amphotericin-b and cilofungin

The echinocandins are large lipopeptide molecules that are inhibitors of beta-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides; Peptides, Cyclic; Treatment Outcome

The echinocandins are large lipopeptide molecules that are inhibitors of beta-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides; Peptides, Cyclic; Treatment Outcome

Analysis of the in vitro sensitivity of clinical isolates of different yeast species to amphotericine B and two inhibitors of cell wall beta-glucane synthesis: the lipopeptide cilofungin and the liposaccharide papulacandin B, as well as the possible interactions among these antifungal types.. The in vitro sensibility of C. albicans strains and other yeast species of clinical origin was studied, using the macrodilution method in RPMI broth as recommended by NCCLS. In six C. albicans and two T. glabrata strains the interaction between amphotericine B and one of the beta-glucan inhibitors was also assessed, by combining one antifungal agent in a two-fold dilution series with subinhibitory concentrations (1/4MIC) of the second antifungal.. Of all three antifungals, amphothericine B proved to be the more active one, with a MIC90 of 1.25 micrograms/ml for C. albicans. MIC90 of cilofungin and papulacandine B is 5 micrograms/ml for both antifungals. The spectrum of action for the different yeast species is broader for papulacandin B than for cilofungin. On the other hand, no synergism has been observed between the two glucane inhibitors and amphotericine B.

Topics: Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Ascomycota; beta-Glucans; Drug Synergism; Echinocandins; Glucans; Microbial Sensitivity Tests; Peptides, Cyclic; Yeasts

We performed antifungal susceptibility tests with cilofungin (LY121019), amphotericin B, and flucytosine against 38 strains of yeasts from patients with esophagitis or fungemia either before, during, or after treatment with cilofungin. Tests were performed using a macrobroth dilution method similar to that proposed by the National Committee for Clinical Laboratory Standards (M27-P) and two microbroth methods. For cilofungin and amphotericin B, minimum inhibitory concentrations from microbroth tests using Antibiotic Medium 3 (AM3) were systematically lower than results from the other two methods that utilized RPMI-1640 medium (RPMI). AM3 did not provide any greater degree of in vitro correlation with clinical results than did RPMI. We conclude that cilofungin and possibly other congeners of the echinocandin class of antifungal agents can effectively be studied using the proposed National Committee for Clinical Laboratory Standards method.

Topics: Amphotericin B; Candida; Candidiasis; Drug Resistance, Microbial; Echinocandins; Esophagitis; Evaluation Studies as Topic; Flucytosine; Fungemia; Humans; Microbial Sensitivity Tests; Peptides, Cyclic; Prospective Studies

(1,3)-beta-D-Glucan synthase is a cell wall synthesis enzyme that is the target of cilofungin, an antifungal agent of the lipopeptide class. Cilofungin's glucan synthase inhibitory activity, MIC, and effective dose 50% in a systemic infection mouse model tend to correlate for Candida albicans. This correlation is not seen in Aspergillus fumigatus. MICs for cilofungin against A. fumigatus were consistently > 125 micrograms/ml while the effective dose 50% in a systemic aspergillosis model was determined to be 20.6 mg/kg. To begin to understand this discrepancy, we examined the A. fumigatus glucan synthase. This cell wall enzyme was prepared and its activity was measured by [14C]-glucose incorporation from UDP-[U-14C]glucose into an acid insoluble polymer formed in the presence of alpha-amylase. Enzyme activity in crude membrane preparations was measured in the presence of several antifungal agents. Enzyme inhibition results showed that 1 microgram/ml of papulacandin B, echinochandin B, aculeacin A and cilofungin all inhibited A. fumigatus glucan synthase activity (40-71%) while 1 microgram/ml of amphotericin B, fluconazole, ketoconazole and nikkomycin did not affect enzyme activity. A correlation was therefore established between the inhibitory effect of cilofungin on the A. fumigatus glucan synthase and the effective dose 50% obtained in a systemic aspergillosis mouse model.

Topics: Amphotericin B; Animals; Aspergillosis; Aspergillus fumigatus; Dose-Response Relationship, Drug; Echinocandins; Fluconazole; Glucosyltransferases; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Peptides, Cyclic; Schizosaccharomyces pombe Proteins; Species Specificity; Survival Analysis

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in no

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Brain; Candidiasis; Cyclophosphamide; Echinocandins; Humans; Kidney; Liver; Male; Mice; Peptides, Cyclic; Spleen

There is insufficient in vivo data on the efficacy of new antifungal agents against invasive Candida tropicalis infection. Disseminated infection with Candida tropicalis in neutropenic mice was treated with cilofungin, fluconazole, or amphotericin B intraperitoneally, and compared to untreated controls. Early survival rates at the end of treatment (day 10) were similar for amphotericin B (97.5%) and fluconazole (100%), and superior to cilofungin (62.6%) which was better than no treatment (0%). Late survival rates (day 31) were highest for amphotericin B (95%), and significantly lower for cilofungin (48.7%) and fluconazole (43.9%), p = 0.0001. Rates of sterilization of the lung, liver, and spleen were high in survivors for all regimens (85.1-100%) but lower for the kidneys: fluconazole, 21.3%; amphotericin B, 39.3%; and cilofungin, 65.5%. Amphotericin B was the most effective agent in this study of disseminated Candida tropicalis (C. tropicalis) infection.

Topics: Amphotericin B; Animals; Candida; Candidiasis; Echinocandins; Female; Fluconazole; Injections, Intraperitoneal; Kidney; Liver; Lung; Mice; Neutropenia; Peptides, Cyclic; Spleen

The effect of a beta glucan synthase inhibitor, cilofungin, amphotericin B and 5-fluorocytosine on opsonization, phagocytosis and intracellular killing of Candida albicans blastospores by glass-adherent human neutrophils was determined by microscopy and dye exclusion staining. Pretreatment of blastospores for 2, 4, 6 and 18 h with 1.25 mg/l cilofungin resulted in 24-28% of neutrophils ingesting compared to 24% with no drug present. There was no significant difference in the phagocytic index with increased incubation time. Percentage ingestion and phagocytic index values were not significantly different when blastospores were pretreated for 2 h in the presence of 3, 7, 15, 31 and 62 mg/l cilofungin. Comparable concentrations of amphotericin B and 5-fluorocytosine gave similar results. In the absence of cilofungin, intracellular killing after 2 h was 54%. In the presence of 1 and 10 mg/l cilofungin, 85-90% of intracellular blastospores were killed. Therapeutic levels of amphotericin B or 5-fluorocytosine did not enhance intracellular killing. These data demonstrate the potentiation of intracellular killing of Candida albicans by neutrophils in the presence of cilofungin.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Echinocandins; Flucytosine; Humans; Microscopy; Neutrophils; Peptides; Peptides, Cyclic; Phagocytosis

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Echinocandins; Infusions, Intravenous; Kidney; Lung; Peptides; Peptides, Cyclic; Rabbits; Spleen

Cilofungin, a lipopeptide antifungal agent, was tested for in vitro activity alone and in combination with ketoconazole, itraconazole, flucytosine and amphotericin B against 102 clinical isolates of Candida species. At 48 hours all isolates of Candida albicans, Candida tropicalis, Candida paratropicalis and Candida glabrata were inhibited by less than or equal to 5 meg/ml of cilofungin. In contrast, the MIC90 for Candida krusei was 10 mcg/ml and for Candida parapsilosis greater than 40 mcg/ml. The interaction of combinations of cilofungin with amphotericin B, itraconazole, ketoconazole and flucytosine was additive or indifferent at 48 hours for 100%, 88%, 78% and 70% of all Candida species isolates, respectively. Overall, cilofungin demonstrated good activity in vitro against most Candida species isolates.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Drug Therapy, Combination; Echinocandins; Flucytosine; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Drug Synergism; Drug Therapy, Combination; Echinocandins; Kidney; Male; Mice; Mice, Inbred ICR; Peptides; Peptides, Cyclic

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Combinations; Echinocandins; Female; Kidney; Mice; Microbial Sensitivity Tests; Organ Size; Peptides; Peptides, Cyclic

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidiasis; Drug Synergism; Echinocandins; Male; Mice; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

The effectiveness of cilofungin (LY121019, referred to hereafter as LY), a lipopeptide, was studied in a murine candidiasis model. CD-1 mice (5 weeks old) were injected intravenously with 3 x 10(5) Candida albicans yeast cells. Intraperitoneal LY or amphotericin B (AmB) therapy was begun 4 days after infection and was continued daily for 2 weeks. LY and AmB were compared at 62.5, 6.25, and 0.625 mg/kg per day, with the LY dose split into two treatments per day. Mice were observed for 30 days postinfection, and survivors were necropsied. AmB at 62.5 mg/kg per day was lethal in the absence of infection. Cumulative mortality for infected controls was 94% (17 of 18). Survival of mice treated with the control diluent for LY was the same as survival with no treatment. Survival after 0.625 mg of LY per kg per day was the same as that of the controls, and 6.25 or 62.5 mg of LY per kg per day was significantly superior. AmB treatment at 0.625 or 6.25 mg/kg per day was protective and superior to the same LY doses. Atrophied kidneys were common in AmB-treated mice, and mice treated with 6.25 mg of AmB per kg per day appeared ill during therapy. The number of CFU recovered from kidneys and spleens of surviving mice reflected the same relationships between drugs and doses as those described for mortality. C. albicans was not cleared from the kidneys of mice in any group, and only in the 6.25-mg/kg-per-day AmB treatment group was not detectable C. albicans found in the spleens. These data indicate that LY or AmB suppresses candida infection but neither is curative in this model.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Echinocandins; Half-Life; Kidney Diseases; Male; Mice; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Spleen

We compared the efficacies of cilofungin and amphotericin B treatment in a murine model of disseminated candidiasis. Three different dosages of each drug plus controls were evaluated. Statistically improved survival was noted only among mice treated with 1 mg of amphotericin B per kg of body weight (P less than 0.05). While all amphotericin B regimens and the two lower-dosage cilofungin regimens significantly reduced yeast cell counts in kidneys compared with the controls, the amphotericin B-treated mice had a significantly higher percentage of sterile kidneys following therapy compared with those treated with cilofungin (P = 0.0001).

Topics: Amphotericin B; Animals; Candidiasis; Echinocandins; Kidney; Male; Mice; Organ Culture Techniques; Peptides; Peptides, Cyclic

We assessed the retinal toxicity of a new antifungal agent, cilofungin, by injecting it into the vitreous body of albino rabbit eyes in dosages of 2.5 micrograms to 320 micrograms. The maximum intravitreal drug concentration (320 micrograms) produced no histological evidence of retinal toxicity. Electroretinography data showed some variations, but no toxicity at the highest dose (320 micrograms). When efficacy was evaluated in vitro against Candida albicans, the minimal inhibitory concentration was 2.50 micrograms/mL, using Sabouraud's broth or M3 medium. The minimal fungicidal concentration was 5 micrograms/mL with Sabouraud's broth, and 10 micrograms/mL with M3 medium. Cilofungin is a potentially safe antifungal for the treatment of candida endophthalmitis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Echinocandins; Electroretinography; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Rabbits; Retina; Vitreous Body

A murine model of focal hepatic candidiasis which we suggest simulates certain conditions of this clinical variant of systemic candidiasis in leukemic patients is described. We have shown that outbred mice inoculated with Candida albicans by the oral-intragastric route as infants (6 days old) and then immunocompromised by cyclophosphamide and cortisone acetate treatment 2 weeks later demonstrate systemic spread of the opportunistic pathogen to the liver, lungs, spleen, and kidneys. Treatment with the immunosuppressive drugs cyclophosphamide and cortisone acetate resulted in alteration of the normal integrity of the mucosal epithelium of the gut as well as in granulocytopenia. Approximately 55% of the animals with C. albicans infections in the liver demonstrated hepatic abscesses. After these same infected, immunocompromised animals were treated with suboptimal dosages of antifungal agents (cilofungin or amphotericin B), either by intraperitoneal or subcutaneous (s.c.) routes, persistent hepatic abscesses were fewer in number and delimited by a distinct outer layer of host tissue but still contained large numbers of the viable pathogen. Blood cell counts indicated that these antifungal drug-treated animals had reestablished approximately the same number of leukocytes per microliter of blood as estimated prior to the immunocompromising drug treatment. Similar conditions in leukemic patients who were in remission and who were undergoing antifungal drug therapy for systemic candidiasis have been reported. Clearance of hepatic infections in mice was accomplished by using appropriate concentrations of amphotericin B administered by daily intraperitoneal or s.c. injection for 5 to 7 days or cilofungin by continuous s.c. infusion for 7 days. However, systemic antifungal therapy did not significantly reduce numbers of C. albicans cells in the stomach and esophagus. Persistent foci of gastrointestinal colonization by C. albicans, especially in the region of the cardial-atrium fold of the stomach of these mice, are reservoirs of the opportunistic pathogen from which reinfection may occur, leading to relapse of systemic candidiasis.

Topics: Agranulocytosis; Amphotericin B; Animals; Body Weight; Candidiasis; Cortisone; Cyclophosphamide; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Esophagitis, Peptic; Immune Tolerance; Incidence; Injections, Intravenous; Injections, Subcutaneous; Liver Diseases; Mice; Microbial Sensitivity Tests; Organ Specificity; Peptides; Peptides, Cyclic

The multiplication of iatrogenic factors, nosocomial diseases and acquired immunodeficiency syndrome is responsible for an ever increasing number of deep opportunistic mycoses, namely candidiasis, aspergillosis and cryptococcosis. The advent of a wide variety of rare opportunistic fungi is a fairly recent and worrying phenomenon. To combat these infections, often very serious, our therapeutic armentarium is rather scanty. Moreover, the prescription of the available drugs is limited by their toxicity, their spectrum and their route of administration or by the emergence under treatment of resistant mutants. Beside old products, such as amphotericin B and 5-fluorocytosine, miconazole and, mainly ketoconazole (both azole derivatives) were the first steps towards oral administration and low toxicity. Fluconazole is a triazole antifungal compound with a very original distribution to the meninges and urinary tract; it is mainly used in candidiasis and cryptococcosis. Another triazole compound, itraconazole, presents the particularity of being active against Aspergillus spp., Cryptococcus spp. and some agents of exotic mycoses. These two products are well tolerated and should soon be available for use in deep visceral mycoses. Other azole derivatives are under study. Among compounds issued from new chemical families, terbinafine (allylamine) is particularly active against dermatophytes, and cilofungine (a polypeptide) against fungi. These drugs are in the experimental stage. Research should be pursued aimed at developing, probably in new chemical families, and agent that is fungicidal in vivo.

Topics: Allylamine; Amphotericin B; Antifungal Agents; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Miconazole; Mycoses; Naphthalenes; Peptides; Peptides, Cyclic; Terbinafine

The in-vitro influence of cilofungin (LY121019) and amphotericin B on human polymorphonuclear leucocytes (PMNs) was studied by a multifunctional approach. Cilofungin at high concentration (greater than or equal to 20 mg/l) increased adherence to plastic and ingestion of Staphylococcus aureus by PMNs in suspension and Candida albicans by adherent PMNs, and slightly decreased MTT reduction and superoxide generation. Amphotericin B and amphotericin B-deoxycholate decreased adherence to plastic (IC50: 5.1 and 8.2 mg/l respectively) and superoxide generation induced by PMA and opsonized zymosan (IC50 1.1 mg/l for amphotericin B-deoxycholate). Variable results were observed for intra-cellular killing and ingestion. The functional assessment was made with four clinical isolates of yeasts (Can. albicans, Can. tropicalis, Can. Torulopsis) (glabrata, Cryptococcus neoformans). The inoculum was preincubated with the antifungals (PRE) or they were added during (PER) or after ingestion (POST) using PMNs in suspension (PRE and PER), or adhering to plastic (PRE, PER and POST). With the scheme PRE, killing was usually increased with amphotericin B-deoxycholate and cilofungin. With Crypt. neoformans, ingestion was also increased by the antifungals and sodium-deoxycholate, probably by altering the capsule. The results of the scheme POST showed that amphotericin B-deoxycholate, but not cilofungin, increased intracellular killing of Can. albicans, Can. tropicalis and Can. glabrata.

Topics: Amphotericin B; Antifungal Agents; Calcium; Chemotaxis; Deoxycholic Acid; Drug Combinations; Echinocandins; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Neutrophils; Peptides; Peptides, Cyclic; Phagocytosis; Superoxides; Tetrazolium Salts; Thiazoles

The efficacy of cilofungin treatment of experimental disseminated candidiasis in rabbits was examined. Cilofungin treatment reduced yeast counts, especially in the kidney, with activity comparable to that of amphotericin B. The peak level of cilofungin in serum was measured at 5 min after administration of a single dose, with no drug detectable after 90 min.

Topics: Amphotericin B; Animals; Candidiasis; Echinocandins; In Vitro Techniques; Male; Peptides; Peptides, Cyclic; Rabbits

The in-vitro activity of cilofungin, a derivative of echinocandin B, was compared with that of amphotericin B in Sabouraud dextrose and Antibiotic Medium No. 3 against 100 clinical isolates of yeasts. Cilofungin appeared to be as effective, as amphotericin B against Candida albicans and yet more effective against Can. tropicalis as far as growth inhibition was concerned. Cilofungin was less active than amphotericin B against Can. (Torulopsis) glabrata and other species of Candida. It was not active against Cryptococcus neoformans. Minimum fungicidal concentrations (MFCs) of cilofungin were highly dependent on the medium, especially with Can. albicans. Low MFCs were observed in Antibiotic Medium 3 and very high MFCs were measured in Sabouraud's medium. Using a killing curve method, the initial rate of killing of amphotericin B was proportional to concentration with Can. albicans, Can. tropicalis, and Can. glabrata. With cilofungin the rate of killing was proportional to concentration only for Can. tropicalis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Cryptococcus neoformans; Echinocandins; Fungi; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

The efficacy of cilofungin (LY121019) for aortic valve endocarditis caused by Candida albicans in rabbits was studied. Vegetation titers were similar for cilofungin-treated and untreated rabbits. No rabbit survived beyond 5 days in either group. All rabbits given amphotericin B survived, and titers were reduced. Cilofungin was ineffective in this model.

Topics: Amphotericin B; Animals; Antifungal Agents; Aortic Valve; Candida albicans; Candidiasis; Echinocandins; Endocarditis; Half-Life; Heart Valve Diseases; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Rabbits

Cilofungin was combined with amphotericin B or flucytosine to determine if synergistic inhibition or killing occurred against 50 strains of various Candida species. Synergistic inhibition of growth occurred only once with amphotericin B and cilofungin and only 2 times with flucytosine and cilofungin. Synergistic killing occurred in 5 strains with the amphotericin B-cilofungin combination and in 7 strains with the flucytosine-cilofungin combination. Antagonism occurred frequently with both the amphotericin B-cilofungin and the flucytosine-cilofungin combinations.

Topics: Amphotericin B; Antifungal Agents; Candida; Drug Interactions; Echinocandins; Flucytosine; Humans; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

Cilofungin was combined with amphotericin B or flucytosine to determine if synergistic inhibition or killing occurred against 50 strains of various Candida species. Synergistic inhibition of growth occurred only once with amphotericin B and cilofungin and only 2 times with flucytosine and cilofungin. Synergistic killing occurred in 5 strains with the amphotericin B-cilofungin combination and in 7 strains with the flucytosine-cilofungin combination. Antagonism occurred frequently with both the amphotericin B-cilofungin and the flucytosine-cilofungin combinations.

Topics: Amphotericin B; Antifungal Agents; Candida; Drug Interactions; Echinocandins; Flucytosine; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

LY121019 is a new semisynthetic lipopeptide antifungal agent with potent in vitro fungicidal activity against multiple clinical strains of Candida albicans and Candida tropicalis but is 10-100 fold less active against Torulopsis glabrata and Candida parapsilosis. Its in vitro activity against Candida albicans and Candida tropicalis is comparable to that of amphotericin B. The in vitro fungicidal activity of this new agent supports further investigations into its use in treatment of Candida infections.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Echinocandins; Humans; Peptides; Peptides, Cyclic

LY121019 and amphotericin B were equally active in vitro against most clinical isolates of Candida albicans and Candida tropicalis. Higher concentrations of LY121019 were required for inhibition of Candida glabrata. Other Candida species were inhibited by amphotericin B but not by LY121019.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Echinocandins; Humans; Peptides; Peptides, Cyclic

LY121019 is a new antifungal antimicrobic that is structurally similar to the lipopeptide agents echinocandin B and aculeacin A. Because of the importance of in vitro test conditions on the activity of other antifungal agents, we studied the effects of inoculum size, time and temperature of incubation, pH, and medium composition on the in vitro activity of LY121019 against Candida albicans, Candida tropicalis, and Candida parapsilosis. LY121019 was highly active against Candida albicans and Candida tropicalis and inactive against Candida parapsilosis. The in vitro activity of LY121019 is marked by a paradoxical dose-response with isolates of Candida albicans and Candida tropicalis and is influenced by choice of inoculum size, time and temperature of incubation, medium composition, and pH. We recommend the use of an inoculum size of less than 10(5) organisms/ml, a defined medium buffered to a pH of 7.0, and incubation at 30 degrees C for 24 hr for future in vitro studies of LY121019.

Topics: Amphotericin B; Antifungal Agents; Candida; Culture Media; Echinocandins; Flucytosine; Humans; Hydrogen-Ion Concentration; Ketoconazole; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Temperature; Time Factors

Cilofungin (LY121019) was compared with amphotericin B in vitro for its inhibitory and fungicidal activity against Candida species. In minimal inhibitory concentration (MIC) tests the two compounds showed comparable inhibitory activity against 31 isolates of C. albicans and C. tropicalis. However, cilofungin was by comparison only weakly active against 19 isolates representing the species C. glabrata, C. kefyr and C. krusei, and essentially inactive against 11 isolates representing C. guilliermondii and C. parapsilosis. The inhibitory activity of cilofungin, unlike that of amphotericin B, was reduced in medium containing serum. Relative inhibition factors (RIFs) for the two compounds confirmed the MIC data: RIFs of 85% and more were obtained in tests with species other than C. albicans and C. tropicalis: for the latter two species, RIFs were in the range 41-66%, indicating drug activity comparable to that of systematically active azole compounds. (RIFs for amphotericin B were less than 40% for all isolates.) Cilofungin was generally less fungicidal than amphotericin B, and it was only rarely fungicidal in tests done in medium containing serum. Because of its inhibitory action and its low toxicity, the compound may prove to be therapeutically useful in infections caused by the two most commonly encountered pathogenic Candida species.

Topics: Amphotericin B; Candida; Culture Media; Echinocandins; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic