A. Wildfeuer

Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole

The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radio-telemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food.The plasma AUC and Cmax of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41–77%) on an empty stomach and 86% (65–102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100–115%) and 102% after the light meal (88–103%), and the criteria for bioequivalence were attained.Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.

In vitro evaluation of voriconazole against clinical isolates of yeasts, moulds and dermatophytes in comparison with itraconazole, ketoconazole, amphotericin B and griseofulvin.

Summary. The in vitro activity of voriconazole (UK‐109, 496), a new antifungal triazole derivative, against 650 clinical isolates of yeasts, moulds and dermatophytes was compared with that of itraconazole, ketoconazole, amphotericin B and griseofulvin. The geometric means of the minimum inhibitory concentrations (MICs) of voriconazole were 0.05 μg ml‐1 against yeasts (n= 187), 0.58 μg ml‐1 against moulds (n= 260) and 0.08 μg ml‐1 against dermatophytes (n= 203). The overall activity of voriconazole against yeasts and moulds was good, being similar to that of itraconazole, ketoconazole and amphotericin B. Voriconazole was highly effective against Aspergillus fumigatus (mean MIC 0.23 μg ml‐1) and other Aspergillus species and showed noteworthy activity (mean MICs 0.08‐0.78 μg ml‐1) against emerging and less common clinical isolates of opportunistic moulds, such as Altenaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp. and Fusarium spp. On the other hand, voriconazole was less active in vitro than the comparative agents studied against various species of zygomycetes, such as Mucor spp., Rhizopus spp. and Absidia spp. Voriconazole and the other two azoles, itraconazole and ketoconazole, were more active than griseofulvin in vitro against most dermatophytes tested.

BIOAVAILABILITY OF FLUCONAZOLE IN THE SKIN AFTER ORAL MEDICATION

Summary. Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 μg ml‐1, sweat 4.58 μg ml‐1, dermis‐epidermis (without stratum corneum) 2.77 μg g‐1 and stratum corneum 73 μg g‐1. Thus, 4 h after the last dose the antimycotic attains a 40‐fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 μg g‐1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 μg g‐1. Even 4–5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2–3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses.

Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility

Summary. Fluconazole shows good penetration into the tissues and body fluids examined and a rapid equilibrium is achieved between the concentrations in the various compartments. The pharmacokinetics of fluconazole after intravenous or oral administration are proportional to the dose. This finding, together with the slow elimination of the triazole (t1/2 30 h), makes it easier to forecast the therapeutically effective dosage. Measurements of fluconazole concentrations in blood can be used to predict levels in some tissues (lung, brain, gynaecological samples), body fluids (sputum, saliva, vaginal secretions) or exudates. Concentrations in cerebrospinal fluid and yitreous humour of the eye reach approximately 80% of the levels found in blood. A very high proportion of fluconazole is excreted unchanged in the urine, where concentrations of the drug are 10–20‐fold higher than in blood. Whilst this pharmacokinetic profile is valuable in the treatment of fungal infections of the urinary tract, it also means that the dosage may need to be decreased in patients with renal impairment. The susceptibility of fungi to fluconazole in vitro and in vivo correlates well with the concentrations of the drug measured in various compartments of the body.

Equivalence of a high-performance liquid chromatographic assay and a bioassay of azithromycin in human serum samples.

Two sensitive methods for the determination of the azalide antibiotic azithromycin in human serum were compared. High-performance liquid chromatography (HPLC) and a microbiological assay were simultaneously applied to 768 serum samples obtained in a clinical study. There was excellent agreement between the azithromycin concentrations measured by HPLC and by the bioassay. The correlation coefficient for the two methods was r2 = 0.96. The precision and the sensitivity of the methods were found to be very similar.

Comparative Tolerability of Intravenous Azithromycin, Clarithromycin and Erythromycin in Healthy Volunteers

ObjectiveTo compare the tolerability of intravenous azithromycin, clarithromycin, erythromycin and placebo.DesignA double-blind, double-dummy, placebo-controlled, four-way crossover study was conducted in 12 healthy male volunteers. The participants were randomised to receive 1-hour intravenous infusions of azithromycin 500mg (2 mg/ml) once daily, erythromycin 500mg (1 mg/ml) three times daily, clarithromycin 500mg (2 mg/ml) twice daily, or placebo (normal saline, 500ml) three times daily, with each regimen administered for 3 days. There was a minimum 4-week washout period before participants switched to an alternative regimen, in random sequence, until all four regimens had been completed. Participants were monitored for infusion site reactions and gastrointestinal (GI) adverse events.ResultsClarithromycin caused clinically significant infusion site pain in 92% of the 12 participants evaluated and was exclusively associated with phlebitis and inflammation. Areas under score-time curves (AUSs) rating the intensity of inflammation and pain were significantly higher for clarithromycin compared with azithromycin (p < 0.0005). Erythromycin infusion caused clinically significant abdominal pain or nausea in 25% of participants. The AUSs for GI tolerability were significantly different for erythromycin compared with azithromycin (p < 0.001). Discontinuation rates due to infusion site reactions were 0% for azithromycin, 50% for clarithromycin, and 8% each for erythromycin and placebo. Treatment with erythromycin was interrupted or discontinued as a result of abdominal pain in 17% of patients and as a result of nausea in 8% of patients.ConclusionsIntravenous azithromycin had better infusion site tolerability than clarithromycin and better GI tolerability than erythromycin. The superior tolerability of azithromycin may avoid the discontinuation of intravenous antimicrobial therapy in seriously ill patients and assist in reducing the duration of hospitalisation and the cost of patient management.

Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells.

Multidrug resistance is expressed not only by bacteria, but also by tumor cells and by some normal cells of the body. It enables eukaryotic cells to exclude not only cytostatic drugs but also non-cytostatic antibiotics. This was demonstrated in genetically engineered multidrug resistant (MDR) cells infected with the facultative intracellular bacterium Listeria monocytogenes for all macrolide antibiotics tested (azithromycin, clarithromycin, erythromycin, josamycin, roxithromycin and spiramycin). In these cells and in conventionally selected MDR cells higher concentrations of the macrolides were necessary to inhibit the growth of L. monocytogenes than in the respective parental cells. This effect was due to a reduced intracellular accumulation, which was shown with a biological assay for all macrolides tested. For azithromycin, the results of this test were confirmed by measurement of the intracellular concentrations with high-performance liquid chromatography (HPLC). Besides the macrolides, MDR cells excluded also antibiotics of other chemical groups which was shown for ciprofloxacin, clindamycin, rifampicin and the streptogramin derivative RP 59500. In addition, in conventionally selected cells higher concentrations of chloramphenicol, doxycyclin, ofloxacin and trimethoprim than in the respective parental cells were necessary to inhibit the growth of L. monocytogenes. In contrast, when using genetically engineered cells, no significant differences were found for these antibiotics. These differences might be due to a higher expression of multidrug resistance in the conventionally selected cells because these cells were also more effective in excluding rhodamine 123 in a flow cytometric assay. In conclusion, expression of multidrug resistance by eukaryotic cells leads to a reduced concentration of macrolides and other antibiotics in these cells and to an impairment of activity against intracellular bacteria.

Pharmacokinetics of ampicillin/sulbactam in patients undergoing colorectal surgery: measurements in serum, the colonic wall and in tissue at the incision site

The concentrations of ampicillin and sulbactam were determined in serum, colonic wall and incision site tissues from 23 patients undergoing elective colorectal surgery after infusion of a high-dose regimen (2 g ampicillin/1 g sulbactam) or a low-dose regimen (1 g ampicillin/0.5 g sulbactam). The results confirmed that ampicilin and sulbactam penetrated well into the tissues studied and reached therapeutically effective concentrations at the various sites. The high dose regimen showed higher concentrations of both compounds in serum and tissues, indicating a longer period of perioperative protection against bacterial pathogens. Thus, about 39 min after the end of the infusion of the high-dose regimen, the mean concentration of ampicillin was 68.8 +/- 31.2 mug/g and of sulbactam 23.4 +/- 6.3 mug/g in the tissue of the colonic wall. Low-dose prophylaxis, showing mean tissue concentrations of ampicillin of 35.6 +/- 7.0 mug/g and of sulbactam of 14.2 +/- 2.4 mug/g about 48 min after the infusion, is appropriate if the duration surgery does not significantly exceed 2 h.

Fluconazol: Vergleich von Pharmakokinetik, Therapie und Empfindlichkeit der Sproßpilze in vitro

Zusammenfassung. Fluconazol penetriert gut in die untersuchten Gewebe bzw. Körperflüssigkeiten und erzielt eine schnelle Äquilibrierung der Konzentrationen zwischen unterschiedlichen Kompartimenten. Die nach intravenöser oder oraler Applikation dosisproportionale Pharmakokinetik und die nur langsame Elimination (t1/2 30 h) des Triazols aus dem Körper erleichtern eine Voraussage für die therapeutisch wirksame Dosierung. Die im Blut gemessenen Fluconazol‐Konzentrationen konnen auch bei Patienten auf verschiedene Gewebe (Lunge, Gehirn, gynäkologische Proben) bzw. andere Körperflüssigkeiten (Sputum, Speichel, Vaginalsekret) oder Exsudate projiziert werden. Im Liquor cerebrospinalis und Kammerwasser des Auges betragen die Konzentrationen des Antimy‐kotikums etwa 80% der Blutspiegel. Die überwiegend renale Ausscheidung von unverandertem Fluconazol bewirkt hingegen im Urin 10–20fach höhere Konzentrationen als im Blut. Dieses pharmakokinetische Profil, das Fluconazol in der Behandlung mykotischer Harnwegsinfekte per se begünstigt, erfordert allerdings bei Patienten mit eingeschränkter Nierenfunktion die Anpassung der systemischen Therapie an eine niedere Dosierung. Die Empfindlichkeit der Sproßpilze korreliert in vitro und in vivo mit den in verschiedenen Kompartimenten des Körpers gemessenen Fluconazol‐Konzentrationen.

A new pharmaceutical concept for the treatment of oropharyngeal and oesophageal candidosis with fluconazole

Summary. Administration of fluconazole in capsule form has proved effective in the prophylaxis and treatment of mucosal candidosis, particularly in immunosuppressed patients. An additional topical effect in oropharyngeal and oesophageal candidosis might be expected with a fluconazole suspension. This hypothesis was therefore tested in a crossover study in 12 healthy volunteers in whom the concentrations of the antimycotic were measured in saliva and plasma after oral administration of 100 mg flaconazole as either a capsule or a suspension. The time courses of the fluconazole concentrations were very similar with the two formulations in plasma, but significantly different in saliva. Thus, the mean Cmax for fluconazole in saliva of 551 μg ml‐1was reached 5 min after ingestion of the suspension, compared with a value of 3 μg ml‐1some 4 h after taking the capsule. The mean concentration of the antimycotic in saliva over the observation period (0–96 h) was more than 80% higher with the suspension than with the capsule.