Combination antibiotic therapy for empiric and definitive treatment of gram-negative infections: insights from the Society of Infectious Diseases Pharmacists. Boyd Natalie,Nailor Michael D Pharmacotherapy The widespread emergence of antibiotic-resistant gram-negative organisms has compromised the utility of current treatment options for severe infections caused by these pathogens. The rate of gram-negative multidrug resistance is worsening, threatening the effectiveness of newer broad-spectrum antibiotic agents. Infections associated with multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are having a substantial impact on hospital costs and mortality rates. The potential for these resistant gram-negative nosocomial pathogens must always be a primary consideration when selecting antibiotic therapy for critically ill patients. Empiric combination therapy directed at gram-negative pathogens is a logical approach for patients with suspected health care-associated infections, particularly those with risk factors for infections caused by multidrug-resistant pathogens. Although in vitro synergy tests have shown potential benefits of continued combination therapy, convincing clinical data that demonstrate a need for combination therapy once susceptibilities are known are lacking. Thus, deescalation to a single agent once susceptibilities are known is recommended for most patients and pathogens. Use of polymyxins, often in combination with other antimicrobials, may be necessary for salvage therapy. 10.1592/phco.31.11.1073
    [Clinically important beta-lactamases of gram-negative bacteria: extended-spectrum beta-lactamases (ESBL)]. Hrabák J Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne Beta-lactamases are the commonest cause of a resistance of gram-negative bacteria to beta-lactam antimicrobial agents. The introduction of the third- and fourth-generation cephalosporins into clinical practise is the reason of an evolution of new beta-lactamases being able to hydrolyze these antibiotics. Extended-spectrum beta-lactamases (ESBLs) are the major group of these enzymes. Most of the ESBLs are mainly structural mutants of penicillinases TEM-1, TEM-2 and SHV-1. For several reasons, ESBL-producing isolates should, by definition, be reported as resistant to all penicillins, cephalosporins and monolactams. Due to seriously reduced antibiotic choice for infections caused by ESBL-producing bacteria, ESBLs pose a serious clinical problem. This review will focus on the characterization and identification of ESBLs, interpretation of sensitivity testing results of ESBL producing bacteria and an appropriate treatment of infections caused by ESBL-producers.
    Global antimicrobial resistance in Gram-negative pathogens and clinical need. Theuretzbacher Ursula Current opinion in microbiology Resistance in Gram-negative bacteria has become a serious problem in many regions of the world as it may reduce the treatment options substantially. Carbapenem-resistance is a good marker for such situations and is most prevalent in Acinetobacter, Pseudomonas but also increasingly in Enterobacteriaceae, especially Klebsiella. This review gives a rough global picture highlighting the epicentres of resistance. The medical need for novel treatment options globally is undeniable even if many countries with good stewardship and infection control conditions are not highly affected. Antibiotic pipelines are encouraging, as new drugs in development reduce the resistance rate to individual pathogens. Despite some progress, efforts to discover and develop novel drugs that are not prone to cross-resistance to existing antibiotic classes should be intensified. 10.1016/j.mib.2017.10.028
    Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens. Karaiskos Ilias,Galani Irene,Souli Maria,Giamarellou Helen Expert opinion on drug metabolism & toxicology INTRODUCTION:The burden of antimicrobial resistance among Gram-negative bacteria is increasing and growing into a major threat of public health. Treatment options for carbapenem-resistant Enterobacteriaceae are limited and resistance rates to existing compounds are mounting. The pipeline includes only a small number of novel anti-infective agents in development or in the market with promising results against multidrug-resistant (MDR) Gram-negative. Areas covered: Herein the authors present the modern available knowledge regarding novel β-lactam-β-lactamase inhibitors, i.e. mechanisms of action, in vitro activity, current PK/PDs, clinical trials and clinical efficacy against MDR and XDR Gram-negatives, as well as toxicity issues. Expert opinion: Ceftazidime-avibactam and meropenem-vaborbactam are promising therapeutic options as both are active against Enterobacteriaceae producing ESBL, AmpC, and KPC, whereas only avibactam inhibits certain class D β-lactamases, mainly OXA-48. New drugs active against Gram-negative MDR isolates including imipenem/cilastatin with relebactam and avibactam combined with aztreonam or ceftaroline are in different stages of development. However, the disadvantage to be seriously considered by the clinician is that β-lactam/β-lactamase inhibitors are ineffective against metallo-β-lactamases (with the exception of aztreonam-avibactam) as well as Acinetobacter baumannii. 10.1080/17425255.2019.1563071
    New antibacterial agents for treating infections caused by multi-drug resistant Gram-negative bacteria. O'Neill A J Expert opinion on investigational drugs BACKGROUND:Infections caused by multi-drug resistant (MDR) Gram-negative bacteria represent an ever-growing area of unmet medical need. To address this need, it is imperative that novel classes of antibiotics demonstrating activity against bacterial strains resistant to established antibiotics are introduced into the clinic. OBJECTIVES:To examine the current status of the Gram-negative antibacterial pipeline, ranging from the more advanced preclinical candidates to drugs recently launched, and look to the future of anti-Gram-negative drug development. METHODS:Information was compiled from scientific and patent literature, conference proceedings and company publications/websites. RESULTS/CONCLUSIONS:None of the antibacterial agents currently in clinical trials that encompass Gram-negative bacteria in their spectrum of activity possess sufficiently novel modes of action to circumvent extant antibiotic resistance mechanisms. Furthermore, although some interesting anti-Gram-negative drug candidates are nearing the beginning of clinical trials, they are limited in number and, even in the best-case scenario, many years away from the clinic. 10.1517/13543784.17.3.297
    The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Li Xian-Zhi,Plésiat Patrick,Nikaido Hiroshi Clinical microbiology reviews The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps. 10.1128/CMR.00117-14
    Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. Kaye Keith S,Pogue Jason M Pharmacotherapy Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase since 2000 in rates of extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an indwelling device), and these facilities are considered important originating sources of such strains for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden, including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and intensive care units. Control of resistant gram-negative infections requires a comprehensive approach, including strategies for risk factor identification, detection and identification of resistant organisms, and implementation of infection-control and prevention strategies. In treating resistant gram-negative infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the choice of empiric therapy. Although only a few agents are available with activity against resistant gram-negative organisms, two recently released β-lactam/β-lactamase inhibitor combinations - ceftolozane/tazobactam and ceftazidime/avibactam - have promising activity against these organisms. In this article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is provided. 10.1002/phar.1636
    Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. Jean Shio-Shin,Lee Wen-Sen,Lam Carlos,Hsu Chin-Wang,Chen Ray-Jade,Hsueh Po-Ren Future microbiology Carbapenemases, with versatile hydrolytic capacity against β-lactams, are now an important cause of resistance of Gram-negative bacteria. The genes encoding for the acquired carbapenemases are associated with a high potential for dissemination. In addition, infections due to Gram-negative bacteria with acquired carbapenemase production would lead to high clinical mortality rates. Of the acquired carbapenemases, Klebsiella pneumoniae carbapenemase (Ambler class A), Verona integron-encoded metallo-β-lactamase (Ambler class B), New Delhi metallo-β-lactamase (Ambler class B) and many OXA enzymes (OXA-23-like, OXA-24-like, OXA-48-like, OXA-58-like, class D) are considered to be responsible for the worldwide resistance epidemics. As compared with monotherapy with colistin or tigecycline, combination therapy has been shown to effectively lower case-fatality rates. However, development of new antibiotics is crucial in the present pandrug-resistant era. 10.2217/fmb.14.135
    [New Antibiotics for Treatment of Highly Resistant Gram-negative Bacteria]. Probst-Kepper Michael,Geginat Gernot Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS New β-lactam/β-lactamase inhibitor (BLI) combinations (ceftolozan/tazobactam, ceftazidim/avibactam, meropenem/vaborbactam, imipenem/relebactam, aztreonam/avibactam) are the focus of newly approved antibiotics or those currently in advanced clinical testing. In contrast to the BLI currently available, the new inhibitors avibactam, vaborbactam and relebactam are not structurally β-lactams.The combination with a BLI protects β-lactam from degradation by broad-spectrum β-lactamases from gram-negative pathogens. The main indications for the new substances are therefore infections with multi-resistant gram-negative bacteria.In clinical use, it should be noted that the BLI does not close efficacy gaps in the β-lactam/BLI combination (e.g. no effect of cephalosporin/BLI combinations on anaerobes or enterococci).Cefiderocol is the first representative of the siderophore cephalosporin antibiotic group to enter phase II clinical testing.Eravacyclin (tetracycline derivative) and plazomicin (aminoglycoside) are new non-β-lactam antibiotics in advanced clinical testing (phase III).In order to maintain the efficacy of new reserve antibiotics for as long as possible, a prescription should only be made if an additional benefit in comparison to established substances has been proven, e.g. by a resistance test. 10.1055/s-0043-110504
    Novel antimicrobial agents against multi-drug-resistant gram-negative bacteria: an overview. Karras George,Giannakaki Venetia,Kotsis Vasilios,Miyakis Spiros Recent patents on anti-infective drug discovery No novel antimicrobial agents against multi-drug-resistant Gram-negative bacteria have been available to daily clinical practice during the last 5 years. On the other hand, resistance rates and mechanisms of those pathogens are increasing worldwide. Pan-resistant (against which none of the currently available antibiotics is effective) strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa have been described. Encouraging is the fact that several novel compounds (some of them with mechanisms of action different to those of the antibiotics commercially available) are through the development stages. We summarize the main such compounds that show potential for offering solution to the treatment of Gram-negative multi-resistant bacteria along with the discussion of some patents associated with the topic. 10.2174/157489112803521922
    Epidemiology and Mechanisms of Resistance of Extensively Drug Resistant Gram-Negative Bacteria. Eichenberger Emily M,Thaden Joshua T Antibiotics (Basel, Switzerland) Antibiotic resistance has increased markedly in gram-negative bacteria over the last two decades, and in many cases has been associated with increased mortality and healthcare costs. The adoption of genotyping and next generation whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our understanding of how antibiotic resistance develops and transmits among bacteria and between patients. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. These fundamental insights into the mechanisms of gram-negative antibiotic resistance have influenced the development of novel antibiotics and treatment practices in highly resistant infections. Here, we review the mechanisms and global epidemiology of antibiotic resistance in some of the most clinically important resistance phenotypes, including carbapenem resistant , extensively drug resistant (XDR) , and XDR . Understanding the resistance mechanisms and epidemiology of these pathogens is critical for the development of novel antibacterials and for individual treatment decisions, which often involve alternatives to β-lactam antibiotics. 10.3390/antibiotics8020037
    The antibiotic pipeline for multi-drug resistant gram negative bacteria: what can we expect? Falagas Matthew E,Mavroudis Andreas D,Vardakas Konstantinos Z Expert review of anti-infective therapy INTRODUCTION:A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians. AREAS COVERED:We searched PUBMED and GOOGLE databases. Combinations of already approved β-lactams or monobactams with new β-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new β-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review. Expert commentary: For the majority of the upcoming antibiotics the currently available data is limited to their microbiology and pharmacokinetics. Their effectiveness and safety against infections due to MDR bacteria remain to be proved. Significant issues are also the impact of these antibiotics on the human intestinal microbiota and their possible co-administration with already-known antimicrobial agents in difficult-to-treat-infections; further studies should be conducted for these objectives. 10.1080/14787210.2016.1204911
    The development of efflux pump inhibitors to treat Gram-negative infections. Blanco Paula,Sanz-García Fernando,Hernando-Amado Sara,Martínez José Luis,Alcalde-Rico Manuel Expert opinion on drug discovery INTRODUCTION:One of the possibilities for reducing the emergence and spread of antibiotic resistance is the use of anti-resistance compounds capable of resensitizing resistant microorganisms to current antimicrobials. For this purpose, multidrug efflux pumps, whose inhibition may increase bacterial susceptibility to several antibiotics, including macrolides to which Gram-negatives are considered intrinsically resistant, have emerged as suitable targets. Areas covered: In the current review, the authors discuss different mechanisms that can be exploited for inhibiting multidrug efflux pumps and describe the properties and the potential therapeutic value of already studied efflux pumps inhibitors. Although efforts have already been made to develop these inhibitors, there are currently no good candidates for treating infectious diseases. Consequently, the authors also discuss potential approaches for their development. Expert opinion: Classical anti-resistance drugs such as beta-lactamases inhibitors, while useful, are only purposeful for treating infections caused by beta-lactamase producers. However, inhibitors of multidrug efflux pumps, which are present on all organisms, can sensitize both susceptible and resistant bacteria to antibiotics belonging to several different structural families. Since some efflux pumps are involved in bacterial infections, their inhibition may also reduce the infectivity of Gram-negative bacterial pathogens. 10.1080/17460441.2018.1514386
    Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and healthcare-associated multidrug-resistant bacteria. Tang Sarah S,Apisarnthanarak Anucha,Hsu Li Yang Advanced drug delivery reviews Alexander Fleming's discovery of penicillin heralded an age of antibiotic development and healthcare advances that are premised on the ability to prevent and treat bacterial infections both safely and effectively. The resultant evolution of antimicrobial resistant mechanisms and spread of bacteria bearing these genetic determinants of resistance are acknowledged to be one of the major public health challenges globally, and threatens to unravel the gains of the past decades. We describe the major mechanisms of resistance to β-lactam antibiotics - the most widely used and effective antibiotics currently - in both Gram-positive and Gram-negative bacteria, and also briefly detail the existing and emergent pharmacological strategies to overcome such resistance. The global epidemiology of the four major types of bacteria that are responsible for the bulk of antimicrobial-resistant infections in the healthcare setting - methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Enterobactericeae, and Acinetobacter baumannii - are also briefly described. 10.1016/j.addr.2014.08.003
    Treatment Options for Carbapenem- Resistant Gram-Negative Infections. Fritzenwanker Moritz,Imirzalioglu Can,Herold Susanne,Wagenlehner Florian M,Zimmer Klaus-Peter,Chakraborty Trinad Deutsches Arzteblatt international BACKGROUND:Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS:This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS:Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION:The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches. 10.3238/arztebl.2018.0345
    The role of new β-lactamase inhibitors in gram-negative infections. Vena Antonio,Castaldo Nadia,Bassetti Matteo Current opinion in infectious diseases PURPOSE OF REVIEW:In recent years, traditional β-lactams have dramatically reduced their effectiveness against gram-negative bacteria mainly because of their ability to express multiple β-lactamase or carabapenemases that are not hydrolyzed by the old β-lactam inhibitors (BLIs) such as clavulanic acid, tazobactam, and sulbactam. New BLIs molecules have been developed to face the need of compounds that are active against multidrug or pandrug resistant gram-negative pathogens. The aim of this review is to summarize the new generation of BLIs and β-lactams combinations. RECENT FINDINGS:A number of new molecules with activity against Ambler class A (e.g., extended-spectrum β-lactamases, serine carbapenemases), class C (e.g., AmpC), or class D (e.g., oxacillinase-48) have been recently approved in combination with old β-lactams for the treatment of multidrug-resistant bacteria, and other agents are under investigation. These new compounds include diazabicyclooctanones non-β-lactam inhibitors (e.g., avibactam, relebactam, nacubactam) and boronic acid inhibitors (e.g., vaborbactam). SUMMARY:Newly approved and investigational new BLIs are expected to offer many advantages for the management of patients with multidrug-resistant gram-negative pathogens. Promising characteristics of new compounds include high activity against multi drug resistance gram-negative bacteria and a favorable safety profile. 10.1097/QCO.0000000000000600
    [The rise of resistant gram-negative bacteria]. Kuijper Ed J,van Dissel Jaap T Nederlands tijdschrift voor geneeskunde During the past few years there has been a global spread of resistant gram-negative bacteria that are insensitive to cephalosporins and carbapenems. Extended spectrum beta-lactamase (ESBL)-producing bacteria are capable of inactivating the newest generation of cephalosporins. It is notable that ESBL-producing bacteria are found predominantly outside the hospital situation in the environment, in food and in meat products, which leads to the presumption that the food chain is contributing to the rapid spread of these bacteria. Several types of carbapenemase-producing bacteria have been distinguished, of which the 'New Delhi metallo beta-lactamase 1 (NDM-1)' type seems to be prevalent in Asia outside the hospital situation in the community, and is now being transmitted to other continents as a result of migration and tourism. With the rise of ESBL- and carbapenemase-producing gram-negative bacteria (which are also often resistant to most other antibiotics) comes the very real concern that treatment of infections such as urinary tract infections that are currently simple to treat with common oral antibiotics will be problematic in the future. The widespread use of antibiotics in animal husbandry is an important factor in the problem of antibiotic resistance. Since economic motives are of importance, a coordinated approach from many parties concerned will be necessary, not just from the medical sector but also from the veterinary and agricultural world, and from food producers and pharmaceutical companies to combat the spread of multiresistant gram-negative bacteria effectively.
    What's new in the treatment of multidrug-resistant gram-negative infections? Mo Yoonsun,Lorenzo Michael,Farghaly Sara,Kaur Kamaljit,Housman Seth T Diagnostic microbiology and infectious disease Eradicating multi-drug resistant (MDR) organisms has been a major challenge in healthcare settings worldwide. Newly approved drugs and those currently in the pipeline may have a promising solution to this issue. The purposes of this review are to describe the various resistance mechanisms of Gram-negative bacteria and to provide a summary of the current literature available on the newer agents, such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and other emerging agents used for the treatment of MDR Gram-negative infections. Given that MDR organisms confer resistance to treatment by various methods, including enzymatic degradation, efflux pumps, and porin mutation, an understanding of mechanisms of bacterial resistance combined with information on newer antimicrobial agents against MDR Gram-negative bacteria will further assist clinicians in determining the best suitable therapy for the treatment of various complicated infections. 10.1016/j.diagmicrobio.2018.08.007
    Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria. Otsuka Yasunari Chemical & pharmaceutical bulletin The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a global problem. Among MDR Gram-negative bacteria, carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii have limited treatment options and present serious threats. Therefore, strong countermeasures must be taken against these bacteria immediately. Accordingly, the focus of this review is on recent advances in the development of promising antibacterial agents against MDR Gram-negative bacteria. These agents include novel tetracyclines, polymyxins, β-lactams, β-lactam/β-lactamase inhibitors, aminoglycosides, and peptide mimetics that have been recently approved or have shown promising results in clinical and preclinical development. This review summarizes these potent antibiotics in terms of their development status, mode of action, spectra of activity, and structure-activity relationship. 10.1248/cpb.c19-00842
    Epidemiology and treatment of antimicrobialresistant gram-negative bacteria in Korea. Kim Young Ah,Park Yoon Soo The Korean journal of internal medicine Antimicrobial resistance is becoming one of the greatest challenges to public health worldwide. Infections by antimicrobial-resistant organisms could result in the failure of treatment, increased medical costs, prolonged hospital stays, and an increased socioeconomic burden. Antimicrobial usage in Korea remains heavy, even after much effort to reduce their use. According to the Korean antimicrobial resistance surveillance system, the resistance rates of many bacteria are increasing. The resistance rate of to imipenem in Korea increased to 85% in 2015, representing a major public threat. The reports of increased carbapenem resistance in Enterobacteriaceae are worrisome. More importantly, some carbapenem-resistant Enterobacteriaceae may result from the production of carbapenemases, which break down carbapenems. There are relatively few treatment options for extensively drug-resistant and carbapenem-resistant Enterobacteriaceae. Most reports are retrospective observational studies. Because there are little published data from randomized controlled trials, more data assessing antimicrobial treatment for extensively drug-resistant and carbapenem-resistant Enterobacteriaceae are needed to make treatment recommendations. 10.3904/kjim.2018.028
    Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria. Nordmann Patrice,Poirel Laurent Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Carbapenem resistance in gram-negative bacteria has caused a global epidemic that continues to grow. Although carbapenemase-producing Enterobacteriaceae have received the most attention because resistance was first reported in these pathogens in the early 1990s, there is increased awareness of the impact of carbapenem-resistant nonfermenting gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Moreover, evaluating the problem of carbapenem resistance requires the consideration of both carbapenemase-producing bacteria as well as bacteria with other carbapenem resistance mechanisms. Advances in rapid diagnostic tests to improve the detection of carbapenem resistance and the use of large, population-based datasets to capture a greater proportion of carbapenem-resistant organisms can help us gain a better understanding of this urgent threat and enable physicians to select the most appropriate antibiotics. 10.1093/cid/ciz824
    Infections by multidrug-resistant Gram-negative Bacteria: What's new in our arsenal and what's in the pipeline? Koulenti Despoina,Song Andrew,Ellingboe Aaron,Abdul-Aziz Mohd Hafiz,Harris Patrick,Gavey Emile,Lipman Jeffrey International journal of antimicrobial agents The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle antimicrobial resistance development, prompts the development of new antibiotic agents and exploration of alternative treatment options. This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram-negative bacteria. 10.1016/j.ijantimicag.2018.10.011
    Antibiotic adjuvants: an alternative approach to overcome multi-drug resistant Gram-negative bacteria. Liu Yuan,Li Ruichao,Xiao Xia,Wang Zhiqiang Critical reviews in microbiology Antibiotic resistance in Gram-negative pathogens has emerged and constituted a global crisis, thereby novel antibiotics and other anti-infective strategies are urgently needed. However, the growing gap between clinical need and drug innovation, coupled with the membrane permeability barrier in Gram-negative bacteria restricts the discovery of Gram-negative antibiotics. Antibiotic adjuvants approach provides an alternative and complementary strategy for new antibiotic discovery. These compounds restore or potentiate the activity of commonly used antibiotics against multi-drug resistant (MDR) Gram-negative bacteria by targeting resistance or enhancing action of antibiotics. In this review, we first provide a brief overview of antibiotic resistance mechanism in Gram-negative bacteria, which can be used to guide the development of new antibiotic adjuvants. Additionally, we summarize the recent achievements in the search for antibiotic adjuvants based on their modes of action. Lastly, we discuss our perspectives in developing next-generation adjuvants such as broad-spectrum adjuvants and hybridization approach, which would contribute to enrich our arsenal against MDR Gram-negative bacteria. 10.1080/1040841X.2019.1599813