Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

Molecular mechanisms of antibiotic resistance.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

/pdf/clinical-epidemiology-of-the-global-expansion-of-klebsiella-hbqmomldb2.pdf

Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases

Antimicrobial-resistant ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens represent a global threat to human health. The acquisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treatment options for serious infections, increased the burden of disease, and increased death rates due to treatment failure and requires a coordinated global response for antimicrobial resistance surveillance. This looming health threat has restimulated interest in the development of new antimicrobial therapies, has demanded the need for better patient care, and has facilitated heightened governance over stewardship practices.

Antimicrobial resistance in ESKAPE pathogens

Dr Benjamin A H Jensen Dr Aarabi Dr Mera A Ababneh Dr Albert Abaka-Yawson Dr Mohamed Salah Abassi Dr Getahun Abate Dr Tarek Mohamed Abd ElAziz Dr Rehab M Abd El-Baky Dr Amir Abdoli Dr Akebe Luther King Abia Dr Fatma Ben Abid Prof Dr Khaled M Aboshanab Mr Ashenafi Abossie Dr Abouelfetouh Dr Maja Abram Dr Sawsan Abuhammad Dr Abulebda Professor Ali Acar Mr Oliver Okoth Achila Dr Stefan Acosta Dr Azeez Adeboye Dr Sanjib Adhikari Prof Dr Muhammad Sohail Afzal Dr Fabio Aguiar-Alves Dr Thomas Agyarko-Poku Dr Irfan Ahmad Dr Suhail Ahmad Dr Hafiz Ahmad Dr Elham Ahmadi Dr Zahra Ahmadinejad Dr Ehsan Ahmadpour Dr Haroon Ahmed Dr Firoz Ahmed Dr Wan M Aizat Dr Abraham Ajayi Dr Ali Akbar Dr Sami Akbulut Dr Hashaam Akhtar Professor Ala-Eddin Al Moustafa Dr Al-Hasan Dr Ali Al-Jumaili Dr Alexandre Alanio Dr Eliana Alcaraz Dr Maria D Alcantar Curiel Dr Gaetano Alfano Prof Dr Abdelazeem Algammal Dr Iftikhar Ali Dr Musa Mohammed Ali Dr Ihsan Ali Dr Mohammad Javed Ali Dr Ali Muhsin Ali Dr Shahzad Ali Dr Sheikh Alif Professor Michael Alifrangis Dr Reem Aljindan Prof Dr Karel Allegaert Dr Rosalie Allison Dr Ammar Almaaytah Dr Dhary Alewy Almashhadany Dr Tarig Alnour Dr Bandar Alosaimi Mr Abdullah Alqarihi Dr Alian A Alrasheedy Dr Eduardo Amaral Dr Gul Ambreen Professor Gobena Ameni Dr Ahmed Ammar Dr Linda Amoah Professor Luca Ampollini Dr Edina Amponsah-Dacosta Dr Mirko Ancillotti Ms Motswedi Anderson Dr Angel Andrade Dr Sergio Angel Dr Angkasekwinai Dr Archana Angrup Dr Enoch Aninagyei Dr Shamshul Ansari Dr Beena Antony Dr Nopporn Apiwattanakul Dr Amjad Islam Aqib Professor Mohammad Arabestani Dr Sheila Araujo Teles Dr Balew Arega Dr Gunjan Arora Dr Muhammad Imran Arshad Dr Yasir Arshad Dr Kovy Arteaga-Livias Dr Mohd Hafiz Arzmi Dr Mohammad Reza Asadi Karam Dr Takanori Asakura Dr Prince Asare Dr Mohammad Asgharzadeh Dr Hossam Ashour Dr Abdullah Tarik Aslan Dr Alaa Atamna Dr Nur Atik Dr Meiji Soe Aung Dr Wah Wah Aung Professor Sergey Avdeev Dr Akshay Avula Dr Babafela Awosile Dr Gajendra Kumar Azad Dr Davood Azadi Mr Zelalem Nigussie Azene Dr Afzal Azim Mr Muhammad Majid Aziz Dr Martin Sima Dr Azer Ozad Duzgun Dr Kenan Cetin Dr Aysegul Copur Cicek Dr Ines Bado Dr Fang Bai Dr J Kevin Baird Dr Andrea Ballini Prof Dr Zulqarnain Baloch Dr Joseph Baruch Baluku Dr Banaei Prof Dr Tuhina Banerjee Dr Tuhina Banerjee Mr Agegnehu Bante Dr Humberto Barrios Camacho Dr Mazin Barry Dr Bruno Barsic Dr Christopher S von Bartheld Dr Dariusz Bartosik Dr Joseph Baruch Baluku Dr Rasha Barwa Dr Saurav Basu Dr George Bayliss

Infection and Drug Resistance

Carbapenem resistance is a major and an on-going public health problem globally. It occurs mainly among Gram-negative pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, and may be intrinsic or mediated by transferable carbapenemase-encoding genes. This type of resistance genes are already widespread in certain parts of the world, particularly Europe, Asia and South America, while the situation in other places such as sub-Saharan Africa is not well documented. In this paper, we provide an in-depth review of carbapenem resistance providing up-to-date information on the subject.

Carbapenem Resistance: A Review

Objectives Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae has spread rapidly in China. In this study, we aimed to investigate the molecular epidemiology of KPC-producing K. pneumoniae isolates in China. Methods Ninety-five carbapenem-resistant K. pneumoniae isolates from 13 hospitals in nine cities covering five provinces in China were analysed. Antibiotic susceptibility was determined by the Etest. Multilocus sequence typing (MLST) and PFGE were used for epidemiological analysis. The genetic structure around bla(KPC) and the encoding genes of extended-spectrum β-lactamases and plasmid-mediated AmpC enzymes were detected by PCR and sequencing. Plasmids were analysed by transformation, restriction and Southern blot. Results All isolates harboured the bla(KPC-2) gene. Seven sequence types (STs) were obtained. The dominant clone was ST11 (61/95), which was identified in isolates from Zhejiang province (four hospitals in Hangzhou and one hospital in Ningbo), Jiangsu province (one hospital in Nanjing) and Anhui province (one hospital in Hefei). Isolates with ST11 showed >80% similarity in PFGE patterns. Plasmids from 14 selected transformants, their original isolates representing different STs and/or regions, had a diversity of HindIII restriction maps. Conclusions The dominant clone of KPC-producing K. pneumoniae in China is ST11, which is closely related to ST258, which has been reported worldwide.

/pdf/st11-the-dominant-clone-of-kpc-producing-klebsiella-lntprwo5hk.pdf

ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China

OBJECTIVES The goal of this study was to investigate the epidemiological characteristics and the surrounding genetic structure of bla(NDM-1) in non-baumannii Acinetobacter spp. in China. METHODS Non-baumannii Acinetobacter spp. were collected from 28 provinces in China and were screened for the presence of bla(NDM-1) using PCR. The following four methods were used to classify the Acinetobacter isolates: the Vitek 2 system, 16S-23S rRNA gene intergenic spacer sequencing, amplified rDNA restriction analysis and partial rpoB sequence analysis. An S1-PFGE assay and Southern blot hybridization were performed to determine the plasmid location of bla(NDM-1). The transferability of bla(NDM-1)-harbouring plasmids was confirmed by conjugation experiments and electrotransformation. The surrounding genetic structure of the bla(NDM-1) gene was analysed using a restriction endonuclease-based cloning approach and primer walking. RESULTS Among 726 non-baumannii Acinetobacter spp., nine isolates collected from six different provinces and assigned to seven different Acinetobacter spp. contained the bla(NDM-1) gene. None of these isolates was directly infectious to the patients or demonstrated an epidemiological importation from abroad. These bla(NDM-1) genes were located on plasmids that could be transferred to Escherichia coli J53 by conjugation and Acinetobacter baylyi ADP1 by electrotransformation. Seven of the nine strains shared a common genetic structure in which bla(NDM-1) was flanked by two copies of ISAba125. CONCLUSIONS The clinical challenge posed by bla(NDM-1) is currently minimal in China; however, more attention should be devoted to monitoring the dissemination of this gene due to its potential transferability via the ISAba125-associated transposon.

Epidemiological characteristics and genetic structure of blaNDM-1 in non-baumannii Acinetobacter spp. in China

Four isolates of Klebsiella pneumoniae and one isolate of Enterobacter cloacae exhibiting resistance to most β-lactam antibiotics, including oxyimino-cephalosporins and carbapenems, were obtained from different patients among four hospitals in China. Pulsed-field gel electrophoresis demonstrated that all the K. pneumoniae isolates belonged to two clone patterns. Multilocus sequence typing showed that the four isolates of K. pneumoniae belonged to two sequence types: ST 23 and ST 351. Conjugation studies with Escherichia coli (EC600) resulted in the transfer of reduced carbapenem susceptibility compared with that of the original isolates. Plasmid restriction analysis and hybridization experiment showed that the five isolates of Enterobacteriaceae carried a common 50 kb blaKPC-2-encoding plasmid.

Detection of a Common Plasmid Carrying blaKPC-2 in Enterobacteriaceae Isolates from Distinct Cities in China

Tigecycline shows great antimicrobial activity against both Gram-positive and Gram-negative bacteria, and has been considered to be an appropriate choice in controlling infection caused by multi-drug resistant (MDR) pathogens, such as carbapenemase-producing Enterobacteriaceae (CPE). Although many clinical trials evaluate the efficacy and safety of tigecycline on adults, rare reports recommend tigecycline to treat pediatric patient. In this study, we presented a clinical case with tigecycline as an anti-infectious agent on a 14-year-old child who was suffering from infection of intraperitoneal abscess caused by Klebsiella pneumoniae carbapenemases (KPC)-producing Escherichia coli with extreme drug resistant profile. By accessing the clinical outcome and efficacy of the patient, and the side effects of tigecycline, our research explored the documented experience of tigecycline on controlling infection caused by CPE isolate in children.

/pdf/tigecycline-treatment-of-infection-caused-by-kpc-producing-38dhuc120m.pdf

Tigecycline treatment of infection caused by KPC-producing Escherichia coli in a pediatric patient

This study reports an infectious case involving an (NDM-1)-producing Citrobacter freundii and further explored the potential threat of the bla(NDM-1) gene by analysing the characteristics of the (NDM-1)-encoding plasmid sequence. A bla(NDM-1)-positive C. freundii with high resistance to carbapenems was separated from a clinical patient suffering from a urinary tract infection. S1 nuclease-based plasmid analysis followed by Southern blot hybridization, a conjugation experiment and electrotransformation confirmed that the bla(NDM-1) gene was located on a plasmid. High-throughput sequencing of the bla(NDM-1)-positive plasmid (pCFNDM-CN) showed that it was a 54 kb IncX-type plasmid and contained a backbone region and a variable region with two β-lactamase genes (bla(NDM-1) and bla(SHV-12)). The NDM-1 composite transposon in the variable region was surrounded by IS26 and IS5-truncated ISAba125, and shared a high sequence similarity to the bla(NDM-1) surrounding structure in Acinetobacter spp. Our research suggested that the NDM-1 composite transposon might play an essential role in mobilization of the bla(NDM-1) gene from Acinetobacter spp. to Enterobacteriaceae.

Genetic characteristics of blaNDM-1-positive plasmid in Citrobacter freundii isolate separated from a clinical infectious patient.

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