Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options.
TL;DR: Current studies on the virulence factors that contribute to A. baumannii pathogenesis are summarized and Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites are discussed.
Abstract: Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of -lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized.
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01 Jan 2009
1,064 citations
TL;DR: A deep neural network capable of predicting molecules with antibacterial activity is trained and a molecule from the Drug Repurposing Hub-halicin- is discovered that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens.
1,002 citations
Cites background from "Biology of Acinetobacter baumannii:..."
...baumannii as one of the highest priority pathogens against which new antibiotics are urgently required (Lee et al., 2017; Perez et al., 2007)....
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TL;DR: Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants.
Abstract: Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens, pathogens which present a great threat to humans and to which new antibiotics are urgently needed the list is categorized according to the urgency of need for new antibiotics as critical, high, and medium priority, in order to guide and promote research and development of new antibiotics. The majority of the WHO list is Gram-negative bacterial pathogens. Due to their distinctive structure, Gram-negative bacteria are more resistant than Gram-positive bacteria, and cause significant morbidity and mortality worldwide. Several strategies have been reported to fight and control resistant Gram-negative bacteria, like the development of antimicrobial auxiliary agents, structural modification of existing antibiotics, and research into and the study of chemical structures with new mechanisms of action and novel targets that resistant bacteria are sensitive to. Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants. Another promising trend was by referring to nature to develop naturally derived agents with antibacterial activity on novel targets, agents such as bacteriophages, DCAP(2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2(hydroxymethyl)propane1,3-diol, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors, and metal-based antibacterial agents.
503 citations
Cites background from "Biology of Acinetobacter baumannii:..."
...baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) organisms, as declared by the WHO that can escape the effect of antibacterial drugs [13]....
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...baumannii infections successfully [13,14]....
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TL;DR: In this article, the major sources responsible for emergence of antibiotic resistance are elucidated and a variety of introductory sources and fate of PPCPs in aquatic environment including human and veterinary wastes, aquaculture and agriculture related wastes, and other anthropogenic activities have been discussed.
198 citations
TL;DR: The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.
Abstract: Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.
190 citations
Cites background from "Biology of Acinetobacter baumannii:..."
...Other RND pumps like AdeIJK exist but may play a less profound role on tetracycline efflux and can be synergistic with AdeABC [183]....
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...The resistance-nodulation-division (RND) family-type pump AdeABC is the best studied and has a broad substrate range including β-lactams, aminoglycosides, erythromycin, chloramphenicol, tetracyclines, fluoroquinolones, and trimethoprim [155]....
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...AdeABC has a three-component structure: Outer membrane protein (adeC), multidrug transporter (adeB), and membrane fusion protein (adeA) [177]....
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...While some of these, like SCO-1 and TEM-1, are narrow-spectrum, others like CARB-10, CTX-M-2, CTX-M-15, GES-14, PER-1, PER-7, and SHV-5 are extended spectrum β-lactamases (ESBLs) [133,134]....
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...According to studies from many countries, overexpression of the efflux pumps AdeABC and AcrAB-TolC efflux systems was observed in clinical tigecycline-resistant isolates [184–186]; this is increasingly affecting utility of this modified tetracycline in treatment....
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References
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Tufts Medical Center1, University of California, San Diego2, Boston Children's Hospital3, University of California, Los Angeles4, Los Angeles Biomedical Research Institute5, Providence Portland Medical Center6, Case Western Reserve University7, United States Department of Veterans Affairs8, University of Virginia9, Johns Hopkins University School of Medicine10
TL;DR: An update on potentially effective antibacterial drugs in the late-stage development pipeline is provided, in the hope of encouraging collaboration between industry, academia, the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention work productively together.
Abstract: The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
4,256 citations
"Biology of Acinetobacter baumannii:..." refers background in this paper
...baumannii, Pseudomonas aeruginosa, and Enterobacter species) that effectively escape the effects of antibacterial drugs (Boucher et al., 2009)....
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...The WHO declared that A. baumannii is one of the most serious ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, and Enterobacter species) that effectively escape the effects of antibacterial drugs (Boucher et al., 2009)....
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TL;DR: This review details the significant advances that have been made in understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.
Abstract: Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.
2,915 citations
"Biology of Acinetobacter baumannii:..." refers background in this paper
...baumannii has spread to civilian hospitals in part by crossinfection of injured military patients repatriated from war zones (Peleg et al., 2008)....
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...Multidrug-resistant (MDR) A. baumannii has spread to civilian hospitals in part by crossinfection of injured military patients repatriated from war zones (Peleg et al., 2008)....
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...This aerobic Gramnegative coccobacillus had been regarded as a low-grade pathogen, but it is a successful pathogen responsible for opportunistic infections of the skin, bloodstream, urinary tract, and other soft tissues (Peleg et al., 2008)....
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TL;DR: In this large cohort, infection was independently associated with an increased risk of hospital death and risk of infection increases with duration of ICU stay.
Abstract: Context Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. Objective To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. Design, Setting, and Patients The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14 414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13 796 adult (>18 years) patients. Results On the day of the study, 7087 of 13 796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P Conclusions Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.
2,710 citations
"Biology of Acinetobacter baumannii:..." refers background in this paper
...Most A. baumannii infections occur in critically ill patients in the intensive care unit (ICU) setting (Fournier and Richet, 2006) and account for up to 20% of infections in ICUs worldwide (Vincent et al., 2009)....
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...baumannii infections occur in critically ill patients in the intensive care unit (ICU) setting (Fournier and Richet, 2006) and account for up to 20% of infections in ICUs worldwide (Vincent et al., 2009)....
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TL;DR: The taxonomic status of Acinetobacter spp.
Abstract: INTRODUCTION 149 TAXONOMY 149 Historical Features 149 Current Taxonomic Status 149 Delineation of Species 149 Species of Clinical Importance 150 LABORATORY IDENTIFICATION 150 Isolation from Clinical Specimens 150 Morphological, Cultural, and Metabolic Characteristics 151 Species Identification 151 NOSOCOMIAL INFECTIONS CAUSED BY ACINETOBACTER SPP. 152 Overview 152 Respiratory Infection 152 Bacteremia 153 Meningitis 153 Urinary Tract Infection 154 Other Miscellaneous Infections 154 PATHOGENESIS OF ACINETOBACTER INFECTIONS 154 Predisposing Factors 154 Virulence of Acinetobacter spp. 154 EPIDEMIOLOGY 155 Human Carriage 155 Persistence in the Hospital Environment 155 TYPING SYSTEMS 156 Biotyping 156 Antibiograms 156 Serotyping 156 Phage Typing 157 Bacteriocin Typing 157 Protein Profiles 157 Multilocus Enzyme Electrophoretic Typing 157 Plasmid Profiles 157 Analysis by Pulsed-Field Gel Electrophoresis 157 Ribotyping 157 PCR-Based Methods 158 CLINICAL ANTIBIOTIC RESISTANCE 158 BIOCHEMICAL AND GENETIC MECHANISMS OF ANTIBIOTIC RESISTANCE 158 Genetics of Resistance 158 b-Lactams 159 Aminoglycosides 159 Quinolones 160 Other Antibiotics 160 THERAPY OF ACINETOBACTER INFECTIONS 160 CONCLUSIONS 160 ACKNOWLEDGMENTS 161 REFERENCES 161
1,654 citations
"Biology of Acinetobacter baumannii:..." refers background in this paper
...Because antibiotic susceptibility and clinical relevance are significantly different between different genomic species, exact identification of Acinetobacter species are required (Bergogne-Berezin and Towner, 1996; Dijkshoorn et al., 1996; Houang et al., 2003; Lee et al., 2007)....
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TL;DR: This review summarizes the worldwide emergence of antibiotic-resistant A. baumannii as a nosocomial pathogen and focuses on its mechanisms of resistance against selected antibiotics.
Abstract: We may soon be facing the end of the “antibiotic era.” The initial and seemingly unstoppable success of antibiotics, the fruit of human ingenuity, has been countered by an escalation of resistance mechanisms in bacteria. This crisis has been described as an “unwinnable war” (www.wellcome.org). The statistics compiled as a result of surveillance efforts illustrate the emergence of many genera of bacteria that are resistant to all antibiotics (57, 60). The genus Acinetobacter epitomizes this trend and deserves close attention. Acinetobacter spp. display mechanisms of resistance to all existing antibiotic classes as well as a prodigious capacity to acquire new determinants of resistance (7). The increasing recovery in the clinic of multidrug-resistant (MDR) Acinetobacter baumannii is a frightening reality (112). This review summarizes the worldwide emergence of antibiotic-resistant A. baumannii as a nosocomial pathogen and focuses on its mechanisms of resistance against selected antibiotics. It concludes with a summary of current strategies in the treatment of MDR A. baumannii and offers perspectives on the control of this global public health threat.
1,164 citations
"Biology of Acinetobacter baumannii:..." refers background in this paper
...The OXA23 enzyme was first identified in an A. baumannii isolate in the United Kingdom in 1985 (Perez et al., 2007)....
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