David J. Drutz

Host defense in cryptococcosis: II. Cryptococcosis in the nude mouse

Abstract In the homozygous state, mice carrying the “nude” (nu) gene are hairless (nude), lack a thymus and have profound deficiency of cell-mediated immunity. Cryptococcosis was studied in BALB/c and Swiss mice, each strain carrying the nu gene. The purpose was to determine the interactions of the nu gene and mouse strain in terms of susceptibility to Cryptococcosis. Mice of both strains could be sensitized to produce delayed-type hypersensitivity reactions to cryptococcal extract in the heterozygous nu/X state, but not in the nu/nu state. Nu/X Swiss mice were more resistant than nu/X BALB/c mice to infection with a highly virulent strain (B) of Cryptococcus neoformans . However, nu/nu BALB/c and nu/nu Swiss mice were both highly susceptible to the same microorganism. Challenge with another cryptococcal strain (A) of much lower virulence for nu/X mice killed 100% of BALB/c and Swiss nu/nu mice. These studies indicate that thymus-dependent immune functions are critical determinants of host resistance to murine Cryptococcosis.

Antibacterial activities of antineoplastic agents.

Fourteen antineoplastic agents were examined for in vitro antibacterial activity against 101 aerobic and anaerobic bacterial isolates representing indigenous human microflora and selected opportunistic pathogens. Only 5-fluorouracil, mitomycin, and etoposide demonstrated inhibitory effects at achievable plasma concentrations, while the remaining drugs lacked appreciable antibacterial activities.

Sensitive bioassay for ketoconazole in serum and cerebrospinal fluid.

Ketoconazole is a broad-spectrum antifungal agent which appears promising for treatment of a variety of systemic mycoses. Pharmacokinetic studies are limited due to a lack of readily available methods for quantitation of ketoconazole in serum or cerebrospinal fluid. We developed a rapid, simple bioassay for measurement of ketoconazole alone or in the presence of therapeutic levels of amphotericin B, using an agar diffusion assay incorporating Candida pseudotropicalis. Pairs of 8-mm wells cut in the seeded assay medium were filled with four duplicate ketoconazole standards and duplicate patient specimens. Zones of inhibition were visible after 7 to 8 h of incubation, but were most easily measured after overnight growth. The assay allowed determinations of serum ketoconazole levels as low as 0.3 microgram/ml with a 4.4% coefficient of variation. Thirty-five serum samples from patients receiving the drug were assayed by this method, and the results were compared with the Coccidioides immitis endospore assay. The correlation coefficient between the assays was 0.90. This assay allows any microbiology laboratory to easily and safely determine ketoconazole levels in serum or cerebrospinal fluid. Images

Amphotericin B in the Treatment of Coccidioidomycosis

SummaryIn the 25 years since its introduction, amphotericin B has demonstrated clear value in the management of coccidioidomycosis. However, its effectiveness is less certain than in diseases due to other fungal aetiological agents, even when the loci of infection and in vitro drug susceptibilities are identical. The refractoriness of coccidioidomycosis may relate to the unique ability of each Coccidioides immitis spherule to release hundreds of endospors, thus maximally challenging host defence mechanisms. Amphotericin B is most likely to be effective where there is evidence of intact cell-mediated immunity against C. immitis (i.e. positive coccidioidin or spherulin skin test; low titre of complement fixing antibody), and structural damage to tissues. When bones and joints are involved, as is frequently the case, adjunctive surgical management is generally required. Patients with structural lung disease (i.e. cysts and/or cavities) show variable, often minimal, response to treatment.Amphotericin B has transformed coccidioidal meningitis from a routinely fatal disease to one where prolonged survival is possible. However, the drug must be given by the intrathecal route, and for periods of years, before the possibility of cure can be considered. Relapses of bone, joint and meningeal coccidioidomycosis are common and should be anticipated, especially in patients with impaired immunity.

Activities of aztreonam and new cephalosporins against infrequently isolated gram-negative bacilli.

The susceptibilities of 159 clinical isolates of glucose nonfermentative gram-negative bacilli were determined for eight new monobactam or beta-lactam antibiotics. Imipemide (N-formimidoyl thienamycin) was effective against the largest number of species, although not against Pseudomonas maltophilia. Cefoperazone and ceftazidime, but not cefsulodin, were active against infrequently isolated Pseudomonas species. Aztreonam, moxalactam, cefotaxime, and ceftizoxime demonstrated selective activity against several species, including certain amino-glycoside-resistant isolates.

Rapid, simple bioassay for 5-fluorocytosine in the presence of amphotericin B.

It is important that serum levels of 5-fluorocytosine (5FC) be measured to insure therapeutic levels while avoiding toxicity. This is particularly true in patients with renal insufficiency. The concurrent use of amphotericin B and 5FC complicates the measurement of 5FC in the serum, since fungi used in conventional bioassay systems are uniformly susceptible to amphotericin B. This paper describes the development of a simple, reliable, 6-h bioassay for 5FC in the presence of amphotericin B. The assay is based upon the fact that 5FC diffuses readily through yeast nitrogen base agar, whereas amphotericin B apparently does not. This assay allows rapid adjustments in therapy of patients receiving both 5FC and amphotericin B and has permitted us to maintain 5FC serum levels between limits of 25 and 120 μg/ml in patients with altered renal function. Images