Combined aztreonam and gentamicin therapy for pseudomonal lower respiratory tract infections.

A multicenter, open-label study was performed to assess the efficacy and safety of aztreonam plus gentamicin in the treatment of lower respiratory tract infections due to Pseudomonas aeruginosa. Patients with documented P aeruginosa infections were given aztreonam 2 g every 8 hours (q8h) plus gentamicin 3 to 5 mg/kg per day in three equal doses. Clindamycin, 600 mg q8h, was added to the regimen for patients with infections also involving gram-positive and/or anaerobic bacteria. Therapy was continued for at least 5 days or until obvious failure to respond to treatment. Of 64 patients with suspected P aeruginosa infections, 57 were eligible for clinical evaluation and 51 for microbiologic evaluation. At entry, impaired host defense was present in 35% of patients, and chronic obstructive pulmonary disease in 28%, in addition to other predisposing conditions such as emphysema, history of tuberculosis, and pneumothorax. The clinical response rate for the combination regimen was 48/57 (84%), which included 27 (47%) cures and 21 (37%) partial responses. The microbiologic response rate was 35/51 (69%), of which 25 (49%) outcomes were classified as eradication and 10 (20%) as eradication with relapse. Superinfection was observed in 3 (6%) patients. The combination of aztreonam and gentamicin was synergistic in the initial isolates obtained from 33 (72%) patients. A total of 16 patients died of pulmonary or other underlying disease, for a mortality rate of 28%. The monobactam-aminoglycoside combination was generally well tolerated. Two other patients were withdrawn because rashes emerged on treatment. This study demonstrates that aztreonam can be administered as one component of a synergistic monobactam-aminoglycoside therapy in the treatment of nosocomial lower respiratory tract infections involving P aeruginosa.

Electrogenic sodium-bicarbonate cotransport in human ciliary muscle cells.

We investigated membrane voltage and intracellular pH (pHi) in cultured human ciliary muscle cells using a cell line (H7CM) and primary-cultured human ciliary muscle cells. 1) Resting potential was 58.9 +/- 1.0 mV in H7CM cells and 61.9 +/- 1.4 mV in primary cultures. The following data are from H7CM cells, but results from primary cultures were basically similar. 2) In HCO3(-)-CO2-buffered solution, removal of extracellular sodium resulted in a depolarization [change in membrane resistance (delta V) = 31.3 +/- 2.8 mV] that was less marked in the absence of HCO3(-)-CO2 (delta V = 0.5 +/- 2.6 mV) and reduced by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) (delta V = 19.3 +/- 1.9 mV). 3) Removal of extracellular HCO3(-)-CO2 led to a depolarization (delta V = 13.2 +/- 0.8 mV) that was abolished in the absence of extracellular sodium and inhibited by DIDS. 4) Intracellular alkalinization led to a depolarization (delta V = 24.7 +/- 2.3 mV), and intracellular acidification resulted in a hyperpolarization (delta V = 9.4 +/- 1.1 mV) that was inhibited by DIDS and dependent on extracellular HCO3(-)-CO2 and sodium. 5) pHi backregulation after an acid load occurred in both the presence and absence of extracellular bicarbonate but not in the absence of extracellular sodium. Our data are consistent with an electrogenic Na(+)-HCO3- cotransport in human ciliary muscle cells, which is activated by intracellular acidification.

Measurements of intracellular calcium and contractility in human ciliary muscle.

Electromechanical and pharmacomechanical coupling was investigated in human ciliary muscle by measuring the intracellular free calcium in single cultured ciliary muscle cells and the contractility in meridional ciliary muscle strips. The basal resting calcium concentration was 75 +/- 8.7 nmol/l, n = 23. Application of acetylcholine (0.1 mmol/l) and carbachol (0.1 mmol/l) resulted in an initial [Ca2+]i peak followed by a recovery phase and a [Ca2+]i plateau. The initial [Ca2+]i peak was still observed in the absence of extracellular calcium and in the presence of verapamil (0.1 mmol/l). During its plateau [Ca2+]i was decreased by withdrawal of extracellular calcium or application of verapamil (0.1 mmol/l). Depolarization induced by a high level of extracellular potassium yielded only a small transient [Ca2+]i peak without a [Ca2+]i plateau. In isolated ciliary muscle strips, muscarinic stimulation (carbachol 0.1 mmol/l) resulted in an initial phasic and a subsequent tonic contraction. Removal of external calcium reduced the phasic contraction to 30.6 +/- 4.4% (n = 8) and completely abolished the tonic one. Verapamil (0.1 mmol/l) had only a slight relaxing effect when applied during the tonic contraction. We conclude that human ciliary muscle contraction is mediated by calcium release from intracellular stores and calcium entry through calcium channels, which are most probably receptor-operated. Depolarization of the muscle cell membrane and calcium entry through voltage-operated calcium channels do not contribute significantly to human ciliary muscle contraction.

Mixed venous CO2 tension during exercise.

A series of experiments was undertaken in a total of 95 adult subjects, of whom 25 had coronary artery disease, to evaluate the extrapolation (Defares) CO2 rebreathing method vs. the equilibrium (Collier) method for estimating mixed venous CO2 tension. Collier values were corrected for the downstream effect, whereas Defares values were uncorrected. Although the methods gave similar mean values in separate series with normal subjects walking on a treadmill set at 123 W for 3 min, Collier values had a coefficient of variation (CV) of 2.5% in duplicate determinations and Defares values had a CV of 4.5%. In paired comparisons Defares values averaged either higher or lower than Collier values depending on variations in technique and the analysis of Defares tracings. Collier values were essentially unaffected by the duration of the rebreathing period (10 vs. 15 s). The Collier technique appears to be superior for the exercise evaluation of cardiac output in healthy and diseased subjects when the goal is obtain values at 82 or 123 W in single test sessions.

Density dependence of expiratory flow and bronchodilator response in asthma.

Change in the magnitude of density dependence of the maximal expiratory flow (D/MEF) following inhalation of isoproterenol was used as a test for predicting the long term response to isoproterenol vs atropine in 24 adult patients with longstanding asthma. Eleven subjects showed a decrease in D/MEF manifested by increase in volume of isoflow (VisoV) and/or decrease in Vmax50 Helox/air following isoproterenol inhalation (group 1). Thirteen subjects manifested an opposite response (group 2). Atropine sulphate (0.08 mg/kg) and isoproterenol hydrochloride (2.5 mg) were then administered by inhalation, each four times a day for seven days in a randomized double-blind cross over fashion to all subjects. One of group 1 but ten of group 2 subjects had a greater subjective and objective improvement with atropine than with isoproterenol (P less than .005). An increase in D/MEF following isoproterenol can be used as a test to predict a better response to atropine than to isoproterenol over a one week period. Such a response occurs in almost half of the adult chronic asthmatic patients. The results are consistent with a preferential dilatation of the large airways by atropine.

Role of single-breath carbon monoxide-diffusing capacity in monitoring the pulmonary effects of bleomycin in germ cell tumor patients.

Serial pulmonary function tests including single-breath carbon monoxide-diffusing capacity (DLCO), forced vital capacity (FVC), and forced expiratory volume in 1 sec were performed in a relatively homogeneous group of male patients with germ cell tumors treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum. Of the pulmonary function tests used, the DLCO was shown to be the most sensitive indicator of subclinical bleomycin pulmonary effects. Decreases in DLCO were both total dose and schedule dependent. Patients receiving their total dose of bleomycin at a rate of 25 +/- 2 (S.D.) units/week developed a linear decrease in DLCO with increasing total doses of bleomycin. Changes in FVC did not correlate with bleomycin total dose. Although both the mean DLCO and FVC decreased after completion of bleomycin therapy, the mean FVC returned to base-line levels rapidly, whereas the decrease in mean DLCO was persistent for several months. When routine volumetric tests (FVC and forced expiratory volume in 1 sec) and DLCO are used in a systematic manner, DLCO is the most sensitive indicator of the subclinical pulmonary effects of bleomycin in germ cell tumor patients treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum.

One- and three-minute exercise response in coronary artery disease.

Treadmill exercise responses of oxygen uptake (VO2), CO2 production (VCO2), and venoarterial CO2 difference (Cv-Ca), measured by CO2 rebreathing (Defares technique) at 1 and 3 min of exercise, were studied in two separate series of control (apparently healthy) and coronary artery disease (CAD) subjects. In the 1-min series there were 21 controls and 15 CAD subjects. In the 3-min series there were 21 controls and 18 CAD subjects. All were males, ages 30--60 yr, and the CAD subjects had histories of myocardial infarction. In both series VO2 at 1 min and power requirement (P ) = 1,000 (VO2-1-1,000) was estimated where P =weight (kg) X grade (fractional) X walking speed (m/min). In the 1-min series (P = 1,000) all measurements were made at 45--60 s in separate test runs. In the 3-min series P was 750 kg.m/min, VCO2 and VO2 were measured at 2.5--3 min exercise, and Cv-Ca was measured at 3--3.25 min in the same test run. Data indicate that the average cardiac output (Q) for control subjects was 15 l/min in both series with lower values for CAD subjects. At 1 min reduced Q was accompanied by reduced VO2 or VCO2 and increased Cv-Ca, whereas at 3 min reduced Q was accompanied by increased Cv-Ca.

Stability of the arterial/alveolar oxygen partial pressure ratio. Effects of low ventilation/perfusion regions.

The alveolar-arterial oxygen partial pressure difference (AaDO2) and the arterial/alveolar oxygen partial pressure ratio (a/APO2) were compared for stability when inspired oxygen concentration (FIO2) changed. The analysis was based on a three-compartment lung model and experimental results in 10 patients with respiratory failure receiving assisted ventilation. It was found that a/APO2 was more stable than AaDO2 and more useful for: (1) comparing gas exchange in patients receiving different levels of FIO2, (2) following gas exchange in the same patient as FIO2 is changed, and (3) estimating the PaO2 expected at a given level of FIO2 if blood gas data are available at another level. However, areas with low ventilation/perfusion (V/Q) ratios may cause sudden changes in a/PO2 at certain critical values of PAO2. Most stable is a/APO2 and, therefore, most useful at FIO2 levels greater than 0.3, and PaO2 levels less than 100 torr.