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.

[Analysis of antibiotic utilization review at Landspitalinn, the University Hospital in Iceland.].

OBJECTIVE: To describe the application of and analyze the cost effects of antibiotic utilization review at Landspitalinn, the National University Hospital in Iceland, and review the use of prophylactic antibiotics in a general surgical ward. MATERIAL AND METHODS: The study was undertaken during a two month period in 1996. Patients in wards 11-A and 11-B (general medical floors), ward 12-G (general surgery service) and 11-E (hematology service) were enrolled. A specialist in infectious diseases and a clinical pharmacist reviewed the antibiotic treatment daily. If felt appropriate a recommendation to change treatment was forwarded. The number of patients treated with antibiotics, recommendations, recommendations accepted, and types of suggestions were recorded. Minimal savings per day were calculated by subtracting the cost of the antibiotic treatment after recommended modifications from the cost of the previous treatment. Prophylactic surgical treatment was examined in ward 12-G during an additional month. RESULTS: One hundred and fifty patients were treated with antibiotics during January and February 1996. The percentage of cases where changes in antibiotic treatment was recommended was 74% in 12-G, 65% in 11-E but 33% and 32% in 11-A and 11-B respectively. In ward 11-E, 80% of the recommendations were accepted and appropriate changes made, corresponding figures for the other wards were 93-100%. The most frequently recommended changes were stopping antibiotics (33%), reducing doses (31%) and switching to oral agents (19%). The minimum savings were estimated at ISK 210 000 per month if the effects of recommendations that were accepted were presumed to have lasted three days. Four percent of prescribed prophylactic surgical treatment was according to approved standards. CONCLUSIONS: The results confirm the need to optimize the use of antibiotics at The National University Hospital. The antibiotic utilization review was well received and acceptance of recommendations was high. The application of antibiotic utilization review to the entire hospital could reduce antibiotic cost by as much as 30-36%.

[Measurements of plasma HIV-1 RNA in Iceland.].

OBJECTIVE: First to measure plasma HIV-1 RNA in Icelandic HIV infected individuals and second to evaluate the initial effects of new combination regimens on viral load and CD4+ cell counts in HIV infected patients in Iceland. MATERIAL AND METHODS: The cohort studied consis notted of all HIV infected individuals we received samples from during the period September 1995 to November 1996. HIV-1 RNA and CD4+ cells were measured initially and subsequently every three to six months except when a change was made in the antiretroviral regimen, when samples were measured before the change, three to four weeks later and then every three to six months. The quantitative measurement of viral RNA was performed using the Amplicor HIV Monitor Test (Roche Diagnostic Sys nottems). CD4+ cell counts were measured by flow cytometry. RESULTS: A total of 44 patients were evaluated. The initial RNA ranged from %lt; 2.6 logio to 6.13 logio with a mean of 5.02 log. CD4+ cell counts ranged from 2 to 641 per mm3 (mean 230 cells/mm3). Eleven patients had never been treated with antiretroviral drugs and had greater than 10 000 viral copies per mL of plasma. Twenty five of the patients were evaluated following a change in or initiation of a new treatment. The initial change in treatment led to a +0.7 to -2.88 log change in plasma RNA (mean -0.9 log) and a mean of 6.9 cells per mm3 increase in CD4+ cells. Saquinavir was added to two reverse transcriptase (RT) inhibitors in 11 patients with a resulting mean of 0.23 log fall in RNA levels (range +0.70 log to -0.78 log). Saquinavir plus one RT inhibitor were added to one RT inhibitor in six patients with a subsequent mean of 0.65 log reduction in viral load (range +0.24 to -2.26 log). Saquinavir plus two RT inhibitors were given to four antiretroviral naive patients with a resulting mean of 2.37 log reduction in viral load (range -1.8 log to -2.67 log). CONCLUSIONS: 1. In a mixed cohort of RT inhibitor naive and treated patients, the viral RNA ranged throughout the range of the RNA assay. 2. Changes in viral load following changes in treatment were quite variable. 3. Saquinavir alone added to two RT inhibitors did not lead to a significant reduction in viral load. 4. In antiretroviral naive patients the viral load was reduced 100 fold following treatment with saquinavir and two RT inhibitors.

[The epidemiology of AIDS in Iceland. The first ten years.].

Objective. To describe the epidemiology of AIDS and HIV infection in Iceland with demographic characteristics and associated risk factors. Design. Survey of national data reported to the Office of the Director General of Public Health in Iceland from November 1985 to December 311994. The dates of diagnosis of HIV infection, AIDS and death due to AIDS were collected from the patients physicians. Patients. All patients diagnosed with HIV and AIDS in Iceland during the study period. Methods. The expanded European AIDS surveillance case definition was used (Lancet 1993 ;341:441). Reporting of individuals with AIDS and HIV infection is semianonymous in Iceland according to the act of law on sexually transmitted diseases. Results. As of December 31 1994 overall 79 males and 14 females were diagnosed with HIV infection. Of those infected 30 males and five females were diagnosed with AIDS. Most of those infected with HIV were 20-29 years old (44%) and most of those diagnosed with AIDS were 30-39 years old (40%). The incidence of AIDS (number of cases/100,000/ year) was 1.36 (2.3 for males and 0.4 for women) during the first 10 years. Of those 35 diagnosed with AIDS 26 died (74%) during this period. The median survival time after the diagnosis of AIDS was 22 months (95% CI; 16-28 months). The majority of the patients with AIDS (91%) and the HIV infected cases (65%) were homosexual or bisexual males but the proportion of those infected by heterosexual contact has been increasing and was at the end of the study period 16%. HIV infection among i.v. drug abusers has been rare in Iceland hitherto. No paediatric cases were observed. Conclusion. The spread of AIDS in Iceland is not as rapid as in many other countries. The incidence rate has not changed significantly during the study period. At the same time the death rate of AIDS patients has been increasing indicating a slowing of the AIDS epidemic. The major changes regarding transmission categories are the increasing proportion of heterosexuals and decreasing proportion of homosexual and bisexual males.

Hepatitis C virus genotypes among blood donors and their recipients in Iceland determined by the polymerase chain reaction.

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.

[Cytomegalovirus infections in healthy adults.].

BACKGROUND: Primary cytomegalovirus (CMV) infections in healthy adults are considered extremely rare. To study the extent of this problem in Iceland we undertook a two year (1989-1990) retrospective study of all new CMV infections in adults. METHODS: All positive tests for CMV antibodies in clinical samples (194) were identified in the sole virology laboratory in Iceland. Patients younger than 16 years and all patients with underlying diseases that could cause immunosuppression were excluded (154). The 40 remaining patients were contacted, their case histories reviewed and their serology for CMV, Epstein-Barr and HIV antibodies remeasured. Primary CMV infection was not confirmed in 14 patients leaving 26 immune competent patients who fullfilled our criteria for primary sym-tomatic CMV infection by the presence of IgM anti-CMV antibodies. RESULTS: Duration of illness in the 26 study patients varied from 1 to 25 weeks, usually 7-10 weeks. Fifteen patients were hospitalized. Diagnostic delay was considerable. Immunological tests (DTH skin test, serum immunoglobulines and lymphocyte differential counts) done 172-2 years after the illness did nor reveal any persistent immune abnormalities except for an absolute increase in the number of CD8+ T lymphocytes Conclusions: We conclude that primary CMV infections in adults are not uncommon and probably underdiagnosed. When adult patients present with non-specific symptoms such as low grade fever, malaise and unexplained fatigue, CMV should be considered or excluded with appropriate serological tests.

[Human listeriosis diagnosed in Iceland 1978-1994.].

Listeriosis has been recognised in Iceland, as a distinct disease entity in sheep called silage disease (votheysveiki), since 1910. The use of silage was introduced in Iceland in the latter part of the 19th century. Because of the climatic conditions it came into widespread use and the connection between silage and listeriosis was first demonstrated in Iceland by Pálsson et al. The first case of human listeriosis was diagnosed in 1961. The diease was not diagnosed again untill 1978 when four cases were identified. In the period between 1978 and 1994 L. monocytogenes was isolated from 36 patients, 11 males and 25 females. During this period the population of Iceland grew from 224.384 to 264.919. If mother and child are counted as one the incidence is approximately 8.3 per million per year. There were nine cases of neonatal infections, nine cases involving pregnant women, 13 cases of immunosuppressed patients and five patients were previously healthy. There were four miscarriages. The patients received conventional treatment of ampicillin and aminoglycoside or in one case chloramphenicol. All neonates but two survived. One older patient with meningitis died and 3 severely immunocompromised patients died. All of the strains were of the most common serotypes, 4b, l/2a and l/2b. The different serotypes were not evenly distributed during the study period. During the years 1978-1984 only one of 13 isolates was serotype l/2a and the rest was 4b. On the other hand all but three strains isolated since 1985 were either 172a or l/2b. During the first part of the study period the majority of cases involved neonates or pregnant women but during the second part most of the patients were old or immunocompromised. Nothing is known about the source of the infection in any of the patients except in one neonate which was considered to be nosocomially infected.

[Helicobacter pylori infection: the efficacy of a short course of azithromycin and fleroxacin treatment.].

The aim of this open pilot study was to assess the efficacy of a short course of fleroxacin and azithromycin in the treatment of Helicobacter pylori infection. Seventeen patients were included. All had H. pylori infection confirmed by urease test and culture. Eight patients had non-ulcer dyspepsia, 8 had duodenal ulcer and 1 had gastric ulcer. The patients were given omeprazole 40 mg on days 1-14, fleroxacin 400 mg on days 7-14 and azithromycin 500 mg on days 7 and 8. Side effects were assessed on a scale 0-4. The patients were gastroscoped 3 months after the treatment finished and urease test and H. pylori culture repeated. If both were negative eradication was regarded as successful. Six patients (35%) were H. pylori negative. However, only 1 (13%) of the patients with non-ulcer dyspepsia became H. pylori negative, whereas 5 (56%) with peptic ulcer did (P=0,131). The mean side effect score for patients with non-ulcer dyspepsia was 12.3, but 2.3 for patients with peptic ulcer (p<0,01). It is concluded that a short course with fleroxacin and azithromycin is inadequate for treatment of H. pylori infection.

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.

Effect of meropenem on the intestinal microflora.

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.

Disposition of alprazolam in human volunteers. Differences between genders.

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.

Penetration of ciprofloxacin and metabolites into human lung, bronchial and pleural tissue after 250 and 500 mg oral ciprofloxacin.

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.

Transintestinal elimination of ciprofloxacin.

This study identified the routes of elimination of ciprofloxacin in two groups of five subjects each: one of healthy volunteers; the other of patients with severe renal failure having mean creatinine clearance of 12 ml/min (range, 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously (IV) over 30 min. In an effort to recover the total drug administered, all urine and feces were collected for 7 days following dosing. Blood samples were drawn at set intervals. Serum, urine, and feces were assayed for ciprofloxacin and metabolites by high-pressure liquid chromatography. The ciprofloxacin elimination half-life was 3.9 +/- 0.4 hr in the healthy volunteers and 11.2 +/- 2.5 hr in the patients with severe renal failure. The total 7-day recovery of ciprofloxacin and its metabolites in urine and feces ranged from 74.0% to 114.7% of the dose (mean, 96.3 +/- 14.1%) in normal subjects and from 48.5% to 109.1% (mean, 88.1 +/- 20.9%) in patients. The dose of ciprofloxacin recovered in urine was 65.3 +/- 10.7% in healthy subjects and 19.0 +/- 15.9% in impaired patients (reduction factor, 3.4). In contrast, the dose recovered in feces was 11.4 +/- 2.6% in the group of normal subjects and 37.2 +/- 12.5% in the group of patients with impaired renal function in a 3.3-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Antibiotic prophylaxis in transurethral surgery. Ceftriaxone versus cephradine versus control. A randomized, prospective study in low risk patients.

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.

Impact of ticarcillin/clavulanate on the intestinal microflora.

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.

Tolerance of intravenous ciprofloxacin.

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.

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%.

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.