Biomedical subjects
Publications and source records attributed to S B Thorsteinsson.
Moulds belonging to the genus Paecilomyces are rare opportunistic pathogens. About 100 cases have been reported in immunocompromised hosts or in relation to surgical procedures. We describe here a cutaneous infection due to P. lilacinus in a renal transplant patient, which responded to voriconazole treatment.
Eight antibody-positive individuals were detected among 12,000 blood donations during the first year of screening blood donors for hepatitis C virus (HCV) antibodies in Iceland. All 8 were found to have a history of intravenous drug abuse. Six of these 8 individuals had previously donated blood to 27 patients who could be traced and examined for HCV infection. The great majority (23/27, 85%) of the recipients had demonstrable HCV antibodies. Furthermore, RNA analysis with the polymerase chain reaction showed that all patients with HCV antibodies had HCV RNA in their serum and in one hemodialysis patient without HCV antibodies viral RNA could be demonstrated. Genotyping of the HCV strains showed that the genotype of the donor was also identified in all but one of the infected recipients of his/her blood or blood products. This study, therefore, substantiates high infectivity of the HCV by blood or blood factor donation and shows that viremic HCV antibody-negative individuals exist.
Ten healthy volunteers were given 500 mg of meropenem by intravenous infusion over 30 min three times daily for seven days. Stool specimens were collected before, during and after meropenem administration. The numbers of enterobacteria and streptococci decreased during the administration period, while the numbers of enterococci increased. There was a decrease in the numbers of clostridia, bacteroides and gram-negative cocci, while the numbers of gram-positive cocci and rods were not changed by the administration of meropenem. The intestinal flora returned to normal in all volunteers within two weeks after the termination of meropenem administration.
Ciprofloxacin (CIP) and metabolite concentrations in lung tissue, parietal pleura and bronchial tissue were assessed in 43 adult patients who underwent lung surgery. A single oral dose of CIP was given for prophylaxis of bacterial infections. Two to 6 h prior to tissues sampling, 23 patients received 250 mg and 20 subjects 500 mg of the substance. Blood plasma samples were obtained at the same time as the lung tissue samples. CIP and its metabolites were assayed chemically by high-pressure liquid chromatography (HPLC). After 250 mg CIP, the individual lung tissue CIP concentrations during the 2- to 6-hour post-dose period ranged from 0.5 to 4.8 mg/kg. In 20 of the 23 lung samples, the CIP concentrations were above 1 mg/kg. After 500 mg CIP, the corresponding lung CIP concentrations ranged from 1.6 to 6.0 mg/kg. The CIP lung concentrations were, irrespective of the dose size, between 2 and 7 times higher than the simultaneous blood plasma concentrations. This indicates an excellent penetration of CIP and its metabolites into lung tissue. Bronchial tissue was obtained in 9 cases. Penetration into bronchial mucosa tissue was good as well, as indicated by tissue/plasma ratio values between 1.5 and 4.4. Individual CIP concentrations in the patients given 250 mg CIP, ranged from 1.0 to 1.6 mg/kg. In the patients who received 500 mg, the range was from 1.7 to 3.4 mg/kg. Tissue/plasma ratio values between 0.8 and 2.1 indicated that penetration to pleural tissues was good as well. Metabolite concentrations in all of the tissues assayed (lung, bronchial mucosa, pleural tissue) were low when compared to the concentrations of CIP. The concentrations in lung, pleural and bronchial tissue will probably permit low doses in the treatment of most respiratory tract infections. The broad spectrum of antibacterial activity, the good tissue penetration, chemical stability and the good safety record of the substance means that the drug is potentially a useful agent for perioperative antibiotic prophylaxis.
The disposition of alprazolam in 16 young healthy volunteers (eight females and eight males) was investigated. All volunteers were given a 1 mg dose of alprazolam. Dose/kg was 13.3 micrograms/kg (SD +/- 0.89 micrograms/kg) on average for male volunteers and 17.5 micrograms/kg (SD +/- 1.84 micrograms/kg) for the female volunteers. Pharmacokinetic parameters were calculated separately for both sexes in order to detect possible gender-dependent differences. The elimination rate constant (beta) for alprazolam proved to be significantly higher in the female population 0.067 hr-1 vs. 0.053 hr-1 (p = 0.03). The closely related parameters, elimination half-life (t1/2) and clearance (Cl) were also significantly different. The total area under the serum concentration curve (AUCtot), maximum serum concentration (cmax) and volume of distribution (Vd) were not significantly different. AUCtot corrected for differences in dose/kg was on the other hand significantly higher in males (p = 0.003) while cmax corrected in the same manner was not.
This study elucidates the routes of elimination of ciprofloxacin and its metabolites in two groups of 5 subjects each, one of healthy volunteers, the other of patients with severe renal failure having a creatinine clearance of 12 ml/min (range 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously over 30 min. In an effort to recover the total dose administered, all urine and faeces were collected for the 7 days following dosing. Blood was collected at set intervals after dosing. Serum, urine, and faeces were assayed by high-pressure liquid chromatography for ciprofloxacin and metabolites. The ciprofloxacin serum half-life in healthy volunteers was 3.9 +/- 0.4 h and in patients with marked renal failure 11.2 +/- 2.5 h. The total amount of ciprofloxacin recovered in urine fell by a multiple of 3.4 from 65.3 +/- 10.7% in healthy subjects to 19.0 +/- 15.9% in patients with renal failure, and the metabolites from 12.2 +/- 2.3% in the former group to 5.8 +/- 5.1% in the latter. In contrast, the amount of ciprofloxacin eliminated in faeces increased, by a similar factor, from 11.4 +/- 2.6% in healthy subjects to 37.2 +/- 12.5% in patients with renal failure. The amount of metabolites in faeces increased analogously from 7.3 +/- 1.6 to 26.2 +/- 6.5%. Since ciprofloxacin was administered intravenously and biliary elimination of the drug and its metabolites is negligible, we propose that elimination by faeces is due primarily to transintestinal elimination. This study demonstrates that transintestinal elimination of ciprofloxacin serves as an extrarenal safety factor compensating for reduced elimination by the renal route.
In this prospective, randomized study, the efficacy of one dose ceftriaxone or 48 hour cephradine therapy was compared to a control group to prevent urinary infection in 179 patients undergoing TUS. Only patients with low risk of developing infections were included. Both cephalosporins significantly reduced the incidence of UTI (ceftriaxone 11.9%, cephradine 17.6% compared to controls 47.2%; p less than 0.0005). Ceftriaxone seemed to have the definite edge in antibacterial spectrum and was easier to administer. Both regimens were well tolerated. Culture of prostatic chips did not have any significant predictive value to determine which patients would develop UTI.
Ten healthy volunteers were given 5.2 g Timentin (5 g ticarcillin plus 0.2 g clavulanate by intravenous bolus three times daily for seven days. Stool specimens were collected before and 2, 3, 5, 7, 14 and 21 days after the start of treatment to study the effect on the normal intestinal microflora. The concentrations of ticarcillin and clavulanate in serum, urine and faeces were determined by a microbiological method and the pharmacokinetics were studied on days 1, 3 and 7. There were no significant differences in the serum concentrations of ticarcillin and clavulanate during the three days. The total 8-h recovery in urine of ticarcillin was 62% of the dose and of clavulanate 19%. The mean serum half-life of ticarcillin was 1.0 h and of clavulanic acid 0.91 h. There were no measurable concentrations of ticarcillin or clavulanate in the faecal specimens. The number of enterobacteria slightly decreased, while there was a minor increase in the number of enterococci and streptococci during the administration of ticarcillin/clavulanate. The anaerobic microflora was also slightly affected. There was a minor decrease in the number of anaerobic cocci, bifidobacteria, eubacteria, lactobacilli and clostridia, but the number of bacteroides was not influenced by the treatment. After treatment the aerobic and anaerobic microflora returned to normal in all volunteers. The present microbiological findings indicate that ticarcillin/clavulanate has a minor ecological impact on the human intestinal microflora.
The pharmacokinetics and elimination of ciprofloxacin and its three major metabolites desethylene ciprofloxacin (M1), sulfonylciprofloxacin (M2), and oxociprofloxacin (M3) were determined in 18 volunteers with normal and varying degrees of reduced renal functions. One dose of 500 mg ciprofloxacin was given orally. Samples were assayed by high-pressure liquid chromatography. Serum concentrations of both ciprofloxacin and its metabolites were only slightly influenced by the renal function. The serum concentrations of the metabolites were less than 10% of the ciprofloxacin levels, even in reduced renal function, and were overlapping within groups of patients arranged according to renal function. Dialysis reduced the serum concentration of the parent compound and its metabolites. The serum half-life of ciprofloxacin in normal renal function was 5.8 +/- 1.2 h; this rose to 10.8 +/- 2.3 h in the group with clearances of 10-30 ml/min. Compared to the latter group, the t1/2 was lower (7.0 +/- 2.9 h) in the patients with terminal renal failure. The period of monitoring has a distinct consequence for the t1/2 of ciprofloxacin. The shorter t1/2 values emanate if monitoring had stopped after 10 or 12 h. A slower gamma-phase of elimination was observed and this was particularly distinct in subjects with renal functions within the normal range. The total renal elimination of the parent compound and its metabolites was approximately 60% over the 48-hour collection period in normal renal function and was reduced by about 20% in the group with clearances within the range of 10-30 ml/min. In renal impairment, there was a shift towards a higher proportion of the dose being eliminated as M2. M1 contributed only up to 2% of the dose in urine. Irrespective of the renal capacity, the amount of M3 recovered in urine was 3-4%.
Available information about the safety of intravenous (i.v.) administration of ciprofloxacin is reviewed. No increased incidence of systemic toxicity is apparent over the oral route. CNS side effects occur, but at a low rate and they are mild. Caution is indicated in patients with tendency for seizures. Laboratory changes are minimal, mainly mild elevations of liver enzymes. No increased risk of crystalluria has been seen. Local side effects in the form of erythema and burning are relatively common in some volunteer studies and are also seen in clinical studies, infusion phlebitis also occurs. It is recommended that i.v. ciprofloxacin is administered in slow infusion through a large or preferably central vein.
Twelve healthy volunteers received single doses of 200, 300, and 400 mg ciprofloxacin intravenously (30-min infusion). Crystals appeared in the urine of only 1 subject after the 400 mg dose. The crystals appeared in the 0-2 h urine specimen only and were observed immediately upon voiding while the urine was maintained at 37 degrees C. The pH of the urine was 7.3. The event was without untoward consequences to the person as evidenced by urinalysis and blood chemistry. Local skin reactions occurred on the arm of the infusion (cutaneous erythema, itching and burning sensation). The reactions were less after the lowest dose. The reactions started within minutes after the beginning of the infusion and disappeared either during the infusions or immediately after the end of administration. These local reactions were of moderate degree and did not necessitate termination of the infusion.
The pharmacokinetics of ciprofloxacin, after administration of single oral doses of 100, 250, 500, and 1,000 mg, and an intravenous dose of 100 mg, were determined in 12 healthy volunteers (six women and six men). Serum concentrations were determined by high-pressure liquid chromatography, and urine samples were assayed microbiologically. The peak serum concentrations and the total areas under the serum concentration curves increased in proportion to the size of the oral dose. The pharmacokinetics of ciprofloxacin were described by a dose-independent linear relationship. The apparent oral bioavailability was 85 percent, based on comparison of the total areas under the serum concentration curves of the 100-mg dose. The serum concentrations during steady state were not significantly higher than after the first dose. The serum half-life ranged from 3.0 to 3.4 hours after the oral doses, and was 2.9 hours after the intravenous dose. The elimination-phase apparent distribution volume coefficient, delta d,area, was 2.76 liters/kg, and the total body clearance was 42.0 liters/hour. The 24-hour urinary excretion was 42.2 +/- 15.6 percent after the 100-mg intravenous dose and 42.5 +/- 17.6 percent after the 500-mg twice-daily oral dose during steady state.
The safety of ciprofloxacin, given via 30- and 60-min intravenous infusions at a dose of 300 mg every 12 h for 4 days, was studied in 12 healthy subjects (6 females, 6 males). Local effects of the drug were assessed by frequent examination at the infusion site while systemic safety was determined by haematological and biochemical tests and by careful microscopic examination of the urine for drug crystals and by electroencephalographic studies performed in all subjects before and after dosing. At the site of infusion erythema, itching and a burning sensation developed 10-15 min after onset of infusion in some subjects. These symptoms were slight and did not necessitate termination of the infusions. The rash disappeared in some instances during the infusion and in others within minutes after the end of infusion. The changes usually disappeared, even during the infusion. The incidence of the adverse reactions was not related to the duration of the infusion (30 or 60 min), but was less (frequency and extent) when the anticubital vein was used for infusion rather than when smaller more peripheral veins were employed. Thrombophlebitis occurred after 1 of 96 administrations, and was followed by a return to normal. The electroencephalograms remained normal in all instances. One subject experienced mild nausea of a few hours duration. Only 1 volunteer showed crystalluria; the two such specimens from this subject had the most alkaline pH of all urine samples collected in this study. The probability of crystalluria upon intravenous administration appears not to be higher than after oral administration of ciprofloxacin.
The pharmacokinetics of ciprofloxacin were evaluated after increasing single oral doses of 100, 250, 500 and 1000 mg, and an intravenous dose of 100 mg given to each of 12 healthy volunteers (6 females and 6 males). Concentrations in serum and urine were determined by microbiological assay. The rise in peak serum concentrations and the values of the total area under the serum concentration curve were proportional to the increase in the oral doses. As the oral dose increased a slight increase was observed in the apparent time lag before absorption from 0.34 h after 100 mg to 0.53 h after 1000 mg. The serum half-life after the intravenous dose was 3.2 h. After the oral doses shorter apparent half-life values were observed. The intravenous dose showed an elimination phase distribution volume of 2.76 l/kg and total body clearance of 40.7 l/h. The total urinary excretion was 42.2 +/- 15.6% of the dose after the intravenous dose; the figure was lower after the oral doses. The bioavailability of the 100 mg oral dose was 83.7% as calculated from the value of the total area under the serum curve after the same oral and intravenous dose in all 12 subjects. Ciprofloxacin thus demonstrates normal linear pharmacokinetics, the rise in serum concentrations being proportional to the dose.
The pharmacokinetics of ciprofloxacin was studied in 12 volunteers during a 5-day course of 500 mg of ciprofloxacin given orally twice a day. The effects on the microflora of saliva and feces were also examined. Serum and urine samples were assayed for ciprofloxacin microbiologically, and the salivary and fecal microflora were examined quantitatively after processing onto a series of selective media. Fecal samples were also investigated for the presence of Clostridium difficile and its cytotoxin. The MICs for new colonizing bacteria were examined in the salivary and fecal samples. There was no accumulation during the course of 5 days with peak serum concentrations identical (2.8 and 2.3 mg/liter) after the first and final doses, and the areas under the serum curves were similar (9.6 mg/liter). The serum half-life was 2.5 h on both days. The changes in the salivary flora were minor and affected only the neisseriae. In the fecal flora, the numbers of enterobacteria and enterococci decreased markedly, whereas the changes in anaerobic flora (anaerobic cocci, fusobacteria, and bacteroids) were not so pronounced. However, 14 days after the drug was discontinued, the salivary and fecal flora were normalized in all respects. No new colonization of ciprofloxacin-resistant bacteria for which MICs were above 1.0 mg/liter was observed. C. difficile or its cytotoxin was not detected.
The pharmacokinetics of metronidazole (M), hydroxymetronidazole (OH-M), and acetylhydroxymetronidazole (A-M) were determined after a single intravenous dose of 0.5 g metronidazole. This was administered as an intravenous infusion during 30 min to 10 healthy volunteers and 24 patients with varying degrees of reduced renal function. Serum and urine concentrations were assayed by high-pressure liquid chromatography. The peak concentrations of the hydroxymetabolite appeared within an hour in the healthy volunteers and after a mean of 2.6 h (range 0.5-12.5 h) in the patients with reduced renal function. Analogously, the peak of the acetylmetabolite appeared later, at an average of 6.9 h and a range of 0.5-36.5 h. A-M was not observed in serum of the healthy subjects nor in 6 of the patients, but was recovered in urine of all subjects. The serum concentrations of M and OH-M were detectable throughout the 48 h monitored. Total urinary recovery in healthy subjects was 108.0% of the dose. This breaks down to 18.4% metronidazole, 62.4% OH-M, and 27.2% A-M. In the patients with reduced renal function, the relative contribution of A-M is higher than that of the other two products. The serum half-life of metronidazole was 7.1 in the healthy subjects and similar in reduced renal function (range 3.5-12.4 h). The serum half-life of OH-M was 18.0 h in the healthy and ranged 9.6-85.5 h in renal impairment. Long half-life values of 8.5-36.5 h were observed for A-M. Accumulation of OH-M and particularly of A-M was marked in reduced renal function. In the normal healthy volunteers, the coefficient of the steady-state distribution volume averaged 0.404 liter/kg of the terminal phase distribution volume 0.542 liter/kg, and the total body clearance 3.1 liter/h. The total body clearance of the unchanged compound was not influenced by reduced renal function.
Ciprofloxacin is one of the newer 4-quinolones. It combines a high antibacterial activity and a broad spectrum with favourable pharmacokinetic properties. The present study was designed to detect the influence of urinary pH and fluid consumption on crystalluria. Six healthy volunteers aged 25-41 years, 3 of each sex, participated in the study. Single doses of 1,000 and 500 mg of ciprofloxacin were given orally. The urinary pH was varied by giving each subject three different diets: a regular diet, a diet supplemented by ammonium chloride to acidify urine, and a diet supplemented by sodium bicarbonate to obtain alkaline urine. The urine volume and pH were measured and microscopically examined at 37 degrees C immediately after voiding. After the very high dose of 1,000 mg ciprofloxacin the regular diet regimen led to crystalluria in only one subject. Even with this high dose, but with the acidifying regimen, no crystals were observed in any one of the volunteers. When bicarbonate was supplemented 5 to 6 volunteers presented crystals in 22 of the 36 urine samples. 21 of the crystalluric urine samples showed a pH greater than or equal to 7.3. After the usual 500-mg dose and regular diet no crystals were observed at all; only in 3 subjects who received bicarbonate supplement crystals have been seen. In the urine of two subjects crystals emerged 'ex vivo' after some hours of storage at both 37 degrees C and room temperature; these results show the importance of sediment observation at 37 degrees C immediately after voiding to differentiate between real and 'ex vivo' crystalluria. Results of different examinations permit the conclusion that the crystals contain mostly unchanged ciprofloxacin as major component and magnesium as characteristic element. Participation of the metabolite 2 in the crystal formation cannot be excluded. No significant change was observed in blood counts and blood chemistry of any subject. Urinalysis showed no modifications except the eventual presence of the typical drug-related crystals. Hematuria never occurred.
During a 2-year period, 67 isolates of Campylobacter ssp. were cultured from 7213 stool specimens submitted for culture from 4019 individuals (1.7%). In the same period considerably more strains of Salmonella were isolated, 164 (4.1%). In the majority of cases campylobacteriosis presented as a mild disease. Some patients however were severely ill and 22 (32.8%) were hospitalized. Clinical resemblance to ulcerative colitis caused diagnostic difficulties in several patients. Two thirds of the patients contracted their disease domestically. There was a marked seasonal variation with peak incidence during the summer months.