amphotericin-b and nikkomycin

The perceptions of coccidioidomycosis as a medical problem has undergone sequential and dramatic metamorphoses since its first description more than a century ago. First thought to be rare and lethal, coccidioidomycosis was subsequently found to be common and often mild. During World War II, its overall impact upon large populations came sharply into focus and the consequences for public health became clearer. Early treatments had significant limitations and toxicities, and therefore treatment of coccidioidomycosis was reserved for only the sickest patients. Since then, safer oral therapies have become commonplace. Despite their availability, there has been no investigation of their use in the less severe and much more common early infections. Even newer drugs such as nikkomycin Z, which might actually cure infections, until very recently have had trouble finding a sponsor to move it through clinical trials. Perceptions once formed by the understanding of coccidioidomycosis as a medical problem now appear to hinder the future study of newer therapeutic opportunities. It is suggested in this review that it is time to revisit and possibly change these perceptions if we are to improve our care of patients.

Topics: Administration, Oral; Aminoglycosides; Amphotericin B; Antifungal Agents; Attitude to Health; Coccidioidomycosis; Granuloma; Humans; Miconazole; Perception; Public Health

A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

Topics: Aminoglycosides; Amphotericin B; Animals; Anthracyclines; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cell Wall; Chitin; Echinocandins; Fungal Proteins; Fungi; Glucans; Mice; Mycoses; Peptides; Peptides, Cyclic; Pyrimidine Nucleosides

The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.

Topics: Alternaria; Aminoglycosides; Amphotericin B; Antifungal Agents; Caspofungin; Cell Wall; Echinocandins; Fluconazole; Itraconazole; Lipopeptides; Melanins; Microbial Sensitivity Tests; Naphthols; Pyrroles; Quinolines

Topics: Aminoglycosides; Amphotericin B; Antifungal Agents; Candida albicans; Caspofungin; Drug Synergism; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

Response surface methods for the study of multiple-agent interaction allow one to model all of the information present in full concentration-effect data sets and to visualize and quantify local regions of synergy, additivity, and antagonism. In randomized wells of 96-well plates, Aspergillus fumigatus was exposed to various combinations of amphotericin B, micafungin, and nikkomycin Z. The experimental design was comprised of 91 different fixed-ratio mixtures, all performed in quintuplicate. After 24 h of drug exposure, drug effect on fungal viability was assessed using the tetrazolium salt 2,3-bis {2-methoxy-4-nitro-5-[(sulfenylamino) carbonyl]-2H-tetrazolium-hydroxide} (XTT) assay. First, we modeled each fixed-ratio combination alone using the four-parameter Hill concentration-effect model. Then, we modeled each parameter, including the 50% inhibitory concentration (IC(50)) effect, versus the proportion of each agent using constrained polynomials. Finally, we modeled the three-agent response surface overall. The overall four-dimensional response surface was complex, but it can be explained in detail both analytically and graphically. The grand model that fit the best included complex polynomial equations for the slope parameter m and the combination index (equivalent to the IC(50) for a fixed-ratio concentration, but with concentrations normalized by the respective IC(50)s of the drugs alone). There was a large region of synergy, mostly at the nikkomycin Z/micafungin edge of the ternary plots for equal normalized proportions of each drug and extending into the center of the plots. Applying this response surface method to a huge data set for a three-antifungal-agent combination is novel. This new paradigm has the potential to significantly advance the field of combination antifungal pharmacology.

Topics: Aminoglycosides; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Confidence Intervals; Drug Combinations; Echinocandins; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Models, Statistical; Peptides, Cyclic

Mortality from invasive pulmonary aspergillosis approaches 80% with few useful therapeutic options available. In these studies, we examined the efficacy of micafungin (MICA) alone or in combination with other antifungals in a model of pulmonary aspergillosis in immunosuppressed DBA/2 mice infected intranasally with conidia of Aspergillus fumigatus 10AF. In the initial study, groups of mice were given saline, or 1, 3 or 10 mg kg(-1) of MICA b.i.d., s.c. All saline controls, and 90% of untreated mice succumbed to infection. The efficacy of MICA was difficult to assess because of an apparent toxicity at 10 mg kg(-1). MICA given at 1 mg/kg significantly prolonged survival over the saline controls (P = 0.008). MICA at 3 or 10 mg kg(-1) versus the saline controls approached significance. No treatment regimen differed in efficacy. The efficacy of combination therapy was assessed, with mice given either no treatment, MICA at 1 mg/kg/dose, 0.8 mg kg(-1) of intravenous amphotericin B (AMB), 100 mg kg(-1) of oral itraconazole (ICZ), or 100 mg/kg/dose of twice-daily subcutaneous nikkomycin Z (NIK). AMB alone and MICA + AMB or MICA +NIK significantly prolonged survival (P < 0.05 - 0.02) over that of the controls. ICZ alone, ICZ+MICA and NIK alone did not significantly prolong survival. MICA alone at 1 mg/kg approached significance in prolonging survival. The combination of MICA and ICZ appeared to be potentially antagonistic. Although AMB+MICA was efficacious, no synergistic activity was noted for any of the regimens. Overall, these results indicate that MICA has moderate activity against pulmonary aspergillosis and might be useful in combination with conventional AMB.

Topics: Aminoglycosides; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Drug Antagonism; Drug Therapy, Combination; Echinocandins; Female; Immunosuppression Therapy; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Mice; Mice, Inbred DBA; Peptides, Cyclic; Survival Analysis

Nikkomycin Z was tested both in vitro and in vivo for efficacy against Histoplasma capsulatum. Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole. The median MIC was 8 microg/ml with a range of 4 to 64 microg/ml for nikkomycin Z, 0.56 microg/ml with a range of 0.5 to 1.0 microg/ml for amphotericin B, and < or =0.019 microg/ml for itraconazole. Primary studies were carried out by using a clinical isolate of H. capsulatum for which the MIC of nikkomycin Z was greater than or equal to 64 microg/ml. In survival experiments, mice treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD) itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at 100 mg/kg/dose BID survived to day 14, while 70% of mice receiving nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving nikkomycin Z at 5 mg/kg/dose BID survived to day 14. All vehicle control mice died by day 12. Fungal burden was assessed on survivors. Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels of Histoplasma antigen in lung and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID. Studies also were carried out with a clinical isolate for which the MIC of nikkomycin Z was 4 microg/ml. All mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice survived. Fungal burden assessed on survivors showed similar levels of Histoplasma antigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID. The three surviving vehicle control mice had significantly higher antigen levels in lung and spleen than other groups (P<0.05). The efficacy of nikkomycin Z at preventing mortality and reducing fungal burden correlates with in vitro susceptibility.

Topics: Aminoglycosides; Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Cells, Cultured; Disease Models, Animal; Histoplasmosis; Itraconazole; Mice

Nikkomycin Z is a chitin synthetase inhibitor. In vitro, nikkomycin Z had good activity against Blastomyces dermatitidis, with an MIC of 0.78 microg/ml and a minimal fungicidal concentration of 3.1 microg/ml. The efficacies of various treatment durations (3, 5, or 10 days) and doses (200, 400, or 1,000 mg/kg of body weight) of nikkomycin Z given twice daily were compared with those of itraconazole at 200 mg/kg given twice daily and amphotericin B at 6.25 mg/kg in a murine model of pulmonary blastomycosis. All treatments prolonged survival compared with untreated controls (P < 0.05 to 0.01); 100% survival was achieved with 5 or 10 days of any nikkomycin Z dose or with amphotericin B. Amphotericin B and nikkomycin Z, but not itraconazole, reduced infection compared with controls. Amphotericin B and the 10-day regimens of all nikkomycin Z doses were equivalent and superior to itraconazole or nikkomycin Z for < or = 5 days at any dose (P < 0.05 to 0.01). Increased duration and/or dosage improved the efficacy of nikkomycin Z, with 10 days of each dose curing 50 to 90% of the animals. Only a 1,000-mg/kg/day dose of nikkomycin Z was curative when treatment lasted less than 10 days. In contrast, itraconazole cured no mice, while amphotericin B cured all mice. Based on the total amount of drug given, amphotericin B was estimated to be 32 times as active as nikkomycin Z and nikkomycin Z was estimated to be 3 times as active as itraconazole. Overall, nikkomycin Z given orally was well tolerated, had good activity against blastomycosis, and could result in biological cure, thus producing results equivalent to those of parenteral amphotericin B.

Topics: Aminoglycosides; Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Blastomycosis; Chitin Synthase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Itraconazole; Lung Diseases, Fungal; Male; Mice; Mice, Inbred Strains