Susceptibility to ketoconazole of Candida albicans strains from sequentially followed HIV-1 patients with recurrent oral candidosis

The MIC values of the antifungal drug ketoconazole were evaluated on 66 Candida albicans strains. These strains were isolated from 26 HIV-1 infected patients with oral recurrent candidosis. Each episode of oral candidosis observed in these patients was orally treated with ketoconazole (200 mg/day) until the clinical disappearance of the lesions. The most frequent MIC values were 20 micrograms/ml and 10 micrograms/ml, observed in 37 and 19 isolates respectively. Only strains from five patients showed changes in their susceptibility to ketoconazole. This fact could indicate that a different strain causes the subsequent reappearance of the oral lesions, rather than the drug selecting resistant fungal strains. Our results stress the role of host characteristics in the occurrence of candidal infections, pointing to the progressing failure of the immunological response as the most important factor responsible for the recurrence of oral candidosis during HIV-1 infection.     

Systemic treatment of skin candidosis: a randomized comparison of terbinafine and ketoconazole

Terbinafine is an antimycotic drug which has a much higher in vitro activity against dermatophytes than against yeasts. To investigate the clinical relevance of these in vitro data, 118 patients with cutaneous candidosis were enrolled in a randomized, double-blind study and allocated to a 4-week treatment with a daily dose of either 250 mg b.i.d. terbinafine or 200 mg once-daily ketoconazole. At the final assessment, 3 weeks after cessation of therapy, mycological cure rates (negative culture and negative microscopy) were 82% in the terbinafine group and 73% in the ketoconazole group. Effective treatment with negative mycology and no or minimal signs or symptoms could be achieved in 65% of those who received terbinafine and in 57% of those randomized to ketoconazole. Five per cent and 7% of the patients taking terbinafine and ketoconazole, respectively, complained about adverse events, which were usually mild and did not lead to discontinuation of treatment. In one patient in the ketoconazole group, abnormal liver enzymes were noted at the final laboratory assessment. The results of this study indicate that terbinafine 500 mg daily can be an alternative to ketoconazole when systemic treatment of skin candidosis is required.     

Effect of Prophylactic Ketoconazole and Nystatin on Fungal Flora

Summary: The effect of prophylactic antifungal drugs on oropharyngeal and anterior nares fungal colonization was studied in 20 patients receiving nystatin and 19 patients receiving ketoconazole. Surveillance cultures were obtained weekly for a mean of 27.1 ± 4.8 days in the nystatin group and 44.0 ±6.7 days in the ketoconazole group. Initially, 63.2% of nystatin patients and 77.8% of ketoconazole patients had yeasts in their oropharynx. Neither drug eliminated oropharyngeal yeast colonization; by the end of the first four weeks of surveillance, 66.7% of the nystatin group and 63.6% of the ketoconazole group still had yeasts in the oropharynx. However, both drugs caused a reduction in the quantity of yeasts grown on successive cultures. Filamentous fungi were isolated in baseline cultures in 42.1% of the nystatin patients and 33.3% of the ketoconazole patients. Prophylaxis did not appear to alter carriage of filamentous fungi in the upper airways. Pathogenic filamentous fungi were only rarely isolated, and this rate did not increase with prophylaxis. Resistance to polyene antifungals (nystatin, amphotericin B) or to ketoconazole did not occur as a result of prophylaxis. Zusammenfassung: Untersuchung über die Pilzflora im Oropharynx und im vorderen Nasenraum unter dem Einfluß einer prophylaktischen antimykotischen Behandlung. 20 Patienten erhielten Nystatin und 19 Patienten Ketoconazol. Wöchentliche Kontrollkulturen wurden in der Nystatin-Gruppe über einen durchschnittlichen Zeitraum von 27,1 ± 4,8 Tagen und in der Ketoconazol-Gruppe über 44,0 ± 6,7 Tage durchgeführt. Zu Beginn der Untersuchung hatten 63,2% der Nystatin-Patienten und 77,8% der Ketoconazol-Patienten Hefen im Oropharynx. Keines der beiden Antimykotika eliminierte die oropharyngeale Hefebesiedlung. Nach 4wöchiger Beobachtung wurden Hefen in der Nystatin-Gruppe bei 76,7% und in der Ketoconazol-Gruppe bei 63,6% im Oropharynx festgestellt. Durch beide Antimykotika wurde jedoch eine Verringerung der kulturell nachweisbaren Hefemengen hervorgerufen. Schimmelpilze fanden sich zu Beginn der Untersuchung bei 42,1% der Nystatin-Patienten und bei 33,3% der Ketoconazol-Patienten. Unter der prophylaktischen Behandlung war keine Verringerung des Vorkommens derartiger Pilze in den oberen Luftwegen feststellbar. Pathogene Schimmelpilze wurden nur sehr selten isoliert und das Vorkommen dieser Pilze stieg unter der prophylaktischen Behandlung nicht an. Eine Resistenz gegenüber Polyen-Antimykotika (Nystatin, Amphotericin B) oder Ketoconazol trat unter der prophylaktischen Behandlung nicht auf.     

The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.     

Antimikrobielle Effekte des in vitro simulierten Ketoconazol-Kantharidinblasenflüssigkeitsspiegel-Profils bei Candida albicans*,**/Antimicrobial Effects of Ketoconazole Concentration Profiles in Cantharidin Blister Fluid,Simulated in Vitro,on Candida albicans

Zusammenfassung: Candida albicans (Isolat Nr. 5125/85) wurde zum einen in Sabouraud-Glukose-Bouillon, zum anderen in einem flüssigen synthetischen Aminosäuremedium gegenüber ständig schwankenden Konzentrationen von Ketoconazol exponiert. Zugrundegelegt wurden die Profile der freien wie die der Gesamtkonzentrationen, die beim Menschen nach einmaliger oraler Gabe von 200 mg in kutaner Kantharidinblasenflüssigkeit gefunden wurden. Parallel zu jedem Versuchsansatz mit Ketoconazol wurde jeweils ein Ansatz ohne Wirkstoff mitgeführt. Bei Verwendung des ersteren, die Hefeform begünstigenden Mediums fand sich nur eine relativ geringe Wachstumshemmung. In dem die Pseudomyzelform begünstigenden synthetischen Medium war demgegenüber — konzentrationsabhängig — ein deutlicher antimikrobieller Effekt zu erkennen (Keimdichtenzunahme in Gegenwart der Gesamtkonzentration auf das 2, lfache, im Kontrollversuch auf das 15, 3fache). Die größere Wirksamkeit von Ketoconazol auf die Pseudomyzelform von Candida albicans wird wiederum bestätigt, zugleich wird die geringere Sicherheitsmarge bei der systemischen Behandlung mit Azolen gegenüber der antimikrobiellen Chemotherapie mit Antibiotika deutlich. Untersuchungen vom vorliegenden Typ — wie sie in der klinischen Bakteriologie schon öfter durchgeführt wurden — könnten auch bei der Untersuchung neuer Antimykotika zunehmend an Bedeutung gewinnen. Summary: Candida albicans was exposed to continously changing concentrations of Ketoconazole in, on the one hand, Sabouraud Dextrose Broth and, on the other hand, a liquid synthetic amino-acid medium. The profiles of the free and total concentrations found in cutaneous cantha-ridin blister-fluid in humans after a single oral dose of 200 mg were used as basic information. For every experiment with ketoconazole, an identical experiment without addition of an antimycotic was carried out Using the first, yeast-promoting medium, only a relatively small growth-inhibition was evident. Using the synthetic amino-acid medium, which promotes the pseudomycelial form, however, a marked, concentration-dependent, antimicrobial effect was observed. (The colonial density of Candida albicans increased 2.1 times in the presence of the total ketoconazole concentrations, compared with 153 times in the control experiment.) The greater effectiveness of ketoconazole against the pseudomycelial form of Candida albicans is again confirmed. At the same time, the smaller safety margin associated with systemic treatment with azoles as compared with anti-microbial therapy with antibiotics, is apparent. Investigations of the present type, which have often been carried out in clinical bacteriology, may also gain significance in the investigation of new antimycotics.     

Visceral paracoccidioidomycosis in a gold miner from Brazil

Zusammenfassung: Es wird über einen 49-jährigen Deutschen berichtet, der nach 15-jährigem Aufenthalt in Südameri-ka an einer Paracoccidioidomykose er-krankte. Er litt an einer Cheilitis, einer erosiven Stomatitis, einer Laryngitis und einer beidseitigen Pilzpneumonie; außer-dem bestand der Verdacht auf ein Pilzgra-nulom des Gehirns. Die Diagnose wurde kulturell und serologisch gesichert. Die Ausbildung typischer Hefeformen mit mul-tiplen Sprossungen (“Steuerradformen”) benötigt oft länger als einen Monat (in die-sem Fall 6 Wochen), was die Diagnostik bei unklaren Krankheitsbildern erschwert. Der Patient wurde zunächst mit Amphotericin B und Sulfamethoxazol/Trimethoprim behandelt. Beide Medikamente muß-ten wegen Nebenwirkungen abgesetzt wer-den, obwohl Amphotericin B gut wirksam war. Ketoconazol war bei unserem Patien-ten weniger gut wirksam, während unter Itraconazol eine weitere deutliche Besse-rung eintrat. Nebenwirkungen wurden unter den beiden letztgenannten Medika-menten nicht beobachtet. Summary: We report on a 49 years old patient who developed paracoccidioidomycosis after working in a gold mine in South America. The patient suffered from cheilitis, stomatitis, laryngitis, and bilateral pneumonia. Additionally, there was evidence for cerebral granuloma. The diagnosis was confirmed by culture and serologic methods. Paracoccidioides brasilien-sis grows slowly and more than a month may elapse (in this case 6 weeks) before typical yeast-like forms with multiple buds (steering-wheel fungus cells) appear in culture, which often complicates the diagnosis if there is no typical clinical picture. The patient was treated with amphotericin B and sulfamethoxazole/trimethoprim, and a clinical response to therapy was observed. However, therapy had to be stopped because of severe side effects. Ketoconazole was less effective, but further clinical improvement was achieved under itraconazole without untoward side effects.     

Pityriasis versicolor—Epidemiological and Therapeutical Study

Seventy-six patients with extensive pityriasis versicolor were divided into 3 groups and treated orally with ketoconazole, 200 mg daily, for 10, 20 or 30 days respectively. 50 patients out of this number completed the study. After 6 months, 46 patients were checked up. Eight of them developed relapses effectively treated with ketoconazole for another 15 days. Six out of these 8 patients belonged to the first group using ketoconazole for 20 days only. On the basis of this observation, we do not consider a 10 days' treatment to be sufficient and recommend that the patient should be treated for at least 20 days. As a preventive measure we recommend a daily bath with salicylic acid and sulphur soap. The frequency of the infection was higher in males (71.4%) than in females (28.6%). The youngest of the male patients was 4 months of age and the oldest 70 years. The youngest female was 4 months old and the oldest 50 years. Pityriasis versicolor was found to be predominant in the age group of 21--30 years. The sites most commonly involved were back, chest and the upper extremities.     

Additive Effect of the Combination of Griseofulvin and Ketoconazole Against Microsporum canis in Vitro: Additiver Effekt der Kombination von Griseofulvin und Ketoconazol gegen Microsporum canis in vitro

The susceptibility of 28 strains of Microsporum canis to griseofulvin, to ketoconazole and to a combination of both antifungal drugs was determined. Griseofulvin proved to be more active than ketoconazole. The combination of both antifungal agents was found to exert an additive effect.     

Prevention of Mycosis in Granulocytopenic Patients with Prophylactic Ketoconazole Treatment/Prophylaktische Mykose-Behandlung mit Ketoconazol bei granulozytopenischen Patienten

Summary: 38 patients with acute leukemia were randomly allocated to receive ketoconazole 400 mg daily p. o. or placebo in a double-blind fashion. Ketoconazole did neither prevent the patients from being colonized with Candida species, nor eradicate the fungi in patients already colonized, but only 2 ketoconazole patients developed clinical mycosis against 9 placebo patients (p = 0.03). The cumulative risk of developing clinical mycosis was significantly different in the two treatment groups (p = 0.003 at day 14). Prophylactic treatment with ketoconazole prevents or postpones the develepment of clinical mycosis in highly predisposed patients and has very few side effects.
Zusammenfassung: 38 Patienten mit akuter Leukämie wurden in einer randomisierten Doppelblindstudie mit Ketoconazol 400 mg pro die gegen Placebo untersucht. Ketoconazol vermochte weder die Kolonisierung von Candida-Spezies zu verhindern, noch beim Patienten bereits kolonisierte Pilze zu vernichten. Klinische Mykosen entwickelten sich bei 2 Ketoconazol-Patienten, gegenüber 9 Placebo-Patienten (p = 0,03). Das kumulative Risiko, eine Mykose zu entwickeln, war deshalb signifikant verschieden in den beiden Behandlungsgruppen (p = 0,003 am 14. Tag). Die prophylaktische Behandlung mit Ketoconazol verhindert oder verzögert die Entwicklung von Mykosen bei hochdisponierten Patienten und weist wenige Nebenwirkungen auf.     

Treatment with Itraconazole of Experimental Coccidioidomycosis in the Wistar Rat/Itraconazol-Behandlung der experimentellen Coccidioidomykose an Wistar-Ratten

Summary: The results obtained in a comparative study between ketoconazole and itraconazole in the treatment of the experimental coccidioidomycosis of the Wistar rat are presented. Animals weighing 250 g were inoculated intracardiacally with 200 arthrospores of Coccidioides immitis. Both drugs were administered once a day by gavage 16 mg/kg for itraconazole and 80 mg/kg for ketoconazole. Two therapeutic schedules of 14 days were used. The first one was set up 3 d before the infecting inoculation (earlier treatment) and the second one 7 d after it (later treatment). The control group of animals received only the solvent of both drugs (PEG 200). 98 animals which received the earlier treatment were evaluated. Only 3/30 rats that received itraconazole showed lung granulomas without spherules and the cultures were negative in all cases. From the 31 animals belonging to the ketoconazole group, 15 showed granulomas, 11 showed spherules and in 10 C. immitis developed in cultures. From the 37 rats used as controls, 35 had lung granulomas, 34 of them with spherules, and the cultures were positive in 35 cases. The later starting scheme was used on 30 rats, 8/10 of the animals treated with ketoconazole showed granulomas with spherules and the cultures were positive in 3 rats with 256 C.F.U./g of the lung; 9/10 of the itraconazole treated rats showed pulmonary granulomas with sporangia, with positive cultures in 2 cases and an average of 231 CF.U./g of the lung. The whole population of the control animals showed granulomas with sporangia and positive cultures, with an average of 18.247 C.F.U./g of the lung. All the treated animals exhibited very small sporangia without endospores. It was concluded that itraconazole was better in the treatment of the earlier schedule and showed similar efficacy to ketoconazole in the later schedule with doses 5 times lower. Zusammenfassung: Die Resultate einer Vergleichsstudie zwischen Ketoconazol and Itraconazol in der Behandlung der experimentellen Coccidioidomykose der Wistar-Ratte werden dargestellt. Es wurden Tiere mit einem Gewicht von 250 g verwendet und 200 Arthrosporen von Coccidioides immitis intrakardial inokuliert. Die Verabreichung beider Medikamente erfolgte 1 x/d in einer Dosierung von 16 mg/kg Itraconazol sowie 80 mg/kg Ketoconazol. Es kamen zwei therapeutische Schemata von 14-tägiger Dauer zur Anwendung, das erste begann 3 d vor der Infektion (Frühtherapie), das zweite 7 d danach (Spättherapie). Die Kontroll-gruppe erhielt ausschlißlich das Lösungsmittel beider Medikamente (PEG 200): 98 Versuchstiere mit Frühtherapie wurden ausgewertet. Nur 3/30 Ratten, denen Itraconazol appliziert wurde, zeigten pulmonale Granulome ohne Spherulen, und die Kulturen waren in allen Fällen negativ. Von 31 mit Ketoconazol behandelten Tieren wiesen 15 Granulome, 11 Spherulen auf, und bei 10 wuchs C. Immitis in Kulturen. Von den 37 Ratten der Kontrollgruppe zeigten 35 Lungengranulome, 34 davon mit Spherulen, und in 35 Fällen waren die Kulturen positiv. Die Spättherapie wurde bei 30 Ratten ange-wandt; 8/10 dieser Tiere, behandelt mit Ketoconazol, zeigten Granulome mit Spherulen, und bei drei Ratten waren die Kulturen positiv mit 256 KfE/g Lunge. 9/10 der mit Itraconazol therapierten Ratten wiesen pulmonale Granulome mit Spherulen auf mit positiven Kulturen in zwei Fällen und einem Durchschnitt von 231 KfE/g Lunge. Die gesamte Kontrollgruppe zeigte Granulome mit Spherulen und positive Kulturen mit einem Durchschnitt von 18.247 KfE/g Lunge. Alle behandelten Tiere wiesen sehr kleine Spherulen ohne Endosporen auf, die Kontrollgruppe hingegen reife Spherulen mit Endosporen. Daraus wird geschlossen, daß Itraconazol in der Friihtherapie besser wirkt und in der Spättherapie dem Ketoconazol vergleichbare Wirksamkeit mit einer fünffach niedrigeren Dosis erzielt