Antimicrobial activity of DU-6859, a new potent fluoroquinolone, against clinical isolates

Sato, Kenichi; Hoshino, Kazuki; Tanaka, Mayumi; Hayakawa, Isao; Osada, Yasuaki

doi:10.1128/aac.36.7.1491

Cited by 117 publications

(66 citation statements)

References 13 publications

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“…1) Fluoroquinolones are important synthetic antimicrobial agents and they have been widely used as therapeutic agents for general bacterial infectious diseases. However, some fluoroquinolones are known to induce phototoxicity as a side effect.…”

Section: Sitafloxacin Hydrate (Stfx Hydrate: (ϫ)-7-[(7s)mentioning

confidence: 99%

Photochemical Behavior of Sitafloxacin, Fluoroquinolone Antibiotic, in an Aqueous Solution.

Araki

Kawai

Ohta

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Sitafloxacin hydrate (STFX hydrate: (Ϫ)-7-[(7S)-1) Fluoroquinolones are important synthetic antimicrobial agents and they have been widely used as therapeutic agents for general bacterial infectious diseases. However, some fluoroquinolones are known to induce phototoxicity as a side effect.2) A large number of studies have been reported to elucidate the mechanism of phototoxicity of fluoroquinolones. We reported that carbon centered radical (· C), hydroxyl radical (· OH), and singlet oxygen ( 1 O 2 ) are generated during photodegradation of fluoroquinolones in neutral aqueous solutions.3) The fluoroquinolones substituted at the 8-position by fluorine generated a high degree of 1 O 2 and · OH against photoirradiation. Such reactive species were related to DNA damage. 4) Some fluoroquinolones are photo-labile compounds and the phototoxicity might arise from photodegradation products. This study was done based on such a background. This report describes the photochemical behavior of STFX in aqueous solution including the identification of major photodegradation products of STFX, the mechanistic consideration of photodegradation, and the effect of pH. Furthermore, the possibility improving the photostability of STFX was examined in the presence of chloride ion. ExperimentalMaterials STFX was synthesized at Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.Structural Elucidation of Photodegradation Products Ninety-four milligrams of STFX hydrate was dissolved in 1 l of purified water and irradiated with fluorescent lamps (Biophotochamber LX-2100 (TAITEC Co., Tokyo)) at approximately 10000 lux for ca. 350000 lux · h. After irradiation, the solution was loaded onto a preparative HPLC system and fractionated.Preparative HPLC was carried out on a gradient system consisting of an LC 10AD pump (Shimadzu Co., Kyoto) equipped with a SPD-6A UV/vis detector (Shimadzu Co.). HPLC conditions were as follows: column, TSKgel ODS-80T M (21.5 mm i.d.ϫ300 mm, Tosoh Co., Tokyo); eluent, 0.05 M phosphate buffer (pH 2.4) : acetonitrileϭ82 : 18 (from 0 to 65 min) to 50 : 50 (from 65 to 100 min); flow rate, 5.0 ml/min (from 0 to 65 min) to 7.0 ml/min (from 65 to 100 min); injection, 2 ml; detection, 278 nm; column temperature, 40°C.The collected fractions were concentrated and lyophilized. Then the sample was redissolved in water and loaded onto a desalting preparative HPLC. HPLC conditions were as follows: column, TSKgel ODS-80T M (21.5 mm i.d.ϫ300 mm, Tosoh Co.); eluent, 0.1% acetic acid and acetonitrileϭ30 : 70; flow rate, 7.0 ml/min; injection, 2 ml; detection, 278 nm; column temperature, 40°C. Isolated photodegradation products were elucidated by using a 1 H-NMR (JNM-GSX500 FT-NMR spectrometer (500 MHz), JEOL Co., Tokyo) and electron impact (EI), chemical ionization (CI), fast atom bombardment (FAB)-MS (JMS-HX110 mass spectrometer, JEOL Co.) spectra.Kinetics of Photodegradation STFX was dissolved in Britton-Robinson buffer solutions of pH 2.0-11.0 and 0.1 mol/l sodium hydroxide (pH 13.0) (STFX, about 50 mg/ml). Each sample solution (2 ml...

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Section: Sitafloxacin Hydrate (Stfx Hydrate: (ϫ)-7-[(7s)mentioning

confidence: 99%

Photochemical Behavior of Sitafloxacin, Fluoroquinolone Antibiotic, in an Aqueous Solution.

Araki

Kawai

Ohta

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…6) Sitafloxacin (STFX): (7- Its antibacterial activity is significantly better than that of other fluoroquinolones. [7][8][9] STFX hydrate is a desired crystalline form used in the clinical drug product that was chosen due to its processability in manufacturing.…”

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confidence: 99%

Characterization of Non-stoichiometric Hydration and the Dehydration Behavior of Sitafloxacin Hydrate

et al. 2012

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Sitafloxacin (STFX) hydrate is a non-stoichiometric hydrate. The hydration state of STFX hydrate varies non-stoichiometrically depending on the relative humidity and temperature, though X-ray powder diffraction (XRPD) of STFX hydrate was not affected by storing at low and high relative humidities. The detailed properties of crystalline water of STFX hydrate were estimated in terms of hygroscopicity, thermal analysis combined with X-ray powder diffractometry, crystallography and density functional theory (DFT) calculation. STFX hydrate changed the water contents continuously and reversibly from an equivalent amount of dihydrate through that of sesquihydrate depending on the relative humidity at 25°C. Thermal analysis and X-ray powder diffraction (XRPD) simultaneous measurement also revealed that STFX hydrate dehydrated into a hydrated state equivalent to monohydrate by heating up to 100°C, whereas XRPD patterns were slightly affected. This indicated that the crystal structure of STFX hydrate was retained at the dehydration level of monohydrate. Single-crystal X-ray structural analysis showed that two STFX molecules and four water molecule sites were contained in an asymmetric unit. STFX molecules formed a channel structure where water molecules were included. At the partially dehydrated state, at least two of four water molecules were considered to be disordered in occupancy and/or coordinates. Insight into the crystal structure of STFX hydrate stored at low and high relative humidities and geometry of the hydrogen bond were helpful to estimate the origin of non-stoichiometric hydration of STFX hydrate.

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“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Nakajima¹,

Kitamura²,

Someya³

et al. 1995

Antimicrob Agents Chemother

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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...

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Antimicrobial activity of DU-6859, a new potent fluoroquinolone, against clinical isolates

Cited by 117 publications

References 13 publications

Photochemical Behavior of Sitafloxacin, Fluoroquinolone Antibiotic, in an Aqueous Solution.

Photochemical Behavior of Sitafloxacin, Fluoroquinolone Antibiotic, in an Aqueous Solution.

Characterization of Non-stoichiometric Hydration and the Dehydration Behavior of Sitafloxacin Hydrate

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

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