In vitro activity of sitafloxacin against clinical strains of Streptococcus pneumoniae with defined amino acid substitutions in QRDRs of gyrase A and topoisomerase IV

Touyama, Masato; Higa, Futoshi; Nakasone, Chikara; Shinzato, Takashi; Akamine, Morikazu; Haranaga, Shusaku; Tateyama, Masao; Nakasone, Isamu; Yamane, Nobuhisa; Fujita, Jiro

doi:10.1093/jac/dkl427

Cited by 12 publications

(7 citation statements)

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“…An amino acid change at Lys-137 in combination with a change in either Ser-79 or Asp-83did not significantly increased the ciprofloxacin MIC compared to isolates with Ser-79 or Asp-83 only changes (Ser-79 only vs Ser-79 + Lys-137: P = 0.330; Asp-83 only vs Asp-83 + Lys-137: P = 0.5511). These data are consistent with previously reported studies in which a mutation at parC resulting in an amino acid change at Lys-137 did not play a significant role in increasing the MIC to fluoroquinolones [30,32]. …”

Section: Resultssupporting

confidence: 93%

“…Previous studies have shown that pneumococci with substitutions at positions 79 and 83 of parC , and 81 and 85 of gyrA are most frequently found in isolates with reduced susceptibility to fluoroquinolones [23-32]. However, many of these studies only sequenced isolates that were resistant to fluoroquinolones, were smaller in sample size, and had been done in a time before the widespread use of the newer generation fluoroquinolones.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the quinolone resistant determining regions in clinical isolates of pneumococci collected in Canada

Patel

Melano

McGeer

et al. 2010

Ann Clin Microbiol Antimicrob

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BackgroundThe objective of this study was to examine Streptococcus pneumoniae isolates collected from a longitudinal surveillance program in order to determine their susceptibility to currently used fluoroquinolones and of the frequency and type of mutations in the quinolone-resistant determining regions (QRDRs) of their parC and gyrA genes.MethodsThe Canadian Bacterial Surveillance Network has been collecting clinical isolates of S. pneumoniae from across Canada since 1988. Broth microdilution susceptibility testing was carried out according to the Clinical and Laboratory Standards Institute guidelines. The QRDRs of the parC and gyrA genes were sequenced for all isolates with ciprofloxacin MIC ≥ 4 mg/L, and a large representative sample of isolates (N = 4,243) with MIC ≤ 2 mg/L.ResultsA total of 4,798 out of 30,111 isolates collected from 1988, and 1993 to 2007 were studied. Of those isolates that were successfully sequenced, 184 out of 1,032 with mutations in parC only, 11 out of 30 with mutations in gyrA only, and 292 out of 298 with mutations in parC and gyrA were considered resistant to ciprofloxacin (MIC ≥ 4 mg/L). The most common substitutions in the parC were at positions 137 (n = 722), 79 (n = 209), and 83 (n = 56), of which substitutions at positions 79 and 83 were associated with 4-fold increase in MIC to ciprofloxacin, whereas substitutions at position 137 had minimal effect on the ciprofloxacin MIC. A total of 400 out of 622 isolates with Lys-137 parC mutation belonged to serotypes 1, 12, 31, 7A, 9V, 9N and 9L, whereas only 49 out of 3064 isolates with no mutations belonged to these serotypes. Twenty-one out of 30 isolates with substitutions at position 81 of the gyrA gene had an increased MIC to ciprofloxacin. Finally, we found that isolates with mutations in both parC and gyrA were significantly associated with increased MIC to fluoroquinolones.ConclusionsNot all mutations, most frequently Lys-137, found in the QRDRs of the parC gene of S. pneumoniae is associated with an increased MIC to fluoroquinolones. The high prevalence of Lys-137 appears to be due to its frequent occurrence in common serotypes.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Characterization of the quinolone resistant determining regions in clinical isolates of pneumococci collected in Canada

Patel

Melano

McGeer

et al. 2010

Ann Clin Microbiol Antimicrob

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“…Treatment with a single antibiotic, such as a ␤-lactam, a third-generation cephalosporin, or an antipneumococcal fluoroquinolone, was considered to be effective previously (11), but with the emergence of MDR S. pneumoniae strains, the use of a ␤-lactam or macrolide as empirical therapy for such infections is of great concern. Emerging evidence shows beneficial effects on outcome with combination therapies, especially with that of a ␤-lactam agent and a macrolide given together to hospitalized patients with pneumococcal pneumonia (12).…”

mentioning

confidence: 99%

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

Majhi

Adhikary

Bhattacharyya

et al. 2014

Antimicrob Agents Chemother

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In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10 6 CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.

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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.…”

mentioning

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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In vitro activity of sitafloxacin against clinical strains of Streptococcus pneumoniae with defined amino acid substitutions in QRDRs of gyrase A and topoisomerase IV

Cited by 12 publications

References 11 publications

Characterization of the quinolone resistant determining regions in clinical isolates of pneumococci collected in Canada

Characterization of the quinolone resistant determining regions in clinical isolates of pneumococci collected in Canada

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

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

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