Paradise
Paradise | Life Science Engineering Business Natural Science
  1. You are here:
  2. Home
  3. Journals
  4. Biological Sciences
Paradise

Volume 1 Number 1 2025

Article Contents

REVIEWS   (Open Access)
Contents Vol 1 (1)

Molecular Epidemiology and Resistance Mechanisms of Extensively Drug-Resistant Gram-Negative Bacteria: Challenges and Emerging Therapeutic Strategies

Bikom Chandra Singha1*, Abul Kalam Azad2

+ Author Affiliations

Paradise 1 (1) 1-8 https://doi.org/10.25163/paradise.1110358

Submitted: 01 June 2025 Revised: 17 March 2025  Published: 19 March 2025 

Abstract

Background: The emergence of extensively drug-resistant (XDR) gram-negative bacteria poses a major global health challenge, contributing to increased mortality, prolonged hospital stays, and escalating healthcare costs. Over the past two decades, advances in whole-genome sequencing and genotyping have improved our understanding of the development and spread of antibiotic resistance. Resistance in XDR infections arises from mechanisms such as target site mutations, enzymatic degradation of antibiotics, and alterations in membrane permeability. Methods: This study examines the epidemiology and molecular resistance mechanisms of three clinically significant gram-negative pathogens: XDR Pseudomonas aeruginosa, XDR Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae (CRE). Literature-based evidence and molecular findings were analyzed to identify resistance patterns, emerging clones, and therapeutic challenges. Results: The findings indicate that these pathogens, classified as “critical threats” by the World Health Organization, often necessitate last-resort antibiotics such as polymyxins and novel β-lactam/β-lactamase inhibitor combinations. Resistance mechanisms differ among species but commonly involve enzymatic activity, genetic mutations, and permeability changes. Molecular diagnostics have shown promise in guiding combination therapies, particularly against metallo-β-lactamase-producing CRE, though routine use remains limited. Several novel antimicrobials—including ceftolozane- tazobactam, plazomicin, vaborbactam, and avibactam offer alternative therapeutic options. Conclusion: The growing threat of XDR gram-negative bacteria underscores the urgent need for ongoing global surveillance, improved diagnostic strategies, and deeper investigation into the molecular epidemiology of resistance. Strengthening antibiotic stewardship and advancing targeted therapies are essential to mitigate treatment challenges and control the spread of these pathogens.

Keywords: Extensively drug-resistant bacteria, Gram-negative pathogens, Antibiotic resistance mechanisms, Molecular epidemiology, Novel antimicrobials

References

Afzal-Shah, M., Woodford, N., & Livermore, D. M. (2001). Characterization of OXA-25, OXA-26, and OXA-27, Molecular Class D β-Lactamases Associated with Carbapenem Resistance in Clinical Isolates of Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 45(2), 583–588. https://doi.org/10.1128/aac.45.2.583-588.2001

Ansaldi, F., Canepa, P., Bassetti, M., Zancolli, M., Molinari, M., Talamini, A., Ginocchio, F., Durando, P., Mussap, M., Orengo, G., Viscoli, C., & Icardi, G. (2011). Sequential outbreaks of multidrug-resistant Acinetobacter baumannii in intensive care units of a tertiary referral hospital in Italy: combined molecular approach for epidemiological investigation. Journal of Hospital Infection, 79(2), 134–140. https://doi.org/10.1016/j.jhin.2011.05.027

Billard-Pomares, T., Clermont, O. P., Castellanos, M., Magdoud, F., Royer, G., Condamine, B., Fouteau, S., Barbe, V., Roche, D., Cruveiller, S., Médigue, C., Pognard, D., Glodt, J., Dion, S., Rigal, O., Picard, B., Denamur, E., & Branger, C. (2013). Antimicrobial agents and chemotherapy. Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/aac

Bodro, M., Sabé, N., Tubau, F., Lladó, L., Baliellas, C., González-Costello, J., Cruzado, J. M., & Carratalà, J. (2014). Extensively Drug-Resistant Pseudomonas aeruginosa Bacteremia in Solid Organ Transplant Recipients. Transplantation, 99(3), 616–622. https://doi.org/10.1097/tp.0000000000000366

Brigante, G., Migliavacca, R., Bramati, S., Motta, E., Nucleo, E., Manenti, M., Migliorino, G., Pagani, L., Luzzaro, F., & Viganò, F. E. (2012). Emergence and spread of a multidrug-resistant Acinetobacter baumannii clone producing both the carbapenemase OXA-23 and the 16S rRNA methylase ArmA. Journal of Medical Microbiology, 61(5), 653–661. https://doi.org/10.1099/jmm.0.040980-0

Cabot, G., Ocampo-Sosa, A. A., Domínguez, M. A., Gago, J. F., Juan, C., Tubau, F., Rodríguez, C., Moyà, B., Peña, C., Martínez-Martínez, L., & Oliver, A. (2012). Genetic Markers of Widespread Extensively Drug-Resistant Pseudomonas aeruginosa High-Risk Clones. Antimicrobial Agents and Chemotherapy, 56(12), 6349–6357. https://doi.org/10.1128/aac.01388-12

Catalano, M., Quelle, L., Jeric, P., Di Martino, A., & Maimone, S. (1999b). Survival of Acinetobacter baumannii on bed rails during an outbreak and during sporadic cases. Journal of Hospital Infection, 42(1), 27–35. https://doi.org/10.1053/jhin.1998.0535

Clancy, C. J., Chen, L., Hong, J. H., Cheng, S., Hao, B., Shields, R. K., Farrell, A. N., Doi, Y., Zhao, Y., Perlin, D. S., Kreiswirth, B. N., & Nguyen, M. H. (2013). Mutations of the ompK36 Porin Gene and Promoter Impact Responses of Sequence Type 258, KPC-2-Producing Klebsiella pneumoniae Strains to Doripenem and Doripenem-Colistin. Antimicrobial Agents and Chemotherapy, 57(11), 5258–5265. https://doi.org/10.1128/aac.01069-13

Correa, A., Del Campo, R., Perenguez, M., Blanco, V. M., Rodríguez-Baños, M., Perez, F., Maya, J. J., Rojas, L., Cantón, R., Arias, C. A., & Villegas, M. V. (2015). Dissemination of High-Risk Clones of Extensively Drug-Resistant Pseudomonas aeruginosa in Colombia. Antimicrobial Agents and Chemotherapy, 59(4), 2421–2425. https://doi.org/10.1128/aac.03926-14

Evans, H. L., Lefrak, S. N., Lyman, J., Smith, R. L., Chong, T. W., McElearney, S. T., Schulman, A. R., Hughes, M. G., Raymond, D. P., Pruett, T. L., & Sawyer, R. G. (2006). Cost of Gram-negative resistance*. Critical Care Medicine, 35(1), 89–95. https://doi.org/10.1097/01.ccm.0000251496.61520.75

Gasink, L. B., Edelstein, P. H., Lautenbach, E., Synnestvedt, M., & Fishman, N. O. (2009). Risk Factors and Clinical Impact of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae. Infection Control and Hospital Epidemiology, 30(12), 1180–1185. https://doi.org/10.1086/648451

He´Ritier, C., Poirel, L., Aubert, D., & Nordmann, P. (2002). Genetic and Functional Analysis of the Chromosome-Encoded Carbapenem-Hydrolyzing Oxacillinase OXA-40 ofAcinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 47(1), 268–273. https://doi.org/10.1128/aac.47.1.268-273.2003

Hu, B., Ye, H., Xu, Y., Ni, Y., Hu, Y., Yu, Y., Huang, Z., & Ma, L. (2010). Clinical and economic outcomes associated with community-acquired intra-abdominal infections caused by extended spectrum beta-lactamase (ESBL) producing bacteria in China. Current Medical Research and Opinion, 26(6), 1443–1449. https://doi.org/10.1185/03007991003769068

Hu, B., Ye, H., Xu, Y., Ni, Y., Hu, Y., Yu, Y., Huang, Z., & Ma, L. (2010). Clinical and economic outcomes associated with community-acquired intra-abdominal infections caused by extended spectrum beta-lactamase (ESBL) producing bacteria in China. Current Medical Research and Opinion, 26(6), 1443–1449. https://doi.org/10.1185/03007991003769068

Hu, B., Ye, H., Xu, Y., Ni, Y., Hu, Y., Yu, Y., Huang, Z., & Ma, L. (2010b). Clinical and economic outcomes associated with community-acquired intra-abdominal infections caused by extended spectrum beta-lactamase (ESBL) producing bacteria in China. Current Medical Research and Opinion, 26(6), 1443–1449. https://doi.org/10.1185/03007991003769068

Kapmaz, M., Erdem, F., Abulaila, A., Yeniaras, E., Oncul, O., & Aktas, Z. (2016). First detection of NDM-1 with CTX-M-9, TEM, SHV and rmtC in Escherichia coli ST471 carrying IncI2, A/C and Y plasmids from clinical isolates in Turkey. Journal of Global Antimicrobial Resistance, 7, 152–153. https://doi.org/10.1016/j.jgar.2016.10.001

Lautenbach, E., Patel, J. B., Bilker, W. B., Edelstein, P. H., & Fishman, N. O. (2001). Extended-Spectrum -Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors for Infection and Impact of Resistance on Outcomes. Clinical Infectious Diseases, 32(8), 1162–1171. https://doi.org/10.1086/319757

Moffatt, J. H., Harper, M., Harrison, P., Hale, J. D. F., Vinogradov, E., Seemann, T., Henry, R., Crane, B., St Michael, F., Cox, A. D., Adler, B., Nation, R. L., Li, J., & Boyce, J. D. (2010). Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production. Antimicrobial Agents and Chemotherapy, 54(12), 4971–4977. https://doi.org/10.1128/aac.00834-10

Mulet, X., Cabot, G., Ocampo-Sosa, A. A., Domínguez, M. A., Zamorano, L., Juan, C., Tubau, F., Rodríguez, C., Moyà, B., Peña, C., Martínez-Martínez, L., & Oliver, A. (2013). Biological Markers of Pseudomonas aeruginosa Epidemic High-Risk Clones. Antimicrobial Agents and Chemotherapy, 57(11), 5527–5535. https://doi.org/10.1128/aac.01481-13

Patel, G., Huprikar, S., Factor, S. H., Jenkins, S. G., & Calfee, D. P. (2008). Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Infection and the Impact of Antimicrobial and Adjunctive Therapies. Infection Control and Hospital Epidemiology, 29(12), 1099–1106. https://doi.org/10.1086/592412

Pouch, S., Kubin, C., Satlin, M., Tsapepas, D., Lee, J., Dube, G., & Pereira. (2015). Epidemiology and outcomes of carbapenem-resistant Klebsiella pneumoniae bacteriuria in kidney transplant recipients. Transplant Infectious Disease, 17(6), 800–809. https://doi.org/10.1111/tid.12450

Robledo, I. E., Aquino, E. E., Sante, M. I., Santana, J. L., Otero, D. M., Leo´N, C. F., & Va´Zquez, G. J. (2009). Detection of KPC in Acinetobacter spp. in Puerto Rico. Antimicrobial Agents and Chemotherapy, 54(3), 1354–1357. https://doi.org/10.1128/aac.00899-09

Seward, R. J., & Towner, K. J. (1998). Molecular epidemiology of quinolone resistance in Acinetobacter spp. Clinical Microbiology and Infection, 4(5), 248–254. https://doi.org/10.1111/j.1469-0691.1998.tb00052.x

Tada, T., Miyoshi-Akiyama, T., Shimada, K., Shimojima, M., & Kirikae, T. (2014). Dissemination of 16S rRNA Methylase ArmA-Producing Acinetobacter baumannii and Emergence of OXA-72 Carbapenemase Coproducers in Japan. Antimicrobial Agents and Chemotherapy, 58(5), 2916–2920. https://doi.org/10.1128/aac.01212-13

Tanguy, M., Kouatchet, A., Tanguy, B., Pichard, É., Fanello, S., & Joly-Guillou, M. (2017). Management of an Acinetobacter baumannii outbreak in an intensive care unit. Médecine Et Maladies Infectieuses, 47(6), 409–414. https://doi.org/10.1016/j.medmal.2017.06.003

Thaden, J. T., Li, Y., Ruffin, F., Maskarinec, S. A., Hill-Rorie, J. M., Wanda, L. C., Reed, S. D., & Fowler, V. G. (2016). Increased Costs Associated with Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Bacteria Are Due Primarily to Patients with Hospital-Acquired Infections. Antimicrobial Agents and Chemotherapy, 61(3). https://doi.org/10.1128/aac.01709-16

Tumbarello, M., Viale, P., Viscoli, C., Trecarichi, E. M., Tumietto, F., Marchese, A., Spanu, T., Ambretti, S., Ginocchio, F., Cristini, F., Losito, A. R., Tedeschi, S., Cauda, R., & Bassetti, M. (2012b). Predictors of Mortality in Bloodstream Infections Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Importance of Combination Therapy. Clinical Infectious Diseases, 55(7), 943–950. https://doi.org/10.1093/cid/cis588

Turton, J. F., Woodford, N., Glover, J., Yarde, S., Kaufmann, M. E., & Pitt, T. L. (2006). Identification of Acinetobacter baumannii by Detection of the bla OXA-51-like Carbapenemase Gene Intrinsic to This Species. Journal of Clinical Microbiology, 44(8), 2974–2976. https://doi.org/10.1128/jcm.01021-06

Vila, J., Ruiz, J., Goni, P., & De Anta, T. J. (1997). Quinolone-resistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii. Journal of Antimicrobial Chemotherapy, 39(6), 757–762. https://doi.org/10.1093/jac/39.6.757

Weiner, L. M., Webb, A. K., Limbago, B., Dudeck, M. A., Patel, J., Kallen, A. J., Edwards, J. R., & Sievert, D. M. (2016). Antimicrobial-Resistant pathogens associated with Healthcare-Associated infections: Summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infection Control and Hospital Epidemiology, 37(11), 1288–1301. https://doi.org/10.1017/ice.2016.174


View Dimensions


View Plumx


View Altmetric



0
Save
0
Citation
78
View
0
Share

Stay connected