F. Scaglione

A New Model Examining Intracellular and Extracellular Activity of Amoxicillin, Azithromycin, and Clarithromycin in Infected Cells

An in vitro infection model was created using a suspension of macrophages, polymorphonuclear leukocytes, lymphocytes, fibroblasts, and human serum to which pathogen and antibiotic were added. Separate intracellular and extracellular antibiotic concentrations and activity against Staphylococcus aureus and Legionella pneumophila were assessed for three antimicrobial agents: amoxicillin, azithromycin and clarithromycin. Amoxicillin was found almost exclusively in extracellular fluid, where it was active; intracellularly, it was ineffective. Azithromycin, in contrast, was primarily concentrated and active intracellularly, with little activity in extracellular fluid. Clarithromycin was present in both compartments and possessed significant activity both intracellularly and extracellularly.

Human pharmacokinetics and distribution in various tissues of ceftriaxone

Multiple-dose pharmacokinetics of ceftriaxone were investigated in 7 patients with bronchopneumonia using an intramuscular regimen of 1 g given every 24 h for 7 days. Serum, sputum, and urine samples were collected serially following the first dose (day 1) and last dose (day 7). Mean peak serum concentrations of ceftriaxone occurred at 2 h on both days and were 67.8 and 75.1 micrograms/ml, respectively, on day 1 and day 7. Ceftriaxone had a half-life of 6.9 h on day 1 and 7.4 h on day 7. The half-life of ceftriaxone in sputum was 5.9 and 6.6 h, respectively, on days 1 and 7. Approximately 50% of the dose of ceftriaxone was recovered in the urine within 24 h on day 1, 60% on day 7. Tissue distribution of ceftriaxone was determined in 103 patients following intramuscular administration of a single 1-gram dose at different times up to 24 h prior to surgery. High concentrations of ceftriaxone were found in lung, tonsil, middle ear mucosa, and nasal mucosa, and therapeutic levels of ceftriaxone persisted for 24 h after administration.

T cell subpopulations in vitiligo: A chronobiologic study

The circadian rhythms of helper (CD4) and suppressor (CD8) T cells from the peripheral blood of 12 vitiligo patients (seven with active disease, five with static) and 12 healthy control subjects were studied. Patients with active vitiligo had a lower percentage of CD4+ cells than did control subjects at 0000 hours and at 0600 and 1200 hours; there were no differences between these values in patients with static vitiligo and those in control subjects. The percentage of CD8+ cells were lower at 1200 and 1800 hours in both active and static vitiligo patients than in control subjects. Cosinor analysis of the CD4+ cells showed a circadian rhythm in static vitiligo, whereas the rhythmicity was lost in active vitiligo. CD8+ cells did not show any circadian rhythm in either active or static vitiligo. Our data show more striking aberrations for T cell subtypes in active vitiligo than in static vitiligo. They suggest that cell-mediated immunity may play a role in the pathogenesis of the disease.

Evaluation of the Immunostimulating Activity of Erythromycin in Man

The effects of erythromycin on the immune system have been studied in healthy volunteers and patients suffering from chronic bronchopneumonial diseases, by means of the following assays: phagocytosis, natural killer activity and superoxide anion production. The tests were performed before and after oral administration of 1 g of erythromycin. The findings suggest that erythromycin enhances phagocytosis by means of increasing ingestion of microorganisms, superoxide anion (O2-) production as well as natural killer activity. Under the experimental conditions described these effects appear 4-6 h after drug intake and reach their maximum around the 8th hour.

Effect of Multiple Doses of Clarithromycin and Amoxicillin on IL-6, IFNγ and IL-10 Plasma Levels in Patients with Community Acquired Pneumonia

Abstract Inflammation is crucial for the pathogenesis of both infectious and chronic obstructive pulmonary diseases. It is therefore important to modulate pulmonary inflammation in patients with these lung disorders. Macrolide antibiotics modulate inflammation in vitro and in in vivo by inhibiting the production of proinflammatory cytokines and prostaglandin E2, neutrophil chemotactic activity and elastase activity. This study evaluates the effect of clarithromycin (500 mg b.i.d. x 7 days) in comparison to amoxicillin (1 g t.i.d. x 7 days) in patients with community acquired pneumonia by testing plasma levels of IL-6, IFNγ and IL-10 before starting therapy and at the 3rd and 7th days of therapy. Clarithromycin significantly decreased plasma levels of IL-6 and significantly increased those of IFNγ and IL-10 at the 3rd and 7th day in comparison to basal levels. In patients treated with amoxicillin a significant decrease in IL-6 plasma levels was observed at the 7th day of therapy, probably in relation to the resolution of inflammatory symptoms. In the same patients IFNγ plasma levels decreased during treatment while IL-10 plasma levels were unaffected.

Ciprofloxacin penetration in pancreatic juice

The penetration of ciprofloxacin in pancreatic juice was investigated in 5 patients with pancreatic fistula. The drug was administered as a single oral dose of 500 mg after which serial samples of pancreatic juice and serum were collected for ciprofloxacin assay. The following pharmacokinetic parameters (mean +/- SD) were estimated from the serum level versus time curves: clearance 11.51 +/- 2.85 (ml/min/kg); Vd area 3.08 +/- 1.20 ml/kg; terminal half-life 3.10 +/- 0.92 h; mean residence time 5.64 +/- 1.40 h. Ciprofloxacin serum levels declined rapidly after the third hour, whereas concentrations in pancreatic juice remained elevated (above 1 mg/1) for nearly 12 h. The pancreatic juice/serum ciprofloxacin concentration ratio increased gradually fom 0.63 +/- 0.45 after 0.5 h to 6.18 +/- 4.59 after 12 h (mean +/- SD). Our data indicate that while the drug elimination half-life from the serum is short, the time-course of ciprofloxacin levels in the pancreatic juice conforms to a much slower disappearance rate. In particular, the ciprofloxacin levels achieved in pancreatic juice are constantly greater than the MICs of the bacteria generally responsible for pancreatic infections.

Penetration of amphotericin B in human lung tissue after single liposomal amphotericin B (AmBisome) infusion.

Abstract The distribution of amphotericin B in lung tissue was studied in 18 patients with primary or secondary lung cancer who underwent thoracotomy and pulmonary resection. At different times before surgery the patients were treated with liposomal amphotericin B 1.5 mg/kg by i.v. infusion over 1h. Blood and lung tissue samples were collected during surgery (one subject for each collecting time) and assayed for amphotericin B levels by HPLC. Due to surgical requirements, it was possible to obtain data from the 10th to the 25th h after the end of infusion. Plasma amphotericin B concentrations progressively decreased from 3.4 μ/ml at the 10th h to 1μg/ml at the 25th h after the end of intravenous infusion. In lung tissue samples the lowest amphotericin B concentration (about 1 μg/g) was observed at the 10th h, then a progressive increase was observed with the highest value (2.5 μg/g) determined at the 25th h.

Immunostimulation by clarithromycin in healthy volunteers and chronic bronchitis patients.

The immune response to infecting pathogens may be either enhanced or depressed by therapeutic antimicrobial agents. Some macrolides have been shown to enhance aspects of the immune response. This study evaluates the effects of clarithromycin, a new broad-spectrum macrolide antibiotic, on leukocyte function in both healthy volunteers (single 500 mg dose) and chronic bronchitis patients (500 mg b.i.d.) by testing blood samples collected at baseline and at 2, 4, 8 and 12 hours after clarithromycin administration. Clarithromycin did not affect leukocyte chemotaxis but did significantly increase (P < 0.01) phagocytosis (both frequency and index), intracellular killing and natural killer activity, in healthy volunteers. In patients, clarithromycin enhanced phagocytosis frequency, index and intracellular killing. Clarithromycin appears to enhance the human immune response; the mechanism, pharmacodynamics, and clinical significance of this enhancement remain unknown.

Macrolidic antibiotics: Effects on primary in vitro antibody responses

The effect of two macrolidic antibiotics, josamycin and erythromycin, on the primary immune response in cultures of human peripheral blood mononuclear cells (PBMC), were studied using a soft agar hemolytic plaque assay. Both compounds induced an appreciable reduction in the primary antibody response in total PBMC cultures. The removal of plastic-adherent cells, however, profoundly modified the effect of macrolides on the immune response. Both josamycin and, to a lesser extent, erythromycin enhanced, rather than suppressed, the antibody response. Furthermore, the macrolide-induced immunodepression in cultures of total PBMC was completely reversed by the addition of catalase (8000 U/ml). Taken together, these findings suggest that the macrolide-induced depression of the antibody response depends upon the presence of adherent monocytic cells and is mediated by the production of hydrogen peroxide.

Bactericidal Kinetics of an in vitro Infection Model of Once-Daily Ceftriaxone plus Amikacin against Gram-Positive and Gram-Negative Bacteria

The in vitro efficacy of ceftriaxone plus amikacin combination against gram-positive and gram-negative bacteria, clinically isolated from patients affected by pneumonia in intensive care units, was compared to that of the 2 drugs used alone. The study was performed using a dynamic model in which the human kinetics of the drugs after intramuscular administration was simulated. The antibacterial activity was tested by determining the bacterial cell count (CFU/ml). Killing curves came out from plotting the log CFU/ml versus time. In the same way, ceftriaxone and amikacin concentrations were assayed by HPLC and fluorescence polarization immunoassay, respectively. The results show that ceftriaxone plus amikacin combination exert a high killing activity against all tested strains. The two antibiotics alone initially have a good killing activity but this is followed by bacterial regrowth for all tested isolates. This data supports the results of several clinical studies which have shown a good therapeutic efficacy of ceftriaxone plus amikacin combination in the treatment of severe infections caused by organisms intermediately sensitive to these drugs.