The defect in host defense that makes the diabetic ketoacidotic (DKA) patient susceptible to mucormycosis has not been identified. Sera from 10 DKA patients and three normal volunteers were tested for their capacity to support the in vitro growth of a common etiologic agent of mucormycosis, Rhizopus oryzae. After equilibration with room air none of the normal or DKA sera, each of which was now extremely alkaline, supported growth of R. oryzae. When the sera were placed in a CO2 atmosphere that permitted simulation of the in vivo clinical pH (normal 7.40 and DKA 7.3-6.6), four of seven DKA sera supported profuse fungal growth. No growth occurred in normal serum. The three DKA sera that did not support fungal growth at pH less than or equal to 7.3 contained less iron (x = 13 micrograms/dl) than the four sera that supported profuse fungal growth (x = 69 micrograms/dl). Increasing the iron content of iron-poor DKA serum that did not support R. oryzae growth allowed profuse growth at acidotic conditions but not at pH greater than or equal to 7.4. Simulated acidotic conditions (pH 7.3-6.6) also decreased the iron-binding capacity of normal serum stepwise from 266 micrograms/dl to 0. Our data indicate that acidosis temporarily disrupts the capacity of transferrin to bind iron and suggest that this alteration abolishes an important host defense mechanism that permits growth of R. oryzae.

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Delivery of ketoconazole to human stratum corneum was studied. Thirteen healthy volunteers, three patients with chronic fungal disease and one patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole daily for various lengths of time. The ketoconazole content of palmar stratum corneum, eccrine sweat, sebum, and serum was measured by high-pressure liquid chromatography (sensitivity, 0.005 to 0.010 microgram/ml). Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 micrograms of ketoconazole per g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from three patients with chronic fungal infection treated for greater than 9 months contained ketoconazole (means, 4.7 micrograms/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 microgram/ml on day 7 and 0.084 microgram/ml on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole containing eccrine sweat demonstrated a 10-fold greater concentration in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. We conclude that eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids.

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