Multi-Pathogen Aminoglycoside Resistance: A Dual Approach in Investigating Bacteria Across Various Clinical Infections
DOI:
https://doi.org/10.31580/pjmls.v7i3.3147Keywords:
Aminoglycoside resistance, multi-pathogen, E. coli, K. pneumoniae, P. aeruginosa, clinical infections, resistance mechanisms, combination therapy.Abstract
Aminoglycosides are vital antibiotics for treating severe Gram-negative bacterial infections, but the evolution of resistance mechanisms creates huge treatment hurdles. This work reviews resistance mechanisms to aminoglycosides such as AMEs, efflux pumps, ribosomal mutations and enzymatic modifications across several pathogens: It also examines the clinical significance of the resistance in different contexts of infection. A contextual and comparative case study investigated genetic and phenotypic resistance to aminoglycosides. A systematic review using PRISMA standards examined clinical trials published between 2010 and 2023 on PubMed and ClinicalTrials.gov. Inclusion criteria for 100 papers on aminoglycoside-resistant Gram-negative infections (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were studies that described mechanisms of aminoglycoside resistance as well as clinical outcomes. Exclusion criteria eliminated research that lacked significant data on pathogen resistance. I2 statistical method used a meta-analytic approach. Finally, 40 articles were reviewed for resistance mechanisms and cross-resistance to other antibiotics. 12 studies were included in the table. AMEs were the most prevalent mechanism of resistance, especially in E. coli and K. pneumoniae. AMEs were also implicated in treatment failures and post-therapy relapses. Among the antibiotics tested, aminoglycoside concentrations were significantly lower in K. pneumoniae and P. aeruginosa, and this decrease was associated with efflux pump overexpression in both bacteria, providing cross-resistance with β-lactams and fluoroquinolones. Hence these mutations are associated with extended hospital stays and poor outcomes in patients. Substantial cross-resistance rates add to the complexity of management interventions. Resistance of multiple pathogenic organisms to the aminoglycoside class of antibiotics remains a major obstacle in clinical infection practice. These results highlight the importance of regular genotypic surveillance of resistance patterns and the necessity of discovering specific drugs for mechanisms such as AME inhibitors or efflux pump inhibitors. Precise treatment protocols drawn from pathogen-specific resistance mechanisms could enhance clinical efficacy while reducing the transmission of MDR pathogens.
References
Lang M, Carvalho A, Baharoglu Z, Mazel D. Aminoglycoside uptake, stress, and potentiation in Gram-negative bacteria: new therapies with old molecules. Microbiology and Molecular Biology Reviews. 2023;87(4):e00036-22.
Saleh NM, Saad SI, El-Sayed M, El-Sayyad GS, Safe FA. Contribution of different mechanisms to aminoglycoside resistance in clinical isolates of Acinetobacter baumannii. Microbial Pathogenesis. 2023;182:106255.
Thy M, Timsit JF, de Montmollin E. Aminoglycosides for the treatment of severe infection due to resistant gram-negative pathogens. Antibiotics. 2023;12(5):860.
Clark JA, Burgess DS. Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance. Therapeutic advances in infectious disease. 2020 :2049936120952604.
Padma K. Overuse and misuse of antibiotics. Journal of Biomedical and Pharmaceutical Research. 2022;11(1).
Wang N, Luo J, Deng F, Huang Y, Zhou H. Antibiotic combination therapy: a strategy to overcome bacterial resistance to aminoglycoside antibiotics. Frontiers in Pharmacology. 2022;13:839808.
Ahmadian L, Norouzi Bazgir Z, Ahanjan M, Valadan R, Goli HR. Role of Aminoglycoside‐Modifying Enzymes (AMEs) in Resistance to Aminoglycosides among Clinical Isolates of P. aeruginosa in the North of Iran. BioMed Research International. 2021;2021(1):7077344.
Wachino JI, Doi Y, Arakawa Y. Aminoglycoside resistance: updates with a focus on acquired 16S ribosomal RNA methyltransferases. Infectious Disease Clinics. 2020 ;34(4):887-902.
Alonso A, Campanario E, Martı́nez JL. Emergence of multidrug-resistant mutants is increased under antibiotic selective pressure in P. aeruginosa. Microbiology. 1999 ;145(10):2857-62.
Impey RE, Hawkins DA, Sutton JM, Soares da Costa TP. Overcoming intrinsic and acquired resistance mechanisms associated with the cell wall of gram-negative bacteria. Antibiotics. 2020 ;9(9):623.
Lomovskaya O, Nelson K, Rubio-Aparicio D, Tsivkovski R, Sun D, Dudley MN. Impact of intrinsic resistance mechanisms on potency of QPX7728, a new ultrabroad-spectrum beta-lactamase inhibitor of serine and metallo-beta-lactamases in Enterobacteriaceae, P. aeruginosa, and Acinetobacter baumannii. Antimicrobial agents and chemotherapy. 2020;64(6):10-128.
Lorusso AB, Carrara JA, Barroso CD, Tuon FF, Faoro H. Role of efflux pumps on antimicrobial resistance in P. aeruginosa. International journal of molecular sciences. 2022;23(24):15779.
Singh NS, Singhal N, Kumar M, Virdi JS. Public health implications of plasmid-mediated quinolone and aminoglycoside resistance genes in E. coli inhabiting a major anthropogenic river of India. Epidemiology & Infection. 2022;150:e78.
.Plattner M, Goyet C, Haldimann K, Gysin M, Juhas M, Becker K, Hobbie SN. Genotypic and phenotypic analyses of aac (3) aminoglycoside-resistance gene diversity point to three distinct phenotypes of contemporary clinical relevance. Journal of Global Antimicrobial Resistance. 2022 ;29:534-6.
Maeda T, Furusawa C. Laboratory Evolution of Antimicrobial Resistance in Bacteria to Develop Rational Treatment Strategies. Antibiotics. 2024 ;13(1):94.
Alneama RT, Al-Massody AJ, Mahmud BM, Ghasemian A. The existence and expression of aminoglycoside resistance genes among multidrug-resistant E. coli isolates in intensive care unit centers. Gene Reports. 2021;25:101315.
Zhang X, Li Q, Lin H, Zhou W, Qian C, Sun Z, Lin L, Liu H, Lu J, Lin X, Li K. High-level aminoglycoside resistance in human clinical K. pneumoniae complex isolates and characteristics of armA-carrying IncHI5 plasmids. Frontiers in Microbiology. 2021;12:636396.
Saeli N, Jafari-Ramedani S, Ramazanzadeh R, Nazari M, Sahebkar A, Khademi F. Prevalence and mechanisms of aminoglycoside resistance among drug-resistant P. aeruginosa clinical isolates in Iran. BMC Infectious Diseases. 2024;24(1):680.
Foudraine DE, Strepis N, Stingl C, Ten Kate MT, Verbon A, Klaassen CH, Goessens WH, Luider TM, Dekker LJ. Exploring antimicrobial resistance to beta-lactams, aminoglycosides and fluoroquinolones in E. coli and K. pneumoniae using proteogenomics. Scientific reports. 2021;11(1):12472.
Harbaoui S, Ferjani S, Abbassi MS, Guzmán-Puche J, Causse M, Elías-López C, Martínez-Martínez L, Boubaker IB. Genetic background of aminoglycoside-modifying enzymes in various genetic lineages of clinical aminoglycosides-resistant E. coli and K. pneumoniae isolates in Tunisia. Journal of Applied Microbiology. 2024;135(7):lxae164.
Saeli N, Jafari-Ramedani S, Ramazanzadeh R, Nazari M, Sahebkar A, Khademi F. Prevalence and mechanisms of aminoglycoside resistance among drug-resistant P. aeruginosa clinical isolates in Iran. BMC Infectious Diseases. 2024 ;24(1):680.
Thacharodi A, Lamont IL. Aminoglycoside-modifying enzymes are sufficient to make P. aeruginosa clinically resistant to key antibiotics. Antibiotics. 2022;11(7):884.
Foudraine DE, Strepis N, Stingl C, Ten Kate MT, Verbon A, Klaassen CH, Goessens WH, Luider TM, Dekker LJ. Exploring antimicrobial resistance to beta-lactams, aminoglycosides and fluoroquinolones in E. coli and K. pneumoniae using proteogenomics. Scientific reports. 2021;11(1):12472.
Auda IG, Salman IM, Odah JG. Efflux pumps of Gram-negative bacteria in brief. Gene Reports. 2020;20:100666.
Ni RT, Onishi M, Mizusawa M, Kitagawa R, Kishino T, Matsubara F, Tsuchiya T, Kuroda T, Ogawa W. The role of RND-type efflux pumps in multidrug-resistant mutants of K. pneumoniae. Scientific reports. 2020;10(1):10876.
Huang Y, Rana AP, Wenzler E, Ozer EA, Krapp F, Bulitta JB, Hauser AR, Bulman ZP. Aminoglycoside-resistance gene signatures are predictive of aminoglycoside MICs for carbapenem-resistant K. pneumoniae. Journal of Antimicrobial Chemotherapy. 2022 ;77(2):356-63.
Atassi G, Medernach R, Scheetz M, Nozick S, Rhodes NJ, Murphy-Belcaster M, Murphy KR, Alisoltani A, Ozer EA, Hauser AR. Genomics of aminoglycoside resistance in P. aeruginosa bloodstream infections at a United States Academic Hospital. Microbiology Spectrum. 2023;11(3):e05087-22.
Zhang Y, Zhang N, Wang M, Luo M, Peng Y, Li Z, Xu J, Ou M, Kan B, Li X, Lu X. The prevalence and distribution of aminoglycoside resistance genes. Biosafety and Health. 2023;5(01):14-20.
Denissen J, Reyneke B, Waso-Reyneke M, Havenga B, Barnard T, Khan S, Khan W. Prevalence of ESKAPE pathogens in the environment: Antibiotic resistance status, community-acquired infection and risk to human health. International journal of hygiene and environmental health. 2022;244:114006.
Lorusso AB, Carrara JA, Barroso CD, Tuon FF, Faoro H. Role of efflux pumps on antimicrobial resistance in P. aeruginosa. International journal of molecular sciences. 2022;23(24):15779.
Costa BO, Cardoso MH, Franco OL. Development of peptides that inhibit aminoglycoside-modifying enzymes and β-lactamases for control of resistant bacteria. Current Protein and Peptide Science. 2020;21(10):1011-26.
Alekseeva MG, Zakharevich NV, Ratkin AV, Danilenko VN. Human Intestinal Microbiome—A Reservoir of Aminoglycoside-N-Acetyltransferases—Drug Resistance Genes. Russian Journal of Genetics. 2022 ;58(9):1072-8.
Butler DA, Rana AP, Krapp F, Patel SR, Huang Y, Ozer EA, Hauser AR, Bulman ZP. Optimizing aminoglycoside selection for KPC-producing K. pneumoniae with the aminoglycoside-modifying enzyme (AME) gene aac (6’)-Ib. Journal of Antimicrobial Chemotherapy. 2021;76(3):671-9.
Jouybari MA, Ahanjan M, Mirzaei B, Goli HR. Role of aminoglycoside-modifying enzymes and 16S rRNA methylase (ArmA) in resistance of Acinetobacter baumannii clinical isolates against aminoglycosides. Revista da Sociedade Brasileira de Medicina Tropical. 2021;54:e05992020.
Nishino K, Yamasaki S, Nakashima R, Zwama M, Hayashi-Nishino M. Function and inhibitory mechanisms of multidrug efflux pumps. Frontiers in Microbiology. 2021;12:737288.
Ebbensgaard AE, Løbner-Olesen A, Frimodt-Møller J. The role of efflux pumps in the transition from low-level to clinical antibiotic resistance. Antibiotics. 2020;9(12):855.
Kakoullis L, Papachristodoulou E, Chra P, Panos G. Mechanisms of antibiotic resistance in important gram-positive and gram-negative pathogens and novel antibiotic solutions. Antibiotics. 2021;10(4):415.
Banerjee S, Lo K, Ojkic N, Stephens R, Scherer NF, Dinner AR. Mechanical feedback promotes bacterial adaptation to antibiotics. Nature Physics. 2021;17(3):403-9.
Galarion LH, Mohamad M, Alzeyadi Z, Randall CP, O’Neill AJ. A platform for detecting cross-resistance in antibacterial drug discovery. Journal of Antimicrobial Chemotherapy. 2021;76(6):1467-71.
Teng J, Imani S, Zhou A, Zhao Y, Du L, Deng S, Li J, Wang Q. Combatting resistance: understanding multi-drug resistant pathogens in intensive care units. Biomedicine & Pharmacotherapy. 2023;167:115564.
Tevyashova AN, Shapovalova KS. Potential for the development of a new generation of aminoglycoside antibiotics. Pharmaceutical Chemistry Journal. 2021;55(9):860-75.
Siqueira MM, Freire PD, Cruz BG, de Freitas TS, Bandeira PN, Dos Santos HS, Nogueira CE, Teixeira AM, Pereira RL, da Cunha Xavier J, Campina FF. Aminophenyl chalcones potentiating antibiotic activity and inhibiting bacterial efflux pump. European Journal of Pharmaceutical Sciences. 2021;158:105695.
Wang N, Luo J, Deng F, Huang Y, Zhou H. Antibiotic combination therapy: a strategy to overcome bacterial resistance to aminoglycoside antibiotics. Frontiers in Pharmacology. 2022;13:839808.
Imran M, Ahmad MN, Dasgupta A, Rana P, Srinivas N, Chopra S. Novel approaches for the treatment of infections due to multidrug-resistant bacterial pathogens. Future Medicinal Chemistry. 2022;14(15):1133-48.
Hitchcock NM, Devequi Gomes Nunes D, Shiach J, Valeria Saraiva Hodel K, Dantas Viana Barbosa J, Alencar Pereira Rodrigues L, Coler BS, Botelho Pereira Soares M, Badaró R. Current clinical landscape and global potential of bacteriophage therapy. Viruses. 2023;15(4):1020.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Pak-Euro Journal of Medical and Life Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
