravenous ciprofloxacin therapy (200 mg every 12 hours). The organisms were eradicated from sputum cultures usually within 1 day after ciprofloxacin therapy was started. Most clinical failures occurred in patients who were infected with Pseudomonas aeruginosa and had multiple underlying diseases. Pseudomonas aeruginosa was isolated from 10 patients with pneumonia, 2 patients with lung abscess, and 1 patient with bronchiectasis. The Pseudomonas isolate acquired resistance during ciprofloxacin treatment in 7 patients with pneumonia and in all of the remaining 3 patients. We conclude that ciprofloxacin is safe and effective at a dosage of 200 mg administered intravenously every 12 hours for nosocomial lower respiratory tract infections caused by Enterobacteriaceae or Haemophilus species. Many patients who had failed previous antibiotic treatment for Enterobacteriaceae infections had good clinical response to ciprofloxacin therapy. Studies using either higher dosages of ciprofloxacin or combination therapy should be conducted to determine if acquired resistance can be avoided in Pseudomonas infections.

Dual individualization of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections.

Dual individualization is the integration of patient-specific pharmacokinetic parameters with the pharmacodynamics (concentration versus response) of the infecting pathogen. This technique allows description of the time of in vivo bacterial eradication, and allows estimation of optimal dosages using small numbers of seriously ill patients. In an ongoing study, 11 patients with nosocomial lower respiratory tract infections were given 200 mg of intravenous ciprofloxacin every 12 hours. Ten blood samples were taken after the first dose, with additional peaks and troughs measured on Day 4 and at the end of treatment. Bacterial isolates had minimal inhibitory concentrations (MICs) determined by standard microdilution techniques. In the 11 patients, there were 14 bacterial isolates, of which seven were Pseudomonas aeruginosa and the remainder were other pathogens. Ciprofloxacin MICs ranged from 0.008 to 1.0 microgram/ml. The pharmacokinetics of ciprofloxacin in these patients varied with renal function, and average peak serum concentrations ranged from 1.7 to 4.9 micrograms/ml. Eradication of bacteria from tracheal aspirates occurred between Days 1 and 7, except in four patients in whom the organism persisted. Correlations were observed between the day of eradication and the length of time ciprofloxacin concentrations remained above the minimal inhibitory concentration (MIC). Essentially all bacteria with MICs of less than 0.25 were eradicated. Of the non-eradicated bacteria, most had either MICs of more than 0.25, or less than 100 percent time above the MIC. The clinical response was satisfactory. It is concluded that 200 mg of intravenous ciprofloxacin every 12 hours is highly effective for bacteria with MICs less than 0.25 microgram/ml, but higher dosages may be required to eradicate organisms with higher MICs.

Homeostatic regulation of airway smooth muscle tone by catecholamine secretion in swine.

We studied the homeostatic secretory response of catecholamine secretion elicited by progressive bronchoconstriction in 18 swine in vivo. The potential reserve of the sympathetic nervous system (SNS) was first assessed by exogenous nicotinic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). A dose of 250 micrograms/kg iv DMPP caused an increase in plasma norepinephrine (NE) concentration from 207 +/- 86 (basal) to 2,625 +/- 448 pg/ml (P less than 0.02) and in plasma epinephrine (EPI) from 10 +/- 5.0 to 1,410 +/- 432 pg/ml (P less than 0.05) in four swine. In four other swine, bronchoconstriction induced by aerosolized prostaglandin F2 alpha caused approximately a fivefold increase in airway resistance without hemodynamic changes. No increase in plasma EPI was observed. However, plasma NE increased from 330 +/- 131 to 1,540 +/- 182 pg/ml (P less than 0.02). In five swine receiving aerosolized acetylcholine (ACh), similar changes in airways resistance were not associated with significant changes in catecholamine concentration when mean arterial blood pressure (MAP) was unchanged. However, inhalation of sufficient ACh to cause a greater than 10% decrease in MAP caused progressive increase in catecholamine secretion. Plasma EPI increased from 32 +/- 16 (MAP = 124 +/- 7 Torr) to 1,165 +/- 522 pg/ml (MAP = 94 +/- Torr). Hypoxemia that occurred with bronchoconstriction (greater than or equal to 50 Torr) did not cause catecholamine secretion. However, severe hypoxemia (PO2 less than 30 Torr) caused large increases in plasma EPI concentrations from 84 +/- 27 to 1,463 +/- 945 pg/ml (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of vagal contractile response by thromboxane mimetic U-46619.

We studied the effect of the thromboxane mimetic U-46619 on tracheal smooth muscle contraction caused by bilateral stimulation of the vagus nerves in 14 mongrel dogs in situ. The parasympathetic contractile response was studied isometrically after beta-adrenergic blockade with 2 mg/kg iv propranolol plus 20 micrograms X kg-1 X min-1 continuous intravenous infusion and blockade of endogenous prostaglandin synthesis with 5 mg/kg iv indomethacin. An initial frequency-response curve was generated by electrical stimulation of the caudal ends of cut cervical vagi over the range of frequencies 2-25 Hz (constant 25 V) at 15-s intervals. In five dogs, 10(-10) to 10(-8) mol of the thromboxane mimetic (15S)-hydroxyl-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U-46619) was injected selectively into the tracheal arterial circulation, causing a transient contractile response (less than or equal to 10 g/cm). Additional frequency response studies were generated 7 min before and 1, 15, 30, 45, and 60 min after U-46619. Substantial augmentation of tracheal contraction to efferent vagal stimulation was observed after U-46619 for all frequencies greater than 4 Hz (P less than 0.02). Augmentation of vagally mediated contraction was not observed in four other dogs after equivalent tracheal contraction was elicited without U-46619. Similarly, in four separate dogs, augmentation of tracheal contraction was not observed when acetylcholine was given instead of vagal stimulation after U-46619. We conclude that the thromboxane analogue, U-46619, causes augmentation of tracheal contractile response induced by efferent vagus nerve stimulation. Potentiation is caused by a prejunctional action of U-46619 and is not induced by nonspecific precontraction with another agonist.

Homeostatic regulation of bronchomotor tone by sympathetic activation during bronchoconstriction in normal and asthmatic humans.

It has been assumed previously that the sympathetic nervous system (SNS) serves to antagonize bronchoconstrictor stimuli. To assess the homeostatic regulatory effect elicited by exogenously induced bronchoconstriction, we studied the effect of inhaled methacholine on the SNS response in 12 normal and 9 asthmatic humans. Exogenous SNS response was assessed as change in plasma epinephrine and norepinephrine concentrations from basal levels during inhalation challenge. A 74 +/- 3% decrease in specific airway conductance (SGaw) (p less than 0.001) was induced in normal subjects and a 78 +/- 7% decrease in asthmatics by methacholine challenge (p less than 0.001). Neither plasma epinephrine nor norepinephrine increased significantly from basal concentrations in normal or asthmatic subjects after maximal challenge (p greater than 0.33). To determine if physiologically achievable epinephrine concentrations potentially could modulate bronchoconstriction, the effect of intravenously infused epinephrine was measured in 11 of these subjects. After the highest dose of methacholine, a 15-min intravenous infusion of epinephrine (0.06 micrograms/kg/min) caused an 85 +/- 7% increase in SGaw in normal subjects (p less than 0.02). In asthmatics, a 319 +/- 68% increase in SGaw (p less than 0.002) was observed with similar changes in plasma epinephrine. Plasma epinephrine concentrations after infusion were comparable to those obtained in 4 normal and 1 asthmatic subject undergoing 60-degree, head-up tilt 1 h after volume depletion with intravenously administered furosemide. We conclude that physiologic concentrations of epinephrine can modulate moderately severe bronchoconstriction. However, the SNS does not regulate bronchomotor tone during mild to moderate bronchoconstriction.