Search

Background Antimicrobial resistance has become one of the most widespread threats to humans. Acinetobacter baumannii is one of the pathogens responsible for healthcare-associated infections (nosocomial). Colistin is considered the last resort antibiotic against infections with pandrug-resistant (PDR) pathogens. Results: Eleven isolates were detected phenotypically as PDR A. baumannii and were confirmed molecularly using 16S rDNA. The MCR-1 gene was not detected within the chromosomal DNA of the selected isolates. Plasmid bearing the MCR-1 gene was identified in 10 selected isolates of A. baumannii that had not been previously observed to carry the MCR-1 gene. Moreover, the use of colistin in combination with anionic antibiotics or natural compound pterostilbene poses a viable therapeutic alternative for PDR and revives colistin’s bactericidal effects on MCR-1-positive A. baumannii. Finally, the transmission electron microscopy studies proved the synergistic effect of these combinations and revealed the disruption of resistant A. baumannii’s outer membrane and alteration of the permeability properties that allowed overcoming the resistance of the isolates to colistin. Conclusions: Antimicrobial resistance of A. baumannii is related to the presence of the transferable plasmid-bearing MCR-1 gene. This study proved the ability of the combinations of colistin with anionic antibiotics and/or natural compound pterostilbene to restore the bactericidal effect of colistin. Overall, these combinations could be novel promising clinical alternatives against the increasing threat of the widespread multidrug-resistant A. baumannii.

BackgroundMultidrug-resistant Acinetobacter baumannii is a common hospital-acquired pathogen. The increase in antibiotic resistance is commonly due to the acquisition of mobile genetic elements carrying antibiotic resistance genes. To comprehend this, we analyzed the resistome and virulome of Mexican A. baumannii multidrug-resistant isolates.MethodsSix clinical strains of A. baumannii from three Mexican hospitals were sequenced using the Illumina platform, the genomes were assembled with SPAdes and annotated with Prokka. Plasmid SPAdes and MobRecon were used to identify the potential plasmid sequences. Sequence Type (ST) assignation under the MLST Oxford scheme was performed using the PubMLST database. Homologous gene search for known virulent factors was performed using the virulence factor database VFDB and an in silico prediction of the resistome was conducted via the ResFinder databases.ResultsThe six strains studied belong to different STs and clonal complexes (CC): two strains were ST208 and one was ST369; these two STs belong to the same lineage CC92, which is part of the international clone (IC) 2. Another two strains were ST758 and one was ST1054, both STs belonging to the same lineage CC636, which is within IC5. The resistome analysis of the six strains identified between 7 to 14 antibiotic resistance genes to different families of drugs, including beta-lactams, aminoglycosides, fluoroquinolones and carbapenems. We detected between 1 to 4 plasmids per strain with sizes from 1,800 bp to 111,044 bp. Two strains from hospitals in Mexico City and Guadalajara had a plasmid each of 10,012 bp pAba78r and pAba79f, respectively, which contained the blaOXA-72 gene. The structure of this plasmid showed the same 13 genes in both strains, but 4 of them were inverted in one of the strains. Finally, the six strains contain 49 identical virulence genes related to immune response evasion, quorum-sensing, and secretion systems, among others.ConclusionResistance to carbapenems due to pAba78r and pAba79f plasmids in Aba pandrug-resistant strains from different geographic areas of Mexico and different clones was detected. Our results provide further evidence that plasmids are highly relevant for the horizontal transfer of antibiotic resistance genes between different clones of A. baumannii.

Background Antimicrobial resistance has become one of the most widespread threats to humans. Acinetobacter baumannii is one of the pathogens responsible for healthcare-associated infections (nosocomial). Colistin is considered the last resort antibiotic against infections with pandrug-resistant (PDR) pathogens. Results: Eleven isolates were detected phenotypically as PDR A. baumannii and were confirmed molecularly using 16S rDNA. The MCR-1 gene was not detected within the chromosomal DNA of the selected isolates. Plasmid bearing the MCR-1 gene was identified in 10 selected isolates of A. baumannii that had not been previously observed to carry the MCR-1 gene. Moreover, the use of colistin in combination with anionic antibiotics or natural compound pterostilbene poses a viable therapeutic alternative for PDR and revives colistin's bactericidal effects on MCR-1-positive A. baumannii. Finally, the transmission electron microscopy studies proved the synergistic effect of these combinations and revealed the disruption of resistant A. baumannii's outer membrane and alteration of the permeability properties that allowed overcoming the resistance of the isolates to colistin. Conclusions: Antimicrobial resistance of A. baumannii is related to the presence of the transferable plasmid-bearing MCR-1 gene. This study proved the ability of the combinations of colistin with anionic antibiotics and/or natural compound pterostilbene to restore the bactericidal effect of colistin. Overall, these combinations could be novel promising clinical alternatives against the increasing threat of the widespread multidrug-resistant A. baumannii. [ABSTRACT FROM AUTHOR]

ABSTRACT: Objectives: Acinetobacter baumannii is a significant opportunistic pathogen causing nosocomial infections. Infections caused by A. baumannii are often difficult to treat because this bacterium is often multidrug-resistant and shows high environmental adaptability. Here, we report on the analysis of three A. baumannii strains isolated from hospital effluents in South Africa. Methods: Strains were isolated on Leeds Acinetobacter agar and were identified using VITEK®2 platform. Antibiotic susceptibility testing was performed using the Kirby-Bauer Disk diffusion method. Whole-genome sequencing was performed. The assembled contigs were annotated. Multilocus sequence type, antimicrobial resistance, and virulence genes were identified. Results: The strains showed two multilocus sequence types, ST231 (FA34) and ST1552 (PL448, FG116). Based on their antibiotic susceptibility profiles, PL448 and FG116 were classified as extensively drug-resistant and FA34 as pandrug-resistant. FA34 harbored mutations in LpxA, LpxC, and PmrB, conferring resistance to colistin, but not mcr genes. All three strains encoded virulence genes for immune evasion (capsule, lipopolysaccharide [LPS]), iron uptake, and biofilm formation. FA34 was related to human strains from South Africa; PL448 and FG116 were related to a strain isolated in the United States from a human wound. Conclusions: The detection of extensively drug- and pandrug-resistant A. baumannii strains in hospital effluents is of particular concern. It indicates that wastewater might play a role in the spread of these bacteria. Our data provide insight into the molecular epidemiology, resistance, pathogenicity, and distribution of A. baumannii in South Africa.

Background: The upgrowth and rapid prevalence of pandrug-resistant Acinetobacter baumannii strains that have a pathogenic activity to cause several infections are of considerable influence on the health of communities worldwide. No infections by these bacterial strains were recorded before 1998, and currently, the numbers are on the rise. Methods: The A. baumannii strains were isolated from male and female patients in Medical Microbiology Department, King Fahd Medical City (KFMC) in Riyadh, Saudi Arabia between 1/1/2020 to 29/12/2020. The statistical analysis was performed base on sex, age, source of samples, and response to commercially available antibiotics. The A. baumannii strains that resisted all the antibiotics including colistin and imipenem were selected for the synergic test. Results: The data showed that 62.28%, 77.07% of 342 A. baumannii strains were isolated from males and patients over 35 years of age. A. baumannii strains (pandrug-A. baumannii) that can resist all tested antibiotics were 8.19%. The major source of the A. baumannii isolates was the respiratory system (>50%). Among all isolates (N = 342), azidothymidine-resistant A. baumannii strains were more than 85%. There is a statistically significant difference (P < 0.05) in the number of colistin-resistant A. baumannii strains isolated from males comparing with the female. The combinations of colistin and silver nanoparticles or imipenem and silver nanoparticles resulted in synergistic action led to reduction of MICs of colistin, imipenem, and silver nanoparticles (more than four-fold reduction). Also, the combinations of colistin and imipenem had high synergistic action. Conclusion: The pandrug-resistant A. baumannii strains may represent a current and future threat that must be fought, and the synergy action of antibiotics and nanoparticles may be one of the available, rapid, and easy strategies to confront this global problem.

Background: The emergence and high ascendancy of infections caused by extensively-drug-resistant (XDR) and pandrug-resistant (PDR) Enterobacterales isolates is a serious clinical and public health challenge. Isolation of PDR Gram-negative bacteria (GNB) in clinical setting is very rare and rarer is the infection caused by XDR GNB. Apart from restricted therapeutic options, these infections are associated with increased mortality and morbidity. Urgent studies to re-evaluate existing therapeutic options and research into new antibiotic molecules are desperately needed. The objectives of this study are to report the emergence of rarely encountered multidrug-resistant (MDR), difficult-to-threat, CRE infections in our hospital and investigate their molecular epidemiology. Methodology: This was a retrospective observational analysis of six patients with severe infections caused by XDR and PDR Enterobacterales isolates at Mubarak AL Kabeer Teaching Hospital, Jabriya, Kuwait, over a period of one and half years. The mechanisms of resistance in these isolates were then prospectively investigated by molecular characterization and genomic studies. Results: The majority of infections were caused by Klebsiella pneumoniae (83.3%, 5/6) and one (16.6%) was caused by Escherichia coli. Three patients had bloodstream infection (BSI), one had both BSI and urinary tract infection (UTI), one had respiratory tract infection, and the last one had UTI. Two patients were infected with OXA-48 producers, one patient was infected with NDM-1 producer, one patient was infected with NDM-5 producer, one patient was infected with both NDM-1 and OXA-48 producer and the last patient was infected with both NDM-5 and OXA-181 producer. For definite treatment, all patients received combination therapy. The mortality rate was high (50.0%). Conclusion: The high mortality rate associated with XDR and PDR Enterobacterales infections and the limited antimicrobial options for treatment highlight the need for improved detection of these infections, identification of effective preventive measures, and development of novel agents with reliable clinical efficacy against them. [ABSTRACT FROM AUTHOR]

The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant Acinetobacter baumannii, even eliminating large inocula (108 CFU/ml) within 30 min. LC99.9 in PBS and 50% pooled human plasma was 2µg/ml (1.4µM) and 8µg/ml (5.6µM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation–reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. C. elegans infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant A. baumannii. [ABSTRACT FROM AUTHOR]

Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel β-lactam-β-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented. [ABSTRACT FROM AUTHOR]

Purpose: Pending approval of new antimicrobials, synergistic combinations are the only treatment option against pandrug-resistant A. baumannii (PDRAB). Considering the lack of a standardized methodology, the aim of this manuscript is to systematically review the methodology and discuss unique considerations for assessing antimicrobial combinations against PDRAB. Methods: Post-hoc analysis of a systematic review (conducted in PubMed and Scopus from inception to April 2021) of studies evaluating antimicrobial combination against A. baumannii, based on antimicrobials that are inactive in vitro alone. Results: Eighty-four publications were reviewed, using a variety of synergy testing methods, including; gradient-based methods (n = 11), disk-based methods (n = 6), agar dilution (n = 2), checkerboard assay (n = 44), time-kill assay (n = 50), dynamic in vitro PK/PD models (n = 6), semi-mechanistic PK/PD models (n = 5), and in vivo animal models (n = 11). Several variations in definitions of synergy and interpretation of each method were observed and are discussed. Challenges related to testing combinations of antimicrobials that are inactive alone (with regards to concentrations at which the combinations are assessed), as well as other considerations (assessment of stasis vs killing, clinical relevance of re-growth in vitro after initial killing, role of in vitro vs in vivo conditions, challenges of clinical testing of antimicrobial combinations against PDRAB infections) are discussed. Conclusion: This review demonstrates the need for consensus on a standardized methodology and clinically relevant definitions for synergy. Modifications in the methodology and definitions of synergy as well as a roadmap for further development of antimicrobial combinations against PDRAB are proposed. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistant K. pneumoniae. Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using in vitro checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant K. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistant K. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells in vitro and demonstrate considerable efficacy and low toxicity in vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistant K. pneumoniae -related infections. [ABSTRACT FROM AUTHOR]

It is fortunate that an international panel of experts proposed definitions for multidrug-resistant (MDR) and extensively drug-resistant (XDR) in the past. In our opinion, these definitions need amendments in order to be semantically more accurate. We suggest for the MDR definition to add to 'MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories' that this non-susceptibility is at most to the total number of all antimicrobial categories minus two, so that the definition reads: MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories and up to (and including) the total number of all antimicrobial categories minus two. We suggest that the experts' definition of XDR as 'non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories)' has to be modified regarding the content of the parenthesis to: (i.e. bacterial isolates remain susceptible to only one or two or even none antimicrobial category [in this latter setting bacterial isolates are resistant to at least one antimicrobial agent in all antimicrobial categories and concurrently there is at least one antimicrobial agent to which the isolate is susceptible to]). [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistant K. pneumoniae. Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using in vitro checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant K. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistant K. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells in vitro and demonstrate considerable efficacy and low toxicity in vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistant K. pneumoniae -related infections.

The upgrowth and rapid prevalence of pandrug-resistant Acinetobacter baumannii strains that have a pathogenic activity to cause several infections are of considerable influence on the health of communities worldwide. No infections by these bacterial strains were recorded before 1998, and currently, the numbers are on the rise. The A. baumannii strains were isolated from male and female patients in Medical Microbiology Department, King Fahd Medical City (KFMC) in Riyadh, Saudi Arabia between 1/1/2020 to 29/12/2020. The statistical analysis was performed base on sex, age, source of samples, and response to commercially available antibiotics. The A. baumannii strains that resisted all the antibiotics including colistin and imipenem were selected for the synergic test. The data showed that 62.28%, 77.07% of 342 A. baumannii strains were isolated from males and patients over 35 years of age. A. baumannii strains (pandrug- A. baumannii) that can resist all tested antibiotics were 8.19%. The major source of the A. baumannii isolates was the respiratory system (>50%). Among all isolates (N = 342), azidothymidine-resistant A. baumannii strains were more than 85%. There is a statistically significant difference (P < 0.05) in the number of colistin-resistant A. baumannii strains isolated from males comparing with the female. The combinations of colistin and silver nanoparticles or imipenem and silver nanoparticles resulted in synergistic action led to reduction of MICs of colistin, imipenem, and silver nanoparticles (more than four-fold reduction). Also, the combinations of colistin and imipenem had high synergistic action. The pandrug-resistant A. baumannii strains may represent a current and future threat that must be fought, and the synergy action of antibiotics and nanoparticles may be one of the available, rapid, and easy strategies to confront this global problem. [ABSTRACT FROM AUTHOR]

Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel β-lactam-β-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented.

Introduction: Multiple resistance to antibiotics is a problem in modern medicine and acceptable definitions are needed to describe it. The widely accepted method for this purpose is the Multiple Drug Resistance (MDR) definition and the older but less used Multiple Antibiotic Resistance (MAR) indexing system. The aim of this study was to analyze their ability for comparing multiple resistance results for the same Enterobacteriaceae members obtained using these two methods and to investigate whether there is a need to improve these definitions. Materials and Methods: Antimicrobial resistance test results of 665 Escherichia coli and 292 Klebsiella spp. strains isolated in the Clinical Microbiology Laboratory of our hospital were evaluated retrospectively. Resistance results were grouped under antibiotic categories and classified as multiple, extensively, and pan-drug resistance groups according to the MDR definition. MAR indices were determined by dividing the number of resistant antibiotics in both microorganism isolates separately and collectively by the number of antibiotics for which susceptibility was tested. The results were divided into subgroups according to the origin of the patients and the clinical samples obtained and were evaluated according to their total results. Than the two resistance classification methods were compared. Results: Among the E. coli and Klebsiella spp. strains analyzed in this study, 45.86% and 40.06% of the strains were classified as multidrug-resistant according to the MDR definition, respectively. However, when these strains were evaluated with the MAR index method, it was found that the resistance rates were (from most to least resistant) 1.65%, 6.46%, 10.97%, 7.36%, 6.61%, and 11.12% in E. coli and 5.13%, 7.87%, 8.56%, 3.79%, 4.10%, and 8.21% percent in Klebsiella spp. Similar results were observed in subgroup analysis. Conclusion: Our study demonstrates that the MAR index method, which is used less frequently in medical research, yields more detailed results than the commonly used MDR method and provides more objective outcomes since it expresses resistance results numerically.

Antimicrobial combinations are at the moment the only potential treatment option for pandrug-resistant A. baumannii. A systematic review was conducted in PubMed and Scopus for studies reporting the activity of antimicrobial combinations against A. baumannii resistant to all components of the combination. The clinical relevance of synergistic combinations was assessed based on concentrations achieving synergy and PK/PD models. Eighty-four studies were retrieved including 818 eligible isolates. A variety of combinations (n = 141 double, n = 9 triple) were tested, with a variety of methods. Polymyxin-based combinations were the most studied, either as double or triple combinations with cell-wall acting agents (including sulbactam, carbapenems, glycopeptides), rifamycins and fosfomycin. Non-polymyxin combinations were predominantly based on rifampicin, fosfomycin, sulbactam and avibactam. Several combinations were synergistic at clinically relevant concentrations, while triple combinations appeared more active than the double ones. However, no combination was consistently synergistic against all strains tested. Notably, several studies reported synergy but at concentrations unlikely to be clinically relevant, or the concentration that synergy was observed was unclear. Selecting the most appropriate combinations is likely strain-specific and should be guided by in vitro synergy evaluation. Furthermore, there is an urgent need for clinical studies on the efficacy and safety of such combinations.

Background: Multidrug-resistant Acinetobacter baumannii is a common hospital-acquired pathogen. The increase in antibiotic resistance is commonly due to the acquisition of mobile genetic elements carrying antibiotic resistance genes. To comprehend this, we analyzed the resistome and virulome of Mexican A. baumannii multidrug-resistant isolates., Methods: Six clinical strains of A. baumannii from three Mexican hospitals were sequenced using the Illumina platform, the genomes were assembled with SPAdes and annotated with Prokka. Plasmid SPAdes and MobRecon were used to identify the potential plasmid sequences. Sequence Type (ST) assignation under the MLST Oxford scheme was performed using the PubMLST database. Homologous gene search for known virulent factors was performed using the virulence factor database VFDB and an in silico prediction of the resistome was conducted via the ResFinder databases., Results: The six strains studied belong to different STs and clonal complexes (CC): two strains were ST208 and one was ST369; these two STs belong to the same lineage CC92, which is part of the international clone (IC) 2. Another two strains were ST758 and one was ST1054, both STs belonging to the same lineage CC636, which is within IC5. The resistome analysis of the six strains identified between 7 to 14 antibiotic resistance genes to different families of drugs, including beta-lactams, aminoglycosides, fluoroquinolones and carbapenems. We detected between 1 to 4 plasmids per strain with sizes from 1,800 bp to 111,044 bp. Two strains from hospitals in Mexico City and Guadalajara had a plasmid each of 10,012 bp pAba78r and pAba79f, respectively, which contained the bla OXA-72 gene. The structure of this plasmid showed the same 13 genes in both strains, but 4 of them were inverted in one of the strains. Finally, the six strains contain 49 identical virulence genes related to immune response evasion, quorum-sensing, and secretion systems, among others., Conclusion: Resistance to carbapenems due to pAba78r and pAba79f plasmids in Aba pandrug-resistant strains from different geographic areas of Mexico and different clones was detected. Our results provide further evidence that plasmids are highly relevant for the horizontal transfer of antibiotic resistance genes between different clones of A. baumannii., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fernández-Vázquez, Hernández-González, Castillo-Ramírez, Jarillo-Quijada, Gayosso-Vázquez, Mateo-Estrada, Morfín-Otero, Rodríguez-Noriega, Santos-Preciado and Alcántar-Curiel.)

Multidrug-resistant Acinetobacter baumannii infections have become a threat for public health worldwide. The aim of the present study was to follow-up resistance patterns of Acinetobacter spp. bloodstream isolates in a Tertiary University Hospital over the last nine years, from 2014 to 2022. Susceptibility patterns were followed for the following antimicrobial agents: amikacin, gentamicin, tobramycin, ciprofloxacin, levofloxacin, imipenem, meropenem, tigecycline, trimethoprim/sulfamethoxazole, and colistin. Minimal inhibitory concentration (MIC) values to ampicillin/sulbactam, cefepime, ceftazidime, minocycline, piperacillin/tazobactam were evaluated from 2020 to 2023. During the study period, 853 Acinetobacter spp. bloodstream infections (BSIs) were recorded, accounting for 5.36% of all BSIs. A . baumannii was isolated in 795 cases (93.2%), during the study period. Most BSIs were recorded in adult intensive care units (ICU) (46.2%) and medical wards (42%). Among A. baumannii isolates, 4.5% were multidrug-resistant, 84.7% were extensively drug-resistant, and 8.5% were pandrug-resistant. Resistance to carbapenems was over 95%. Resistance to tigecycline increased significantly during the last years of the study (2020-2022); A. baumannii isolates with MIC ≤ 2 μg/mL accounted for 28.5% of all isolates. Resistance to colistin exhibited an increasing pattern up to 42.2% in 2022. Increasing resistance rates and the evolution of pandrug-resistant isolates call for the urgent application of preventive and response actions.

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC 50 and MIC 90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC 90 , 2 mg/L), followed by minocycline (MIC 90 , 8 mg/L). TP-6076 exhibited MIC 90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC 90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics. [ABSTRACT FROM AUTHOR]

The rapid emergence (from 0% before 1998 to 6.5% in 2000) of pandrug-resistant Acinetobacter baumannii (PDRAB) was noted in a university hospital in Taiwan. To understand the epidemiology of these isolates, we studied 203 PDRAB isolates, taken from January 1999 to April 2000: 199 from 73 hospitalized patients treated at different clinical settings in the hospital and 4 from environmental sites in an intensive-care unit. Pulsed-field gel electrophoresis analysis and random amplified polymorphic DNA (RAPD) generated by arbitrarily primed polymerase chain reaction of these 203 isolates showed 10 closely related genotypes (10 clones). One (clone 5), belonging to pulsotype E and RAPD pattern 5, predominated (64 isolates, mostly from patients in intensive care). Increasing use of carbapenems and ciprofloxacin (selective pressure) as well as clonal dissemination might have contributed to the wide spread of PDRAB in this hospital.

Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii remains a significant cause of morbidity and mortality. Increasing antimicrobial resistance influences the selection of antibiotic treatment especially pandrug-resistant A. baumannii . A retrospective cohort study was conducted in the Medical Intensive Care Unit to identify the risk factors of VAP caused by multidrug-resistant A. baumannii (MDR-AB), extensively drug-resistant A. baumannii (XDR-AB) and pandrug-resistant A. baumannii (PDR-AB). All 337 adult patients with confirmed A. baumannii VAP were included. The incidence of MDR-AB, XDR-AB and PDR-AB were 72 (21.4%), 220 (65.3%) and 12 (3.6%), respectively. The risk factor for MDR-AB was prior use of carbapenems (OR 5.20; 95% CI 1.41–19.17). Risk factors for XDR-AB were the prior use of carbapenems (OR, 6.30; 95% CI, 1.80–21.97) and a high Sequential Organ Failure Assessment (SOFA) score (OR 1.35; 95% CI 1.07–1.71). In PDR-AB, the risk factors were the prior use of colistin (OR, 155.95; 95% CI, 8.00–3041.98), carbapenems (OR, 12.84; 95% CI, 1.60–103.20) and a high Simplified Acute Physiology Score (SAPS II) (OR 1.10; 95% CI 1.01–1.22). In conclusion, previous exposure to antibiotics and severity of VAP were risk factors of drug-resistant A. baumannii . Judicious use of carbapenems and colistin is recommended to prevent the antimicrobial-resistant strains of this organism. [ABSTRACT FROM AUTHOR]

Objectives: Acinetobacter baumannii is a significant opportunistic pathogen causing nosocomial infections. Infections caused by A. baumannii are often difficult to treat because this bacterium is often multidrug-resistant and shows high environmental adaptability. Here, we report on the analysis of three A. baumannii strains isolated from hospital effluents in South Africa., Methods: Strains were isolated on Leeds Acinetobacter agar and were identified using VITEK®2 platform. Antibiotic susceptibility testing was performed using the Kirby-Bauer Disk diffusion method. Whole-genome sequencing was performed. The assembled contigs were annotated. Multilocus sequence type, antimicrobial resistance, and virulence genes were identified., Results: The strains showed two multilocus sequence types, ST231 (FA34) and ST1552 (PL448, FG116). Based on their antibiotic susceptibility profiles, PL448 and FG116 were classified as extensively drug-resistant and FA34 as pandrug-resistant. FA34 harbored mutations in LpxA, LpxC, and PmrB, conferring resistance to colistin, but not mcr genes. All three strains encoded virulence genes for immune evasion (capsule, lipopolysaccharide [LPS]), iron uptake, and biofilm formation. FA34 was related to human strains from South Africa; PL448 and FG116 were related to a strain isolated in the United States from a human wound., Conclusions: The detection of extensively drug- and pandrug-resistant A. baumannii strains in hospital effluents is of particular concern. It indicates that wastewater might play a role in the spread of these bacteria. Our data provide insight into the molecular epidemiology, resistance, pathogenicity, and distribution of A. baumannii in South Africa., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The increasing and rapid spread of metallo-beta-lactamase (MBL) producing Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae represents an emerging public health threat. However, limited data is available on MBL production in clinical isolates of E. coli and K. pneumoniae from Nepal. We have therefore undertaken this study to ascertain the incidence of MBL production in clinical isolates of E. coli and K. pneumoniae at a tertiary care teaching hospital in central Nepal. Methods: A total of 401 consecutive, non-duplicate isolates of E. coli (n = 216) and K. pneumoniae (n = 185) were recovered from various clinical samples between July and December, 2012. These isolates were screened for the detection of carbapenemase production on the basis of their reduced susceptibility to meropenem or ertapenem by the disc diffusion method. The screened isolates were further phenotypically studied for carbapenemase production by modified Hodge test (MHT). MBL production was detected by performing combined disc test by using imipenem discs with and without ethylenediaminetetraacetic acid (EDTA), which chelates zinc required for MBL activity. Results: Out of 216 E. coli isolates, a total of 41 isolates (18.98%) and out of 185 K. pneumoniae isolates, a total of 39 isolates (21.08%) were suspected to be carbapenemase- producers on the basis of their reduced susceptibility to meropenem or ertapenem. Interestingly, all the initially suspected isolates of E. coli and K. pneumoniae for carbapenemase production were found to be positive in both MHT and combined disc test. However, few weakly positive reactions were observed in MHT. All the MBL producing isolates were multidrug-resistant (MDR). In addition, 75.60% E. coli and 71.79% of K. pneumoniae isolates producing MBL were found to be “pandrug- resistant”. Conclusions: Our findings showed MBL production in a considerable number of E. coli and K. pneumoniae isolates with MDR and pandrug-resistant phenotypes. Combined disc method can provide a sensible choice for phenotypic detection of MBL production in clinical microbiology laboratories as detection of MBL in bacterial isolates is indispensable for establishing the effective antibiotic policies and infection control strategies in the hospital setting. [ABSTRACT FROM AUTHOR]

The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant Acinetobacter baumannii , even eliminating large inocula (10 8 CFU/ml) within 30 min. LC 99.9 in PBS and 50% pooled human plasma was 2 μg/ml (1.4 μM) and 8 μg/ml (5.6 μM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation-reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. C. elegans infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant A. baumannii ., Competing Interests: Authors MV and GL were employed by Cognosci, Inc. Author RM was employed by Shanghai Nanoport, Thermofisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhang, Wang, Zhao, Sun, Yu, Vitek, Li, Ma, Wang, Hu and Chen.)

Clin Microbiol Infect 2010; 16: 888–894 Treatment limitations exist for drug-resistant Acinetobacter baumannii central nervous system (CNS) infection. We conducted a retrospective study and systematic literature review to identify patients with drug-resistant A. baumannii CNS infection who received primary or adjunct intrathecal or intraventricular (IT/IVT) colistin. In a case series of seven Thai patients and 17 patients identified in the literature, clinical and microbiological cure rates with IT/IVT colistin therapy were 83% and 92%, respectively. Three patients (13%) developed chemical ventriculitis and one (4%) experienced treatment-associated seizures. Death was associated with delayed IT/IVT colistin therapy compared to survival (mean time from diagnosis to IT/IVT colistin, 7 vs. 2 days; p 0.01). The only independent predictor of mortality was the severity of illness (APACHE II score > 19, adjusted odds ratio 49.5; 95% CI 1.7–1428.6; p 0.02). This case series suggests that administration of primary or adjunctive IT/IVT colistin therapy was effective for drug-resistant A. baumannii CNS infection. [ABSTRACT FROM AUTHOR]

Antimicrobial combinations are at the moment the only potential treatment option for pandrug-resistant A. baumannii. A systematic review was conducted in PubMed and Scopus for studies reporting the activity of antimicrobial combinations against A. baumannii resistant to all components of the combination. The clinical relevance of synergistic combinations was assessed based on concentrations achieving synergy and PK/PD models. Eighty-four studies were retrieved including 818 eligible isolates. A variety of combinations (n = 141 double, n = 9 triple) were tested, with a variety of methods. Polymyxin-based combinations were the most studied, either as double or triple combinations with cell-wall acting agents (including sulbactam, carbapenems, glycopeptides), rifamycins and fosfomycin. Non-polymyxin combinations were predominantly based on rifampicin, fosfomycin, sulbactam and avibactam. Several combinations were synergistic at clinically relevant concentrations, while triple combinations appeared more active than the double ones. However, no combination was consistently synergistic against all strains tested. Notably, several studies reported synergy but at concentrations unlikely to be clinically relevant, or the concentration that synergy was observed was unclear. Selecting the most appropriate combinations is likely strain-specific and should be guided by in vitro synergy evaluation. Furthermore, there is an urgent need for clinical studies on the efficacy and safety of such combinations. [ABSTRACT FROM AUTHOR]

Abstract: The evolving problem of antimicrobial resistance in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae has led to the emergence of clinical isolates susceptible to only one class of antimicrobial agents and eventually to pandrug-resistant (PDR) isolates, i.e. resistant to all available antibiotics. We reviewed the available evidence from laboratory and clinical studies that reported on polymyxin-resistant and/or PDR P. aeruginosa, A. baumannii or K. pneumoniae clinical isolates. Eleven laboratory studies reported on isolates with resistance to polymyxins, three of which (including two surveillance studies) also included data regarding PDR isolates. In addition, two clinical studies (from Central and Southern Europe) reported on the clinical characteristics and outcomes of patients infected with PDR isolates. These data suggest that polymyxin-resistant or PDR P. aeruginosa, A. baumannii and K. pneumoniae clinical isolates are currently relatively rare. However, they have important global public health implications because of the therapeutic problems they pose. The fears for the dawn of a post-antibiotic era appear to be justified, at least for these three Gram-negative bacteria. We must increase our efforts to preserve the activity of available antibiotics, or at least expand as much as possible the period of their use, whilst intense research efforts should be focused on the development and introduction into clinical practice of new antimicrobial agents. [Copyright &y& Elsevier]

Pandrug-resistant A. baumannii (PDRAB) is increasingly being reported but remains rare. Several case studies show that A. baumannii can acquire resistance to last resort antibiotics during treatment by single-step chromosomal mutations. However, re-emergence of the ancestral susceptible strain after withdrawal of antibiotics has been described, possibly due to fitness cost associated with acquired resistance. Therefore, PDRAB may be a transient phenotype. Epidemiological data to show this process in larger cohorts are currently lacking. In this study of 91 hospitalized patients with PDRAB we showed the frequent (60%) isolation of non-PDRAB, often susceptible only to colistin, aminoglycosides and/or tigecycline, preceding and/or following PDRAB isolation. However, the isolation of PDRAB in two outpatients, 25 and 36 days after their discharge from the hospital, suggests the potential of some PDRAB strains to persist even in the absence of antimicrobial pressure.

• Two clinical draft genome sequences of K. pneumoniae were performed. • The strains have pandrug-resistant and extensively drug-resistant profiles. • The strains have ST258 which is considered a high-risk clone worldwide. • Multiple antimicrobial resistance genes were identified in both genomes. • There is concern about PDR K. pneumoniae high-risk clones in Brazilian hospitals. [ABSTRACT FROM AUTHOR]

Forty-two multidrug-resistant (MDR) Acinetobacter baumannii isolates were obtained during outbreaks in a Korean hospital. The co-carriage of blaOXA-23, blaOXA-51, blaPER-1 and armA was observed in 23 isolates, and they were susceptible only to colistin and minocycline. The MDR A. baumannii isolates were found to belong to sequence group 1 using sequence-based typing. [ABSTRACT FROM AUTHOR]

Objectives: Bacteria resistant to different classes of antimicrobial agents are a major threat to humanity and risk leading the world towards the return of the pre-antimicrobial era. This study was undertaken to detect the incidence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria in a tertiary-care hospital in Bhubaneswar, Odisha, India., Methods: Positive bacterial cultures from different clinical samples were identified using a VITEK ® 2 compact system and the antimicrobial susceptibility profile of different Gram-negative bacteria was analysed., Results: A total of 2489 clinical samples were collected and processed for culture during the period January 2013 to April 2017. Of 1103 pure bacterial cultures, 690 (62.6%) were Gram-negative bacteria. The antimicrobial susceptibility profile of Gram-negative bacterial strains revealed that 41.3% (n=285) were XDR and 8.1% (n=56) were PDR. Rates of colistin and tigecycline resistance were 16% and 51.9%, respectively., Conclusion: This situation demands regular surveillance of antimicrobial resistance of Gram-negative bacteria and implementation of an efficient infection control programme., (Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Introduction: In the era of multidrug-resistant, extensively drug-resistant (XDR) and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the threat of untreatable infections particularly those caused by carbapenemase-producing bacteria, that is, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Therefore, all the presently available antibiotics, as well as for the near future compounds, are presented and discussed., Areas Covered: Current knowledge concerning mechanisms of action, in vitro activity and interactions, pharmacokinetic/pharmacodynamics, clinical efficacy and toxicity issues for revived and novel antimicrobial agents overcoming current resistance mechanisms, including colistin, tigecycline, fosfomycin, temocillin, carbapenems, and antibiotics still under development for the near future such as plazomicin, eravacycline and carbapenemase inhibitors is discussed., Expert Opinion: Colistin is active in vitro and effective in vivo against XDR carbapenemase-producing microorganisms in the critically ill host, whereas tigecycline, with the exception of P. aeruginosa, has a similar spectrum of activity. The efficacy of combination therapy in bacteremias and ventilator-associated pneumonia caused by K. pneumoniae carbapenemase producers seems to be obligatory, whereas in cases of P. aeruginosa and A. baumannii its efficacy is questionable. Fosfomycin, which is active against P. aeruginosa and K. pneumoniae, although promising, shares poor experience in XDR infections. The in vivo validity of the newer potent compounds still necessitates the evaluation of Phase III clinical trials particularly in XDR infections.