New therapies for pneumococcal meningitis

The treatment of pneumococcal meningitis remains a major challenge, as reflected by the continued high morbidity and case fatality of the disease. The worldwide increase of penicillin-resistant pneumococci and more recently cephalosporin- and vancomycin-tolerant pneumococci has jeopardised the efficacy of standard treatments based on extended spectrum cephalosporins alone or in combination with vancomycin. This review provides a summary of newly developed antibiotics tested in the rabbit meningitis model. In particular, newer β-lactam monotherapies (cefepime, meropenem, ertapenem), recently developed quinolones (garenoxacin, gemifloxacin, gatifloxacin, moxifloxacin) and a lipopeptide antibiotic (daptomycin) are discussed. A special emphasis is placed on the potential role of combination treatments with some of the new compounds, which are of interest based on the background of increasing resistance problems due to their often synergistic activity in the rabbit model of pneumococcal meningitis.     

Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selection

The choice of antimicrobial dosing in clinical practice in the past was based upon a ‘penicillin mentality’, that is, on the assumption that the in vivo antimicrobial efficacy is dependent on the duration of drug levels above the minimum inhibitory concentration of target microorganisms. Really, a rational antimicrobial therapy is strongly related to a basic understanding of the influence the patient has on the antibiotic (pharmacokinetics [PKs]) and the patient’s response to the specific drug effects (pharmacodynamics [PDs]). PK/PD parameters are essential in facilitating the translation of microbiological activity into clinical situations, ensuring a successful outcome. This review will analyze the typical patterns of antimicrobial activity and the corresponding PK/PD parameters, with a special focus on a PK/PD dosing approach with the most commonly utilized antimicrobial agent classes.     

Effect of glycosylation of a synthetic MUC1 mucin-core-related peptide on recognition by anti-mucin antibodies

Human epithelial mucins are heterogeneously glycosylated proteins associated with breast and ovarian cancer. Several peptide-reactive anti-mucin MUC1 monoclonal antibodies are used in experimental and diagnostic assays but it is not known how glycosylation of the mucin influences antibody recognition. In this report we show that increasing glycosylation of a synthetic 25-amino acid fragment of the MUC1 core protein with N-acetylgalactosamine (GalNAc) elicits different responses in its recognition by two anti-MUC1 antibodies, C595 and HMFG1. We propose that increasing glycosylation of the synthetic mucin fragment produces an alteration in the structure of the epitope which enhances binding in C595, but not in HMFG1.     

Heteroresistance: a concern of increasing clinical significance?

Recent studies have focused on issues related to heteroresistance, including its definition, methods of detection and frequency. Most such studies have reported data concerning infections caused by Staphylococcus aureus, but the clinical significance of heteroresistance is unclear. Six studies have described infections caused by S. aureus strains that were heteroresistant to vancomycin, with two suggesting an association between the emergence of heteroresistance and treatment failure or mortality, and four suggesting no such association. Further studies are required to evaluate the clinical implications of heteroresistance in an era in which rates of antimicrobial resistance are increasing alarmingly worldwide.     

利奈唑胺治疗多重耐药革兰阳性细菌性心内膜炎的研究进展

利奈唑胺是新型噁唑烷酮类抗生素,可口服,也可静脉应用.其口服生物利用度为100%,组织穿透能力强,即使在心脏瓣膜或赘生物上其局部浓度亦高.利奈唑胺与其他抗生素无交叉耐药性.虽然体外试验表明利奈唑胺主要是抑菌性的,但其对多重耐药革兰阳性菌,如凝血酶阴性葡萄球菌(CNS)、耐甲氧西林金葡菌(MRSA)、耐万古霉素肠球菌(VRE)等均有抗菌活性.已经证实,利奈唑胺能有效治疗动物模型实验性IE.利奈唑胺治疗人类IE时,既有成功也有失败的报道.一般来说,利奈唑胺耐受性好.长期治疗偶可引起可逆性骨髓抑制,如贫血及血小板减少.最近美国心脏学会(AHA)公布的指南建议,虽然利奈唑胺不作为IE治疗的一线药物,但对多重耐药革兰阳性菌株引起的IE,尤其对"标准疗法"有禁忌证或治疗失败,或不能耐受糖肽类抗生素者来说,还是一个重要的治疗选择.     

守宫硫酸糖肽对人乳腺癌细胞 SKBR3增殖的影响及其机制

目的：观察守宫硫酸糖肽（ GSPP）对人乳腺癌细胞SKBR3增殖的影响,并探讨其作用机制。方法体外培养SKBR3细胞,分别加入GSPP 100μg／mL、碱性成纤维细胞生长因子（ bFGF ）5 ng／mL、GSPP 100μg／mL联合bFGF 5 ng／mL,并设PBS阴性对照组。72 h后分别用台盼蓝染色法检测增殖细胞数,流式细胞仪检测细胞周期, ELISA法检测CyclinD1。结果与阴性对照组比较,GSPP对SKBR3细胞增殖有抑制作用（P＜0．01）,bFGF对SK-BR3细胞增殖有促进作用（P＜0．01）,二者合用细胞数目与PBS阴性对照比较无统计学差异。 GSPP将细胞周期阻滞在G0／G1期,并抑制CyclinD1分泌（P均＜0．05）;bFGF降低G0／G1期细胞比例,并促进CyclinD1分泌（P均＜0．05）;GSPP同bFGF合用的G0／G1期细胞比例及CyclinD1分泌均与PBS阴性对照组比较无统计学差异。结论GSPP 通过抑制CyclinD1分泌抑制SKBR3细胞增殖;GSPP 可拮抗bFGF 对细胞增殖的促进作用。     

Crystal molecular structures of two tripeptides related to the sequence coding for N-glycosylation

The crystal structures of two tripeptides related to the sequence coding for N-glycosylation of peptides have been solved: Boc-Asn(Me)-Ala-Ser-OMe, 1, and Boc-Asn(Me)-Pro-Ser-NHMe, 2. Both molecules contain an “Asx-turn” characterized by a hydrogen bond between the Ser-NH and Asn-CγOγ sites. Moreover, the Pro-Ser sequence is βI-folded in 2. The Ser hydroxyl group is also intramolecularly hydrogen-bonded in both molecules, but two different hydrogen bondings are observed. In 1, the Ser-Oγ H bond interacts with the Asn-CγOγ carbonyl, in good agreement with one of the mechanisms which have been proposed for the N-glycosylation of peptides. In 2, the Ser-OγH bond turns out to be involved in an intra-residue interaction with Ser-C'O, and this conformational change is essentially the consequence of chemically different C-terminus functions.     

False synergy between vancomycin and β-lactams against glycopeptide-intermediate Staphylococcus aureus (GISA) caused by inappropriate testing methods

The combination of vancomycin and beta-lactams is often considered synergistic and has been recommended for the treatment of glycopeptide-intermediate Staphylococcus aureus (GISA) infections. In this study, the combination of vancomycin or teicoplanin with different beta-lactams was tested. When using NaCl 4% w/v, for better expression of heterogeneous resistance to beta-lactams, with a longer (48-h) incubation period and a higher (10(7) CFU/mL) inoculum, the association of vancomycin with beta-lactams was antagonistic. However, a synergistic effect was observed for teicoplanin under the same conditions.