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The direct effect of clarithromycin and azithromycin on human polymorphonuclear leukocyte (PMN) functions and their intracellular activity against Staphylococcus aureus, phagocytosed by human monocytes, were studied. The presence of both antibiotics, in the range of concentrations from 0.25 to 20 micrograms/ml, did not affect chemotaxis, opsonized-zymosan phagocytosis, respiratory burst measured by nitroblue tetrazolium reduction and phorbol myristate acetate-induced superoxide production, or the microbicidal activity of human PMNs against Candida albicans. Both macrolides were bactericidal against staphylococci in the monocyte system, while bacteriostatic activity was found in cell free system. At concentrations equal to the minimum inhibitory concentrations (MICs) (0.75 and 0.1 respectively for azithromycin and clarithromycin) more than 99% of intraphagocytic S. aureus were killed after 24 h incubation. Increasing the concentrations of each drug above the MICs (5 and 10 MICs) did not alter the killing rate of intracellular bacteria. Moreover, no differences between the intracellular bioactivity of these antibiotics were demonstrated, despite their different uptake kinetics.

A questionnaire survey was performed on the use of investigations and their impact on treatment of adult lower respiratory tract infection in the community. Data on the management of 2,056 such infections were obtained simultaneously from general practitioners in France, Germany, Italy, Spain and the UK. Diagnostic tests were only performed in 29% of cases. Chest radiographs were performed most frequently (22%), followed by peripheral blood white cell count (15%) and microbiological examination of sputum (7%), with major differences being found in the frequency of these tests both by clinical diagnosis and country. A change in initial antibiotic therapy was made in 12% of cases, with use of investigation being significantly linked to such changes. Second- and third-line antibiotics were significantly different to first-line therapy, with macrolides the most frequently prescribed second-line and quinolones the most frequently prescribed third-line antibiotics.

Recent macrolide derivatives, roxithromycin, azithromycin and clarithromycin show more favourable pharmacokinetic characteristics in comparison to old ones and some differences in antibacterial activity. With the aim of improving our understanding of some aspects of their action against respiratory pathogens, we determined the MICs and MBCs of Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis and Haemophilus influenzae. Azithromycin was the most active agent against Haemophilus influenzae and Moraxella catarrhalis, while clarithromycin was more active against Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus with MICs similar to those of erythromycin. The bactericidal activity of all tested derivatives was weak against Staphylococcus aureus (MBC/MIC ratio approximately 16) and against Moraxella catarrhalis (MBC/MIC ratio, 8-16), but good against Staphylococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae (MBC/MIC ratio, 2-4). The determination of killing curves in the presence of 2 MIC and 10 MIC of azithromycin, clarithromycin and roxithromycin confirmed their weak bactericidal activity against Staphylococcus aureus and Moraxella catarrhalis as well as their effective activity against Streptococcus pyogenes and Streptococcus pneumoniae. Azithromycin showed the highest bactericidal activity against Haemophilus influenzae. As expected, the three derivatives produced a quite prolonged PAE when exposed to 5 MIC for 1 h, ranging between 2-4 h. The bactericidal activity and the prolonged PAE of new macrolides for the most common respiratory pathogens should assure a good clinical activity in respiratory infections including those sustained by Haemophilus influenzae, which is less susceptible to erythromycin and other old macrolides.

A survey of first-line antibiotic prescription in community-acquired lower respiratory tract infection (LRTI) by general practitioners (GP) was carried out simultaneously, using the same methodology in France, Germany, Italy, Spain and the UK. Data were obtained from 2,056 patients and 605 GPs. There was no antibiotic prescription in 17% of all LRTIs and 13% of community-acquired pneumonia (CAP) in the five countries taken together; and in 32% of all LRTIs and in 23% of CAP in Germany. Of patients with acute bronchitis, exacerbation of chronic bronchitis and viral lower respiratory tract infection, 87, 92 and 71% received antibiotics, respectively. The most frequent prescriptions were penicillins in France and the UK, third-generation cephalosporin in Italy, tetracycline in Germany and macrolide in Spain. The daily dosage of aminopenicillin prescribed was: 41% or = 1.5 g and or = 3 g. In Italy, 53% of all antibiotics were injected in all LRTIs, and 71% in CAP; in contrast, antibiotic injection was lower than 2% both in the UK and Germany, with an average of 14% in the five countries combined. We conclude that there are variations in antibiotic prescription by GPs in Western Europe; differences are likely to be multifactorial, but could, in part, be explained by differences in health systems and sources of information available to GPs.

The Author provides a review of clinical experience with tobramycin as therapy for lower respiratory tract infections, in comparison to other aminoglycosides, including the pharmacokinetics and toxicity, dwelling on oto- and nephrotoxicity. The article includes a discussion of various dosing regimens of the aminoglycosides, focussing on efficacy and toxicity arising from once-daily administration. The Author then provides a more detailed description of tobramycin's pharmacokinetics, indications for its use, and the possibilities of once-daily dosing, concluding that toxicity is favorably influenced by a single daily administration as well as efficacy, and that patient compliance and reduced hospital costs are other advantages of this regimen.

Among third-generation cephalosporins, cefodizime (CFDZ) has shown to modulate many functions of the host defense system against infections. The aim of the present study was to assess the in vitro CFDZ-dependent modulation of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and IL-8 release from lipopolysaccharide (LPS)-stimulated human peripheral mononuclear cells (MNCs). Two other third-generation cephalosporins: ceftriaxone (CFX) and ceftazidime (CFT), were also tested under the same experimental conditions. At concentrations ranging from 200 to 50 micrograms/ml, CFDZ significantly decreased TNF-alpha and IL-6 release from maximally (LPS 1 microgram/ml) stimulated MNCs (42% inhibition of TNF-alpha release with 100 micrograms/ml of CFDZ). On the other hand, CFDZ revealed a marked stimulatory effect on IL-8 release (200 micrograms/ml of CFDZ induced 51.5% enhancement of IL-8 release). On the contrary, both CFX and CFT failed to exert any significant effect on TNF-alpha, IL-6 or IL-8 release.

The immunological and clinical effects of two oral treatment schedules of RU 41740 (standard for 3 months vs. long-term for 6 months) were assessed in 40 patients with chronic bronchitis by a controlled, double-blind, randomized trial. Both treatments significantly improved phagocytosis index of both neutrophils and monocytes, and the phagocytosis frequency and the candidacidal activity of neutrophils, showing the maximum stimulation at the end of the third course of treatment. Both treatment schedules reduced the number and the duration of infectious exacerbations of chronic bronchitis with respect to those observed in the corresponding period of the previous year. However, no significant difference between standard and long-term treatment with RU 41740 was found with respect to the immunological and clinical effect and tolerability.

The role of mycobacterial lipoarabinomannan (LAM) in regulating the granulomatous response and its effects on cells involved in early responses to tuberculosis have not been clearly defined. The aim of this study was to acquire further evidence about the mechanisms by which LAM takes part in the host response to mycobacterial infections.We compared the in vitro ability of mannosylated LAM (ManLAM) and LAM lacking the terminal mannosyl units (AraLAM) to induce distinct responses in human polymorphonuclear (PMNs) and mononuclear phagocytes [both monocytes and 48-hr monocyte-derived macrophages (MDMs)]. The responses examined were chemotaxis, transient changes in free cytosolic calcium, phagocytosis and metabolic activation.AraLAM and ManLAM affected mononuclear, but not polymorphonuclear, phagocyte functions. Both forms of LAM were chemotactic for monocytes and MDMs. The LAM-induced chemotactic response required new protein synthesis, did not induce a rise in cytosolic free calcium levels and was partially inhibited (about 50%) by genistein, but not by calphostin C or PD 98059. Lastly, at physiologic doses ManLAM significantly reduced phagocytosis of M. tuberculosis and zymosan particles by MDMs.Different phagocytic cells can exhibit variable responses to AraLAM and ManLAM. Moreover, LAMs affect cell functions through different mechanisms. Protein synthesis and activation of protein tyrosine kinases are important intermediates in the signal transduction pathway of the chemotactic response of mononuclear phagocytes to AraLAM and ManLAM; whereas ManLAM-induced inhibition of macrophage phagocytic ability could depend on the binding of macrophage mannose receptors and/or the insertion of this molecule into cellular plasma membrane. Together these data highlight the danger of making generalizations regarding the activity of LAMs on immune defenses.

The in vitro activity of combinations of sparfloxacin/oxacillin, sparfloxacin/fosfomycin, and oxacillin/fosfomycin was investigated against 16 methicillin-resistant Staphylococcus aureus (MRSA) isolates and 12 methicillin-resistant Staphylococcus epidermidis (MRSE) isolates moderately resistant to sparfloxacin. Synergic interactions were observed more frequently against MRSE than against MRSA strains. The most effective combination on both species was fosfomycin plus oxacillin, synergistic against ten of 16 MRSA and eight of 12 MRSE strains.

Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymorphonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL. The uptake kinetics of AZ were time-dependent over an 18 h period, while those of CL were similar to erythromycin (ER) kinetics, with a maximum level of incorporation being obtained after a 60 min incubation. The accumulation of both drugs was influenced by extracellular antibiotic-concentrations, PMN viability, extracellular calcium, physiological environmental temperature and pH. The uptake was not modified by inhibitors of cell metabolism or activators of cell membranes. After removal of extracellular antibiotic, the release of AZ from PMNs was very slow: nearly 50% of the drug remained cell-associated after 24 h incubation. The efflux of this derivative was significantly enhanced when drug-loaded PMNs were stimulated by phorbol-myristate acetate (PMA). The kinetics of CL release indicated that this macrolide behaved like ER. Nevertheless, about 10% of the initial cell-associated antibiotic showed a prolonged retention. On the whole, these data suggest that diffusion through cell membranes and trapping into acidic compartments of PMNs are important events in CL and AZ uptake.

BACKGROUND: Mediators released by alveolar macrophages, as well as by T cells, play an important part in modulating local immune processes in sarcoidosis. Among alveolar macrophage secretory products, arachidonic acid metabolites are known to regulate inflammatory and immune reactions. It has been suggested that cyclo-oxygenase and lipoxygenase pathway metabolites of arachidonic acid modulate the evolution of the granulomatous inflammatory response in the lung differently. METHODS: Alveolar macrophages recovered from the bronchoalveolar lavage (BAL) fluid of 32 patients with sarcoidosis in different states of disease activity and 10 normal subjects were evaluated for their ability to release prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). Alveolar macrophages were cultured in the presence or absence of opsonised zymosan (500 micrograms/ml), and PGE2 and LTB4 levels in the culture supernatants were determined by enzyme immunoassay (EIA). RESULTS: Stimulated alveolar macrophages from patients with active sarcoidosis released higher LTB4 levels than those from normal subjects, but no differences in PGE2 release were observed between the two groups. The time course of LTB4 release by activated alveolar macrophages showed that normal cells produced similar levels of the hydroxyacid during the early and late times of culture while LTB4 release by activated cells from patients with sarcoidosis increased markedly after 60 minutes of culture, remaining elevated until 24 hours. Indomethacin (3 x 10(6) M) caused the expected inhibition of PGE2 formation without affecting LTB4 release. CONCLUSIONS: These results suggest that alveolar macrophages from the BAL fluid of patients with active sarcoidosis are primed to release LTB4, which may contribute to the locally heightened immune response.

BACKGROUND: The purpose of this study was to identify factors on which European general practitioners (GPs) base their decisions to admit to hospital patients with lower respiratory tract infections (LRTI). METHODS: A survey was carried out from December 1993 to January 1994 to identify factors that affect GPs' decisions to admit to hospital patients with LRTI by collecting data on 2056 patients from 605 GPs in France, Germany, Italy, Spain, and the UK. RESULTS: Only 93 (4.5%) of the patients included in the study were admitted to hospital. Univariate analysis showed that age > 60 years, institutionalisation of the patient, concomitant diseases, cardiac insufficiency, asthma, a diagnosis of pneumonia, and clinical signs such as chest pain, cyanosis, tachypnoea and hypotension significantly (odds ratio (OR) > 2.0, p < 0.002) influenced the decision to admit to hospital. No influence could be shown for sex, smoking habits, history of bronchiectasis or chronic bronchitis, the presence of fever, chills, myalgia, cough or purulent sputum, and the diagnoses of acute bronchitis, influenza or exacerbation of chronic bronchitis. In the multivariate analysis only the presence of chest pain (OR 2.3, 95% confidence interval (CI) 1.5 to 3.5), cyanosis (OR 4.1, 95% CI 2.4 to 7.1), dyspnoea (OR 4.9, 95% CI 3.1 to 7.9), and hypotension (OR 2.9, 95% CI 1.6 to 5.2), as well as a diagnosis of pneumonia (OR 6.6, 95% CI 4.3 to 10) (all p < 0.00001) remained as factors that significantly affected the decision to admit to hospital. CONCLUSIONS: Clinical signs of severe infection and a diagnosis of pneumonia are the main factors that induce GPs to admit patients with LRTI to hospital in Europe.

A pooled data analysis of two double-blind studies encompassing 1137 episodes of community-acquired pneumonia in hospitalised adults, of which 560 were treated with sparfloxacin and 577 were randomised to comparator antibacterial agents (amoxycillin/clavulanic acid, erythromycin or amoxycillin administered at reference dosages), was performed. The global efficacy rate at the end of treatment in evaluable patients treated with sparfloxacin was 88.3% compared with 84.1% in those who received comparator antibacterial agents. This analysis verified the efficacy of this new aminofluoroquinolone, given orally once daily, in the treatment of community acquired pneumonia. The overall outcome favoured sparfloxacin for use in the empirical treatment of community-acquired pneumonia.

Bombesin-related peptides (BRP) are present in the lung during foetal life and are mitogenic for normal bronchial epithelial cells, pulmonary fibroblasts, and small-cell lung carcinoma cell lines. Increased levels of BRP have been described in the adult lung of cigarette smokers and in smoking related lung diseases. BRP have also been involved in the network of neuroimmune interactions, having been shown to modulate the phagocytic function of monocytes and alveolar macrophages. BRP have recently been shown to modulate the release of procoagulant activity (PCA) by human monocytes and alveolar macrophages after a 24 h culture. The aim of this study was to evaluate the effect of bombesin on cell-associated PCA of alveolar macrophages (AMs) obtained from asymptomatic subjects. In basal conditions, AMs were found to possess a low procoagulant activity, that was not affected by their preincubation (4 h at 37 degrees C) with phorbol myristate acetate (1 microgram-mL-1). On the contrary, endotoxin (lipopolysaccharide (LPS)) induced a significant increase of procoagulant activity of macrophages when used at a concentration of 1 microgram.mL-1, in the same experimental conditions; whilst a lower (1 ng.mL-1) concentration of LPS nonsignificantly enhanced cell-associated PCA. Treatment of AMs with synthetic bombesin (BN) alone (10(-6) to 10(-10) M) did not enhance cell-associated PCA, whilst a significant effect was seen when BN was added to the lower concentration of LPS (BN 10(-6) M+LPS 1 ng.mL-1: 12.6 U.10(-6) cells; LPS alone 1 ng.mL-1: 7.8 U.10(-6) cells).(ABSTRACT TRUNCATED AT 250 WORDS)

In general practice Community-acquired Pneumonia (CAP) is most often treated on an empyrical basis. Therefore, it is of the utmost importance to know the epidemiology of respiratory pathogens in order to give some guidelines for the empirical management of CAP. At present in cases of mild and moderate severity, ampicillin or amoxycillin, preferably in association with sulbactam and clavulanic acid respectively, and macrolides are the antibiotics of first choice. The latter can be an alternative to beta-lactams when Legionella, Mycoplasma and Chlamydia are the suspected etiologic agents or when patients are allergic to penicillins. They can also be used in combination with beta-lactams when etiological diagnosis is extremely uncertain. The course and severity of the disease, a chest radiograph, the results of microbiological and other laboratory examinations will determine the choice of further antibiotic treatment and other therapeutic measures, if necessary.

The in vitro effects of cefixime and cefdinir (CI 983), two so-called third-generation oral cephalosporin derivatives, on human polymorphonuclear and mononuclear phagocyte functions (random migration and chemotaxis, specific and nonspecific phagocytosis, nitroblue tetrazolium reduction, superoxide production, microbicidal activity) were studied. Neither antibiotic, in the range of its attainable therapeutic concentration, exhibited any toxic effect on random migration, chemotaxis, metabolic activation and microbicidal mechanisms of phagocytic cells. Cefixime did not interfere in phagocytosis while cefdinir enhanced both phagocytosis frequency and index. The modulating effect on phagocytosis exerted by cefdinir was achieved at very low antibiotic concentrations (0.06 mg/l for polymorphonuclear leukocytes and 0.03 mg/l for monocytes) when non-opsonized zymosan particles were used as phagocytic challenge. Moreover, the effect was demonstrated both in the presence of cefdinir and after pretreatment of cells with the antibiotic and its removal by washings. As for specific phagocytosis, parameters were slightly increased by cefdinir but only the phagocytosis index was significantly improved in the presence of 2 mg/l of antibiotic.

Efficacy and tolerability of flurithromycin ethylsuccinate were evaluated in lower respiratory tract infections. One hundred and ten patients (38 women, 72 men; age range 18-87 years) were treated with on 375 mg tablet 12-hourly for a mean duration of 8.7 days. One hundred and five patients were evaluable for efficacy. Overall clinical cure rate was 62.9%; improvement was recorded in 19% of patients for a total satisfactory clinical response rate of 81.9%. Sputum production decreased in most patients, being absent after treatment in 47% (only one patient was negative at baseline); sputum was purulent or mucopurulent in 80% of subjects before and in 20% after treatment. Bacteriological evaluation was possible in 72 patients: pathogen eradication was achieved in 80.2% of cases. Eight patients out of 110 reported adverse reactions, mainly gastrointestinal; in one case treatment had to be discontinued. These results demonstrate that flurithromycin ethylsuccinate is safe and effective in the treatment of lower respiratory tract infections.

The potential for interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) to induce neutrophil and mononuclear phagocyte accumulation in the lungs of patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis (IPF) was investigated. Bronchoalveolar lavage (BAL) fluids from 12 patients with IPF and 15 with sarcoidosis were concentrated by reversed-phase chromatography, and their IL-8 and MCP-1 concentrations assessed by enzyme-linked immunosorbent assay (ELISA), chemotaxis, and enzyme-releasing assays with monocytes and neutrophils. ELISA revealed significantly elevated concentrations of MCP-1 (20.1 ng/mg albumin) in the BAL fluids of patients with pulmonary sarcoidosis and those with IPF (41.8 ng/mg) in comparison to 11 normal individuals (4.24 ng/mg) and 15 patients with chronic bronchitis (CB) (5.16 ng/mg). Similarly, the chemotactic activity for monocytes (MCP-1 equivalent) was strongly increased in patients with sarcoidosis (86.03 ng/mg) as well as in those with IPF (54.47 ng/mg). The chemoattractant activity of normal individuals and CB patients was 7- or 3-fold lower, respectively. Patients with IPF and sarcoidosis also had elevated IL-8 levels (15.5 and 26.0 ng/mg, respectively; normals: 2.14 ng/mg; and CB patients: 4.23 ng/mg) and greater neutrophil chemotaxis (60.25 and 49.68 ng/mg, respectively; normals: 0.35 ng/mg; and CB patients: 11.06 ng/mg). These data suggest that increased levels of both MCP-1 and IL-8 may be characteristic for sarcoidosis or IPF. It appears likely that both of these chemoattractants contribute to the influx of monocytes and neutrophils into the pulmonary alveolus and interstitium in these diseases.

The main features and the present position of tetracyclines are reviewed. The mechanism of their action, bacterial resistance and the most recent findings are reported. Their decreased use is due to the availability of new, active, better-tolerated antibiotics. However, tetracyclines still have a place in the treatment of chlamydial and rickettsial infections, brucellosis and Lyme disease. In respiratory infections, they can be employed when necessary in infections caused by Chlamydia psittaci, C. pneumoniae, Mycoplasma pneumoniae , and also by Streptococcus pneumoniae and Haemophilus influenzae , whose rates of resistance now seem lower than in the past when tetracyclines were more largely prescribed.

The intracellular activity of flurithromycin, erythromycin, roxithromycin and miocamycin against susceptible clinical isolates of Staphylococcus aureus, phagocytosed by human monocytes, was investigated. Intracellular bioactivity was studied in a 24-hour assay, using experimental conditions which allowed the intracellular growth of bacteria. A colony counting method was used to differentiate between intracellular bacteriostatic and bactericidal activity of antibiotics. Moreover, the effect of macrolides against extracellular staphylococci was assessed. All agents showed higher intracellular than extracellular activity against staphylococci. At low concentration (0.1 mg/l) they had intracellular bacteriostatic activity. At concentrations higher than the minimal inhibitory ones (1 and 5 mg/l), miocamycin only still produced a bacteriostatic effect while flurithromycin, erythromycin and roxithromycin also showed intracellular bactericidal activity.

The ability of flurithromycin and erythromycin to enter human polymorphonuclear phagocytes were studied and compared by a velocity centrifugation gradient technique. Both macrolides were markedly concentrated by human cells and attained cellular to extracellular concentration ratios (C/E)or = 10. The incorporation was rapid and essentially complete after 60 min incubation. When PMNs were pretreated with formaldehyde, or incubated at low temperatures (4-25 degrees C) or at low pH, the transport ratios of both molecules were reduced. Sodium fluoride and 2,4-dinitrophenol, which decreased erythromycin uptake, did not affect flurithromycin penetration. Perturbation of cell membrane by phorbol myristate acetate, but not by formyl methionyl leucyl peptide, affected C/E ratios of both antibiotics. The addition of amino acids or nucleosides did not influence their transfer into PMNs.

Bombesin-related peptides (BRP), a family of neuropeptides showing carboxy-terminal homology with the amphibian bombesin, are present in humans in many body systems (CNS, lung, gastro-intestinal tract) with a variety of biological activities. In the lung, BRP are mitogens for normal bronchial epithelial cells and fibroblasts, chemoattractant for monocytes and exert bronchoconstrictive activity. Increased levels of BRP have been described in the lung of cigarette smokers and in smoking-related diseases. Moreover appreciable quantities of BRP have been recently found in lysates of peripheral monocytes and alveolar macrophages of man and guinea pig. It has therefore been inferred that these peptides may play a role in the immunological function of lung tissue. The aim of this study was to determine the amount of BRP present in peripheral-blood mononuclear cells (PBMNC), monocytes and alveolar macrophages (AM) of normal subjects (n = 36) and chronic bronchitis patients (n = 36). Patients with chronic bronchitis showed a significant increase in BRP levels in all cell types (PBMNC, monocytes and AM) (p0.005) in comparison with normal subjects. In addition levels of BRP in monocytes and AM were found to be nearly four times higher than in PBMNC in both groups of subjects. We can therefore confirm previous observations concerning the presence of BRP in human cells of the monocyte-macrophage lineage. Furthermore our results demonstrate that BRP levels are increased in monocytes of chronic bronchitis patients and imply a potential role for these neuropeptides in lung immunological response in smoking-related diseases.

Studies with cefodizime in animals have shown that this new aminothiazolyl cephalosporin, possessing a broad antibacterial spectrum, positively influences a number of immunological parameters. In most investigations in which different dosage regimens were compared, a bell-shaped dose-response relationship was determined, i.e. activity after higher doses returned to near-baseline levels. This finding is typical of most immunomodulating agents. On this basis, the results obtained in healthy subjects were reviewed. Studies for investigating the biological response modifying (BRM) properties of cefodizime have been conducted in this population with either 2 g once daily i.v. or — in the majority — with 2 × 2 g/day i.v. After seven days of treatment with 1 × 2 g daily, no relevant changes could be demonstrated in healthy subjects, whereas there was an increase in monocyte and granulocyte chemotaxis in a parallel group of patients with multiple myeloma. In contrast, treatment with 2 × 2 g daily induced higher lymphocyte responsiveness and significantly increased nonspecific phagocytosis of both neutrophils and monocytes. The experience in healthy volunteers clearly demonstrates that the latter dose, usually the highest required for antibiotic treatment with cefodizime, is still located on the upward slope of the dose-response curve of positive BRM effects.

An apparently healthy boy was suffering from recurrent Aspergillus infections. No classical conditions of immunodeficiency were found. Studies on the patient's phagocytic system revealed neutrophils and monocytes to function normally except in Aspergillus killing (microbicidal activity for bacteria and Candida was normal). Aspergillus killing mechanisms may be complex and peculiarly selective, possibly involving both oxygen-dependent and independent mechanisms.

Some data exist showing that rifampicin can reduce or abolish the tuberculin reaction in guinea pigs infected with tubercle bacilli [1] as well as the development both of immediate and delayedhypersensitivity reactions in rabbits inoculated with bovine serum albumin [2]. In addition some authors showed that rifampicin could interfere in the blastic transformation of lymphocytes [3, 4] and in the metabolism of some mammalian cells [5]. We sought to determine whether or not rifampicin could directly influence the phenomena of delayed hypersensitivity both in vitro and in vivo (independent of its antimycobacterial activity).

Among the newer cephalosporins, cefodizime, an α-methoxy-imino-2-thiazolyl derivative, has been reported to display direct and indirect effect on some components of the host defense system against infection [3–7]. The aim of our research was to study the in vitro and ex vivo direct effect of cefodizime on human mononuclear and polymorphonuclear phagocytes in order to better understand the mechanism of its immunomodulating properties.

This review summarizes the experience gained on interactions between antimicrobial agents and some reactions of the host defense system (adherence, chemotaxis, phagocytosis, microbicidal activity of leukocytes, complement system, antibody production, cell-mediated immunity) and attempts a critical evaluation. The data collected from the literature are often conflicting and there seem to be differences of behavior among derivatives belonging to the same family of antibiotics. Therefore it is quite difficult to draw a correct conclusion from these data. So far it has not been possible to understand the impact that the interference of antibiotics in natural and immunologic reactions of the host defense has on the outcome of chemotherapy, mainly in patients with some degree of immunodepression. In this instance, in fact, the interference with certain immunologic reactions could influence the therapeutic activity of specific antibiotics that are endowed with inhibitory activity. However, so far no controlled study or clear demonstration has shown that antibiotics with different activity on the immunologic reactions can have different efficacy in immunodepressed patients.

Repeated transfers of strains of Escherichia coli and Staphylococcus aureus in medium containing subminimal inhibitory concentrations (sub-MICs) of gentamicin caused a moderate increase in the minimal inhibitory concentration of gentamicin. At the end of such transfers, E. coli K12 produced aminoglycoside phosphotransferase(3')-I [APH(3')], AND E. coli R112, which carries the plasmid-coded enzyme APH(3')-I, also produced the acetylating enzyme aminoglycoside acetyltransferase(2') [AAC(2')]. E. coli R148, which produces aminoglycoside phosphotransferase(3')-II [APH(3')-II], did not change its output of enzymes. Repeated transfers to media containing increasing concentrations of gentamicin resulted in the development of complete resistance to all aminoglycosides without the concurrent development of any demonstrable new enzyme activity. With repeated transfers in drug-free medium, a complete reversal to susceptibility to gentamicin, but not to other aminoglycosides, was obtained for strains that had previously been transferred in sub-MICs of gentamicin, whereas strains that had been transferred in increasing concentrations of gentamicin did not revert to their original sensitivity to aminoglycosides despite repeated transfers in drug-free medium.

A double-blind trail was performed to investigate the effects of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, on host defenses and its efficacy in reducing the number of exacerbation in 29 evaluable patients with chronic bronchitis, out of 36 patients who entered the study. The drug enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes. Increased candidacidal activity of monocytes was also observed. These effects, already detectable after one course of therapy and during the entire period of treatment, were no longer detectable when tested 6 months after the end of treatment. A significantly (p less than 0.05) larger number of patients in the treated group than in the placebo group had no exacerbations during drug administration (0-3 months). Moreover, patients treated with RU 41740 had significantly fewer and shorter episodes of acute exacerbation. The positive decreases in these two parameters persisted throughout the follow-up.

A simple, easy to use, kinetic model allowing the simulation of the main epidemiological parameters of tuberculosis and of the financial costs associated with the implementation of different anti-tuberculous policies, has been developed and described. The model, which has been denominated "ESKIMO" (Epidemiological Simulation Kinetic Model) can be utilized on a personal computer and requires, for its use, the knowledge of a series of easily available census data relative to a given country or geographical area, an essential epidemiological profile of the disease in the same area and data which characterize one or more antituberculous treatments in therapeutic and financial terms. The rationale of the model, which is a multicompartemental system, derive from an analysis of the relationships (transfer rates) between sub-populations of individuals in relation to tuberculosis either when the dynamic state of the system is governed by "natural forces" (no treatment) or when an external action is applied to it with an aim to alter its internal pathways in a favourable sense (vaccination, long-term hospitalization, chemotherapy). The model is based on the assumption that the main objective of any antituberculous program is the reduction in size of the subpopulation of patients who can infect other individuals and therefore perpetuate the disease. Validation and projection tests carried out through Eskimo seem to indicate that concentrating the analysis on the effect of various treatments on this group of patients simplifies the calculations while the relative precision of the estimates of other parameters is very satisfactory. The results of several simulations substantiate and quantify the opinions expressed by several experts in the past that the policy of applying cheap regimens of low efficacy to a relatively small fraction of the patients' population, as frequently done in developing countries, not only does not alter the trend of the disease but produces essentially negative results (increase in the number of new cases and in the frequency of resistant M. tuberculosis). Treatment with highly effective regimens of the same number of patients as those treated now (constant coverage) and therefore without the extra costs resulting from the improvement of the available sanitary infrastructures, produces much better results in clinical terms and overall saving of financial resources.

We studied the effects of rifamycin SV, rifampicin and rifapentine on human phagocyte functions. Rifamycins inhibited in vitro neutrophil chemotaxis in the range of their therapeutic levels, and they significantly affected the survival of a rifamycin-sensitive strain of Staphylococcus aureus inside human monocytes. Both effects were related to the intraphagocytic penetration of these antibiotics. For the ex vivo studies, 600 mg of rifampicin were orally administered to five subjects with defective S. aureus killing. A significant reduction of neutrophil chemotaxis and increased activity against S. aureus were shown 150 and 210 min after administration of the drug.