The bile canalicular network in vitro

In 7 PHA--and PPD stimulated lymphocyte cultures from healthy human donors the maintained immunosuppressive effect of Rifampicin was investigated. Concentrations of 5-200 mug RMP/ml culture medium were used. A significant decrease in the transformation rate was found at 20 mug/ml and higher concentrations. A vitality examination (trypan blue staining) on lymphocytes after 72 hours cultivation in a RMP-containing medium with the same concentrations showed no increase of stained cells as compared with the controls. It is suggested that the observed inhibition of lymphocyte reactivity is to be attributed to an immunosuppressive effect of RMP and not to a toxic influence.     

Determination of erythema-effective solar radiation in Japan and Germany with a spore monolayer film optimized for the detection of UVB and UVA--results of a field campaign

A centrifugation method was used to investigate the accumulation of 14C-rifampicin by Staphylococcus aureus and Escherichia coli, and to characterize the mechanism of rifampicin transport into S. aureus. For both species, drug accumulation was rapid with the steady-state concentration (SSC) reached within 40 s of drug exposure. Rifampicin accumulation by S. aureus was temperature and pH dependent; the lower the experimental temperature and the lower the experimental pH, the lower was the concentration of rifampicin accumulated. Accumulation was unaffected by the presence of inhibitors of antibiotic efflux, carbonyl cyanide m-chlorophenylhydrazone (CCCP), dinitrophenol (DNP), or reserpine. Exposure to increasing concentrations of rifampicin suggested that the accumulation process was saturable above a rifampicin concentration of 0.2 mg/L. Michaelis-Menten kinetics gave an apparent Km and Vmax for rifampicin, calculated from a Lineweaver-Burk plot, of 0.05 mg/L (0.06 microM) and 3.8 ng rifampicin per second, respectively. However, calculations suggest that these values reflect those for binding of rifampicin to its target, RNA polymerase.     

Fundamental and clinical evaluation of cefozopran in low birth weight infants and neonates

We conducted fundamental and clinical evaluations of a cephem antibiotic, cefozopran (SCE-2787, CZOP), in infants with low birth weights and mature infants. (1) Blood concentrations CZOP was intravenously given in bolus dose of 20 mg/kg to the newborn. The blood antibiotic concentrations were 69.7 micrograms/ml at 30 minutes after administration and the elimination half life was 2.99 hours in mature infants aged 1 to 3 days. They were 38.7 micrograms/ml and 2.85 hours in those aged 4 to 7 days, and 40.8 micrograms/ml and 3.81 hours in those aged 8 days or elder, respectively. In infants with lower birth weights aged 4 to 7 days the blood antibiotic concentrations were 48.6 micrograms/ml at 30 minutes after i.v. administration and the elimination half life was 3.77 hours. The blood antibiotic concentrations at 30 minutes after intravenous doses of 10, 20 and 50 mg/kg in mature infants aged 8 days or elder were 21.1, 40.8 and 153.6 micrograms/ml (value at 60 minutes) and the elimination half lives were 2.24, 3.81 and 3.07 hours, respectively. Administration of CZOP at doses of 20 and 40 mg/kg by intravenous drip infusion over 30 minutes gave the blood drug concentrations of 48.0 and 103.2 micrograms/ml at the end of the infusion and the half lives were 2.60 and 3.33 hours, respectively. (2) Urinary excretion The urinary excretion rates after i.v. bolus doses of 10, 20 and 40 mg/kg were 28.4 to 58.6% of dose. The urinary excretion rate after i.v. drip infusion of 40 mg/kg over 30 minutes was 49.0% of dose. (3) Transfer into cereblospinal fluid The transfer of the antibiotic into cereblospinal fluid in patients with serous meningitis was 4.1 to 15.5 micrograms/ml at 1 hours after administration. (4) Clinical results The clinical efficacy was judged "good" or "excellent" in 2 of the 3 patients with septicemia and in all of the 10 patients with suspected septicemia. It was judged "excellent" in all of the 9 patients with pneumonia, 3 with urinary tract infections and 3 with intrauterine infections. Prophylactic use of the antibiotic was effective in all of the 12 patients. Of the patients in whom bacteriological evaluation was successful, 7 of the 10 causative organisms were confirmed to be eradicated. No adverse drug reactions of signs and symptoms were recognized. Fourteen abnormal alterations of the laboratory test values such as elevation of gamma-GTP and that of GPT were recognized in 8 patients (16.7%). None of them were particularly serious. These results indicate that CZOP is a drug useful for treatment and prevention of infections in infants with lower birth weights as well as in mature infants.     

Pharmacokinetics of rifampicin in gastrectomized persons (author's transl)

A laboratory method was developed whereby the presence of Rifampicin in the blood is determined microbiologically by means of a diffusion test. The organism used was Sarcina lutea. The tests established that the Rifampicin levels in the blood of pylorogastrectomized persons were significantly higher then they were in a normal control group. The daily changes in the Rifampicin levels were simulated and checked by analogue computer. The findings indicated that the increased absorption in gastrectomized persons cannot be due to accelerated passage and that it is presumably attributable to chemical and physical factors. The results are analysed statistically and summarized in graphs.     

The effect of trauma on the ocular penetration of intravenous ciprofloxacin

PURPOSE: To study the intraocular pharmacokinetics of intravenously administered ciprofloxacin following eye trauma. METHODS: Twenty-three New Zealand albino rabbits and 12 Yorkshire pigs each received a surgically induced scleral injury to the right eye. Following repair, each rabbit received a single 30-mg intravenous infusion of ciprofloxacin. Each pig received either two 200-mg doses or two 400-mg doses of intravenous ciprofloxacin given 12 hours apart. Vitreous and serum samples were harvested at 0.5, 1, 4, 6, and 12 hours after antibiotic administration in rabbits and 1 hour after the second dose in pigs. Bioassays for ciprofloxacin were performed on each sample, and results were statistically compared by t test. The untraumatized left eye in each animal served as a control. RESULTS: The mean vitreous concentration of ciprofloxacin in traumatized rabbit eyes was 0.37 microgram/ml. This level was sustained above levels in control eyes (0.18 microgram/ml) for at least 4 hours following antibiotic administration. In control eyes, intravitreal levels peaked at 1 hour. Mean vitreous concentrations +/- SD in traumatized pig eyes were 0.091 +/- 0.017 microgram/ml in swine that had received 200-mg doses of ciprofloxacin vs 0.312 +/- 0.153 microgram/ml in swine that had received 400-mg doses (P = .02). Mean vitreous concentrations of ciprofloxacin in control eyes were not affected by increasing dosage. CONCLUSION: In both animal models, experimental surgical trauma increased intravitreal ciprofloxacin delivery. In addition, systemically administered ciprofloxacin achieved intravitreous levels exceeding minimum inhibitory concentrations for common ocular pathogens, suggesting a role for ciprofloxacin in the prophylaxis of posttraumatic endophthalmitis.     

Genesis of methicillin-resistant Staphylococcus aureus (MRSA), how treatment of MRSA infections has selected for vancomycin-resistant Enterococcus faecium, and the importance of antibiotic management and infection control

We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management.     

Magnitudes and mutual orientations of dipolar and shielding interaction tensors determined from the orientation dependence of spinning sidebands of slowly rotating powder samples

Rifampicin (RMP), antituberculous drug, has been controversially described for many years as an immunosuppressant. The goal of this work was to determine the influence of RMP on selected parameters of the immune response in vivo and in vitro. In vivo (in B6AF1 mice) the influence of long-term treatment on primary humoral response and cellular response was evaluated. Drug dose was 50 mg/kg. In vitro (using peripheral blood of volunteers) the influence of RMP on mitogen induced proliferation, metabolic activity of granulocytes and leukocyte induced angiogenesis by diverse subpopulation of mononuclear cells was examined. The concentrations tested were 7 and 70 micrograms/ml. RMP slightly stimulated production of anti-SRBC antibodies and suppressed cellular response in mice, decreased PHA and ConA induced proliferation in higher concentration and strongly inhibited chemiluminescence at concentration used. RMP inhibited also leukocytes induced angiogenesis.     

Production of enterotoxins by Bacteroids fragilis strains--effect of clindamycin

Four B. fragilis strains were examined: one nonenterotoxigenic (NTBF) and three producing enterotoxin (ETBF). The growth of cultures was determined and enterotoxin, which is released to the culture medium during growth of strains, was detected. BHI broth and BHI broth with addition of subinhibitory doses (sub-MIC) of clindamycin were applied. Bacterial cultures were incubated at 37 degrees C for 48 hours. After 4, 8, 16, 24, 48 hours of cultivation, samples of bacterial cultures were collected and the optical density was measured. Then the samples were centrifuged, supernatants were filtered through 0.45 micron filters and concentrated three times with 5000 D ultrafilters. Prepared samples were kept frozen at -70 degrees C until used. The titre of enterotoxin in samples was determined on human colon adenocarcinoma cell line HT 29/C1. Neutralization assay was performed with culture filtrates, which were enterotoxin-positive and with rabbit anti-enterotoxin serum. The results of the experiments indicate that enterotoxin is detected after 16 hours of incubation of ETBF strains. Clindamycin at subinhibitory concentrations (sub-MIC) inhibits the growth of B. fragilis cultures. The antibiotic causes also delay and decrease in enterotoxin production by ETBF strains.     

Cephacetrile--application of pharmacokinetic data to dosage determination

This pharmacokinetic investigation was based on the determination of serum and urinary levles of cephacetrile in 50 subjects given single intramuscular or intravenous doses of 0.5 or 1 gm of the antibiotic; 30 normal subjects, 10 patients with renal insufficiency, and 10 patients with chronic nephritis undergoing maintenance haemodialysis were included in this study. In normal subjects, mean serum half-life was 1.09 hours (Ke = 0.6337) after intramuscular injection of 0.5 gm cephacetrile, 1.31 hours (Ke = 0.5276) after intramuscular injection of 1 gm, and 0.89 hours (Ke = 0.7806) after intravenous injection of 1 gm. Absorption half-life was 0.45 hours after intramuscular injection of 1 gm cephacetrile. The urinary elimination of cephacetrile over the first 6 hours after injection was on the average 72.7% of the administered dose. After intravenous injection of 1 gm of the antibiotic, the plasma clearance of cephacetrile was 407 ml/min., and its renal clearance 313 ml/min. A linear correlation was found between the values of overall elimination rate constant (Ke) and creatinine clearance in the subjects under investigation (Ke = 0.0080 + 0.0061 ClCr). The established pharmacokinetic characteristics were used to calculate the maintenance and loading doses as well as the intervals between injections adjusted to creatinine clearance. These data constitute true dosage schemes adapted to the particular case of each patient according to his kidney function.     

Antibiotic concentrations in ascitic fluid of patients with ascites and bacterial peritonitis

Thirty-six paired specimens of serum and ascitic fluid from 21 patients with peritonitis and ascites, most with sponetaneous bacterial peritonitis and alcoholic cirrhosis, were assayed for antibiotic content. Antibiotics assayed and number of determinations were gentamicin, 14; tobramycin, 7; ampicillin, 5; clindamycin, 3; penicillin G, 2; cephalothin, 2; chloramphenico, 2; and cefazolin, 1. In 31 pared specimens the ascitic fluid antibiotic concentration was about one half or more of the simultaneous serum level and in 17 assays exceeded 90% of the serum level. All antibiotics studied penetrated ascitic fluid equally well. Clinical response to antibiotic therapy was good in 12 of 16 patients with culture-proven bacterial peritonitis. Antibiotic levels in ascitic fluid exceeded the minimal inhibitory concentration of the infecting organisms in all but one patient who responded. Direct intraperitoneal instillation of antibiotics does not appear to be necessary routinely; however, there may be an initial lag of several hours before antibiotic concentrations is ascites achieve therapeutic levels.     

Pharmacokinetic and clinical evaluation of azithromycin in pediatrics

Azithromycin (AZM), a new macrolide antibiotic, in fine granules and in capsules was administered at a standard dose of 10 mg/kg once daily for 3 days to pediatric patients with bacterial infections. AZM was studied for its pharmacokinetic and clinical evaluation. 1. AZM possessed potent activity against Gram-positive bacteria and Gram-negative bacteria that had been clinically isolated. 2. Plasma samples were collected from two patients diagnosed as having pneumonia or enteritis, and urine samples were collected from one patient diagnosed as having pneumonia for drug level determination. The drug concentrations in plasma were 0.095 and 0.204 microgram/ml just before the end of treatment, and 0.017 and 0.096 microgram/ml at 48 hours post-treatment. The drug concentrations in urine were 5.16 micrograms/ml and 5.63 micrograms/ml during a period between 24 and 48 hours and between 48 and 72 hours after the start of treatment, respectively. 3. The drug was found effective in 37 of 38 cases with various pediatric infections. AZM treatment eradicated bacteria in 17 of 30 strains (56.7%). 4. One patient complained of mild vomiting, while abnormal laboratory test results indicating mild eosinophilia were reported in four cases.     

A conversation with a physician and a cancer patient. Interview by Judith D Burke

The influence of Ca2+ on the growth, antibiotic production and differentiation of Streptomyces albogriseolus 444 was studied. Consumption of the calcium ions by the strain was followed up. It was shown that Ca2+ changed the dynamics of the biomass accumulation and had no significant effect on the antibiotic production. Calcium present in the medium was assimilated more intensively during the first 24 hours of the strain growth. The own antibiotic nigericin exogenously added to the medium increased the calcium assimilation. In the presence of Ca2+ the nigericin stimulation of the strain differentiation was higher.     

Potentiation of pirarubicin activity in multidrug resistant cells by rifampicin

The effect of the anti-tuberculosis drug rifampicin on pirarubicin activity was investigated in multidrug-resistant cells overexpressing P-glycoprotein. Rifampicin increased the sensitivity of pirarubicin to anthracycline-resistant mouse leukemic P388 cells and significantly enhanced the cytotoxicity and intracellular accumulation of pirarubicin in resistant cells, but had no effect in parent cells. By contrast, two other rifamycins, rifamycin B and SV, had no effect on pirarubicin accumulation in resistant cells. Rifampicin also enhanced pirarubicin-induced apoptosis and G2/M blockade on the cell cycle in resistant cells. These results show that rifampicin enhances the cytotoxic action of pirarubicin in resistant cells, at least partly via the inhibition of cellular pirarubicin efflux.     

Penetration of antibiotics in diseased antral mucosa

OBJECTIVES: To investigate extracellular concentrations of antibiotics in inflammatory diseased sinus mucosa in critically ill patients and to find out whether there were any correlations between the concentrations of antibiotics in extracellular tissue and the presence of bacterial infection. DESIGN: Prospective case series. Sinoscopic findings were used as the criterion standard. SETTING: The general and the neurosurgical intensive care units of a tertiary care hospital. PATIENTS: Critically ill patients, nasotracheally intubated or tracheotomized, who received ventilator treatment (> 7 days) and antibiotic therapy. INTERVENTIONS: Bilateral sinoscopies were performed; antral secretions were collected for bacterial cultures; and serum and tissue samples were obtained for bioassay of antibiotic concentrations. RESULTS: The concentrations of all antibiotics found in extracellular fluid were lower than those found in serum samples. CONCLUSION: Measurable extracellular tissue concentrations of antibiotics were found in the antral mucosa, demonstrating that inflammatory maxillary sinus disease does not impede the antibiotic penetration of the mucosa or antibiotic activity in the extracellular tissue.     

Determination of kynurenic acid by capillary electrophoresis with laser-induced fluorescence detection

We have investigated the influence of three structurally different but functionally related compounds [1, 10 ortho-phenanthroline (phenanthroline), Rifampicin and aurin tricarboxylic acid (ATA)] on the rate and the extent of proliferation of progesterone-responsive T47D human breast cancer cells. These compounds have previously been used in this laboratory and have been shown to modulate properties of nucleic acid binding proteins. Because p53 and the progesterone receptor (PR) are both DNA binding proteins that appear to regulate proliferation of breast cells, alterations in T47D cell p53 and PR levels were examined to determine their relevance in cell proliferation. T47D cells were grown in the absence of phenol red and in the presence of 5% fetal calf serum with or without charcoal stripping in the presence of the inhibitors. The rate of proliferation of cells grown in Rifampicin containing medium exhibited nearly 70% inhibition. Phenanthroline, a known metal chelator, was an effective inhibitor of proliferation at 3 mM reducing the cell number by more than 75%. ATA (0.24-2.4 micrograms/ml) inhibited the growth of the cells by nearly 50%. Analysis of the mechanism of action of these compounds revealed that treatment with these compounds caused specific changes in the molecular composition of T47D cell PR. Whereas ATA caused increased stability of PR isoforms, Rifampicin induced a upshift in the mobility of PR in SDS gels-a phenomenon associated with hyperphosphorylation of steroid receptors (SRs). Phenanthroline treatment (> 2 mM) caused a complete down-regulation of PR and the tumor suppressor protein, p53. The downregulation of p53 paralleled the changes in the molecular composition of PR. We propose that the inhibition of T47D cell proliferation by phenanthroline, Rifampicin and ATA results from a number of cellular changes that include regulation of p53 and PR.     

Clinical impairment of sequential finger movements in Parkinson''s disease

The in vitro effects of phenylephrine solution on ciliary beat frequency (CBF) in terms of different concentrations and exposure times were investigated using a video-computerized analysis technique. Nasal epithelial cells were taken from inferior turbinate of 10 volunteers by scraping the nasal mucosa with a cytology brush. CBF was measured in five different concentrations including 0.125%, 0.25%, 0.5%, 1%, and 2.5%. Each specimen was incubated in different solution for 6 days and CBF was measured at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, and 6 days. CBF decreased significantly after 12-hour incubation in 0.125% phenylephrine solution and after 8-hour incubation in 0.25% phenylephrine solution, both clinically used concentrations. There were significant decreases in CBF after incubation in 0.5% phenylephrine for 2 hours, in 1% for 1 hour, and in 2.5% for 30 minutes (P < 0.05, repeated measure analysis of variance [ANOVA]). CBF of the nasal respiratory ciliated cells significantly decreased with increasing concentrations of phenylephrine solution and with increasing incubation times at the same concentration (P < 0.05, repeated measure ANOVA). The results of this study suggest that phenylephrine may inhibit ciliary beat in vitro by its pharmacological effect at lower concentrations than clinically used ones.     

Gentamicin penetration into normal rabbit nucleus pulposus

STUDY DESIGN: Radioactively labeled gentamicin was administered to 24 rabbits to assess the concentration of antibiotic in the nucleus pulposus. OBJECTIVES: The purpose of the study was to investigate the pharmacokinetics of gentamicin penetration into normal rabbit nucleus pulposus. SUMMARY OF BACKGROUND DATA: Disc space infection is a complication of spinal surgery that can be prevented by prophylactic antibiotics. Gentamicin can be used in conjunction with other antibiotics as a prophylactic agent. One previous study demonstrated that a similar antibiotic, tobramycin, penetrates the disc, but no data have been reported on the pharmacokinetics of disc penetration. METHODS: Twenty-four rabbits were given an intravenous injection of gentamicin labeled with iodine 125. Four rabbits were killed at hourly intervals 1 to 6 hours after injection. Specimens of nucleus pulposus, blood, whole liver, and saline-perfused liver were obtained and prepared. The radioactivity in the specimens was measured. RESULTS: The gentamicin concentration in the nucleus pulposus peaked at 2 hours and remained at this level for the duration of the experiment. Twenty percent of the gentamicin recovered from the nucleus pulposus was tissue bound. CONCLUSIONS: Gentamicin concentration in the rabbit nucleus pulposus does not peak until 2 hours after an intravenous bolus of drug. If gentamicin penetrates human nucleus pulposus in a similar fashion, this study could have implications for the timing of administration of this agent for prophylaxis.     

Effect of antibiotics on interferon production in mice

Neomycin, chloramphenicol, gentamycin, rifampicin and oxytetracycline were tested for their influence on virus induced interferon (IF) production in mice. Repeated intraperitoneal (i.p.) injections of antibiotics were given to produce significant serum concentrations during the time of IF production, induced by i.p. injections of Newcastle disease virus (NDV). IF titres in antibiotic-treated mice determined 6 hours after induction were compared to titres in control mice given NDV only. The IF production was not significantly modified in most of the antibiotic treated mice. Only the highest dose of chloramphenicol (2500 mug/mouse) appeared to cause a reduction in IF production (p less than 0.10). Addition of antibiotics in vitro did not alter the antiviral titres of IF.     

Age correlation of the time lag in signal change on EPI-fMRI

Rifampicin synoviorthesis has been empirically used for the treatment of haemophilic synovitis for some time. This paper reports on the experience of three Latin American centers with this treatment and compares it with radioactive synoviorthesis results. Chemical synoviorthesis with rifampicin is best indicated in younger patients (< 15 years) and small joint (ankles and elbows).     

Chronic granulomatous disease (CGD): in vitro enhancement of bactericidal activity of CGD phagocytes by rifampicin

In a series of 29 experiments on CGD patients, we have studied the in vitro bactericidal capacity of normal and CGD phagocytes against penicillin, streptomycin and rifampicin sensitive Staphylococcus aureus. The bactericidal activity of phagogyte preparations was tested at different intervals during a 21 hour incubation. The CGD-phagocyte bactericidy peaks after 90 min when penicillin is used; in contrast, a significant enhancement of the bactericidal activity is noted with rifampicin and best noted after 21 hours of incubation. To elucidate the mode of action of this antibiotic, a rifampicin resistant S. aureus was used in a series of experiments; The results point to a mixt type of action: antimicrobial and metabolic.