cilofungin and Agranulocytosis

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

Cilofungin (LY-121019) is a fungicidal cell wall-active 1,3-beta-glucan synthetase inhibitor with a short plasma half-life and saturable nonlinear plasma pharmacokinetics. To optimize the in vivo efficacy of this compound, we studied the effects of its linear and nonlinear pharmacokinetics during continuous versus intermittent intravenous infusion of cilofungin in the treatment of experimental disseminated candidiasis in persistently granulocytopenic rabbits. Six groups of rabbits were studied, untreated controls (n = 32) and five cilofungin dosage regimen groups consisting of the following: 25 mg/kg of body weight intravenously twice daily (VLoINT) (n = 9); 50 mg/kg twice daily (LoINT) (n = 9); 90 mg/kg twice daily (HiINT) (n = 11); 5 mg/kg/h for 18 h/day (LoCI) (n = 7); and 10 mg/kg/h for 18 h/day (HiCI) (n = 7). All regimens achieved plasma concentrations exceeding the MIC for Candida albicans (0.25 microgram/ml). In vitro timed kill assays found that the fungicidal activity and rate of kill by cilofungin above the MIC for C. albicans was concentration dependent. At the lower dosage regimens (VLoINT, LoINT, and LoCI), cilofungin followed linear plasma pharmacokinetics, whereas at higher doses (HiCI and HiINT), nonlinear kinetics consistent with a saturated elimination pathway(s) were observed. Only HiCI and HiINT produced a 10(3)- to 10(4)-fold reduction in CFU per gram in candidiasis of the brain (P less than or equal to 0.001). HiCI and HiINT also significantly reduced infection in the choroid (P less than or equal to 0.05). All regimens, except VLoInt, significantly (P less than or equal to 0.01) reduced tissue infections in lung, liver, spleen, and kidney. However, only the regimens with nonlinear saturation kinetics (HiCI and HiINT) produced a 10(6) reduction in the spleen and a > 10(5) reduction of C. albicans in the kidney and liver. A simple doubling of the dosage from LoCI to HiCI resulted in tissue concentrations that were 10 times higher and a 10(2)- to 10(4)-fold-greater antifungal effect. There was a direct correlation (r2 = 0.83) between tissue concentrations of cilofungin and antifungal activity. Thus, continuous and intermittent infusion dosage regimens that elicit nonlinear saturation plasma pharmacokinetics of cilofungin were associated with increased antifungal activity against experimental disseminated candidiasis.

Topics: Agranulocytosis; Animals; Antifungal Agents; Aspergillus; Candidiasis; Echinocandins; Female; Infusions, Intravenous; Infusions, Parenteral; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Rabbits

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