Masakatsu Tsuji

In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains

ABSTRACT S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the first set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all ≤1 μg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of ≥8 μg/ml. In the second set, the MIC values of S-649266 were ≤4 μg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of ≤2 μg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.

In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria

OBJECTIVES S-649266 is a parenteral siderophore cephalosporin antibiotic with a catechol moiety on its side chain. The in vitro antimicrobial activity of S-649266 against non-fermenting Gram-negative bacteria was evaluated and compared with the activities of meropenem, levofloxacin, cefepime, ceftazidime and piperacillin/tazobactam. METHODS MIC values of S-649266 were determined in Mueller-Hinton broth or Iso-Sensitest broth supplemented with apo-transferrin. RESULTS S-649266 showed potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. MIC90s of S-649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively. CONCLUSIONS S-649266 is a novel antibiotic with potent in vitro activity against a range of non-fermenting Gram-negative bacteria, including MDR strains.

Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa

ABSTRACT Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.

Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases

ABSTRACT To better understand the antibacterial activity of S-649266 against carbapenemase producers, its stability against clinically relevant carbapenemases was investigated. The catalytic efficiencies (kcat/Km) of IMP-1, VIM-2, and L1 for S-649266 were 0.0048, 0.0050, and 0.024 μM−1 s−1, respectively, which were more than 260-fold lower than that for meropenem. Only slight hydrolysis of S-649266 against KPC-3 was observed. NDM-1 hydrolyzed meropenem 3-fold faster than S-649266 at 200 μM.

In Vivo Antibacterial Activity of S-3578, a New Broad-Spectrum Cephalosporin: Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Experimental Infection Models

ABSTRACT The in vivo antibacterial activity of S-3578, a new parental cephalosporin, was compared with those of cefepime, ceftriaxone, ceftazidime, imipenem-cilastatin, and vancomycin. The efficacy of S-3578 against systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA) SR3637 (50% effective dose [ED50], 7.21 mg/kg of body weight) was almost the same as that of vancomycin. In contrast, cefepime and imipenem-cilastatin were less active against this pathogen (ED50s, >100 and >100 mg/kg, respectively). S-3578 was the most effective compound against penicillin-resistant Streptococcus pneumoniae SR20946 (ED50, 1.98 mg/kg). S-3578 (10 mg/kg) induced a significant reduction in the numbers of viable MRSA SR17764 and Pseudomonas aeruginosa SR10396 organisms in polymicrobial pulmonary infections. The therapeutic efficacy of S-3578 was more potent than that of the combination of vancomycin and ceftazidime. High levels of S-3578 were detected in plasma in vivo, and its efficacy against experimentally induced infections in mice caused by MRSA and P. aeruginosa reflected its potent in vitro activity. We conclude that S-3578 is a promising new cephalosporin for the treatment of infections caused by gram-positive and -negative bacteria, including MRSA and P. aeruginosa.

Occurrence of PER-1 Producing Clinical Isolates of Pseudomonas aeruginosa in Japan and their Susceptibility to Doripenem

The acquisition of resistance by extended-spectrum β-lactamases (ESBL) has been reported primarily for Enterobacteriaceae, but there are few reports on the isolation of ESBL-producing Pseudomonas aeruginosa. PER-1-type ESBL producing P. aeruginosa has been found in various regions around the world but there are no reports of clinical isolates in Japan. During our susceptibility surveillance studies over a 10 year period, we found four clinical isolates resistant to ceftazidime due to production of PER-1. They were resistant to ceftazidime but susceptible in the presence of clavulanic acid, a class A β-lactamase inhibitor. The strains had the ability to hydrolyze ceftazidime. They also had the gene for PER-1-type ESBL. This is the first report of the isolation of PER-1 producing strains in Japan. These four strains were resistant to ceftazidime, cefepime and aztreonam with MICs of 64 μg/ml or more, but were more susceptible to carbapenem antibiotics. In particular, doripenem, which is a novel carbapenem antibiotic, showed good antibacterial activity with a MIC of 2 or 4 μg/ml, which was more potent than meropenem and imipenem. Doripenem also showed good therapeutic efficacy against a systemic infection of mice with a PER-1 producing strain, and was also more potent in vivo than imipenem or meropenem.

Pharmacodynamics of S-3578, a Novel Cephem, in Murine Lung and Systemic Infection Models

ABSTRACT S-3578 is a novel beta-lactam with enhanced activity against drug-resistant gram-positive cocci such as methicillin-resistant Staphylococcus aureus (MRSA). We used murine penicillin-resistant Streptococcus pneumoniae lung infection and neutropenic murine systemic MRSA infection models to determine the pharmacokinetic (PK)-pharmacodynamic (PD) parameter that best correlated with efficacy. Pharmacokinetic studies revealed that the maximum concentration in serum/dose values for S-3578 and cefepime in plasma in the lung infection model were 1.21 to 1.54 and 0.97 to 1.29, respectively; those for S-3578 in plasma in the systemic infection model were 0.78 to 1.02. The area under the concentration-time curve (AUC)/dose values for S-3578 and cefepime in plasma in the lung infection model were 0.98 to 1.13 and 0.77 to 1.04, respectively, and those for S-3578 in plasma in the systemic infection model were 1.03 to 1.11. The half-lives of S-3578 and cefepime in plasma in the lung infection model were 0.29 to 0.38 and 0.29 to 0.34, respectively, and those of S-3578 in plasma in the systemic infection model were 0.40 to 0.61. The time above the MIC was the PK-PD parameter that best correlated with efficacy in the murine lung infection model (R2 = 84 and 92% for S-3578 and cefepime in plasma, respectively). There was a twofold increase in the dose of S-3578 in the systemic infection model compared to that in the pneumonia model, yet the AUCs were the same. This may be due to the different MICs for the two pathogens.

Phase Stability and Mechanical Properties of Ti-Ni Shape Memory Alloys Containing Platinum Group Metals

In order to develop Ti-Ni base shape memory alloys (SMAs), the effects of ternary additions on phase constitution and mechanical properties were investiga ted for TiNi alloys containing some platinum group metals: Ir, Rh and Pt. All the al loys fabricated were made by Ar arc melting method using high purity elemental materials fol owed by hot-forging at 1173-1673K in Ar and furnace cooling. Then X-ray diffraction analysis a nd tensile tests were carried out at room temperature (RT). It was found that, whe n the amount of ternary is lower than 10mol%, all the additions reduce martensitic transf ormation temperature ( Ms) of TiNi and B2 phase becomes stable. Besides monoclinic, L1 0 and B19 phases appear for TiNi containing 40-50mol%Ir, 30-50mol%Rh and 20-50mol%Pt, respectively. The t ensile ductility at RT decreases with increasing the amount of terna ry additions, and the ductility becomes very limited when monoclinic (TiIr), L1 0 (TiRh) and B19 (TiPt) phases appear in the Ti-Ni-Ir, Ti-Ni-Rh and Ti-Ni-Pt systems, respectively . Strength strongly depends on Ms and crystal structure of the apparent phase. Small work hardening is recognized in all the alloy systems. Introduction Ti-Ni SMAs exhibit several smart functions represented by shap e memory effect and superelasticity. The applications of the Ti-Ni alloys are, how ever, still limited mainly because the martensitic transformation temperature ( Ms) is below 400K in the binary systems [1]. Then, in order to expand the applications related with SMAs, shape memory alloys actuated at higher temperature than binary Ti-Ni are required. Several investigations have been done for the improvement of actuation temperature of Ti-Ni by a lloying additives [2-4]. Most of additional elements such as Co, Fe, Mn, Cr and V reduce Ms. On the other hand, some refractory metals such as Hf and Zr and platinum group meta ls (PGMs) such as Pd and Materials Science Forum Online: 2003-08-15 ISSN: 1662-9752, Vols. 426-432, pp 2333-2338 doi:10.4028/www.scientific.net/MSF.426-432.2333

In Vitro and In Vivo Antibacterial Activities of S-1090, a New Oral Cephalosporin

S-1090, a new oral cephalosporin, was active against selected gram-negative bacteria and methicillin-susceptible clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus warneri, against which it had excellent activity. S-1090 was the most active compound against Streptococcus pyogenes and Streptococcus agalactiae among the agents compared. The in vivo efficacy of S-1090 against systemic and urinary and respiratory tract infections caused by gram-positive and -negative bacteria was superior to that expected from the in vitro and in vivo activities of the agents against which it was compared.

Potent oxazolidinone antibacterials with heteroaromatic C-ring substructure.

Novel oxazolidinone analogues bearing a condensed heteroaromatic ring as the C-ring substructure were synthesized as candidate antibacterial agents. Analogues 16 and 21 bearing imidazo[1,2-a]pyridine and 18 and 23 bearing [1,2,4]triazolo[1,5-a]pyridine as the C-ring had excellent in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). They also showed promising therapeutic effects in a mouse model of lethal infection. Preliminary safety data (inhibitory effects on cytochrome P450 isoforms and monoamine oxidases) were satisfactory. Further evaluation of 18 and 23 is ongoing.