G. Gialdroni Grassi

Clinical Efficacy of Ofloxacin in Lower Respiratory Tract Infections A Multicentre Study

SummaryA multicentre clinical trial was carried out to determine the activity and tolerability of ofloxacin in the treatment of lower respiratory tract infections. 667 patients were randomly allocated to 1 of 3 different twice daily dosage regimens: 400mg (245 patients), 600mg (211) or 800mg (211). The mean duration of treatment was 8.77 ± 2.62 days. Satisfactory overall clinical results (i.e. cured or improved) were obtained in 612 of 667 patients (91.8%). Eradication of pathogens was achieved for 279 of 354 isolated strains (78.8%). Side effects were observed in 31 patients and consisted of gastrointestinal disturbance (22), skin rash (1), neurological disturbance (3) and others (5). No significant alteration of haematological parameters was reported.

In vitro and ex vivo Enhancement of Nonspecific Phagocytosis by Cefodizime

The in vitro and ex vivo effects of cefodizime on some functional activities of both human neutrophils and monocytes were studied. In vitro experiments were performed with antibiotic concentrations ranging from 1 to 200 micrograms/ml. For the ex vivo study, 7 adult healthy controls were treated intravenously with 4 g/day of cefodizime for 6 days. We found that the drug modulated phagocytosis frequency and index when nonopsonized zymosan and heat-killed Candida albicans were used as phagocytic challenge both in vitro (from 25 micrograms/ml) and ex vivo 12 h after the last administration of cefodizime. No effect on the other phagocyte functional parameters was shown. The in vitro enhancement of nonspecific phagocytosis was demonstrated both in the presence of cefodizime and when phagocytes and particles were separately incubated with the drug.

Cefodizime Modulates in vitro Tumor Necrosis Factor-Alpha, lnterleukin-6 and Interleukin-8 Release from Human Peripheral Monocytes

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.

Effect of different combinations of sparfloxacin, oxacillin, and fosfomycin against methicillin-resistant staphylococci

The in vitro activity of combinations of sparfloxacin/oxacillin, sparfloxacin/fosfomycin, and oxacillin/fosfomycin was investigated against 16 methicillin-resistantStaphylococcus aureus (MRSA) isolates and 12 methicillin-resistantStaphylococcus 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.

Comparative antimicrobial activity and post-antibiotic effect of azithromycin, clarithromycin and roxithromycin against some respiratory pathogens

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.

Defective phagocyte Aspergillus killing associated with recurrent pulmonary aspergillus infections

SummaryAn apparently healthy boy was suffering from recurrentAspergillus infections. No classical conditions of immunodeficiency were found. Studies on the patients phagocytic system revealed neutrophils and monocytes to function normally except inAspergillus killing (microbicidal activity for bacteria andCandida was normal).Aspergillus killing mechanisms may be complex and peculiarly selective, possibly involving both oxygen-dependent and independent mechanisms.ZusammenfassungEin offensichtlich gesunder Junge machte rekurrierendeAspergillus-Infektionen durch. Klassische Formen der Immundefizienz waren nicht nachzuweisen. Bei der Untersuchung des Phagozytose-Systems wiesen die neutrophilen Granulozyten und Monozyten mit Ausnahme der Abtötung vonAspergillus normale Funktionen auf (die mikrobizide Aktivität für Bakterien undCandida war normal). Die Mechanismen für das Abtöten vonAspergillus sind wahrscheinlich komplex und auf eigentümliche Weise selektiv; dabei sind möglicherweise Sauerstoff-abhängige und -unabhängige Vorgänge beteiligt.

Double-Blind Trial RU 41740 vs. Placebo: Immunological and Clinical Effects in a Group of Patients with Chronic Bronchitis

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.

Cefodizime host-defence enhancement: Considerations of dose-response relationships in healthy volunteers

SummaryStudies 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.ZusammenfassungTierexperimentelle Untersuchungen mit Cefodizim haben gezeigt, daß dieses neue Aminothiazolyl- Cephalosporin, das über ein breites antibakterielles Spektrum verfügt, eine Reihe von immunologischen Parametern günstig beeinflußt. In den meisten Untersuchungen zeigte sich eine glockenförmige Dosis-Wirkungsbeziehung, das heißt, bei höheren Dosierungen näherte sich die Aktivität wieder den Ausgangswerten an, eine Beobachtung, die für Immunmodulatoren typisch ist. Die Daten der klinisch-pharmakologischen Untersuchungen wurden hinsichtlich dieses Dosis-Wirkungsverhaltens analysiert. Im Rahmen von immunologischen Untersuchungen wurde Cefodizim in Dosen von 1 × 2 g täglich oder — häufiger — 2 × 2 g täglich i.v. verabreicht. Nach siebentägiger Behandlung mit 1 × 2 g/d konnte bei gesunden Probanden keine relevante Wirkung gezeigt werden, wohl aber in einer Parallelgruppe von Myelompatienten ein Anstieg der Chemotaxis von Monozyten und Granulozyten. In Studien mit der höheren Dosis von 2 × 2 gpro die konnte dagegen eine gesteigerte Lymphozyten-Stimulierbarkeit und eine signifikant höhere unspezifische Phagozytose-Tätigkeit von Neutrophilen und Monozyten induziert werden. Diese Befunde bei gesunden freiwilligen Probanden zeigen klar, daß die Dosis von 2 × 2 g Cefodizim täglich — die üblicherweise höchste Dosis im Rahmen der antibiotischen Therapie — am ansteigenden Schenkel der immunologischen Dosis-Wirkungskurve liegt.

Bioactivity of flurithromycin and other macrolides against intracellular susceptible staphylococci

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.

Uptake of Flurithromycin by Human Polymorphonuclear Phagocytes: Partial Characterization of the Entry Mechanism

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.