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Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 7511

Special Issue Editor

Dr. Dimitra Petropoulou

E-Mail Website
Guest Editor
General Panarcadian Hospital of Tripolis, "Evaggelistria", Erythrou Stavrou Street End, 22131 Tripolis, Arcadia, Greece
Interests: acinetobacter; antimicrobial sensitivity

Special Issue Information

Dear Colleagues,

The global emergence of antimicrobial resistance in Gram-negative bacteria is one of the major health challenges worldwide, resulting in significant comorbidity and limited treatment options. Indeed, carbapenem-resistant pathogens are categorized as a global priority by the World Health Organization (WHO), and many infection control programs are conducted to prevent infections caused by these microbes. Moreover, the Centers for Disease Control and Prevention (CDC) has reported that carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant A. baumannii (CRAb) are classified in the "urgent" threat level, being associated annually with 1,100 and 700 mortalities, respectively, and carbapenem resistance in P.aeruginosa is rising.

Identifying the molecular pattern involved in the resistance mechanism is the driving force behind the development of new therapeutic strategies that include finding alternative microbe targets, the use of bacteriophages, new antibacterial molecules, and monoclonal antibodies.

This Special Issue aims to present the latest findings in the field of molecular pathways concerning pathogenesis, virulence, and control strategies, including advances in developing and validating new therapeutic strategies for carbapenem-resistant Gram-negative bacteria.

Original investigations as well as concise review manuscripts from experts in relevant research fields are invited for publication. Papers only containing clinical trials/data, without molecular investigations, will not be considered.

Dr. Dimitra Petropoulou
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • antimicrobial activity
  • molecular mechanisms of antimicrobial resistance
  • molecular epidemiology
  • novel antimicrobial agents
  • new therapeutic targets
  • carbapenem-resistant enterobacterales
  • carbapenem-resistant non-fermenters
  • carbapenem-resistant A. baumannii
  • carbapenem-resistant P.aeruginosa

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Published Papers (5 papers)

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Research

13 pages, 691 KiB  
Article
Gram-Negative Bacilli Blood Stream Infection in Patients with Severe Burns: Microbiological and Clinical Evidence from a 9-Year Cohort
by María Fernanda Fuentes-González, Diana Fernández-Rodríguez, Claudia A. Colín-Castro, Melissa Hernández-Durán, Luis Esaú López-Jácome and Rafael Franco-Cendejas
Int. J. Mol. Sci. 2024, 25(19), 10458; https://doi.org/10.3390/ijms251910458 - 28 Sep 2024
Viewed by 428
Abstract
Bloodstream infection is one of the most important and increasing complications in patients with severe burns. Most of the species affecting this population are Gram-negative bacilli that exhibit antimicrobial resistance. We conducted this study to determine the antimicrobial susceptibility profile and resistance mechanisms [...] Read more.
Bloodstream infection is one of the most important and increasing complications in patients with severe burns. Most of the species affecting this population are Gram-negative bacilli that exhibit antimicrobial resistance. We conducted this study to determine the antimicrobial susceptibility profile and resistance mechanisms of these bacterial infections and their clinical associations on morbidity and mortality. We analyzed a retrospective cohort of burn patients. All patients included in this study had monobacterial blood stream infections during their hospital stay. We performed phenotypic and genotypic tests to determine the antimicrobial resistance mechanism and profile of each strain. Univariate and multivariate logistic regression analysis was performed between variables. We found 109 patients with monobacterial bacteremia. Pseudomonas spp. (50.7%), A. baumannii (46.4%), and Klebsiella spp. (13.8%) were the most common causative microorganisms. The Pseudomonas spp. isolates showed resistance to imipenem (81.5%), mainly by class A and class B carbapenemases. The A. baumannii isolates conferred resistance to imipenem (56.2%), mainly by class D carbapenemases. One quarter of Klebsiella spp. showed resistance to 3rd generation cephalosporins. We also observed that a total body surface area greater than 40% and three or more different types of invasive procedures might be related to increased mortality. Multidrug resistance is highly present. The extent of the burned area and a high number of different types of invasive procedures had an impact in decreasing survivorship in burn patients with bacteremia. Full article
(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria)
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19 pages, 8990 KiB  
Article
In Vitro and In Vivo Assessments of Newly Isolated N4-like Bacteriophage against ST45 K62 Capsular-Type Carbapenem-Resistant Klebsiella pneumoniae: vB_kpnP_KPYAP-1
by Shanmuga Priya Natarajan, Soon-Hian Teh, Ling-Chun Lin and Nien-Tsung Lin
Int. J. Mol. Sci. 2024, 25(17), 9595; https://doi.org/10.3390/ijms25179595 - 4 Sep 2024
Viewed by 630
Abstract
The rise of carbapenem-resistant Klebsiella pneumoniae (CRKP) presents a significant global challenge in clinical and healthcare settings, severely limiting treatment options. This study aimed to utilize a bacteriophage as an alternative therapy against carbapenem-resistant K. pneumoniae. A novel lytic N4-like Klebsiella phage, [...] Read more.
The rise of carbapenem-resistant Klebsiella pneumoniae (CRKP) presents a significant global challenge in clinical and healthcare settings, severely limiting treatment options. This study aimed to utilize a bacteriophage as an alternative therapy against carbapenem-resistant K. pneumoniae. A novel lytic N4-like Klebsiella phage, vB_kpnP_KPYAP-1 (KPYAP-1), was isolated from sewage. It demonstrated efficacy against the K62 serotype polysaccharide capsule of blaOXA-48-producing K. pneumoniae. KPYAP-1 forms small, clear plaques, has a latent period of 20 min, and reaches a growth plateau at 35 min, with a burst size of 473 plaque-forming units (PFUs) per infected cell. Phylogenetic analysis places KPYAP-1 in the Schitoviridae family, Enquatrovirinae subfamily, and Kaypoctavirus genus. KPYAP-1 employs an N4-like direct terminal repeat mechanism for genome packaging and encodes a large virion-encapsulated RNA polymerase. It lacks integrase or repressor genes, antibiotic resistance genes, bacterial virulence factors, and toxins, ensuring its safety for therapeutic use. Comparative genome analysis revealed that the KPYAP-1 genome is most similar to the KP8 genome, yet differs in tail fiber protein, indicating variations in host recognition. In a zebrafish infection model, KPYAP-1 significantly improved the survival rate of infected fish by 92% at a multiplicity of infection (MOI) of 10, demonstrating its potential for in vivo treatment. These results highlight KPYAP-1 as a promising candidate for developing phage-based therapies targeting carbapenemase-producing K. pneumoniae. Full article
(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria)
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13 pages, 1084 KiB  
Article
Genomic Surveillance Uncovers a 10-Year Persistence of an OXA-24/40 Acinetobacter baumannii Clone in a Tertiary Hospital in Northern Spain
by Maitane Aranzamendi, Kyriaki Xanthopoulou, Sandra Sánchez-Urtaza, Tessa Burgwinkel, Rocío Arazo del Pino, Kai Lucaßen, M. Pérez-Vázquez, Jesús Oteo-Iglesias, Mercedes Sota, Jose María Marimón, Harald Seifert, Paul G. Higgins and Lucía Gallego
Int. J. Mol. Sci. 2024, 25(4), 2333; https://doi.org/10.3390/ijms25042333 - 16 Feb 2024
Cited by 3 | Viewed by 1161
Abstract
Infections caused by carbapenem-resistant Acinetobacter baumannii are a global threat causing a high number of fatal infections. This microorganism can also easily acquire antibiotic resistance determinants, making the treatment of infections a big challenge, and has the ability to persist in the hospital [...] Read more.
Infections caused by carbapenem-resistant Acinetobacter baumannii are a global threat causing a high number of fatal infections. This microorganism can also easily acquire antibiotic resistance determinants, making the treatment of infections a big challenge, and has the ability to persist in the hospital environment under a wide range of conditions. The objective of this work was to study the molecular epidemiology and genetic characteristics of two blaOXA24/40 Acinetobacter baumannii outbreaks (2009 and 2020-21) at a tertiary hospital in Northern Spain. Thirty-six isolates were investigated and genotypically screened by Whole Genome Sequencing to analyse the resistome and virulome. Isolates were resistant to carbapenems, aminoglycosides and fluoroquinolones. Multi-Locus Sequence Typing analysis identified that Outbreak 1 was mainly produced by isolates belonging to ST3Pas/ST106Oxf (IC3) containing blaOXA24/40, blaOXA71 and blaADC119. Outbreak 2 isolates were exclusively ST2Pas/ST801Oxf (IC2) blaOXA24/40, blaOXA66 and blaADC30, the same genotype seen in two isolates from 2009. Virulome analysis showed that IC2 isolates contained genes for capsular polysaccharide KL32 and lipooligosacharide OCL5. A 8.9 Kb plasmid encoding the blaOXA24/40 gene was common in all isolates. The persistance over time of a virulent IC2 clone highlights the need of active surveillance to control its spread. Full article
(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria)
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11 pages, 3217 KiB  
Communication
Co-Existence of blaNDM-1, blaOXA-23, blaOXA-64, blaPER-7 and blaADC-57 in a Clinical Isolate of Acinetobacter baumannii from Alexandria, Egypt
by Sandra Sánchez-Urtaza, Alain Ocampo-Sosa, Ainhoa Molins-Bengoetxea, Jorge Rodríguez-Grande, Mohammed A. El-Kholy, Marta Hernandez, David Abad, Sherine M. Shawky, Itziar Alkorta and Lucia Gallego
Int. J. Mol. Sci. 2023, 24(15), 12515; https://doi.org/10.3390/ijms241512515 - 7 Aug 2023
Cited by 4 | Viewed by 2042
Abstract
The increasing rates of antimicrobial resistance among carbapenem-resistant Acinetobacter baumannii in the Middle East and North Africa are one of the major concerns for healthcare settings. We characterised the first A. baumannii isolate harbouring five β-lactamases identified in Egypt. The isolate Ale25 was [...] Read more.
The increasing rates of antimicrobial resistance among carbapenem-resistant Acinetobacter baumannii in the Middle East and North Africa are one of the major concerns for healthcare settings. We characterised the first A. baumannii isolate harbouring five β-lactamases identified in Egypt. The isolate Ale25 was obtained from an ICU patient of a hospital from Alexandria. The isolate was phenotypically and genotypically screened for carbapenemase genes. The isolate was resistant to carbapenems, aminoglycosides, fluoroquinolones and cefiderocol. Whole-Genome Sequencing identified five β-lactamase genes, blaNDM-1, blaOXA-23, blaOXA-64, blaPER-7 and blaADC-57, together with other antibiotic resistance genes, conferring resistance to sulfonamides, macrolides, tetracyclines, rifamycin and chloramphenicol. Virulome analysis showed the presence of genes involved in adhesion and biofilm production, type II and VI secretion systems, exotoxins, etc. Multi-Locus Sequence Typing analysis identified the isolate as Sequence Types 113Pas and 2246Oxf, belonging to International Clone 7. Sequencing experiments revealed the presence of four plasmids of 2.7, 22.3, 70.4 and 240.8 Kb. All the β-lactamase genes were located in the chromosome, except the blaPER-7, gene which was found within the plasmid of 240.8 Kb. This study highlights the threat of the emergence and dissemination of these types of isolates. Full article
(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria)
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16 pages, 1365 KiB  
Article
Induced Heteroresistance in Carbapenem-Resistant Acinetobacter baumannii (CRAB) via Exposure to Human Pleural Fluid (HPF) and Its Impact on Cefiderocol Susceptibility
by Vyanka Mezcord, Jenny Escalante, Brent Nishimura, German M. Traglia, Rajnikant Sharma, Quentin Vallé, Marisel R. Tuttobene, Tomás Subils, Ingrid Marin, Fernando Pasteran, Luis A. Actis, Marcelo E. Tolmasky, Robert A. Bonomo, Gauri Rao and María S. Ramirez
Int. J. Mol. Sci. 2023, 24(14), 11752; https://doi.org/10.3390/ijms241411752 - 21 Jul 2023
Cited by 7 | Viewed by 2159
Abstract
Infections caused by Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates, such as hospital-acquired pneumonia (HAP), bacteremia, and skin and soft tissue infections, among others, are particularly challenging to treat. Cefiderocol, a chlorocatechol-substituted siderophore antibiotic, was approved by the U.S. Food and Drug Administration (FDA) in [...] Read more.
Infections caused by Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates, such as hospital-acquired pneumonia (HAP), bacteremia, and skin and soft tissue infections, among others, are particularly challenging to treat. Cefiderocol, a chlorocatechol-substituted siderophore antibiotic, was approved by the U.S. Food and Drug Administration (FDA) in 2019 and prescribed for the treatment of CRAB infections. Despite the initial positive treatment outcomes with this antimicrobial, recent studies reported a higher-than-average all-cause mortality rate in patients treated with cefiderocol compared to the best available therapy. The cause(s) behind these outcomes remains unconfirmed. A plausible hypothesis is heteroresistance, a phenotype characterized by the survival of a small proportion of cells in a population that is seemingly isogenic. Recent results have demonstrated that the addition of human fluids to CRAB cultures leads to cefiderocol heteroresistance. Here, we describe the molecular and phenotypic analyses of CRAB heteroresistant bacterial subpopulations to better understand the nature of the less-than-expected successful outcomes after cefiderocol treatment. Isolation of heteroresistant variants of the CRAB strain AMA40 was carried out in cultures supplemented with cefiderocol and human pleural fluid (HPF). Two AMA40 variants, AMA40 IHC1 and IHC2, were resistant to cefiderocol. To identify mutations and gene expression changes associated with cefiderocol heteroresistance, we subjected these variants to whole genome sequencing and global transcriptional analysis. We then assessed the impact of these mutations on the pharmacodynamic activity of cefiderocol via susceptibility testing, EDTA and boronic acid inhibition analysis, biofilm formation, and static time-kill assays. Heteroresistant variants AMA40 IHC1 and AMA40 IHC2 have 53 chromosomal mutations, of which 40 are common to both strains. None of the mutations occurred in genes associated with high affinity iron-uptake systems or β-lactam resistance. However, transcriptional analyses demonstrated significant modifications in levels of expression of genes associated with iron-uptake systems or β-lactam resistance. The blaNDM-1 and blaADC-2, as well as various iron-uptake system genes, were expressed at higher levels than the parental strain. On the other hand, the carO and ompA genes’ expression was reduced. One of the mutations common to both heteroresistant strains was mapped within ppiA, a gene associated with iron homeostasis in other species. Static time-kill assays demonstrated that supplementing cation-adjusted Mueller–Hinton broth with human serum albumin (HAS), the main protein component of HPF, considerably reduced cefiderocol killing activity for all three strains tested. Notably, collateral resistance to amikacin was observed in both variants. We conclude that exposing CRAB to fluids with high HSA concentrations facilitates the rise of heteroresistance associated with point mutations and transcriptional upregulation of genes coding for β-lactamases and biofilm formation. The findings from this study hold significant implications for understanding the emergence of CRAB resistance mechanisms against cefiderocol treatment. This understanding is vital for the development of treatment guidelines that can effectively address the challenges posed by CRAB infections. Full article
(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Epidemiology and Emerging Therapeutic Strategies in Carbapenem-Resistant Gram-Negative Bacteria)
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