Sigurdur B. Thorsteinsson

Cutaneous infection caused by Paecilomyces lilacinus in a renal transplant patient: treatment with voriconazole.

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.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.

Pharmacokinetic Profile of Fosfomycin Trometamol

The pharmacokinetics of fosfomycin trometamol has been assessed in 12 healthy volunteers given oral doses of 2, 3, and 4 g of fosfomycin and 3 g intravenously of fosfomycin as fosfomycin sodium, all in the fasting state. The assay was microbiological (Proteus mirabilis ATCC 21100). There was a gradual rise in both peak serum concentrations and total area under the curve by rising oral doses, from 16.0 mg/l and 106.7 mg x h/l, after 2 g to 30.9 mg/l and 189.7 mg x h/l after 4 g respectively. The serum half-life was 4 h after the oral doses and 2.1 h after the intravenous dose. After the oral doses, the amounts excreted in urine in the active form ranged from 36 to 40% compared to 93% after the intravenous dose. The bioavailability was slightly below 40%. Concentrations in urine covers the usual urinary tract pathogens after oral doses of 2, 3, and 4 g.

Transintestinal elimination of ciprofloxacin

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.

Tolerance of Intravenously Administered Ciprofloxacin

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.

Tolerance of Ciprofloxacin at Injection Site, Systemic Safety and Effect on Electroencephalogram

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.

Pharmacokinetics of Metronidazole and Its Metabolites in Reduced Renal Function

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.

Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

The pharmacokinetics of azlocillin at intravenous doses of 1.0, 2.0 and 5.0 g and of 2.0 g mezlocillin were studied in a cross-over study on 10 healthy volunteers. The serum concentrations and total area under the serum curves for azlocillin increased more than expected from the multiples of the dose size. Likewise, the percentage of urinary excretion of an antibacterially active agent increased steadily with higher doses. The same applied to the serum half-life (t 1/2), whereas the total body clearance was reduced. All these characteristics are indicative of dose-dependent, i.e. capacity-limited pharmacokinetics. The t 1/2 was 0.89, 0.98, and 1.53 h for each dose. For 2.0 g mezlocillin, the serum values, urinary recovery, and t 1/2 were lower than the values after the same dose of azlocillin. The t 1/2 was 0.64 h. The total body clearance was 12,0, 9.2, and 6.4 liters/h for the three doses of azlocillin and 14.4 liters/h for 2. g mezlocillin. Dose dependence appears to be more pronounced with azlocillin than found previously with mezlocillin. Unchanged azlocillin and its biotransformation products are excreted more slowly than mezlocillin and its metabolites.

Elimination of Ciprofloxacin and Three Major Metabolites and Consequences of Reduced Renal Function

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%.

Endobronchial Actinomycosis Secondary to a Tooth Aspiration

We report a middle aged smoker with recurrent pneumonia caused by endobronchial actinomycosis secondary to a tooth aspiration. Unlike previously reported cases, our patient was not chronically debilitated. The case suggests that a follow-up bronchoscopy is beneficial after the initiation of antibiotic therapy for endobronchial actinomycosis.