Concentrations Of Amphotericin Research Articles

Lysozyme-enhanced killing ofCandida albicansandCoccidioides immitisby amphotericin B

The concentration of amphotericin B required to inhibit the growth in chemically defined media of 3 strains of Candida albicans and the spherule and mycelial growth phases of Coccidioides immitis S...

Effects of Rifamycin Derivatives, Alone and in Combination with Amphotericin B, Against Histoplasma capsulatum

Several derivatives of rifamycin SV inhibited ribonucleic acid synthesis and decreased the viability of Histoplasma capsulatum. Both of these effects were enhanced by low concentrations of amphotericin B. The relative potency of the different rifamycin derivatives against H. capsulatum, when used in combination with amphotericin B or alone, was the same as that reported for the inhibition of the reverse transcriptase of ribonucleic acid tumor viruses.

Polyene antibiotic action on lecithin liposomes: Effect of cholesterol and fatty acyl chains

The effect of cholesterol incorporation upon amphotericin B and nystatin susceptibility of lecithin liposome systems containing various fatty acids has been studied. Cholesterol was shown to: 1) confer sensitivity to low concentrations of amphotericin B in liposomes derived from egg lecithin, and 2) suppress the amphotericin B and nystatin-induced response in liposomes derived from dipalmitoyl or distearoyl lecithins. This clear cut difference cannot be explained by mechanisms of drug action so far presented. They are discussed in connection with the possibility that susceptibility to these polyene antibiotics is related to the over-all state of the membrane organization, in particular to the over-all conformation of membrane components.

Influence of amphotericin, amiloride, ionophores, and 2,4-dinitrophenol on the secretion of the isolated cat's pancreas.

The isolated cat pancreas was perfused with a Krebs-Henseleit-solution containing different concentrations of Amphotericin, Amiloride, Gramicidin, Dinitrophenol, Valinomycin, and Nigericin. In order to separate functionally the effects of these substances on the mitochondrial and the plasma membrane, we tested their influence on the secretory flow rate under aerobic and anaerobic conditions. A Na+−K+- and a HCO3 −-ATPase have been found in membrane fractions of pancreatic homogenates. Since there is a possibility that these enzymes are involved in active ion transport, we tested the effect of all substances on the level of activity of both Na+K+-ATPase and HCO3 −-ATPase. The following were found: All tested substances except Gramicidin had an effect on pancreatic electrolyte secretion. Concerning the aerobic experiments, the inhibitory effect of Dinitrophenol and the ionophores might be due to uncoupling of oxidative phosphorylation. The results of the anaerobic experiments are interpreted as being due to changes of cell membrane permeability. As the effects of Nigericin, Valinomycin and Amiloride in the anaerobic experiments correspond to the effects of these substances on the ATPase activity, we suggest that these enzymes might be involved in the active transport processes of NaHCO3 −-secretion.

Amphotericin B potentiation of rifampicin as an antifungal agent against the yeast phase of Histoplasma capsulatum.

Rifampicin, at high concentrations, inhibited growth and RNA synthesis in the yeast phase of Histoplasma capsulatum. These effects were potentiated by low concentrations of amphotericin B. The combination of the two agents was fungicidal, whereas each alone, at much higher concentrations, was only fungistatic.

A selective oleic acid albumin agar medium for tubercle bacilli.

Summary A selective medium for Mycobacterium tuberculosis and Myco. bovis has been developed containing polymyxin B 200 units per ml, carbenicillin 100 μ per ml, amphotericin B 10 μ per ml and trimethoprim 10 or 20 μ per ml in 7H10 oleic acid albumin agar. When the centrifuged deposit from sputum, liquefied by treatment with dithiothreitol, was plated directly on to the selective medium, less than 1 per cent. of plates were contaminated and the viable counts were about 240 per cent. higher than parallel counts after treatment of the deposit with NaOH and plating on 7H10 medium without drugs. A comparison of results on medium with and without the selective drugs showed that the drugs slowed the early growth of Myco. tuberculosis in slide culture and reduced viable counts by, at most, 10 per cent. Improved anti-fungal cover could be obtained with no reduction in viable counts by increasing the concentration of amphotericin B to 50 μ per ml.

A comparativein vitrostudy of amphotericin B, clotrimazole and 5-fluorocytosine against clinically isolated yeasts

Minimum inhibitory concentrations of amphotericin B, clotrimazole and 5-fluorocytosine have been determined against 413 yeast strains isolated from clinical material. All 343 strains of Candida albicans were inhibited by 4 μg/ml of amphotericin B and by 16 μg/ml of clotrimazole, while 40 (11·7%) were resistant (MIC≥ 50 μg/ml) to 5-fluorocytosine. The 53 strains of Torulopsis glabrata were more sensitive to amphotericin B and less sensitive to clotrimazole than were the C. albicans strains, and 14 (24%) were resistant to 5-fluorocytosine. At concentrations of the drugs attainable in vivo (2–3, 3 and 100 μg/ml respectively), 83·4%, 16·7% and 89% of all the strains isolated would be inhibited by amphotericin B, clotrimazole and 5-fluorocytosine. From these in vitro results, it is possible that 5-fluorocytosine may show greater activity in vivo than clotrimazole against yeasts responsible for candidiasis in humans.

Effect of rapid intravenous infusion on serum concentrations of amphotericin B.

The magnitude of the concentrations of amphotericin B produced in serum of patients with systemic mycoses may significantly influence the outcome of therapy with this drug. Since amphotericin B is conventionally administered in intravenous infusions lasting 4 to 6 hr, we asked whether faster infusions of this drug might yield higher serum concentrations without an increase in dose. This question was studied in three patients who received 16 infusions of this drug: eight infusions administered slowly (5 hr) and eight administered rapidly (45 min). Serum concentrations after each rapid infusion were compared with those after a slow infusion administered to the same patient. The mean serum concentration of amphotericin B 1 hr after the rapid infusions (2.02 mug/ml) was significantly higher (P < 0.001) than the mean serum concentration of amphotericin B 1 hr after the slow infusions of this drug (1.18 mug/ml). Mean serum concentrations 18 and 42 hr after rapid infusion remained slightly but not significantly higher than respective mean concentrations after slow infusions. By yielding higher initial serum concentration, rapid intravenous infusion may be therapeutically more effective than slow infusion of amphotericin B. Although rapid infusions caused no more toxicity than did slow infusions, the lack of greater toxicity with rapid infusion of amphotericin B should be further documented prior to extensive clinical application of this procedure.

Effect of Rapid Intravenous Infusion on Serum Concentrations of Amphotericin B 1

The magnitude of the concentrations of amphotericin B produced in serum of patients with systemic mycoses may significantly influence the outcome of therapy with this drug. Since amphotericin B is conventionally administered in intravenous infusions lasting 4 to 6 hr, we asked whether faster infusions of this drug might yield higher serum concentrations without an increase in dose. This question was studied in three patients who received 16 infusions of this drug: eight infusions administered slowly (5 hr) and eight administered rapidly (45 min). Serum concentrations after each rapid infusion were compared with those after a slow infusion administered to the same patient. The mean serum concentration of amphotericin B 1 hr after the rapid infusions (2.02 mug/ml) was significantly higher (P < 0.001) than the mean serum concentration of amphotericin B 1 hr after the slow infusions of this drug (1.18 mug/ml). Mean serum concentrations 18 and 42 hr after rapid infusion remained slightly but not significantly higher than respective mean concentrations after slow infusions. By yielding higher initial serum concentration, rapid intravenous infusion may be therapeutically more effective than slow infusion of amphotericin B. Although rapid infusions caused no more toxicity than did slow infusions, the lack of greater toxicity with rapid infusion of amphotericin B should be further documented prior to extensive clinical application of this procedure.

In Vitro Sensitivity of Torulopsis glabrata to Amphotericin B, 5-Fluorocytosine, and Clotrimazole (Bay 5097)

Thirty-five strains of Torulopsis glabrata were tested by a tube dilution method for their susceptibility to amphotericin B, 5-fluorocytosine, and clotrimazole (Bay 5097). Amphotericin B was the most active in vitro, inhibiting all strains at a concentration of 1 mug/ml and killing all strains at 2 mug/ml. 5-Fluorocytosine inhibited over 80% of strains at 0.24 mug/ml, but three strains required >/=7.8 mug/ml for killing. A concentration of 2 mug of clotrimazole per ml inhibited less than 50% of strains, and 8 mug/ml killed only 10% of strains. Most strains of T. glabrata were killed by therapeutically achievable concentrations of amphotericin B and 5-fluorocytosine, but not clotrimazole.

A pharmacologic guide to the clinical use of amphotericin B.

A decade of experience has shown amphotericin B to be the most useful broad-spectrum antifungal antibiotic. Yet many practical questions concerning its use have remained unanswered. One such question has been the relative efficacy of intravenous infusion every day (QD) versus every other day (QOD). Early investigations with amphotericin B employed intravenous injections once each day. Gradually, it became apparent that a double dose QOD often was better tolerated. The patient ate better on the day without infusion and could be ambulated more readily on that day. Depletion of usable peripheral veins by phlebitis was slowed and the physician's time in starting infusions was halved. Renal toxicity was approximately the same on both regimens. Although QOD therapy has now received wide usage, no comparison of therapeutic effect of QD and QOD amphotericin B has been reported. Concentrations of amphotericin B in serum have been reported for either regimen alone, but differences among laboratories in techniques of assay have made comparison of reports difficult. A study of 2 patients receiving amphotericin B intravenously QOD at a dose of 1.2 mg/kilogram of body weight did show that serum concentrations of amphotericin B remained above the minimal concentrations required to inhibit many fungi in vitro [1]. Another practical question has concerned the frequency and dosage of intrathecally administered amphotericin B in the therapy of fungal meningitis. Although intrathecal injections frequently have been given once or twice a week, data on the relative efficacy or concentrations ob-

The effect of amphotericin B on the fungal flora in feces.

Doses of 600 mg., 3 Gm., and 6 Gm. of amphotericin B were administered daily in 28 clinical trials. Only 8 of the 26 (31 per cent) fungal strains present in initial stool specimens were eliminated. Fifteen new fungal strains appeared during therapy and only 3 of these were subsequently eliminated. The drug was most effective against species of Candida other than C. albicans and virtually ineffective against Saccharomyces sp. and Torulopsis glabrata. Maximum serum levels of amphotericin B in these patients were less than 0.25 p.g per milliliter. The concentration of amphotericin B in the stool specimens of patients receiving 3 Gm. per day was 6.0 to 27.8 mg. per gram. Failure to eradicate fungi from the stools was probably not due to the development of resistance to amphotericin B. Twelve patients experienced some nausea and vomiting and 2 developed cramping abdominal pain. Severe diarrhea and systemic toxicity did not occur.

Amphotericin B in treatment of disseminated moniliasis.

Three patients with disseminated moniliasis were treated with intravenous injections of amphotericin B. Two were apparently cured. They previously had disseminated moniliasis following abdominal surgery. Both patients had received large doses of antimicrobial drugs and adrenal steroids prior to the onset of moniliasis. In the first case the fungi had direct access to the blood stream through indwelling intravenous polyethylene catheters; the mode of entry in the second was not established. A third patient with rheumatic heart disease developed fatal monilial endocarditis after mitral commissurotomy, the infection apparently having been introduced at the time of surgery. Each of the three strains of the offending organism isolated from the blood stream was inhibited by a small concentration of amphotericin B in vitro.