Co-trimoxazole effect on human alveolar macrophages of AIDS patients.

Compelling evidence suggests that co-trimoxazole prophylaxis reduces mortality in HIV-infected patients, although it is unclear whether these effects are directly related to antimicrobial activities. We evaluated in vitro phagocytosis and killing of Staphylococcus aureus in alveolar macrophages (AM) obtained from AIDS patients who smoke, treated (n=19) or not treated (n=13) with co-trimoxazole, as compared to non-HIV-infected healthy smokers (n=15). Phagocytosis and killing of Staphylococcus aureus by AM obtained from non-co-trimoxazole treated AIDS patients were significantly lower compared to non-HIV-infected healthy smokers. In contrast, AIDS patients treated with co-trimoxazole prophylaxis showed phagocytosis and killing levels similar to those of healthy controls. These results might help to clarify the observed positive effect of co-trimoxazole on survival in HIV-infected patients.

Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis.

Multidrug-resistant (MDR) tuberculosis (TB) is a form of TB that is resistant to some of the first-line drugs used for the treatment of the disease. It is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs. Levofloxacin (LFX) represents one of the few second-line drugs recently introduced in the therapeutic regimens for MDR TB. We report our experience concerning in vitro activity and clinical safety of LFX in long term second-line regimens for MDR TB. IN VITRO ACTIVITY ON MYCOBACTERIA: The in vitro activity of ciprofloxacin, ofloxacin and LFX was studied on 28 strains belonging to different species of Mycobacteria. In Dubos medium, LFX inhibited the growth of both library and MDR clinical Mycobacteria strains in a range of 0.25-1 mcg/ml. In International Union Tuberculosis Medium (IUTM) the minimum inhibitory concentrations (MIC) were slightly higher, but LFX activity was not affected by the higher complexity of the medium. CLINICAL EXPERIENCE: Four patients with MDR TB were treated with a second-line regimen comprising oral LFX 500 mg twice daily, for at least 9 months. Two isolates obtained from the patients reported here showed multi resistance to isoniazid and rifampin, one to rifampin and streptomycin and one to isoniazid and ethambutol. During therapy, no significant alteration of either liver function tests, blood tests or any other described side effect of the fluoroquinolone class was observed. The 3 patients with pulmonary MDR TB showed radiologic and clinical improvement. CONCLUSION: We confirm the higher in vitro activity of LFX compared to older fluoroquinolones. Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d. administered in a range of 9-24 months were well tolerated and safe.

Comparison of the efficacy and safety of isepamicin and amikacin in the treatment of acute lower respiratory tract infections caused by gram-negative organisms.

In a prospective multicentre open trial, hospitalised adult patients with acute lower respiratory tract infections, mainly pneumonia or bronchitis, were randomised to receive either isepamicin 8 or 15 mg/kg once daily depending on the severity of the infection or amikacin 7.5 mg/kg twice daily. Patients with infections known to be caused by Pseudomonas aeruginosa were to be given concomitant treatment with ceftazidime. In the intent-to-treat population, i.e. patients who received at least one dose randomised treatment, a clinical cure or improvement at the end of treatment was seen in 112/125 (90%) isepamicin patients and 55/60 (92%) amikacin patients. The corresponding rates for patients with a primary diagnosis of pneumonia were 45/52 (87%) and 25/28 (89%). Cure/improvement rates for patients with P. aeruginosa as the causative pathogen (34 of whom also received ceftazidime) were 28/30 (93%) and 16/18 (89%), respectively. In the efficacy population (patients who had a valid pretreatment culture and who met other evaluability criteria), total elimination (documented or presumed if infection had resolved) of target pathogens occurred in 54/63 (86%) of isepamicin patients and 25/30 (83%) of amikacin patients. P. aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were commonly isolated pathogens. Treatment-related adverse were mainly mild or moderate in severity and occurred in 10% of isepamicin patients and 13% of amikacin patients. Four patients (3 isepamicin and 1 amikacin) discontinued treatment because of severe adverse events and a further isepamicin patient withdrew because of a mild adverse event. Nephrotoxicity and ototoxicity occurred infrequently.

[Signs of inflammatory activity in thoracic sarcoidosis. A high-resolution computerized tomography study]. / Segni di attività infiammatoria nella sarcoidosi toracica. Studio con Tomografia Computerizzata ad alta risoluzione.

Sarcoidosis is characterized by the presence of non-caseating granulomas. Lymphadenopathy and diffuse parenchymal abnormalities often involve the chest. This study was aimed at finding out signs that could be suggestive of disease activity and if the lesions are reversible after therapy. Sixty-three patients underwent chest radiography, high resolution CT, functional studies, bronchoalveolar lavage and 67Ga scintigraphy. Twenty-three patients were followed-up. Lymphadenopathies, nodular opacities and acinar opacities resolved after steroid therapy; bronchiolectasies, bronchiectasies, septal thickening and parenchymal distorsion did not disappeared after therapy and are therefore considered as irreversible lesions. Ground glass opacities are an uncommon finding; they are due to fibrosis or to widespread interstitial granulomas rather than alveolitis. The prognostic meaning of ground glass opacities is uncertain. Therefore, disease activity findings are mainly lymphadenopathies, nodules and consolidations. Nevertheless these findings not necessarily imply a bad prognosis, as acute sarcoidosis seems to respond well to steroid therapy, even with complete remission. It remains debated if a CT study is worthwhile in all the new cases of sarcoidosis or only in the clinically more severe ones.

Activity of aztreonam in pneumology, Part 2: Influence on phagocytosis and intracellular killing of human alveolar macrophages.

The study aim was to evaluate the activity of aztreonam on phagocytosis and intracellular killing of Staphylococcus aureus ATCC6538 by human alveolar macrophages. Drug concentrations of 1, 10, 25, 100 micrograms/ml were assayed in culture medium. Aztreonam induces dose-dependent phagocytosis up to 25 micrograms/ml concentrations; with a phagocytosis index (PIa) of 1.18 +/- 0.2 at 1 microgram/ml; of 1.27 +/- 0.2 at 10 micrograms/ml; of 1.42 +/- 0.3 at 25 micrograms/ml. No phagocytosis increase or inhibition, with unchanged cell viability compared to controls, is shown at 100 micrograms/ml aztreonam (PI 1.03 +/- 0.3). Intracellular killing acts in a similar way: the killing index (KIa) is 1.27 +/- 0.3 at 1 microgram/ml concentrations; 1.38 +/- 0.3 at 10 micrograms/ml; 1.61 +/- 0.4 at 25 micrograms/ml whereas at 100 micrograms/ml the KIa is 1.03 +/- 0.3. This study shows aztreonam's ability to stimulate macrophages' functional activity against a microorganism (S. aureus) which is not susceptible to its antibacterial activity.

Semi-quantitative X-ray microanalysis of bronchoalveolar lavage samples from silica-exposed and nonexposed subjects.

To evaluate the possibility of quantifying alveolar dust burden in conditions of exposure to silica, four groups of subjects were submitted to bronchoalveolar lavage (BAL): 10 healthy control subjects and 39 patients affected by diffuse interstitial lung disease (DILD) never exposed to dust, 23 silicotic patients and 12 chronic bronchitis patients with a history of occupational exposure to silica dust. Five to ten million BAL recovered cells were analysed with an energy-dispersive X-ray microanalysis (EDXA) system to determine the silicon content, expressed in a semi-quantitative way as silicon to sulphur (Si/S) ratio. The results were independent of smoking habit. The Si/S median values (interquartile range in brackets) for the four groups were 0.53 (0.5-0.65), 0.60 (0.41-0.8), 1.23 (1.06-1.39), 1.31 (1.11-1.97), respectively. Silicotics and simply exposed individuals did not show a significant discrepancy, but they were both significantly different in comparison with normal and DILD patients without history of exposure (p less than 0.001). 14.3% false negative cases were found, and 4.1% false positive cases (none among normal subjects). We did not see any significant relationships between the amount of silicon and the duration of exposure or the degree of chest X-ray involvement. A study of cytocentrifuge slides from the same subjects by polarizing light microscopy revealed a lower sensitivity (34% false negative cases).(ABSTRACT TRUNCATED AT 250 WORDS)

Aztreonam activity in pneumology. Part 1: Clinical activity and pulmonary bioavailability of two different administration regimens.

Twenty-three patients suffering from lower respiratory tract infections caused by Gram-negative germs were treated with aztreonam (AZT) administered according to two different regimens: 17 subjects (Group A) with 2 g i.v. every 12 h and 6 patients (Group B) with 4 g in 100 ml of saline every 24 hours. Group A included 8 cases of superinfected bronchiectasis, 8 purulent bronchitis and 1 gangrene caused by Gram-negative and anaerobic agents. Group B comprised 6 patients with severe bronchiectasis infection. Pseudomonas aeruginosa was isolated from the sputum in 10/23 cases. The treatment was performed for 10 days on the average. The local and systemic tolerability was good. Group B, with higher antibiotic sputum concentrations for at least 12 hours, attained a better response than Group A: with clinical cure in 100% vs 76% cured plus 18% improved patients; therapy lasted 9.5 days for Group B vs 10.8 days for Group A. Moreover, in 14 subjects affected by pulmonary interstitial diseases who underwent diagnostic broncho-alveolar lavage, we dosed AZT in lavage fluids about 1 hour after the injection of a 2 g dose (Group C: 8 cases) or a 4 g dose (Group D: 6 cases). In group D antibiotic concentrations were significantly higher (P less than 0.005) than group C, while all the parameters that usually define the intensity of the alveolar alterations were not significantly different. Therefore, aztreonam administration in a daily monodose seems able to assure higher and longer lasting concentrations at the site of infection.

[Treatment of tuberculosis]. / Terapia della tubercolosi.

Tuberculosis appears to be a diagnostic challenge and an important therapeutical problem in industrialized and in developing countries, where most infections occur. Besides several rifamycin derivatives, new molecules (fluorinated quinolones, macrolides, beta-lactam antibiotics) are being explored in the face of increasing bacterial-resistance with the aim of improving the efficacy and safety of anti-tuberculous drugs, shortening the period of treatment or allowing intermittent regimens. At present, in severe forms of the disease three or more of the available anti-tuberculous agents must be administered simultaneously for at least 3-4 months and two for the following 6-7 months. Nevertheless, a variety of highly effective 6 months regimens are currently used for the treatment of less severe tuberculosis.

[Treatment of mycobacteriosis]. / Terapia delle micobatteriosi.

At present the increased incidence of infections with mycobacteria other than tuberculosis and leprae bacilli seems to be correlated with several causes: improved diagnostic techniques, prolonged life expectancy, immunodepression. Rational chemotherapy depends upon the identification of the etiologic mycobacterium and the determination of its drug susceptibility. Besides the "classic" treatment with 3 or 4 antituberculous and, sometimes, nonantituberculous chemotherapics, clinical trials are in progress to assess the effectiveness of new molecules: rifamycin derivatives, fluorinated quinolones, anti-lepromatous drugs, and the latest macrolides. Yet at present, national and international data do not permit to define a standard treatment for every mycobacteriosis; in fact, the drug resistance is high and varies not only between different strains but also within the same strain; moreover, there are discrepancies between in vitro and in vivo results. When possible, appropriated surgery for circumscribed disease is recommended.

Activities of human alveolar macrophages (HAMs). Note 1: Observations on phagocytosis and bacterial killing in the presence of miocamycin.

We studied the activity of human alveolar macrophages (HAMs) obtained by bronchoalveolar lavage (BAL) from human lungs. In particular, we studied in vitro phagocytosis and bacterial killing in basal conditions and in the presence of miocamycin (MOM), a macrolide antibiotic. At a dose of 600 mg every 12 hours, MOM concentrations in the serum were 2.60 micrograms/ml 1 hour after administration and 0.75 microgram/ml 8 h after. The antibiotic cannot be assayed by the microbiological method in the acellular liquid of alveolar lavage. After penetrating the HAMs, it can be detected at a concentration of about 0.4 mcirograms/1.10(6) HAMs. MOM was able to penetrate HAM cytoplasm without altering their vitality. As a matter of fact, the Trypan blue exclusion dye test was not modified after long incubation in the presence of MOM. The HAMs, resuspended in a RPMI 1640 enriched medium, were able to phagocytize either live Staphylococci or inert Latex beads of 1 micron. MOM stimulated the HAM phagocytosis on both Staphylococci and Latex beads. The increase in Latex phagocytosis, a relatively inert substance on which MOM should not be active, is a confirmation of the antibiotic's directed stimulation of the HAMs. Finally, we have seen that the HAMs, which were noteworthy in killing the phagocytized bacteria, were stimulated by MOM after only 30 minutes of contact with the antibiotic.

Bronchoalveolar lavage in the normal lung. 2. Cell distribution and cytomorphology.

Bronchoalveolar lavage, performed on 15 healthy volunteers, enabled quantification and characterization of the alveolar cell populations. The subjects studied were 8 nonsmokers (5 males, 3 females) and 7 smokers (6 males, 1 female). It was found that in the smokers the macrophages increased compared with nonsmokers, both in absolute number (419,000 vs. 138,000/ml; p less than 0.005) and in percentage (93.8 +/- 3.0 vs. 88.1 +/- 4.8%; p less than 0.02), causing a significant increase in the total number of cells recovered after bronchoalveolar lavage (471,000 vs. 163,000/ml; p less than 0.005). Lymphocytes and neutrophils do not significantly vary in the two groups, even though among the smokers there is a tendency for the concentration of these cells to increase in the lavage liquids. The importance of the data obtained from healthy subjects lies in the possibility thus afforded of having reference values for the study of various lung pathologies with bronchoalveolar lavage.

Chemiluminescence measurement of phagocytic activity of pulmonary macrophages in sarcoid alveolitis.

The phagocytic activity of alveolar macrophages in a group of patients with stage I and stage II fresh sarcoidosis has been studied in comparison with a group of healthy volunteers. The phagocytic activity has been measured by means of chemiluminescent emission recording. While no difference in the emission of chemiluminescence has been detected in polymorphonuclear leukocytes of patients and control subjects, a greater emission of chemiluminescence has been noted in the alveolar macrophages of sarcoid patients. Such a difference is statistically significant; its possible relation to alveolar inflammation has been considered.