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D W Warnock

Publications and source records attributed to D W Warnock.

At least 73 records · Page 4Linked to original sources
PubMed1995

Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis.

We examined the effect of different fluconazole treatment regimens on the emergence of azole drug resistance among Candida species recovered from the mouths of 54 HIV-infected individuals. Patients were assigned to one of three treatment groups depending on their history of oral candidosis and fluconazole use. Mouthwashes obtained at regular intervals were cultured and isolates identified using standard methods. Antifungal broth micro-dilution tests were performed to determine IC30s of fluconazole and ketoconazole. Sixty-four Candida albicans isolates from 20 patients with no evidence of oral candidosis who had not received fluconazole all had IC30s of < or = 4 mg/L. Thirty-four (83%) of 41 C. albicans isolates from ten patients receiving intermittent, short-term fluconazole treatment for oral candidosis had IC30s of < or = 4 mg/L, but only two isolates (5%) had IC30s > or = 64 mg/L. In contrast, 26 (40%) of 65 C. albicans isolates from 15 patients given long-term fluconazole (50-200 mg/day or 150 mg/week) were classified as resistant having IC30s of fluconazole of > or = 64 mg/L. Ten of these 26 fluconazole-resistant isolates were susceptible to ketoconazole with IC30s of < or = 4 mg/L suggesting azole drug cross-resistance is not inevitable. Tests on multiple colonies from individual isolation plates showed that it was not unusual to obtain differing IC30 values, indicating that a sweep inoculum is essential if resistance is to be detected. Nine (60%) of the 15 patients given long-term fluconazole harboured isolates of C. albicans that were resistant to fluconazole at some time during the study period. All had low CD4 counts and were approaching the final stage of their illness. Three patients on long-term treatment had resistant organisms at the outset of the study; in the remainder, resistant strains emerged during the study period. In six of the nine cases, emergence of resistance in vitro correlated with persistent clinical signs of oral infection. Thirty-six isolates of Candida species other than C. albicans were also recovered from patients receiving long-term fluconazole and 29 (81%) of these had IC30s of > or = 64 mg/L. Our experience with C. albicans in patients with HIV infection, suggests that the long-term azole drug use may be an important factor in the development of fluconazole resistance as such resistance was rare and transient in patients on intermittent short-term treatment.

Antifungal Agents↗
PubMed1995

Multiple dose pharmacokinetics of an oral solution of itraconazole in patients receiving chemotherapy for acute myeloid leukaemia.

The multiple dose pharmacokinetics of a solution of itraconazole given orally were measured in an open study of 20 patients undergoing remission induction chemotherapy for acute myeloid leukaemia. Patients were given itraconazole 5 mg/kg od, 2.5 mg/kg bd, 2.5 mg/kg od or 1.25 mg/kg bd. The mean daily dose of itraconazole was 407 mg for patients receiving 5 mg/kg/day and 148 mg in patients receiving 2.5 mg/kg/day. Mean concentrations of 493 and 495 micrograms/L were achieved on day 8 in patients who received 5 mg/kg/d od or 2.5 mg/kg bd itraconazole respectively. However, mean concentrations were significantly lower for those who received 2.5 mg/kg od itraconazole being 110 micrograms/L on day 8. Mean areas under the serum-concentration time curves were also markedly higher in patients receiving 5 mg/kg/day than in those receiving 2.5 mg/kg/day itraconazole and were 22,382 and 5615 micrograms.h/L on day 15 respectively. These findings suggest that the serum concentrations attained with an oral solution of 5 mg/kg itraconazole either once daily or in two divided doses are suitable for antifungal prophylaxis in patients receiving chemotherapy for acute myeloid leukaemia.

Adolescent↗
PubMed1995

Itraconazole susceptibilities of fluconazole susceptible and resistant isolates of five Candida species.

The in-vitro susceptibilities of 1380 isolates of five Candida species were determined in order to establish whether isolates resistant to fluconazole were cross-resistant to itraconazole. IC50 values were determined by a broth microdilution method. 690 Candida albicans isolates, seven Candida glabrata isolates, seven Candida krusei isolates, 120 Candida parapsilosis isolates and 37 Candida tropicalis isolates were susceptible to both fluconazole (IC50 < or = 32 mg/L) and itraconazole (IC50 < or = 4 mg/L). Twenty eight of 160 C. albicans isolates (17.5%), 180 of 293 C. glabrata isolates (61.4%), six of 48 C. krusei isolates (12.5%), and 10 of 18 C. tropicalis isolates (55.5%) resistant to fluconazole (IC50 > or = 64 mg/L) were also resistant to itraconazole (IC50 > or = 8 mg/L). In contrast, drug-specific resistance to itraconazole was not observed in any of the isolates tested. However, the itraconazole IC50s for fluconazole susceptible isolates were lower than those for fluconazole resistant isolates, which suggests that patients who fail fluconazole treatment might require itraconazole at higher dosages than usual.

Antifungal Agents↗
PubMed1995

Antifungal drug susceptibility testing. Working Party of the British Society for Antimicrobial chemotherapy.

This article describes the current situation with regard to intrinsic and acquired resistance to antifungal compounds and progress with the development of standardized methods of susceptibility testing for amphotericin B, flucytosine, and the azoles. Recommendations for testing of isolates from patients destined to receive antifungal drug treatment, or in whom therapeutic failure or relapse is suspected, are presented.

Antifungal Agents↗
PubMed1995

Fungal complications of transplantation: diagnosis, treatment and prevention.

Invasive fungal infection remains a major problem in transplant recipients. The commonest causes of infection are Candida, and Aspergillus spp., although a growing number of other organisms (including species of Fusarium and Trichosporon) have been reported to cause infection in neutropenic bone marrow transplant recipients. The clinical manifestations of these infections are described and methods of diagnosis are discussed. As in other groups of immunocompromised patients, the diagnosis is often difficult to establish, but transplant recipients who are given empirical treatment with amphotericin B have increased rates of survival. The roles of lipid-associated forms of amphotericin B and of the triazole compounds, itraconazole and fluconazole, in the treatment and prevention of fungal infection are discussed.

Amphotericin B↗
PubMed1995

Use of the Pastorex aspergillus antigen latex agglutination test for the diagnosis of invasive aspergillosis.

AIMS: To evaluate the Pastorex aspergillus antigen latex agglutination test for the diagnosis of invasive aspergillosis in patients undergoing liver or bone marrow transplantation. METHODS: Serum samples were taken at least twice weekly post-transplant and tested for Aspergillus antigen. Latex agglutination test results were compared with microbiological examination of respiratory, urine and bile specimens. Serum samples from liver transplant patients were also tested for antibodies to Aspergillus fumigatus by counter immunoelectrophoresis. RESULTS: Eight of the 91 patients studied developed invasive aspergillosis. Positive latex agglutination tests were obtained in eight of 187 (4.3%) serum samples from four of these eight patients. The other four patients with invasive aspergillosis gave consistently negative latex agglutination tests. A positive latex agglutination test was the first indication of invasive aspergillosis in two patients; these patients were already on amphotericin B. Positive latex agglutination tests were the only evidence of invasive aspergillosis in one patient who subsequently died of the infection. False positive latex agglutination tests were obtained in five of 83 (6%) patients with no evidence of invasive aspergillosis and misleading positive cultures seen in nine of 83 (10.8%). No antibodies were detected in three of four liver transplant patients with invasive aspergillosis. Conversely, antibodies were detected in 63 of 262 (24%) serum samples from 43 liver transplant patients with no evidence of invasive aspergillosis; one of these patients had an antibody titre of 1:2 on four separate occasions. CONCLUSIONS: The Pastorex aspergillus antigen latex agglutination test, when used alone, lacks sensitivity and specificity for the early diagnosis of invasive aspergillosis. A diagnosis was made in all patients with invasive aspergillosis when both culture and antigen tests were performed although using these criteria a false positive diagnosis would have been made in 13 of 83 (15.6%) patients. Microbiological and serial serological investigations for antigen should both be performed and the results considered in conjunction with radiological and clinical evidence.

Aspergillosis↗
PubMed1995

Evaluation of the AUXACOLOR system, a new method of clinical yeast identification.

AIMS: To compare the AUXACOLOR yeast identification system with the API 20C system. METHODS: Yeast isolates (n = 215), comprising 16 species, were identified using the AUXACOLOR system and the API 20C system. Isolates that could not be identified with the API 20C system or which produced discrepant results in the two systems were identified by assimilation and fermentation procedures. RESULTS: AUXACOLOR correctly identified 150 (85.7%) of 175 germ tube negative isolates while API 20C identified 155 (88.6%). Incorrect identifications were more common with API 20C (7.4%) than with AUXACOLOR (3.7%). Of 110 isolates of four common pathogens (Candida glabrata, C parapsilosis, C tropicalis, and Cryptococcus neoformans), 82.7% (91/110) were identified by AUXACOLOR while API 20C identified 74.5% (82/110). Of 65 less common germ tube negative isolates, 55.4% (36/65) were identified by AUXACOLOR while API 20C identified 63.1% (41/65). CONCLUSION: Although it has a limited database of 26 species, the AUXACOLOR system is a useful method for identification of germ tube negative clinical yeast isolates. Compared with the API 20C, the AUXACOLOR system is simpler and quicker to set up, easier to interpret, and comparable in cost.

Candida↗
PubMed1994

Multiple dose pharmacokinetics of an oral solution of itraconazole in autologous bone marrow transplant recipients.

The pharmacokinetics of itraconazole oral solution were measured in seven patients receiving chemotherapy followed by autologous bone marrow transplantation for leukaemia or lymphoma. Patients received 5 mg/kg/day itraconazole either as a once or twice daily dose. Drug concentrations reached steady state by day 15, in both groups. The mean pre-dose itraconazole serum concentration at hour 0, day 8 was 385 ng/mL in the od group and 394 ng/mL in the bd group, rising to 762 and 845 ng/mL by day 15, respectively. The mean AUCs for 0-24 h on day 8, 15 and 22 were 17,310 and 13,302 ng/mL/h, 24,476 and 25,154 and 22,621 and 21,423, for the od and bd groups, respectively. Thus serum concentrations of itraconazole suitable for antifungal prophylaxis can be attained in neutropenic patients, with the administration of an oral solution in a dosage of 5 mg/kg as either an od or bd schedule, following pre-autograft high-dose cytotoxic chemotherapy.

Adult↗
PubMed1993

Fluconazole resistance in Candida glabrata.

We report a case of infection with Candida glabrata in which the organism became resistant to fluconazole and in which pre- and posttreatment isolates were available for comparison. The organism was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Fluconazole was a potent inhibitor of cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) in lysates of cells from both susceptible and resistant cultures (50% inhibitory concentration, 0.2 microM), indicating that resistance was unrelated to changes in P-450DM. Instead, it appeared to arise from a permeability barrier to fluconazole, since resistant cells were unable to take up radiolabelled drug.

Aged↗
PubMed1993

Management of persistent vulvo vaginal candidosis due to azole-resistant Candida glabrata.

CASE REPORT--SUBJECTS--Three cases are described of long-standing vaginal candidosis due to Candida glabrata. These had failed to respond to local and systemic antifungals. In each case the infecting strain appeared resistant to a range of azole drugs in vitro. CLINICAL COURSE--Case one--This patient recovered following prolonged treatment with oral itraconazole in combination with oral and vaginal nystatin. Case two. Yeasts were eradicated from this patient following cyclical treatment with oral dydrogesterone; prolonged vaginal treatment with nystatin may have helped. Case three. This patient did not respond to a prolonged course of oral itraconazole in combination with vaginal and oral nystatin, oral medroxyprogesterone or intravaginal boric acid. Eradication of C glabrata was finally achieved by local application of 1% gentian violet. Shortly after eradication of the C glabrata infection, both Case two and Case three developed infections with other Candida species responsive to azole antifungals.

Administration, Oral↗
PubMed1992

Acremonium infection in a neutropenic patient.

Acremonium species (previously Cephalosporium) are saprophytic moulds of low pathogenicity commonly found in the environment. We report a case of repeated acremonium fungaemia in a neutropenic patient, probably associated with a Hickman line. Fungaemia was accompanied by fever and a papular skin rash, both of which appeared to resolve when the neutrophil count recovered without antifungal chemotherapy, only to return when the patient next became neutropenic.

Acremonium↗
PubMed1992

Effect of methotrexate on the germination and growth of Aspergillus fumigatus and Aspergillus flavus strains.

Methotrexate at concentrations of greater than or equal to 10(-5) M caused a significant reduction in the rate of germ tube formation of spores of Aspergillus fumigatus, but not of Aspergillus flavus, after 7 h incubation. At 10(-3) M the drug caused a significant reduction in germ tube elongation of A. fumigatus and A. flavus strains during the first 7 h of germination. After 18 h incubation, drug concentrations of greater than or equal to 4 x 10(-4) M produced greater than 80% reduction in growth of all strains tested. Potentiation of the antifungal effect against A. fumigatus was detected in tests in which methotrexate at 10(-4) M was used in combination with amphotericin B at 5 x 10(-7) M.

Amphotericin B↗