Evaluation of predictors of third-generation cephalosporin non-susceptibility and factors affecting recurrence or death in bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes.

Factors involved in the susceptibility of third-generation cephalosporins (3GCs) to bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes were investigated based on a case-case-control design. Antimicrobial therapy administered 30 days prior to bacteremia and hospitalization within 90 days were common risk factors for the 3GC susceptible and 3GC non-susceptible groups, while hospitalization from an institution or another hospital was a specific risk factor for the 3GC non-susceptible group. We also attempted to examine the factors affecting the clinical outcome of bacteremia. Hospitalization more than 14 days before the onset of bacteremia was an independent factor indicating poor clinical outcome. In contrast, the implementation of source control was an independent predictor of successful treatment. Although a longer hospital stay before the onset of bacteremia was associated with worse clinical outcomes, implementation of source control may have contributed to improved treatment outcomes for bacteremia.

The Clinical Evaluation of Third-generation Cephalosporins As Definitive Therapy for Enterobacter spp. and Klebsiella aerogenes Bacteremia.

Objective Third-generation cephalosporins (3GCs) may be susceptible in vitro to Enterobacter spp. and Klebsiella aerogenes. However, treatment with mainly fourth-generation cephalosporins or carbapenems is currently recommended. Diversification of antimicrobial agents in therapy is required to avoid the selection pressure of resistant organisms by broad-spectrum antimicrobial agents. This study investigated the clinical efficacy of 3GC therapy for Enterobacter spp. and Klebsiella aerogenes bacteremia in a multicenter, retrospective, observational study. Methods Patients with Enterobacter spp. or Klebsiella aerogenes detected in blood cultures and treated with a susceptible antimicrobial agent were included in the study. Propensity score matching was performed to align patient background bases, and clinical outcomes between the 3GC and non-3GC groups were compared. Treatment success was defined as having no need for treatment escalation or the addition of other antimicrobial agents, no recurrence, or no death within 30 days. Results The study included 188 cases, of which 57 and 131 were included in the 3GC and non-3GC treatment groups, respectively; 53 patients in each group were matched by propensity score matching. There were no significant differences between groups in rates of switching to a susceptible antimicrobial or adding another agent, relapse within 30 days, or death within 30 days. In the 3GC group, source control was associated with favorable clinical outcomes. Conclusion Definitive 3GC therapy for susceptible Enterobacter spp. and Klebsiella aerogenes bacteremia is as clinically effective and valuable a targeted therapy as non-3GC therapy and can be implemented under conditions in which infection source control measures are in place.

Metal-dependent regioselective homocoupling of stannyl- and alkyl-substituted alkynes on group 4 elements. Formation of unsymmetrical titanacyclopentadienes and symmetrical zircona-cyclopentadienes.

Homocoupling of stannyl- and alkyl-substituted alkynes with Cp2TiBu2 gave unsymmetrical titanacyclopentadienes (αß isomers) with >95% regioselectivities, whereas the coupling with Cp2ZrBu2 provided symmetrical zirconacyclopentadienes (αα isomers) with >93% selectivities. This is the first example of metal-dependent regioselective homocoupling of unsymmetrical alkynes on group 4 elements.

Lithiation of palladated dihydropentacene: a new route for the introduction of substituents from both of electrophiles and nucleophiles to pentacene.

Dibromodihydropentacene compound 1 was palladated and then lithiated to give a lithiated-palladated intermediate. Both of the lithium moiety and the palladium complex moiety on dihydropentacene unexpectedly survived in the solution. The Li and Pd moieties reacted with electrophiles and nucleophiles respectively to give the substituted dihydropentacene products. Aromatization of these dihydropentacenes gave substituted pentacene derivatives.

Formation of a spiro compound via coupling of a cyclopentadienyl ligand with a diene moiety of titanacyclopentadiene.

The treatment of titanacyclopentadienes with bismuth(iii) chloride gave spiro compounds in moderate yields. Two carbon atoms of the diene moiety of the titanacyclopentadiene were connected to one carbon atom of the Cp ligand. This is in sharp contrast to the formation of dihydroindene derivatives, where two carbon-carbon bonds were formed between the diene moiety and the adjacent two carbon atoms of the Cp ligand.

Atropisomeric Chiral Diiododienes (Z,Z)-2,3-Di(1-iodoalkylidene)tetralins: Synthesis, Enantiomeric Resolution, and Application in Asymmetric Catalysis.

The C2-symmetric tetralin-fused 1,4-diiodo-1,3-butadiene derivatives, (Z,Z)-2,3-di(1-iodoalkylidene)tetralin 1a-c, are atropisomeric and can be resolved into the two persistent axially chiral enantiomers by HPLC on a chiral stationary phase. The enantiomerically pure compounds can serve as chiral organocatalysts for dearomatizing spirolactonization to show good performance in up to 73% ee.

Palladium-Catalyzed SN2'-Cyclization of Ambivalent (Bromoalkadienyl)malonates: Preparation of Medium- to Large-Membered Endocyclic Allenes.

A palladium-catalyzed reaction for preparing various endocyclic allenes was developed. The substrates for the reaction were readily available ω-(pronucleophile-tethered)-3-bromo-1,3-alkadienes, and a palladium-catalyst facilitated their unimolecular SN2'-cyclization in the presence of potassium tert-butoxide to give the corresponding 9- to 16-membered endocyclic allenes in fair yields of up to 67% together with the dimeric 16- to 32-membered endocyclic bis-allenes and other oligomeric/polymeric intermolecular reaction products. For higher yields of the monomeric endocyclic allenes, the reaction needed to be conducted under high-dilution conditions. Using a chiral palladium catalyst, axially chiral endocyclic allenes were obtained in up to 70% ee.

Planar-Chiral Phosphine-Olefin Ligands Exploiting a (Cyclopentadienyl)manganese(I) Scaffold To Achieve High Robustness and High Enantioselectivity.

A series of 2-methyl-1,3-propenylene-bridged (η5-diarylphosphinocyclopentadienyl)(phosphine)manganese(I) dicarbonyl complexes 2 have been developed as a new class of phosphine-olefin ligands based on a planar-chiral transition-metal scaffold, which show better robustness as well as higher enantioselectivity over phosphine-olefin ligands 1 with a planar-chiral (η6-arene)chromium(0) framework. The practical enantiospecific and scalable synthesis of 2 has been established. Phosphine-olefin ligands 2 enable construction of an effective chiral environment around a transition-metal center upon coordination, and thus their rhodium(I) complexes exhibit excellent catalytic performance in the various asymmetric addition reactions of arylboron nucleophiles. Complex 2b, which has a bis(3,5-dimethylphenyl)phosphino group on the cyclopentadienyl ring, is found to be a superior chiral ligand in the rhodium-catalyzed asymmetric 1,4-addition reactions of arylboronic acids to various cyclic/acyclic enones giving the corresponding arylation products in over 99% ee. On the other hand, 2c and 2d, which have bis[3,5-bis(trifluoromethyl)phenyl]phosphino and bis(3,5-di-tert-buthyl-4-methoxyphenyl)phosphino groups, respectively, are highly efficient chiral ligands in the rhodium-catalyzed asymmetric 1,2-addition reactions of the arylboron nucleophiles to imines or aldehydes showing up to 99.9% ee. The X-ray crystallographic studies of (R)-2b and [RhCl((S*)-2b)]2 reveal the absolute configuration of 2b and its phosphine-olefin bidentate coordination to a rhodium(I) cation. Structural comparison with [RhCl((R*)-1b)]2 postulates the origins of the higher enantioselectivity of newly developed phosphine-olefin ligands 2.

Pitavastatin suppresses hyperglycaemia-induced podocyte injury via bone morphogenetic protein-7 preservation.

Podocytes form the essential components of the glomerular filtration barrier and play a critical role in diabetic nephropathy. Recent evidence suggests that HMG-CoA reductase inhibitors (statins) exert renoprotective effects. We investigated whether pitavastatin directly suppresses hyperglycaemia-induced podocyte injury using cultured podocytes and, if so, the mechanism of the beneficial effects. Cultured podocytes were exposed to media containing normal (NG; 5 mmol/L) or high (HG; 25 mmol/L) glucose for 1 week. HG increased the lethal injury of podocytes and disruption of F-actin fibers, and reduced the mRNA expression of novel podocyte markers, synaptopodin and Wilms tumor-1 (WT-1), in association with decreased bone morphogenetic protein-7 (BMP-7) expression. Pitavastatin (100 nmol/L) reduced podocyte injury and restored the mRNA expression of synaptopodin and WT1; however, these protective effects were abolished by BMP-7 siRNA. Additionally, pitavastatin suppressed HG-induced Rho kinase activation, as assessed by the phosphorylation level of myosin phosphatase targeting subunit 1 (MYTP1), and C3 exotoxin, a Rho inhibitor, mimicked the effect of pitavastatin on BMP-7 preservation. Pitavastatin attenuates hyperglycaemia-induced podocyte injury via Rho-Rho kinase-dependent BMP-7 preservation.

Formation of Seven-Membered Carbocycles via 7-endo Mode Cyclization of Lithioheptatrienes.

The highly selective synthesis of triene derivatives was achieved by a zirconocene-mediated three-component coupling reaction, and the trienes were efficiently subjected to 7-endo mode cyclization. The reaction of unsymmetrical zirconacyclopentadienes prepared from two different alkynes with N-bromosuccinimide (NBS) followed by treatment with allyl halides in the presence of CuCl afforded the corresponding heptatrienes in good yields. When the trienes reacted with an organolithium reagent, 7-endo mode cyclization occurred smoothly to give the corresponding cycloheptadiene.

Halogen Exchange Reaction of Aliphatic Fluorine Compounds with Organic Halides as Halogen Source.

The halogen exchange reaction of aliphatic fluorine compounds with organic halides as the halogen source was achieved. Treatment of alkyl fluorides (primary, secondary, or tertiary fluorides) with a catalytic amount of titanocene dihalides, trialkyl aluminum, and polyhalomethanes (chloro or bromo methanes) as the halogen source gave the corresponding alkyl halides in excellent yields under mild conditions. In the case of a fluorine/iodine exchange, no titanocene catalyst is needed. Only C-F bonds are selectively activated under these conditions, whereas alkyl chlorides, bromides, and iodides are tolerant to these reactions.

Enantioselective synthesis of planar-chiral ferrocene-fused 4-pyridones and their application in construction of pyridine-based organocatalyst library.

A couple of planar-chiral ferrocene-fused 4-pyridone derivatives 2a and 2b were synthesized in enantiomerically pure form by scalable asymmetric transformations. Pyridones 2 are versatile precursors to various ferrocene-fused pyridine derivatives, which are useful nucleophilic asymmetric organocatalysts.

Enantioselective synthesis of macrocyclic heterobiaryl derivatives of molecular asymmetry by molybdenum-catalyzed asymmetric ring-closing metathesis.

Winding vine-shaped molecular asymmetry is induced by enantioselective ring-closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E-selective ring-closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96% ee.

Simultaneous induction of axial and planar chirality in arene-chromium complexes by molybdenum-catalyzed enantioselective ring-closing metathesis.

The molybdenum-catalyzed asymmetric ring-closing metathesis of the various Cs -symmetric (π-arene)chromium substrates provides the corresponding bridged planar-chiral (π-arene)chromium complexes in excellent yields with up to >99 % ee. With a bulky and unsymmetrical substituent, such as N-indolyl or 1-naphthyl, at the 2-positions of the η(6) -1,3-diisopropenylbenzene ligands, both biaryl-based axial chirality and π-arene-based planar chirality are simultaneously induced in the products. The axial chirality is retained even after the removal of the dicarbonylchromium fragment, and the chiral biaryl/heterobiaryl compounds are obtained with complete retention of the enantiopurity.

Coupling of titanacyclopentadienes with a Cp ligand and elimination of one substituent.

Titanacyclopentadienes, prepared from [Cp2TiBu2] and either two equivalents of an alkyne or a diyne, were treated with PMe3 (3 equiv) at 50 °C for 3 h and then with azobenzene at room temperature for 12 h to give 4,5,6-trisubstituted indene derivatives with the loss of one substituent in good yields. This reaction contrasts sharply with our previously reported reaction for the formation of 4,5,6,7-tetrasubstituted indene derivatives without the loss of substituents by the treatment of titanacyclopentadienes with azobenzene without PMe3. (13)C NMR spectroscopy of the product derived from a (13)C-enriched complex revealed that the five carbon atoms originating from a Cp ligand were arranged linearly in the trisubstituted indene derivatives, in contrast to the 4,5,6,7-tetrasubsituted indene derivatives, in which the corresponding five carbon atoms are arranged in a ring.

Phosphine-olefin ligands based on a planar-chiral (π-arene)chromium scaffold: design, synthesis, and application in asymmetric catalysis.

The NMR and X-ray crystallographic studies clarified that planar-chiral alkenylene-bridged (phosphino-π-arene)(phosphine)chromium complexes 3 were capable of coordinating to a rhodium(I) cation in a bidentate fashion at the (π-arene)-bound phosphorus atom and at the olefin moiety. The P-olefin chelate coordination of 3 constructs the effective chiral environment at the metal center, and thus, these rhodium complexes display high performances in various rhodium-catalyzed asymmetric 1,4- and 1,2-addition reactions with arylboron nucleophiles. The control experiments demonstrated that the (η(2)-olefin)-Rh interaction as well as the bridging structure in 3 played the pivotal roles in the high enantioselectivity of the Rh-catalyzed asymmetric reactions. To enhance the synthetic utilities of these phosphine-olefin ligands, an enantiospecific and scalable synthetic method was developed. The novel synthetic method is flexible in terms of the substituent variation, and a library of the planar-chiral (arene)chromium-based phosphine-olefin ligands was established by the combinatorial approach. Among the newly prepared ligand library, compound 3g, which is with a bis(3,5-dimethylphenyl)phosphino group on the η(6)-arene ring, was found to be a far better chiral ligand in the rhodium-catalyzed asymmetric reactions showing excellent enantioselectivity and high yields.

Successful telaprevir treatment in combination of cyclosporine against recurrence of hepatitis C in the Japanese liver transplant patients.

Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection.

Influence of cytochrome P450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mRNA expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients.

Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

Atropisomeric chiral dienes in asymmetric catalysis: C(2) -symmetric (Z,Z)-2,3-bis[1-(diphenylphosphinyl)ethylidene]tetralin as a highly active Lewis base organocatalyst.

Diene catalysts with a twist: The title C2 -symmetric tetralin-fused 1,3-butadiene derivative is atropisomeric and can be resolved into the two helical enantiomers. The optically pure compound showed excellent enantioselectivity as well as unusually high catalytic activity as a chiral Lewis basic organocatalyst in the asymmetric allylation of various aldehydes with ß-substituted allyltrichlorosilanes.

Kinetic resolution of planar-chiral 1,2-disubstituted ferrocenes by molybdenum-catalyzed asymmetric intraannular ring-closing metathesis.

Planar chirality: Ring-closing metathesis of 1,2-diallylmetallocenes afforded the corresponding 4,7-dihydroindenyl species in high yields. The metallocenes are planar chiral with two different allylic substituents, and kinetic resolution of the racemic 1,2-diallylmetallocene derivatives was realized by molybdenum-catalyzed asymmetric ring-closing metathesis with excellent enantioselectivity (see scheme).