Multiple transmissible genes encoding fluoroquinolone and third-generation cephalosporin resistance co-located in non-typhoidal Salmonella isolated from food-producing animals in China

The aim of this study was to identify genes conferring resistance to fluoroquinolones and extended-spectrum β-lactams in non-typhoidal Salmonella (NTS) from food-producing animals in China. In total, 31 non-duplicate NTS were obtained from food-producing animals that were sick. Isolates were identified and serotyped and the genetic relatedness of the isolates was determined by pulsed-field gel electrophoresis of XbaI-digested chromosomal DNA. Antimicrobial susceptibility was determined using Clinical and Laboratory Standards Institute methodology. The presence of extended-spectrum β-lactamase (ESBL) and fluoroquinolone resistance genes was established by PCR and sequencing. Genes encoded on transmissible elements were identified by conjugation and transformation. Plasmids were typed by PCR-based replicon typing. The occurrence and diversity of numerous different transmissible genes conferring fluoroquinolone resistance [qnrA, qnrD, oqxA and aac(6′)-Ib-cr] and ESBLs (CTX-M-27 and CTX-M-14), and which co-resided in different isolates and serovars of Salmonella, were much higher than in European countries. Furthermore, different plasmids encoded fluoroquinolone resistance (ca. 6 kb) and β-lactam resistance (ca. 63 kb) and these co-resided in isolates with mutations in topoisomerase genes (gyrA and parC) giving very resistant Salmonella. The presence of multidrug-resistant bacteria in food-producing animals in countries that export foodstuffs suggests that global transfer of antibiotic resistances from country to country on food is possible.     

Analysis of a new fluoroquinolone derivative (Q-35) in human scalp hair as an index of drug exposure and as a time marker in hair

Summary Scalp hair samples were obtained every month for three months after administration from healthy male volunteers who participated in the phase I study of a new antimicrobial fluoroquinolone derivative (Q-35). Hairs were cut into 1 cm long pieces successively from the scalp end. Corresponding pieces of 5 hair strands were dissolved in 1M NaOH and assessed for Q-35 by HPLC. The drug was detectable in the hairs of all subjects taking either a single (400 mg,n = 6) or repeated oral doses of Q-35 (400 mg/day for 6.5 days, total 2600 mg,n = 6). The hair portions containing the drug were shown in most subjects to move outwards along the hair shafts month by month in proportion to the hair growth rate of about 1 cm/month. Q35 (600 mg/day) was also given to 6 healthy male volunteers for 6.5 days (total 3900 mg) and hair samples were obtained 1 and 3 months after administration. When Q-35 was analyzed along a single hair shaft, the drug was detectable only in 1–2 consecutive 1 cm long pieces, which were also shown to move outwards along the hair shaft with time. A detailed analysis revealed that the drug was contained only in 2–4 consecutive 2.5 mm long pieces of a single hair collected after 3 months, showing that there was no significant axial diffusion of the drug along the hair shaft with time. These findings indicate the utility of measuring this fluoroquinolone derivative in human scalp hair as an index of drug exposure and as a time marker for analyzing other drug(s) in hair.     

盐酸洛美沙星合成工艺研究

盐酸洛美沙星以２，３，４－三氟硝基苯经不原，缩合环合，乙基化，水解，再与２－甲基哌嗪缩合，成盐等六步完成。工艺简单，反应条件温和，总收率达４０％以上。     

淋病奈瑟菌的耐药性及氟喹诺酮耐药基因突变的分析

目的了解本地区淋病奈瑟菌(NG)流行株对5种抗生素的敏感性,分析NG的耐药性特点,为淋病的治疗提供实验依据。方法纸片扩散法检测108株NG对5种抗生素的敏感性,用产色头孢硝噻吩法检测β内酰胺酶,用聚合酶链反应(PCR)扩增NGgyrA和parC基因的氟喹诺酮耐药决定区(QRDR)相关序列并作测序分析。结果108株NG中检出84株对青霉素耐药(77.8%),由质粒介导的产青霉素酶NG(PPNG)为60株(55.6%);四环素耐药率为61.1%,其中质粒介导高度耐四环素NG(TRNG)为28株,占25.9%;环丙沙星耐药率为83.3%;未发现对大观霉素和头孢曲松的耐药菌株。耐氟喹诺酮的22株NG均发生gyrA基因的91、95氨基酸位点突变,原91位氨基酸全部由丝氨酸转变为苯丙氨酸,parC基因的氨基酸突变位点分别为86、87和91。结论青霉素、四环素以及氟喹诺酮类药物已不宜作为本地区治疗淋病的常规药物;大观霉素、头孢曲松可作为治疗淋病的首选药物,基因检测分析证明了NGgyrA和parC基因突变与氟喹诺酮耐药性有关。     

Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus β-lactams

Enterobacteriaceae bloodstream infections (EB-BSIs) are a common manifestation of Gram-negative sepsis and are initially managed with empirical intravenous antibiotics. Upon stabilisation and source control, patients are often transitioned to an oral agent. Fluoroquinolones (FQs) plays a prominent role in stepdown therapy for severe infections owing to favourable pharmacokinetic parameters; however, serious adverse events (AEs) have been documented with their use. A total of 224 adults with EB-BSI initiated on empirical intravenous antibiotics with stepdown to oral β-lactam (BLM) (n?=?84) or FQ (n?=?140) were studied to compare clinical success and identify risk factors for treatment failure. Subgroups of early versus late oral stepdown and short versus extended duration of therapy (DOT) were assessed. Stepdown therapy with oral BLM was non-inferior to oral FQ (86.9% vs. 87.1%; mean difference 0.2%, 97.5% CI ?10.3 to 10.7). Microbiological success (94.0% vs. 97.9%; P?>?0.05) and 30-day re-admission (14.3% vs. 14.3%; P?>?0.05) were similar. Patients were more likely to complete their BLM course without an AE compared with FQs (91.7% vs. 82.1%; P?=?0.049). Clinical success was comparable between early and late stepdown (86.7% vs. 87.5%; P?>?0.05) and short versus extended DOT (88.2% vs. 86.7%; P?>?0.05). Negative predictors of clinical success identified by logistic regression were complicated diabetes (OR?=?0.35, 95% CI 0.15–0.83) and urinary abnormality (OR?=?0.39, 95% CI 0.16–0.94). These findings suggest that oral BLMs were non-inferior to FQs as stepdown therapy for EB-BSI, with less AEs.     

In vitro and in vivo anti- Helicobacter pylori activity of Y-904, a new fluoroquinolone

 Y-904 is a new fluoroquinolone with a broad antimicrobial spectrum. In particular, it has anti-Helicobacter pylori activity superior to that of existing fluoroquinolones. In the present study it was examined for its in vitro antibacterial activity against 51 clinical isolates of H. pylori, including clarithromycin- and metronidazole-resistant strains. The minimum inhibitory concentration of Y-904 at which 90% of isolates were inhibited was close to that of amoxicillin and clarithromycin and lower than that of levofloxacin and metronidazole (0.1, 0.1, 0.2, 3.13, and 12.5 μg/ml, respectively). Y-904 showed equally strong activity at pH 5.5 as at pH 7.0. At 10 times the minimum inhibitory concentration, Y-904 decreased the viable count of H. pylori to below 10⁻⁵ within 2 h after exposure. No significant change in the minimum inhibitory concentration was observed when H. pylori, Staphylococcus aureus, and Escherichia coli were successively subcultured in medium containing subinhibitory concentrations of Y-904. Y-904 also strongly inhibited the supercoiling activity of DNA gyrase from H. pylori ATCC43504 (IC₅₀, 1.48 μg/ml). A study of Y-904 treatment in H. pylori-infected Mongolian gerbils using twice-daily oral administration for 7 days demonstrated that the complete clearance dose of Y-904 was 1 mg/kg and that its potency was around 10, 30, and 30 times that of amoxicillin, clarithromycin, and levofloxacin, respectively. These results indicate that Y-904 is a promising candidate for the eradication of H. pylori infection. Received: November 8, 2002 / Accepted: March 10, 2003 Acknowledgments We thank Dr. T. Sugiyama, Dr. M. Kato (Hokkaido University, Sapporo, Japan), and Dr. K. Sakurai (Showa University, Yokohama, Japan) for graciously providing the clinical isolates of H. pylori. We are also grateful to Mr. K. Honjo for assistance in the in vitro antibacterial studies and to Mr. S. Miyoshi for pharmacokinetic data.     

In vitro method for prediction of the phototoxic potentials of fluoroquinolones

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.     

Optimal use of fluoroquinolones in the intensive care unit setting

Fluoroquinolones have become a staple antimicrobial in a variety of settings for a wide spectrum of infectious diseases. Although fluoroquinolones have been associated with a broad spectrum of adverse events, the side effect profile is generally acceptable. Their use in the intensive care unit as empiric therapy is becoming compromised due to the development of multiple drug resistant gram negative pathogens and collateral damage with C difficile & MRSA. Fluoroquinolones should be used along with another antibiotic of different chemical structure, mechanism of action, and pharmacodynamic profile to ensure adequate initial antimicrobial coverage and maximize the likelihood of a favorable clinical and microbiologic response.     

氟喹诺酮类抗生素治疗UTI的应用现状及其引起的细菌抗药性的研究(英文)

抗生素已经成为一种重要的高效药物用于治疗细菌性感染。随着时间推移,抗生素的成功使用也伴随着许多问题产生,如滥用抗生素,具有抗药性细菌的快速传播。氟喹诺酮类抗生素是一类属于氟喹诺酮家族的人工合成具有抗菌活性的药物,已非常广泛地应用于临床和兽类,最主要用于治疗UTI类的疾病。细菌对氟喹诺酮类抗生素抗药性的产生主要通过目标基因突变和增加药物外泵作用的突变实现。