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Zhu J.,Shanghai JiaoTong University | Ding B.,Fudan University | Ding B.,Key Laboratory of Clinical Pharmacology of Antibiotics | Xu X.,Fudan University | And 8 more authors.
Frontiers in Microbiology | Year: 2015

Objectives: To identify the mechanism of in vivo development of carbapenem resistance in Klebsiella pneumoniae. Methods: Seven sequential isolates of K. pneumoniae were obtained from twin infants with pneumonia. Antimicrobial susceptibility testing was performed by agar dilution method. Carbapenemases including KPC and MβL were initially screened using phenotypic methods, and carbapenemase-encoding genes were identified by polymerase chain reaction and amplicon sequencing. Plasmids of all clinical isolates and the conjugants of resistant isolates were estimated by S1 pulsed-field gel electrophoresis (PFGE). Molecular typing were conducted by PFGE of XbaI-digested genomic DNA and multilocus sequence typing. Results: For old brother, the first and third isolates were susceptible to meropenem, whereas the second and fourth isolates were resistant (MICs 16 mg/L). The first and second isolates from the young brother were susceptible to meropenem whereas the third isolate was resistant. All the resistant isolates produced NDM-1 metallo-β-lactamase. PFGE of XbaI-digested DNA revealed almost identical patterns with similarity indices of above 92% for all the seven isolates. All the isolates had the same sequence type named sequence type 37 (ST37). Conclusion: To our knowledge, this is the first documented case of development of carbapenem resistance in vivo mediated by NDM-1 metallo-β-lactamase in K. pneumoniae during treatment of pneumonia with meropenem. © 2015 Zhu, Ding, Xu, Zhu, Yang, Zhang and Hu.


Liu Y.,Fudan University | Liu Y.,Key Laboratory of Clinical Pharmacology of Antibiotics | Ye X.,Fudan University | Ye X.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 5 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2014

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia, which is often empirically treated with macrolides such as erythromycin and azithromycin. Recent studies have found a gradual increase in the numbers of macrolide-resistant strains due to mutations in the 23S rRNA gene. A2063G is the most common mutation, followed by A2064G. We developed a Cycleave PCR method for detecting macrolide-resistant strains of M. pneumoniae. With use of this method, the resistant strains can be quickly separated from the susceptible ones. In this work, via this method, both M. pneumoniae and resistance mutants were successfully identified from 101 clinical isolates as well as from 136 nasopharyngeal specimens. The findings of this study may allow clinicians to determine the treatment plan more rapidly and may provide a convenient method to conduct surveillance for genetic mutations conferring antibiotic resistance. © 2014 Elsevier Inc.


Sheng Z.-K.,Fudan University | Sheng Z.-K.,Key Laboratory of Clinical Pharmacology of Antibiotics | Hu F.,Fudan University | Hu F.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 13 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Of 26 tigecycline-nonsusceptible Klebsiella pneumoniae (TNSKP) clinical isolates, 25 had nonsynonymous mutations in ramR and/or acrR (23 in ramR and 10 in acrR). Eight TNSKP isolates possessed overexpression of ramA, acrB, rarA, and oqxB simultaneously, while 8 and 1 TNSKP strains had upregulation of ramA and acrB and of rarA and oqxB, respectively. Thus, resistance mechanisms of 9 TNSKP isolates cannot be explained by the present pathways. This study underscores the role of RamA in TNSKP and suggests the presence of novel tigecycline resistance mechanisms. © 2014, American Society for Microbiology. All Rights Reserved.


Chen C.,Fudan University | Chen C.,Key Laboratory of Clinical Pharmacology of Antibiotics | Sun J.,Shanghai JiaoTong University | Guo Y.,Fudan University | And 13 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

The vanM gene was first found in a vancomycin-resistant Enterococcus faecium (VREm) isolate in Shanghai in 2006. In this study, we found that, in 70 VREm strains isolated in nine Shanghai hospitals from 2006 to 2014, vanM was more prevalent than the vanA gene (64.3% [45/70] versus 35.7% [25/70]). The vanM-type isolates showed similar antimicrobial susceptibility patterns with the vanA types. The vanM-type VREm emerged and disseminated in Shanghai. Copyright © 2015 Chen et al.


Guo Q.,University of Pittsburgh | Guo Q.,Fudan University | Guo Q.,Key Laboratory of Clinical Pharmacology of Antibiotics | Spychala C.N.,University of Pittsburgh | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2016

Objectives: The objective of this study was to conduct a comparative analysis with reported IncR plasmids of a Klebsiella pneumoniae IncR plasmid carrying an MDR region. Methods: MDR K. pneumoniae isolates were serially identified from two inpatients at a hospital in the USA in 2014. MDR plasmid pYDC676 was fully sequenced, annotated and compared with related plasmids. Antimicrobial susceptibility testing, PFGE and MLST were also conducted. Results: The K. pneumoniae isolates were identical by PFGE, belonged to ST37 and harboured an identical ~50 kb IncR plasmid (pYDC676). pYDC676 possessed the backbone and multi-IS loci closely related to IncR plasmids reported from aquatic bacteria, as well as animal and human K. pneumoniae strains, and carried an MDR region consisting of armA, blaDHA-1 and qnrB4, a combination that has been reported in IncR plasmids from K. pneumoniae ST11 strains in Europe and Asia. A plasmid with the identical IncR backbone and a similar MDR region containing blaDHA-1 and qnrB4 has also been reported in ST37 strains from Europe, suggesting potential dissemination of this lineage of IncR plasmids in K. pneumoniae ST37. Conclusions: K. pneumoniae ST37 strains with an MDR IncR plasmid carrying armA, blaDHA-1 and qnrB4 were identified in a hospital in the USA, where these resistance genes remain rare. The IncR backbone may play a role in the global dissemination of these resistance genes. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Guo B.,Fudan University | Guo B.,Key Laboratory of Clinical Pharmacology of Antibiotics | Zhang J.,Fudan University | Zhang J.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 7 more authors.
Biomedical Chromatography | Year: 2012

Nemonoxacin (TG-873870) is a novel C-8-methoxy nonfluorinated quinolone with higher activity than ciprofloxacin, levofloxacin and moxifloxacin against Gram-positive pathogens including methicillin-susceptible or methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae with various resistant phenotypes. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated to determine the concentration of nemonoxacin in human plasma and urine. Protein precipitation and liquid-liquid extraction were employed for plasma and urine sample preparations, respectively, and extract was then injected into the system. Separation was performed on a C18 reversed-phase column using acetonitrile-0.1% formic acid as a mobile phase. Both analyte and internal standard (gatifloxacin) were determined using electrospray ionization and the MS data acquisition via the selected reaction monitoring in positive-ion mode. The lower limit of quantification was 5ng/mL and the calibration curves were linear in the concentration range of 5-1000ng/mL. The accuracy, precision, selectivity, linearity, recovery, matrix effect and stability were validated for TG-873870 in human plasma and urine. The method was successfully applied to a pharmacokinetic study enrolling 12 healthy Chinese volunteers administered nemonoxacin malate capsules. © 2012 John Wiley & Sons, Ltd.


Qin X.,Fudan University | Qin X.,Key Laboratory of Clinical Pharmacology of Antibiotics | Yang Y.,Fudan University | Yang Y.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 5 more authors.
Journal of Medical Microbiology | Year: 2014

Carbapenems are first-line agents for the treatment of serious nosocomial infections caused by multidrug-resistant Enterobacteriaceae. However, resistance to carbapenems has increased dramatically among Enterobacteriaceae in our hospital. In this study, we report clonal dissemination caused by carbapenem-resistant Enterobacter aerogenes (CREA). In 2011, CREA was identified from 12 patients admitted to the neurosurgical ward. All 12 clinical isolates were non-susceptible to cefotaxime, ceftazidime, cefoxitin, ertapenem, imipenem or meropenem. All isolates carried the gene encoding Klebsiella pneumoniae carbapenemase-2 (KPC-2), except for the isolate E4. However, a remarkably lower expression level of the porin OmpF was detected in the non-KPC-2-producing isolate E4 on SDS-PAGE compared with the carbapenem-susceptible isolate. Epidemiological and molecular investigations showed that a single E. aerogenes strain (PFGE type A), including seven KPC-2-producing clinical isolates, was primarily responsible for the first isolation and subsequent dissemination. In a case-control study, we identified risk factors for infection/colonization with CREA. Mechanical ventilation, the changing of sickbeds and previous use of broad-spectrum antibiotics were identified as potential risk factors. Our findings suggest that further studies should focus on judicious use of available antibiotics, implementation of active antibiotic resistance surveillance and strict implementation of infection-control measures to avoid the rapid spread or clonal dissemination caused by carbapenem-resistant Enterobacteriaceae in healthcare facilities. © 2014 SGM.


O'Hara J.A.,University of Pittsburgh | Hu F.,University of Pittsburgh | Hu F.,Fudan University | Hu F.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 5 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Of 20 Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli isolates identified at hospitals in western Pennsylvania, 60% belonged to the epidemic ST131-fimH30 subclone. IncFIIk was the most common replicon type for the blaKPC-carrying plasmids (n = 8). All IncFIIk plasmids possessed a scaffold similar to that of pKpQIL, and seven of them were borne by ST131-fimH30 isolates. IncN plasmids conferred resistance to trimethoprim-sulfamethoxazole, and IncA/C plasmids conferred resistance to gentamicin. Three blaKPC-carrying plasmids (IncA/C and IncN) possessed blaSHV-7/12 and qnrA1 or qnrS1. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Ahn C.,University of Pittsburgh | Syed A.,University of Pittsburgh | Hu F.,University of Pittsburgh | Hu F.,Fudan University | And 4 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2014

Microbiological data regarding Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter spp. are scarce. In this study, 11 unique KPC-producing Enterobacter isolates were identified among 44 ertapenem-nonsusceptible Enterobacter isolates collected between 2009 and 2013 at a hospital system in Western Pennsylvania. All cases were healthcare-associated and occurred in medically complex patients. While pulsed-field gel electrophoresis showed diverse restriction patterns overall, multilocus sequence typing identified Enterobacter cloacae isolates with sequence types 93 and 171 from 2 hospitals each. The levels of carbapenem minimum inhibitory concentrations were highly variable. All isolates remained susceptible to colistin and tigecycline, and the majority, to amikacin and doxycycline. A blaKPC-carrying IncN plasmid conferring trimethoprim-sulfamethoxazole resistance was identified in 3 of the isolates. Spread of blaKPC in Enterobacter spp. appears to be due to a combination of plasmid-mediated and clonal processes. © 2014 Elsevier Inc.


Ding B.,Fudan University | Ding B.,Key Laboratory of Clinical Pharmacology of Antibiotics | Hu F.,Fudan University | Hu F.,Key Laboratory of Clinical Pharmacology of Antibiotics | And 8 more authors.
Journal of Clinical Microbiology | Year: 2015

Carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Acinetobacter baumannii were isolated from a single patient, each producing different carbapenemases (NDM-1, KPC-2, IMP, and OXA-23, respectively). The NDM-1-producing E. Coli strain was preceded by a clonally related carbapenem-susceptible strain a month earlier, suggesting in vivo acquisition of blaNDM-1. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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