The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam-β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

New β-Lactam-β-Lactamase Inhibitor Combinations.

Sequence type 11 (ST11) carbapenem-resistant Klebsiella pneumoniae (CRKP) has become the dominant clone in China. In this review, we trace the prevalence of ST11 CRKP in the China Antimicrobial Surveillance Network (CHINET), the key antimicrobial resistance mechanisms and virulence evolution. The recent emergence of ST11 carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) strains in China due to the acquisition of a pLVPK-like virulence plasmid, which may cause severe infections in relatively healthy individuals that are difficult to treat with current antibiotics, has attracted worldwide attention. There is a very close linkage among IncF plasmids, NTEKPC and ST11 K. pneumoniae in China. Hybrid conjugative virulence plasmids are demonstrated to readily convert a ST11 CRKP strain to a CR-hvKP strain via conjugation. Understanding the molecular evolutionary mechanisms of resistance and virulence-bearing plasmids as well as the prevalence of ST11 CRKP in China allows improved tracking and control of such organisms.

Virulence evolution, molecular mechanisms of resistance and prevalence of ST11 carbapenem-resistant Klebsiella pneumoniae in China: A review over the last 10 years.

Abstract Background Klebsiella pneumoniae is a gram-negative rod belonging to the order Enterobacterales and having a wide distribution in the environment, including the human colon. Recently, the bacterium is one of the known problems in the healthcare setting as it has become resistant to last-resort drugs like carbapenems. The colonized person can serve as a reservoir for his/herself and others, especially in the healthcare setting leading to nosocomial and opportunistic infections. Therefore, we aimed to quantitatively estimate the rate of prevalence and incidence of colonization with carbapenem-resistant K. pneumoniae . Methods A literature search was conducted on PubMed/MEDLINE, Google Scholar, Science Direct, Cochrane Library, WHO Index Medicus, and university databases. The study includes all published and unpublished papers that addressed the prevalence or incidence of K. pneumoniae colonization. Data were extracted onto format in Microsoft Excel and pooled estimates with a 95% confidence interval calculated using Der-Simonian-Laird random-effects model. With the use of I 2 statistics and prediction intervals, the level of heterogeneity was displayed. Egger’s tests and funnel plots of standard error were used to demonstrate the publication bias. Results A total of 35 studies were included in the review and 32 records with 37,661 patients for assessment of prevalence, while ten studies with 3643 patients for incidence of colonization. The prevalence of carbapenem-resistant K. pneumoniae colonization varies by location and ranges from 0.13 to 22%, with a pooled prevalence of 5.43%. (3.73–7.42). Whereas the incidence of colonization ranges from 2 to 73% with a pooled incidence of 22.3% (CI 12.74–31.87), both prevalence and incidence reports are majorly from developed countries. There was a variation in the distribution of carbapenem resistance genes among colonizing isolates with KPC as a prominent gene reported from many studies and NDM being reported mainly by studies from Asian countries. A univariate meta-regression analysis indicated continent, patient type, study design, and admission ward do not affect the heterogeneity ( p value&gt;0.05). Conclusion The review revealed that colonization with K. pneumoniae is higher in a healthcare setting with variable distribution in different localities, and resistance genes for carbapenem drugs also have unstable distribution in different geographic areas. 

/pdf/prevalence-and-incidence-of-carbapenem-resistant-k-2kg9k5ql.pdf

Prevalence and incidence of carbapenem-resistant K. pneumoniae colonization: systematic review and meta-analysis

Antibiotic-resistant Enterobacteriaceae are regularly detected in livestock. As pathogens, they cause difficult-to-treat infections and, as commensals, they may serve as a source of resistance genes for other bacteria. Slaughterhouses produce significant amounts of wastewater containing antimicrobial-resistant bacteria (AMRB), which are released into the environment. We analyzed the wastewater from seven slaughterhouses (pig and poultry) for extended-spectrum β-lactamase (ESBL)-carrying and colistin-resistant Enterobacteriaceae. AMRB were regularly detected in pig and poultry slaughterhouse wastewaters monitored here. All 25 ESBL-producing bacterial strains (19 E. coli and six K. pneumoniae) isolated from poultry slaughterhouses were multidrug-resistant. In pig slaughterhouses 64% (12 of 21 E. coli [57%] and all four detected K. pneumoniae [100%]) were multidrug-resistant. Regarding colistin, resistant Enterobacteriaceae were detected in 54% of poultry and 21% of pig water samples. Carbapenem resistance was not detected. Resistant bacteria were found directly during discharge of wastewaters from abattoirs into water bodies highlighting the role of slaughterhouses for environmental surface water contamination.

Antibiotic-Resistant Enterobacteriaceae in Wastewater of Abattoirs.

Emergence of 16S rRNA methyltransferases among carbapenemase-producing Enterobacterales in Spain studied by whole-genome sequencing

In total, 97 carbapenem-resistant Enterobacteriaceae (CRE) were collected from 17 hospitals located in Nanjing, Southeast China, and analyzed for epidemiological characteristics. Antimicrobial susceptibility was determined; followed by determination of the prevalence of resistance determinants, including extended-spectrum β-lactamase (ESBLs), plasmid-mediated AmpC enzyme (pAmpCs), plasmid-mediated quinolone resistance genes (PMQRs), fosfomycin resistance gene and exogenously acquired 16S rRNA methyltransferase (16S-RMTase) using PCR and DNA sequencing. The sequence types (STs) of CRE were determined by multi-locus sequence typing (MLST). The plasmid profiles were detected by PCR-based replicon typing (PBRT). All the CRE strains displayed high MIC50 and MIC90 for nearly all clinical available antibiotics, except for aztreonam/avibactam, minocycline, ceftazidime/avibactam, tigecycline, and colistin. KPC-2 (79.4%) and NDM (19.6%) were the main carbapenemases, CTX-M (76.3%) and SHV (60.8%) were the predominant ESBLs. In addition, oqxAB (70.1%) and qnr (63.9%) were the major PMQRs; rmtB (47.4%) was the main 16S-RMTase; fosA (76.3%) and fosA3 (37.1%) were the fosfomycin resistance gene. PBRT analysis showed presence of IncR (66.0%) and IncFII (64.9%) replicon types in the majority of the isolates, followed by IncFIB (46.4%) and IncX3 (16.5%). The IncFII and IncR replicon-types were found mainly in K. pneumoniae (68.8%), whereas the IncX3 replicons dominated in E. coli isolates (100.0%). The three dominating MLST-types ST11, ST15 and ST268 comprised 68.0% of the 77 K. pneumoniae. Seven distinct STs were identified among 8 E. coli. The treatment for infections caused by CRE isolates is challenged by the presence of multiple resistance determinants and plasmid replicons. Our results highlighted the expansion of blaKPC-2 carrying K. pneumoniae ST11, the new emergency of single blaNDM-5 carrying K. oxytoca ST36, as well as blaIMP-4 and blaNDM-1 co-carrying E. cloacae ST418, which alert us on the urgency for antimicrobial resistant surveillance, to prevent dissemination of these highly transmissible and dangerous lineages.

/pdf/epidemiological-characteristics-of-carbapenem-resistant-2c1vb5u9tz.pdf

Epidemiological characteristics of carbapenem-resistant Enterobacteriaceae collected from 17 hospitals in Nanjing district of China

To continuously evaluate the effect of environmental cleaning and hand hygiene compliance on the colonization and infection rates of multidrug-resistant Acinetobacter baumannii (MDR-AB) in the patients within an intensive care unit (ICU).
 Environmental cleaning on the high-touch clinical surfaces (HTCS) within a comprehensive ICU was evaluated through monitoring fluorescent marks when the overall compliance with hand hygiene during 2013–2014 was monitored. Meanwhile, samples from the HTCS and inpatients were collected and sent for bacterial culture and identification. The drug susceptibility testing was further implemented to monitor the prevalence of MDR-AB. The genetic relatedness of MDR-AB collected either from the HTCS or inpatients was analyzed by pulsed field gel electrophoresis (PFGE) when an outbreak was doubted. The overall compliance with hand hygiene remained relatively stable during 2013–2014. Under this circumstance, the clearance rate of fluorescence marks on the environmental surfaces within ICUs significantly increased from 21.9 to 85.7%, and accordingly the colonization and infection rates of MDR-AB decreased from 16.5 to 6.6‰ and from 7.4 to 2.8‰, respectively, from the beginning to the end of 2013. However, during 2014, because of frequent change and movement of environmental services staff, the clearance rate of fluorescence marks decreased below 50.0%, and the overall colonization and infection rates of MDR-AB correspondingly increased from 9.1 to 11.1‰ and from 1.5 to 3.9‰, respectively. PFGE displayed a high genetic relatedness between the MDR-AB strains analyzed, indicating a dissemination of MDR-AB during the surveillance period. For the easily disseminated MDR-AB within ICUs, the clearance rate of fluorescence labeling on HTCS is negatively correlated with the hospital infection rate of MDR-AB. Such an invisible fluorescence labelling is an effective and convenient method to continuously monitor cleanness of medical environment within hospitals.

/pdf/impact-of-environmental-cleaning-on-the-colonization-and-3aw92r9762.pdf

Impact of environmental cleaning on the colonization and infection rates of multidrug-resistant Acinetobacter baumannii in patients within the intensive care unit in a tertiary hospital

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Epidemiological characteristics of carbapenem-resistant Enterobacteriaceae collected from 17 hospitals in Nanjing district of China

Impact of environmental cleaning on the colonization and infection rates of multidrug-resistant Acinetobacter baumannii in patients within the intensive care unit in a tertiary hospital