In vitro and in vivo antifungal activities of DU-6859a, a fluoroquinolone, in combination with amphotericin B and fluconazole against pathogenic fungi

Abstract

DU-6859a is an investigational fluoroquinolone agent with potent bactericidal activity, but by itself it has no antifungal activity. When combined with amphotericin B (AmB), however, DU-6859a clearly enhanced the in vitro antifungal activity of AmB against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, and Cryptococcus neoformans in microdilution checkerboard studies. Positive interactions of DU-6859a with AmB against Aspergillus fumigatus were dependent on the medium used; yeast nitrogen base supplemented with amino acids, ammonium sulfate, and 1% glucose was better for demonstrating synergism, while in RPMI 1640 medium, unexpected antagonism between the drugs occurred against three of the strains tested. In combination with fluconazole (Flu), DU-6859a increased the activity of Flu against C. albicans both in synthetic amino acid medium fungal and in supplemented yeast nitrogen base. An in vitro time-kill study revealed that DU-6859a combined with AmB significantly suppressed the regrowth of C. albicans compared with the suppression brought about by AmB used alone in a concentration-dependent fashion. Furthermore, in a model of C. albicans infection in mice, the fungal load in infected kidneys was significantly less in mice given the combination treatment of DU-6859a plus either AmB or Flu, and thus, the combination treatment resulted in prolonged survival of infected mice compared with treatment with either antifungal alone. The prolonged survival in mice given the combined treatment was also observed in mice with A. fumigatus infection, indicating that DU-6859a potentiated the actions of the antifungal agents in vivo as well as in vitro.In patients with immune deficiencies induced both iatrogenically and congenitally or by human immunodeficiency virus infection, deep-seated mycoses caused by Candida species, Aspergillus species, and Cryptococcus neoformans occur frequently and often become life-threatening (1,3,4,29). A triazole antifungal agent, fluconazole (Flu), is fungistatic only against fungi susceptible to this agent (16,27). A polyene antifungal antibiotic, amphotericin B (AmB), remains the drug of choice, although its severe adverse effects such as nephrotoxicity are a dose-limiting factor (9,20). A great deal of experimental and clinical effort with the aim of increasing antifungal activities while reducing adverse effects has been made for the last two decades. These efforts include the combined use of two distinct antimicrobial agents: AmB plus flucytosine, a cytosine analog (2, 18), AmB plus rifampin (15, 18), and azoles plus nikkomycin, a competitive fungal chitin synthase inhibitor (11).It has been verified that DU-6859a, a fluoroquinolone agent, possesses a broad spectrum of potent bactericidal activity (14,22), but by itself it has no antifungal activity. The bactericidal activities of fluoroquinolones are largely based on their inhibitory effects on bacterial DNA gyrase (topoisomerase II) (23, 24); however, some other effects have recently been suggested (7, 13). The...

Analysis of Growth Characteristics of Filamentous Fungi in Different Nutrient Media

“…There might be other situations, which are difficult to prove experimentally, in which a poor medium, although it supports fungal growth, acts synergistically with the drug in inhibiting growth, resulting in an appearance of better activity. The discrepancy in the interaction of a fluoroquinolone with amphotericin B against A. fumigatus in YNB (synergistic) and in RPMI (antagonistic) (22), as well as the higher activity of miconazole in richer media (36), could be explained by the growth curves. The high growth in YNB and the poor growth in RPMI correlate with different levels of metabolic activity.…”

“…Differences in MICs for filamentous fungi were also observed when conidia (fungus in the lag phase) and hyphae (fungus in the log or stationary phase) were cultivated in RPMI 1640 (12). In another study where RPMI and YNB were employed the interaction between antimicrobial agents and fungi depended on the type of medium used (22).…”

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…The above in vitro observations are supported by limited animal data-synergistic interactions of ciprofloxacin plus fluconazole, ciprofloxacin plus AMB and fluconazole plus ofloxacin in vivo in mice with C. albicans infection are described. 129 However, liposomal AMB and moxifloxacin were not synergistic in a rabbit model of C. albicans endophthalmitis for this species. 130,131 In another study, moxifloxacin protected cyclophosphamide-injected mice against C. albicans bronchopneumonia and reduced mortality rates.…”

“…126 Animal models of invasive aspergillosis have supported the enhanced efficacy of antifungals when combined with fluoroquinolones. 129 Genus-specific differences between Candida and Aspergillus in the interactions of fluoroquinolones with individual antifungals may be related to different affinities of each quinolone for fungal topoisomerases. 127 Determing the clinical relevance (or lack thereof) of these experimental interactions is indicated.…”

New Improved Quinlone Derivatives Against Infection

“…Laboratory work has indicated that inhibition of DNA gyrase is not specific and activity against nonbacterial targets has been shown (Dykstra et al, 1994, Fostel et al, 1996. Nakajima et al, (Nakajima et al, 1995) have reported that quinolone augmented the activity of amphotericin B and fluconazole against a variety of fungi in both in vitro and in vivo assays of combined antifungal activity. Based on theses studies, we aimed to evaluate the antifungal activities of enoxacin and its derivatives against common fungal pathogens; Aspergillus purasiticus, Saccharomyces cervics, Candida albicans and Fusraium solani.…”