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.

The rapid spread of carbapenem-resistant Enterobacteriaceae

Infections due to multidrug-resistant Enterobacteriaceae have become major international public health problem due to the inadequate treatment options and the historically lagged pace of development of novel antimicrobial drugs. Inappropriate antimicrobial use in humans and animals coupled with increased global connectivity aided to the transmission of drug-resistant Enterobacteriaceae infections. Carbapenems are the medications of choice for extended-spectrum beta-lactamase and AmpC producers, but alternatives are currently needed because carbapenem resistance is increasing globally. This review pointed to discuss emerging drug-resistant Enterobacteriaceae, its epidemiology and novel treatment options for infections, which date back from 2010 to 2019 by searching Google Scholar, PubMed, PMC, Hinari and other different websites. The occurrence of carbapenem-resistant Enterobacteriaceae is reported worldwide with great regional variability. The rise of carbapenem-resistant Enterobacteriaceae poses a threat to all nations. Enzyme synthesis, efflux pumps, and porin mutations are the main methods by which Enterobacteriaceae acquire resistance to carbapenems. The major resistance mechanism among these is enzyme synthesis. Most carbapenem resistance is caused by three enzyme groups: Klebsiella pneumoniae carbapenemase (Ambler class A), metallo-s-lactamases (Ambler class B), and oxacillinase-48 (Ambler class D). Ceftazidime-avibactam, which was newly licensed for carbapenemase producers, is the most common treatment option for infections. Meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam are recently reported to be active against carbapenem-resistant Enterobacteriaceae; and are also in ongoing trials for different populations and combinations with other antibacterial agents. Overall, treatment must be tailored to the patient's susceptibility profile, type and degree of infection, and personal characteristics.

/pdf/emerging-carbapenem-resistant-enterobacteriaceae-infection-wllv7wvcz9.pdf

Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A Review.

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.

Bloodstream infections (BSI) have a substantial impact on morbidity and mortality worldwide. Despite scarcity of data from many low- and middle-income countries (LMICs), there is increasing awareness of the importance of BSI in these countries. For example, it is estimated that the global mortality of non-typhoidal Salmonella bloodstream infection in children under 5 already exceeds that of malaria. Reliable and accurate diagnosis of these infections is therefore of utmost importance. Blood cultures are the reference method for diagnosis of BSI. LMICs face many challenges when implementing blood cultures, due to financial, logistical, and infrastructure-related constraints. This review aims to provide an overview of the state-of-the-art of sampling and processing of blood cultures, with emphasis on its use in LMICs. Laboratory processing of blood cultures is relatively straightforward and can be done without the need for expensive and complicated equipment. Automates for incubation and growth monitoring have become the standard in high-income countries (HICs), but they are still too expensive and not sufficiently robust for imminent implementation in most LMICs. Therefore, this review focuses on "manual" methods of blood culture, not involving automated equipment. In manual blood cultures, a bottle consisting of a broth medium supporting bacterial growth is incubated in a normal incubator and inspected daily for signs of growth. The collection of blood for blood culture is a crucial step in the process, as the sensitivity of blood cultures depends on the volume sampled; furthermore, contamination of the blood culture (accidental inoculation of environmental and skin bacteria) can be avoided by appropriate antisepsis. In this review, we give recommendations regarding appropriate blood culture sampling and processing in LMICs. We present feasible methods to detect and speed up growth and discuss some challenges in implementing blood cultures in LMICs, such as the biosafety aspects, supply chain and waste management.

/pdf/best-practices-of-blood-cultures-in-low-and-middle-income-2ubkwl9d5n.pdf

Best Practices of Blood Cultures in Low- and Middle-Income Countries

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

Background
Carbapenemase-producing Klebsiella pneumoniae (CPKP) strains have emerged as a major problem for healthcare systems. The aim of this study was to determine the circulating clones and analyze the clinical and molecular characteristics of CPKP in our hospital.

/pdf/clonal-dissemination-of-kpc-2-producing-klebsiella-49cv8ma5fy.pdf

Clonal dissemination of KPC-2 producing Klebsiella pneumoniae ST11 clone with high prevalence of oqxAB and rmtB in a tertiary hospital in China: results from a 3-year period.

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

Clonal dissemination of KPC-2 producing Klebsiella pneumoniae ST11 clone with high prevalence of oqxAB and rmtB in a tertiary hospital in China: results from a 3-year period.