Smith Shadomy

The Evolution of Pulmonary Cryptococcosis: Clinical Implications from a Study of 41 Patients With and Without Compromising Host Factors

Over 14 years 41 patients were diagnosed as having pulmonary cryptococcosis. Cryptococcus neoformans remained localized to the lung in 12 cases and disseminated in the remaining 29. Thirty-four patients were compromised hosts. Disseminated disease developed in 28 of these 34, and four of these 28 patients with disseminated disease presented with concomitant pulmonary and meningeal infections. In all the remaining 24 central nervous system involvement developed 2 to 20 weeks after the finding of an abnormal chest roentgenogram. Seven patients were normal hosts, and in six of these cases disease remained localized to the lung. Four important conclusions were drawn from this study: pulmonary cryptococcosis is rarely considered in the differential diagnosis of an abnormal chest roentgenogram, thereby leading to missed diagnoses and therapeutic errors; the natural history of untreated pulmonary cryptococcosis in compromised hosts is extrapulmonic dissemination; compromised hosts with pulmonary cryptococcosis should receive antifungal therapy because of a high propensity for dissemination; and normal hosts in whom dissemination has been excluded generally do not need antifungal therapy.

In vitro and in vivo evaluation of antifungal agents

The evaluation of any antifungal agent involves the determination of its in vitro and in vivo activity against pathogenic and/or opportunistic fungi. The in vitro evaluation is followed by an in vivo evaluation in animal models, and clinical trials in humans. From the first report of the efficacy of the iodides for the treatment of sporotrichosis (1903) until the introduction of the imidazoles (azoles, 1960s), the number of antifungal agents available was very limited, including griseofulvin (1939), nystatin (1950), amphotericin B (1956), and flucytosine (1964). This paper briefly reviews the status of the antifungal agents currently used, and gives a more in depth evaluation of progress during recent years in the search for new antifungal drugs. Efforts to improve the efficacy of the current antifungal agents are also reviewed.

In-vitro studies with SF 86–327, a new orally active allylamine derivative

SF 86-327 (Sandoz Forschungsinstitut) is an orally active allylamine derivative related to naftifine. The antifungal activity of SF 86-327 was compared in vitro with those of naftifine, ketoconazole, and itraconazole (R 51,211, Janssen Pharmaceutica) by agar dilution. 120 fungal isolates were tested. Also, the antifungal activities of SF 86-327 and naftifine against 18 dimorphic pathogens were assayed in vitro by broth dilution. Results of these studies support claims that SF 86-327 is a broad spectrum antifungal agent. Results of the broth dilution studies also revealed that SF 86-327 was both fungistatic and fungicidal in vitro for isolates of Blastomyces dermatitidis, Histoplasma capsulatum and Sporothrix schenckii at concentrations as low as 0.05 micrograms ml-1 (18 isolates tested, MIC90 = 0.39 micrograms ml-1, MFC90 = 12.5 micrograms ml-1).

Dematiaceous fungal pathogens isolated from nature

This study was conducted to demonstrate the presence of pathogenic dematiaceous fungi in nature. Using hamster and mouse inoculation techniques, 43 isolates of dematiaceous fungi were recovered from 39 samples of woody plant material and soil from the Virginia environment. Thirteen species were identified and included 4 Phialophora spp., 3 Cladosporium spp., 2 Exophiala spp., Sporothrix sp., Wangiella dermatitidis, Bispora betulina, and Scytalidium lignicola. Evidence is presented for the first isolations of C. trichoides from nature in the United States; these isolates proved to be pathogenic for mice in which they produced disease and death in a course similar to that seen in man. Natural isolates of Phialophora verrucosa, Phialophora repens, Exophiala jeanselmei, and Wangiella dermatitidis were identical to those species isolated from man using the following criteria: morphology, 12% gelatin reaction, and survival in laboratory animals.

In vitro studies with R 51,211 (itraconazole).

The in vitro activity of R 51,211 (itraconazole, accepted generic name; Janssen Pharmaceutica, Beerse, Belgium), a new orally active triazole, was compared with those of two existing orally active azoles, ketoconazole and BAY n 7133, and a topical agent, Ro 14-4767/002. An agar dilution procedure (Kimmig agar) was performed with 148 isolates of pathogenic fungi. Incubation was at 30 degrees C from 48 h to 7 days. R 51,211 was dissolved in 0.2 N HCl in absolute ethanol, ketoconazole was dissolved in 0.2 N HCl alone, BAY n 7133 was dissolved in absolute ethanol, and Ro 14-4767/002 was dissolved in dimethyl sulfoxide. R 51,211 and Ro 14-4767/002 were the most active drugs against isolates of Histoplasma capsulatum, and R 51,211 showed the greatest activity in vitro against isolates of Blastomyces dermatitidis and Cryptococcus neoformans. Ro 14-4767/002 was the most active drug against 30 isolates of dermatophytes, followed by R 51,211, ketoconazole, and BAY n 7133. R 51,211 showed the best activity in vitro against 19 isolates of Aspergillus fumigatus and Aspergillus flavus, as well as 19 isolates of dematiaceous fungi. All four drugs had 90% MICs of greater than or equal to 16 micrograms/ml when tested with isolates of zygomycetous fungi.

In Vitro Activity of 5-Fluorocytosine Against Candida and Torulopsis Species

One hundred yeasts were studied. Tests included detailed identification and determination of 24- and 48-hr minimal inhibitory concentrations and minimal fungicidal concentrations of 5-fluorocytosine (5-FC). Final identifications included 57 isolates of Candida albicans, 15 isolates of C. tropicalis, 13 isolates of C. parapsilosis, 7 isolates of Torulopsis glabrata, 3 isolates of C. guilliermondii, 2 isolates each of C. stellatoidea and Cryptococcus neoformans, and 1 isolate of Candida krusei. Twenty-three original identifications were in error; these involved mostly C. albicans, C. tropicalis, C. parapsilosis, and T. glabrata. Inhibitory end point readings based on 24 hr of incubation were misleading. Whereas 79 of 91 isolates of Candida appeared to be inhibited at 24 hr by 12.5 μg or less of 5-FC/ml, only 52 were inhibited at 48 hr; whereas only 12 isolates appeared to be resistant to 100 μg/ml after 24 hr, 37 were resistant after 48 hr. Susceptibility varied amount the different species. C. tropicalis was the most susceptible, with 10 of 15 isolates (66.7%) being inhibited by 12.5 μg or less/ml and 7 (46.7%) being killed by 100 μg or less/ml. C. albicans was similarily susceptible; 33 of 57 isolates (57.9%) were inhibited by 12.5 μg or less/ml and 25 (43.9%) were killed by 100 μg or less/ml. C. parapsilosis was quite resistant, as only 4 of 13 isolates (30.8%) were inhibited by 12.5 μg or less/ml and 3 (23.1%) were killed by 100 μg or less/ml.

In Vitro Studies with Combinations of 5-Fluorocytosine and Amphotericin B

Synergistic antifungal activity of 5-fluorocytosine (5-FC) and amphotericin B was studied using an abbreviated checkerboard titration scheme. 5-FC was titrated in twofold increments (100 to 0.05 μg/ml) in the absence and presence of graded increments of amphotericin B (1.0. 0.5, 0.1, 0.05, and 0.01 μg/ml) in buffered yeast nitrogen base. A limited number of experiments were performed using expanded dual titration checkerboard schemes and growth curve studies. Forty-eight isolates of yeastlike organisms were tested; two were inhibited by the buffer system. Evidence of synergy, as indicated by a fourfold or greater reduction of the minimal inhibitory concentration of 5-FC in the presence of subinhibitory concentrations of amphotericin B, was seen with 11 of 46 isolates, or 24%, at the fungistatic level and with three isolates, or 7% at the fungicidal level. Indifferent results were obtained for 44 and 74% of the isolates, respectively, at the fungistatic and fungicidal levels. Antagonism was observed with three isolates.

In Vitro Activities of Five Oral Cephalosporins Against Aerobic Pathogenic Bacteria

Cefaclor (Lilly 99638) and cefatrizine (BL-S640, SK&F 70771) are orally absorbed, broad-spectrum semisynthetic cephalosporins. They were compared in vitro with cephalexin, cephaloglycin, and cepharadine against a variety of aerobic pathogenic bacteria by an agar dilution procedure. Cefaclor and cefatrizine were found to be similar or superior to cephalexin, cephaloglycin, and cephradine in terms of activity against gram-positive cocci other than enterococci. Only cefatrizine demonstrated any potentially useful activity against some susceptible isolates of enterococci. Cefaclor and cefatrizine also were highly active, equally or more so than the other oral cephalosporins, against several gram-negative species including Escherichia coli, Enterobacter aerogenes, and Klebsiella pneumoniae. None of the cephalosporins were particularly active against Enterobacter cloacae. Both cefaclor and cefatrizine were active against Proteus mirabilis; cefatrizine was uniquely active against indolepositive Proteus species.

Therapeutic Failures with Miconazole

A retrospective review of therapeutic failures of miconazole in three patients is presented. Miconazole, a new imidazole derivative, is a broad-spectrum antifungal agent purportedly effective topically, orally, and parenterally against a number of species of fungi. Three patients with the following culturally proven deep fungal infections were treated with miconazole: (i) destructive arthritis (Sporothrix schenckii), (ii) meningoencephalitis (Cryptococcus neoformans), and (iii) disseminated aspergillosis (Aspergillus fumigatus). All the organisms were susceptible in vitro to 1.56 μg or less of miconazole per ml using a broth dilution technique. In each patient, miconazole administered intravenously in dosages of 30 mg/kg per day failed to control or eradicate infection. Miconazole serum levels ranged from <0.5 to 4.35 μg/ml as determined by radial diffusion bioassay. Cerebrospinal fluid levels were virtually undetectable. In one patient (C. neoformans), miconazole was given intraventricularly in doses of 15 mg without response. Therapeutic failures were attributed to suboptimal body fluid levels of miconazole. The reason(s) for such low levels of activity was not clear, but may have been poor penetrance into tissues, in vitro inactivation, and/or unusually rapid excretion. Untoward reactions from miconazole included fever, chills, nausea, vomiting, and phlebitis. Images

A comparison of bifonazole (bay h 4502) with clotrimazole in vitro

The antifungal activity of a new topical imidazole, bifonazole (BAY h 4502, Bayer AG Institute for Chemotherapy), was compared in vitro with that of clotrimazole (BAY b 5097, Schering Corporation) in tests with 67 pathogenic and commensal yeasts, 45 dermatophytes and 14 miscellaneous pathogenic fungi by an agar dilution method. Three media, Kimmigs agar, Sabourauds agar, and casein-yeast extract-glucose agar were used. Bifonazole was inhibitory for nearly all the yeasts tested including Candida albicans, C. parapsilosis, and Torulopsis glabrata with geometric mean minimal inhibitory concentrations (G-MIC) averaging 5 micrograms ml-1 on all three media. Clotrimazole was the more active drug against these same species with G-MICs ranging from 0 . 25 to 2 . 10 micrograms ml-1. Results with bifonazole were affected by choice of medium with Kimmigs agar generally giving the lowest MICs; results with clotrimazole were also affected by choice of medium but to a lesser degree. In nearly all instances, both bifonazole and clotrimazole were inhibitory for the dermatophytic fungi at concentrations of 0 . 50 micrograms ml-1 or less and clotrimazole was the more active drug. Choice of medium was, in general, not a factor with these latter fungi which included Epidermophyton, Trichophyton, and Microsporum species. Both drugs were active against species of Aspergillus (G-MICs of 3 . 18 micrograms ml-1), Fusarium (G-MICs ranging from 1 . 59 to 12 . 70 micrograms ml-1) and Scopulariopsis (G-MICs of 1 . 78 micrograms ml-1); clotrimazole was the more active drug by factors of 2- to 4-fold on all three media. Bifonazole MICs were shown to vary with pH (maximal activity at pH 6 . 5) with selected yeasts when tested on Kimmigs agar. Differences in results obtained with varying inoculum sizes for these same yeasts generally were unremarkable. With selected species of yeasts and dermatophytes, it was determined that the ratio of minimal fungicidal to inhibitory concentrations (MFC/MIC) was much lower for bifonazole than for clotrimazole.