Dissemination of carbapenem and colistin resistance in Gram-negative bacteria: the emerging role of novel β-lactam/β-lactamase inhibitors for managing a global dilemma

Mohamed T. Ateeba, Mohammed A. El-Kholy, Mustafa Alseqely, Eva A. Edward, Mostafa El-Nakeeb

Abstract


Antibiotic resistance places an escalating burden on global health systems. In 2021, an estimated 4.71 million deaths were associated with bacterial antimicrobial resistance, with 1.14 million directly attributable to resistant infections; projections suggest nearly 39 million deaths from antimicrobial-resistant diseases between 2025 and 2050. Of particular concern is the growing prevalence of carbapenem-resistant Gram-negative bacteria, which has eroded the effectiveness of carbapenems, formerly first-line agents for infections caused by extended-spectrum β-lactamase (ESBL) producers. The clinical reintroduction of colistin, which was discontinued giving its severe toxicity, as a last-resort therapy has been undermined by rising colistin resistance, amplified by widespread and unregulated veterinary use and the spread of plasmid-mediated mcr genes. In response, several new β-lactam/β-lactamase inhibitor combinations (meropenem/vaborbactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, cefiderocol) and newer agents (aztreonam/avibactam, sulbactam/durlobactam) offer improved efficacy and safety profiles compared with colistin and other revived antibiotics. However, their impact is constrained by limited availability and high cost in low- and middle-income countries such as Egypt. This review examines epidemiologic trends and the molecular mechanisms of action and resistance of carbapenems and colistin. It also evaluates clinical evidence and the mechanisms underlying last-line and novel β-lactam/β-lactamase-inhibitor agents.

 

Received on, 13 November 2025

Accepted on, 08 December 2025

Published on, 14 December 2025


Keywords


Antibiotic resistance; carbapenem-resistant; Gram-negative bacteria; colistin resistance; β-lactam/β-lactamase inhibitors; Egypt

Full Text:

PDF

References


Gogry FA, Siddiqui MT, Sultan I, Haq QMR. Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria. Vol. 8, Frontiers in Medicine. 2021.

Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 2022;399(10325).

Naghavi M, Vollset SE, Ikuta KS, Swetschinski LR, Gray AP, Wool EE, et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. The Lancet. 2024;404(10459).

Wise MG, Karlowsky JA, Mohamed N, Hermsen ED, Kamat S, Townsend A, et al. Global trends in carbapenem- and difficult-to-treat-resistance among World Health Organization priority bacterial pathogens: ATLAS surveillance program 2018–2022. J Glob Antimicrob Resist. 2024;37.

World Health Organization. Global antibiotic resistance surveillance report 2025: WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS). Geneva; 2025.

Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection. 2012;18(3).

Salam MA, Al-Amin MY, Salam MT, Pawar JS, Akhter N, Rabaan AA, et al. Antimicrobial Resistance: A Growing Serious Threat for Global Public Health. Vol. 11, Healthcare (Switzerland). 2023.

Sakalauskienė GV, Malcienė L, Stankevičius E, Radzevičienė A. Unseen Enemy: Mechanisms of Multidrug Antimicrobial Resistance in Gram-Negative ESKAPE Pathogens. Vol. 14, Antibiotics. 2025.

World Health Organization. WHO Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. Geneva; 2024.

Carcione D, Intra J, Andriani L, Campanile F, Gona F, Carletti S, et al. New Antimicrobials for Gram-Positive Sustained Infections: A Comprehensive Guide for Clinicians. Vol. 16, Pharmaceuticals. 2023.

Krell T, Matilla MA. Antimicrobial resistance: progress and challenges in antibiotic discovery and anti-infective therapy. Microb Biotechnol. 2022;15(1).

Prasad NK, Seiple IB, Cirz RT, Rosenberg OS. Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020. Antimicrob Agents Chemother. 2022;66(5).

Butler MS, Paterson DL. Antibiotics in the clinical pipeline in October 2019. Vol. 73, Journal of Antibiotics. 2020.

Larsson DGJ, Flach CF. Antibiotic resistance in the environment. Vol. 20, Nature Reviews Microbiology. 2022.

Chiu S, Hancock AM, Schofner BW, Sniezek KJ, Soto-Echevarria N, Leon G, et al. Causes of polymyxin treatment failure and new derivatives to fill the gap. Vol. 75, Journal of Antibiotics. 2022.

Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clinical Infectious Diseases. 2024;

Aslan AT, Akova M. The Role of Colistin in the Era of New β-Lactam/β-Lactamase Inhibitor Combinations. Vol. 11, Antibiotics. 2022.

Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority — A WHO Resolution. New England Journal of Medicine. 2017;377(5).

Holland TL, Baddour LM, Bayer AS, Hoen B, Miro JM, Fowler VG. Infective endocarditis. Nat Rev Dis Primers. 2016 Sep 1;2(1):16059.

Kavanagh N, Ryan EJ, Widaa A, Sexton G, Fennell J, O’Rourke S, et al. Staphylococcal osteomyelitis: Disease progression, treatment challenges, and future directions. Vol. 31, Clinical Microbiology Reviews. 2018.

Arefian H, Heublein S, Scherag A, Brunkhorst FM, Younis MZ, Moerer O, et al. Hospital-related cost of sepsis: A systematic review. Vol. 74, Journal of Infection. 2017.

Liang L, Moore B, Soni A. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2017 [Internet]. 2020. Available from: https://hcup-us.ahrq.gov/reports/statbriefs/sb261-Most-Expensive-Hospital-Conditions-2017.pdf

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801.

Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219).

Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3).

Martin GS, Mannino DM, Eaton S, Moss M. The Epidemiology of Sepsis in the United States from 1979 through 2000. New England Journal of Medicine. 2003;348(16).

Hajj J, Blaine N, Salavaci J, Jacoby D. The “Centrality of Sepsis”: A Review on Incidence, Mortality, and Cost of Care. Healthcare. 2018 Jul 30;6(3):90.

Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16).

Kern W V., Rieg S. Burden of bacterial bloodstream infection—a brief update on epidemiology and significance of multidrug-resistant pathogens. Vol. 26, Clinical Microbiology and Infection. 2020.

Alwazzeh MJ, Alnimr A, Al Nassri SA, Alwarthan SM, Alhajri M, AlShehail BM, et al. Microbiological trends and mortality risk factors of central line-associated bloodstream infections in an academic medical center 2015–2020. Antimicrob Resist Infect Control. 2023;12(1).

Chow JW, Yu VL. Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: A commentary. Vol. 11, International Journal of Antimicrobial Agents. 1999.

Zha L, Li S, Guo J, Hu Y, Pan L, Wang H, et al. Global and regional burden of bloodstream infections caused by carbapenem-resistant Gram-negative bacteria in 2019: A systematic analysis from the MICROBE database. International Journal of Infectious Diseases. 2025 Apr;153:107769.

Tabah A, Buetti N, Staiquly Q, Ruckly S, Akova M, Aslan AT, et al. Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study. Intensive Care Med. 2023;49(2).

Kadri SS, Lai YL, Warner S, Strich JR, Babiker A, Ricotta EE, et al. Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals. Lancet Infect Dis. 2021;21(2).

Gücer LS, Pınarlık F, Farzana R, Ataç N, GENÇ Z, Madran B, et al. Antimicrobial Resistance Rates and Treatment Options in Bloodstream Infections: A Prospective Observational Study. J Glob Antimicrob Resist. 2024;39.

Stewardson AJ, Marimuthu K, Sengupta S, Allignol A, El-Bouseary M, Carvalho MJ, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19(6).

Allel K, Stone J, Undurraga EA, Day L, Moore CE, Lin L, et al. The impact of inpatient bloodstream infections caused by antibiotic-resistant bacteria in low- and middle-income countries: A systematic review and meta-analysis. PLoS Med. 2023;20(6 June).

Codjoe FS, Donkor ES. Carbapenem Resistance: A Review. Vol. 6, Medical sciences (Basel, Switzerland). 2017.

Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: Past, present, and future. Vol. 55, Antimicrobial Agents and Chemotherapy. 2011.

Hashizume T, Tamaki S, Matsuhashi M, Ishino F, Nakagawa J ichi. Studies on the mechanism of action of imipenem (N-formimidoylthienamycin) in vitro: Binding to the penicillin-binding proteins (pbps) in escherichia coli and pseudomonas aeruginosa, and inhibition of enzyme activities due to the pbps in e. coli. J Antibiot (Tokyo). 1984;37(4).

Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to enterobacteriaceae producing extended-spectrum β-lactamases: A systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy. 2012;67(12).

Peirano G, Pitout JDD. Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae: Update on Molecular Epidemiology and Treatment Options. Vol. 79, Drugs. 2019.

Castanheira M, Mendes RE, Jones RN, Sader HS. Changes in the frequencies of β-lactamase genes among Enterobacteriaceae isolates in U.S. hospitals, 2012 to 2014: Activity of ceftazidime-avibactam tested against β-lactamase-producing isolates. Antimicrob Agents Chemother. 2016;60(8).

Castanheira M, Simner PJ, Bradford PA. Extended-spectrum β-lactamases: An update on their characteristics, epidemiology and detection. Vol. 3, JAC-Antimicrobial Resistance. 2021.

Maslikowska JA, Walker SAN, Elligsen M, Mittmann N, Palmay L, Daneman N, et al. Impact of infection with extended-spectrum β-lactamase-producing Escherichia coli or Klebsiella species on outcome and hospitalization costs. Journal of Hospital Infection. 2016;92(1).

Tompkins K, van Duin D. Treatment for carbapenem-resistant Enterobacterales infections: recent advances and future directions. Vol. 40, European Journal of Clinical Microbiology and Infectious Diseases. 2021.

Ma J, Song X, Li M, Yu Z, Cheng W, Yu Z, et al. Global spread of carbapenem-resistant Enterobacteriaceae: Epidemiological features, resistance mechanisms, detection and therapy. Vol. 266, Microbiological Research. 2023.

Zhang Y, Wang Q, Yin Y, Chen H, Jin L, Gu B, et al. Epidemiology of carbapenem-resistant enterobacteriaceae infections: Report from the China CRE Network. Antimicrob Agents Chemother. 2018;62(2).

Halat DH, Moubareck CA. The current burden of carbapenemases: Review of significant properties and dissemination among gram-negative bacteria. Vol. 9, Antibiotics. 2020.

Quale J, Bratu S, Gupta J, Landman D. Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2006;50(5).

Smith HZ, Hollingshead CM, Kendall B. Carbapenem-Resistant Enterobacterales. 2025.

Rabaan AA, Eljaaly K, Alhumaid S, Albayat H, Al-Adsani W, Sabour AA, et al. An Overview on Phenotypic and Genotypic Characterisation of Carbapenem-Resistant Enterobacterales. Vol. 58, Medicina (Kaunas, Lithuania). 2022.

Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-β-lactamases: Structure, function, epidemiology, treatment options, and the development pipeline. Antimicrob Agents Chemother. 2020;64(10).

Hirvonen VHA, Spencer J, van der Kamp MW. Antimicrobial Resistance Conferred by OXA-48 β-Lactamases: Towards a Detailed Mechanistic Understanding. Antimicrob Agents Chemother. 2021 May 18;65(6).

Doumith M, Ellington MJ, Livermore DM, Woodford N. Molecular mechanisms disrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK. Journal of Antimicrobial Chemotherapy. 2009;63(4).

Farra A, Islam S, Strålfors A, Sörberg M, Wretlind B. Role of outer membrane protein OprD and penicillin-binding proteins in resistance of Pseudomonas aeruginosa to imipenem and meropenem. Int J Antimicrob Agents. 2008;31(5).

García-Fernández A, Miriagou V, Papagiannitsis CC, Giordano A, Venditti M, Mancini C, et al. An ertapenem-resistant extended-spectrum-β-lactamase-producing Klebsiella pneumoniae clone carries a novel OmpK36 porin variant. Antimicrob Agents Chemother. 2010;54(10).

Lomovskaya O, Zgurskaya HI, Totrov M, Watkins WJ. Waltzing transporters and “the dance macabre” between humans and bacteria. Vol. 6, Nature Reviews Drug Discovery. 2007.

King DT, Sobhanifar S, Strynadka NCJ. The Mechanisms of Resistance to β-Lactam Antibiotics. In: Handbook of Antimicrobial Resistance. New York, NY: Springer New York; 2017. p. 177–201.

Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Vol. 3, Therapeutic Advances in Infectious Disease. 2016.

Zhang Y, Li Z, He X, Ding F, Wu W, Luo Y, et al. Overproduction of efflux pumps caused reduced susceptibility to carbapenem under consecutive imipenem-selected stress in acinetobacter baumannii. Infect Drug Resist. 2018;11.

Miyachiro MM, Contreras-Martel C, Dessen A. Penicillin-Binding Proteins (PBPs) and Bacterial Cell Wall Elongation Complexes. In 2019. p. 273–89.

Ranjitkar S, Reck F, Ke X, Zhu Q, McEnroe G, Lopez SL, et al. Identification of Mutations in the mrdA Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of Escherichia coli Clinical Isolates with Mutations in ftsI (PBP3) and Which Carry bla NDM-1 . mSphere. 2019;4(4).

Lange F, Pfennigwerth N, Höfken LM, Gatermann SG, Kaase M. Characterization of mutations in Escherichia coli PBP2 leading to increased carbapenem MICs. Journal of Antimicrobial Chemotherapy. 2019;74(3).

Fang R, Liu H, Zhang X, Dong G, Li J, Tian X, et al. Difference in biofilm formation between carbapenem-resistant and carbapenem-sensitive Klebsiella pneumoniae based on analysis of mrkH distribution. Microb Pathog. 2021;152.

Wang G, Zhao G, Chao X, Xie L, Wang H. The characteristic of virulence, biofilm and antibiotic resistance of klebsiella pneumoniae. Vol. 17, International Journal of Environmental Research and Public Health. 2020.

Sharma D, Garg A, Kumar M, Rashid F, Khan AU. Down-Regulation of Flagellar, Fimbriae, and Pili Proteins in Carbapenem-Resistant Klebsiella pneumoniae (NDM-4) Clinical Isolates: A Novel Linkage to Drug Resistance. Front Microbiol. 2019;10.

Cusumano JA, Caffrey AR, Daffinee KE, Luther MK, Lopes V, LaPlante KL. Weak biofilm formation among carbapenem-resistant Klebsiella pneumoniae. Diagn Microbiol Infect Dis. 2019;95(4).

Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Vol. 40, Clinical Infectious Diseases. 2005.

Storm DR, Rosenthal KS, Swanson PE. Polymyxin and related peptide antibiotics. Vol. Vol. 46, Annual Review of Biochemistry. 1977.

Baron S, Hadjadj L, Rolain JM, Olaitan AO. Molecular mechanisms of polymyxin resistance: knowns and unknowns. Int J Antimicrob Agents. 2016;48(6).

El-Sayed Ahmed MAEG, Zhong LL, Shen C, Yang Y, Doi Y, Tian GB. Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019). Vol. 9, Emerging Microbes and Infections. 2020.

Kempf I, Jouy E, Chauvin C. Colistin use and colistin resistance in bacteria from animals. Int J Antimicrob Agents. 2016;48(6).

Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2).

Azzam A, Salem H, Nazih M, Lotfy EM, Hassan FE, Khaled H. Prevalence, trends, and molecular insights into colistin resistance among gram-negative bacteria in Egypt: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob. 2025;24(1).

Umair M, Hassan B, Farzana R, Ali Q, Sands K, Mathias J, et al. International manufacturing and trade in colistin, its implications in colistin resistance and One Health global policies: a microbiological, economic, and anthropological study. Lancet Microbe. 2023;4(4).

Miranda C, Igrejas G, Capita R, Alonso-Calleja C, Poeta P. Worldwide Colistin Use and Spread of Resistant- Enterobacteriaceae in Animal Production . In: The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions. 2022.

Kempf I, Fleury MA, Drider D, Bruneau M, Sanders P, Chauvin C, et al. What do we know about resistance to colistin in Enterobacteriaceae in avian and pig production in Europe? Vol. 42, International Journal of Antimicrobial Agents. 2013.

Catry B, Cavaleri M, Baptiste K, Grave K, Grein K, Holm A, et al. Use of colistin-containing products within the European Union and European Economic Area (EU/EEA): development of resistance in animals and possible impact on human and animal health. Vol. 46, International Journal of Antimicrobial Agents. 2015.

Nang SC, Li J, Velkov T. The rise and spread of mcr plasmid-mediated polymyxin resistance. Vol. 45, Critical Reviews in Microbiology. 2019.

Thomson KM, Dyer C, Liu F, Sands K, Portal E, Carvalho MJ, et al. Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS). Lancet Infect Dis. 2021;21(12).

World Health Organization. WHO’s list of medically important antimicrobials: a risk management tool for mitigating antimicrobial resistance due to non-human use. . Geneva; 2024.

Garcia JF, Diez MJ, Sahagun AM, Diez R, Sierra M, Garcia JJ, et al. The online sale of antibiotics for veterinary use. Animals. 2020;10(3).

Sabnis A, Edwards AM. Lipopolysaccharide as an antibiotic target. Biochim Biophys Acta Mol Cell Res. 2023;1870(7).

Yu Z, Qin W, Lin J, Fang S, Qiu J. Antibacterial mechanisms of polymyxin and bacterial resistance. Vol. 2015, BioMed Research International. 2015.

Velkov T, Thompson PE, Nation RL, Li J. Structure-activity relationships of polymyxin antibiotics. Vol. 53, Journal of Medicinal Chemistry. 2010.

Cajal Y, Rogers J, Berg OG, Jain MK. Intermembrane molecular contacts by polymyxin B mediate exchange of phospholipids. Biochemistry. 1996;35(1).

Sampson TR, Liu X, Schroeder MR, Kraft CS, Burd EM, Weiss DS. Rapid killing of Acinetobacter baumannii by polymyxins is mediated by a hydroxyl radical death pathway. Antimicrob Agents Chemother. 2012;56(11).

Deris ZZ, Akter J, Sivanesan S, Roberts KD, Thompson PE, Nation RL, et al. A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity. Journal of Antibiotics. 2014;67(2).

Matsushita K, Ohnishi T, Kaback HR. NADH-Ubiquinone Oxidoreductases of the Escherichia coli Aerobic Respiratory Chain. Biochemistry. 1987;26(24).

Yu Z, Zhu Y, Fu J, Qiu J, Yin J. Enhanced NADH metabolism involves colistin-induced killing of bacillus subtilis and paenibacillus polymyxa. Molecules. 2019;24(3).

Aquilini E, Merino S, Knirel YA, Regué M, Tomás JM. Functional identification of Proteus mirabilis eptC gene encoding a core lipopolysaccharide phosphoethanolamine transferase. Int J Mol Sci. 2014;15(4).

Boll M, Radziejewska-Lebrecht J, Warth C, Krajewska-Pietrasik D, Mayer H. 4-Amino-4-deoxy-L-arabinose in LPS of enterobacterial R-mutants and its possible role for their polymyxin reactivity. FEMS Immunol Med Microbiol. 1994;8(4).

SIDORCZYK Z, ZÄHRINGER U, RIETSCHEL ET. Chemical structure of the lipid A component of the lipopolysaccharide from a Proteus mirabilis Re‐mutant. Eur J Biochem. 1983;137(1–2).

Poirel L, Jayol A, Nordmanna P. Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Vol. 30, Clinical Microbiology Reviews. 2017.

Gunn JS. The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Vol. 16, Trends in Microbiology. 2008.

Yan A, Guan Z, Raetz CRH. An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli. Journal of Biological Chemistry. 2007;282(49).

Yusof NY, Norazzman NII, Hakim SNWA, Azlan MM, Anthony AA, Mustafa FH, et al. Prevalence of Mutated Colistin-Resistant Klebsiella pneumoniae: A Systematic Review and Meta-Analysis. Vol. 7, Tropical Medicine and Infectious Disease. 2022.

Jayol A, Poirel L, Brink A, Villegas MV, Yilmaz M, Nordmann P. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin. Antimicrob Agents Chemother. 2014;58(8).

Petrou VI, Herrera CM, Schultz KM, Clarke OB, Vendome J, Tomasek D, et al. Structural biology: Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation. Science (1979). 2016;351(6273).

McConville TH, Annavajhala MK, Giddins MJ, Macesic N, Herrera CM, Rozenberg FD, et al. CrrB Positively Regulates High-Level Polymyxin Resistance and Virulence in Klebsiella pneumoniae. Cell Rep. 2020;33(4).

Groisman EA. The pleiotropic two-component regulatory system PhoP-PhoQ. Vol. 183, Journal of Bacteriology. 2001.

Park SY, Groisman EA. Signal-specific temporal response by the SalmonellaPhoP/PhoQ regulatory system. Mol Microbiol. 2014;91(1).

Mmatli M, Mbelle NM, Maningi NE, Osei Sekyere J. Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae : a Systematic Review of Current Reports . mSystems. 2020;5(6).

Tiwari V, Panta PR, Billiot CE, Douglass M V., Herrera CM, Trent MS, et al. A Klebsiella pneumoniae DedA family membrane protein is required for colistin resistance and for virulence in wax moth larvae. Sci Rep. 2021;11(1).

Todor H, Herrera N, Gross CA. Three Bacterial DedA Subfamilies with Distinct Functions and Phylogenetic Distribution. mBio. 2023;14(2).

Huang L, Feng Y, Zong Z. Heterogeneous resistance to colistin in Enterobacter cloacae complex due to a new small transmembrane protein. Journal of Antimicrobial Chemotherapy. 2019;74(9).

Nirwan PK, Chatterjee N, Panwar R, Dudeja M, Jaggi N. Mutations in two component system (PhoPQ and PmrAB) in colistin resistant Klebsiella pneumoniae from North Indian tertiary care hospital. Journal of Antibiotics. 2021;74(7).

Miyashiro T, Goulian M. Stimulus-dependent differential regulation in the Escherichia coli PhoQ-PhoP system. Proc Natl Acad Sci U S A. 2007;104(41).

Lippa AM, Goulian M. Feedback inhibition in the PhoQ/PhoP signaling system by a membrane peptide. PLoS Genet. 2009;5(12).

Cheng YH, Lin TL, Pan YJ, Wang YP, Lin YT, Wang JT. Colistin resistance mechanisms in Klebsiella pneumoniae strains from Taiwan. Antimicrob Agents Chemother. 2015;59(5).

Zowawi HM, Forde BM, Alfaresi M, Alzarouni A, Farahat Y, Chong TM, et al. Stepwise evolution of pandrug-resistance in Klebsiella pneumoniae. Sci Rep. 2015;5.

Jayol A, Nordmann P, Desroches M, Decousser JW, Poirel L. Acquisition of broad-spectrum cephalosporin resistance leading to colistin resistance in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60(5).

Cheng YH, Lin TL, Lin YT, Wang JT. Amino acid substitutions of crrb responsible for resistance to colistin through crrc in klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60(6).

Kim SJ, Shin JH, Kim H, Ko KS. Roles of crrAB two-component regulatory system in Klebsiella pneumoniae: growth yield, survival in initial colistin treatment stage, and virulence. Int J Antimicrob Agents. 2024;63(1).

De Majumdar S, Yu J, Fookes M, McAteer SP, Llobet E, Finn S, et al. Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation. PLoS Pathog. 2015;11(1).

Schurek KN, Sampaio JLM, Kiffer CRV, Sinto S, Mendes CMF, Hancock REW. Involvement of pmrAB and phoPQ in polymyxin B adaptation and inducible resistance in non-cystic fibrosis clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009;53(10).

Muller C, Plésiat P, Jeannot K. A two-component regulatory system interconnects resistance to polymyxins, aminoglycosides, fluoroquinolones, and β-lactams in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2011;55(3).

Gutu AD, Sgambati N, Strasbourger P, Brannon MK, Jacobs MA, Haugen E, et al. Polymyxin resistance of Pseudomonas aeruginosa phoQ mutants is dependent on additional two-component regulatory systems. Antimicrob Agents Chemother. 2013;57(5).

Gogry FA, Siddiqui MT, Haq QMR. Emergence of mcr-1 conferred colistin resistance among bacterial isolates from urban sewage water in India. Environmental Science and Pollution Research. 2019;26(32).

Doumith M, Godbole G, Ashton P, Larkin L, Dallman T, Day M, et al. Detection of the plasmid-mediated mcr-1 gene conferring colistin resistance in human and food isolates of Salmonella enterica and Escherichia coli in England and Wales. Journal of Antimicrobial Chemotherapy. 2016;71(8).

Xavier BB, Lammens C, Ruhal R, Kumar-Singh S, Butaye P, Goossens H, et al. Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Eurosurveillance. 2016 Jul 7;21(27).

Wang X, Wang Y, Zhou Y, Li J, Yin W, Wang S, et al. Emergence of a novel mobile colistin resistance gene, mcr-8, in NDM-producing Klebsiella pneumoniae article. Emerg Microbes Infect. 2018;7(1).

Yang YQ, Li YX, Lei CW, Zhang AY, Wang HN. Novel plasmid-mediated colistin resistance gene mcr-7.1 in Klebsiella pneumoniae. Journal of Antimicrobial Chemotherapy. 2018;73(7).

AbuOun M, Stubberfield EJ, Duggett NA, Kirchner M, Dormer L, Nunez-Garcia J, et al. Erratum: mcr-1 and mcr-2 (mcr-6.1) variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015 (Journal of Antimicrobial Chemotherapy (2017) 72 (2745-2749) DOI: 10.1093/jac/dkx286). Vol. 73, Journal of Antimicrobial Chemotherapy. 2018.

Carroll LM, Gaballa A, Guldimann C, Sullivan G, Henderson LO, Wiedmann M. Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible salmonella enterica serotype typhimurium isolate. mBio. 2019;10(3).

Wang C, Feng Y, Liu L, Wei L, Kang M, Zong Z. Identification of novel mobile colistin resistance gene mcr-10. Emerg Microbes Infect. 2020;9(1).

Hussein NH, AL-Kadmy IMS, Taha BM, Hussein JD. Mobilized colistin resistance (mcr) genes from 1 to 10: a comprehensive review. Vol. 48, Molecular Biology Reports. 2021.

Bastidas-Caldes C, de Waard JH, Salgado MS, Villacís MJ, Coral-Almeida M, Yamamoto Y, et al. Worldwide Prevalence of mcr-mediated Colistin-Resistance Escherichia coli in Isolates of Clinical Samples, Healthy Humans, and Livestock—A Systematic Review and Meta-Analysis. Vol. 11, Pathogens. 2022.

Elbediwi M, Li Y, Paudyal N, Pan H, Li X, Xie S, et al. Global burden of colistin-resistant bacteria: Mobilized colistin resistance genes study (1980–2018). Microorganisms. 2019;7(10).

Javed H, Saleem S, Zafar A, Ghafoor A, Shahzad A Bin, Ejaz H, et al. Emergence of plasmid-mediated mcr genes from Gram-negative bacteria at the human-animal interface. Gut Pathog. 2020;12(1).

Karaiskos I, Galani I, Souli M, Giamarellou H. Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens. Expert Opin Drug Metab Toxicol. 2019;15(2).

Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The “Old” and the “New” antibiotics for MDR Gram-negative pathogens: For whom, when, and how. Vol. 7, Frontiers in Public Health. 2019.

Sargianou M, Stathopoulos P, Vrysis C, Tzvetanova ID, Falagas ME. New β-Lactam/β-Lactamase Inhibitor Combination Antibiotics. Pathogens. 2025 Mar 24;14(4):307.

Egyptian Drug Authority. The Eighth list. Egyptian Drug Authority. Cairo, Egypt; 2025.

Coppola N, Maraolo AE, Onorato L, Scotto R, Calò F, Atripaldi L, et al. Epidemiology, Mechanisms of Resistance and Treatment Algorithm for Infections Due to Carbapenem-Resistant Gram-Negative Bacteria: An Expert Panel Opinion. Vol. 11, Antibiotics. 2022.

Yahav D, Giske CG, Grāmatniece A, Abodakpi H, Tam VH, Leibovici L. New β-Lactam–β-Lactamase Inhibitor Combinations. Clin Microbiol Rev. 2020 Dec 16;34(1).

Bassetti M, Giacobbe DR, Vena A, Poulakou G, Rossolini GM, Soriano A, et al. Meropenem–Vaborbactam for Treatment of Carbapenem-Resistant Enterobacterales: A Narrative Review of Clinical Practice Evidence. Vol. 14, Infectious Diseases and Therapy. 2025.

Karaiskos I, Galani I, Daikos GL, Giamarellou H. Breaking Through Resistance: A Comparative Review of New Beta-Lactamase Inhibitors (Avibactam, Vaborbactam, Relebactam) Against Multidrug-Resistant Superbugs. Vol. 14, Antibiotics. 2025.

Falcone M, Giordano C, Leonildi A, Galfo V, Lepore A, Suardi LR, et al. Clinical Features and Outcomes of Infections Caused by Metallo-β-Lactamase-Producing Enterobacterales: A 3-Year Prospective Study from an Endemic Area. Clinical Infectious Diseases. 2024;78(5).

McCreary EK, Heil EL, Tamma PD. New perspectives on antimicrobial agents: Cefiderocol. Vol. 65, Antimicrobial Agents and Chemotherapy. 2021.

Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother. 2018;62(1).

Ong’Uti S, Czech M, Robilotti E, Holubar M. Cefiderocol: A New Cephalosporin Stratagem Against Multidrug-Resistant Gram-Negative Bacteria. Vol. 74, Clinical Infectious Diseases. 2022.

Sato T, Yamawaki K. Cefiderocol: Discovery, Chemistry, and in Vivo Profiles of a Novel Siderophore Cephalosporin. Clinical Infectious Diseases. 2019;69.

Abdul-Mutakabbir JC, Alosaimy S, Morrisette T, Kebriaei R, Rybak MJ. Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug-Resistant Gram-Negative Pathogens. Vol. 40, Pharmacotherapy. 2020.

Grabein B, Arhin FF, Daikos GL, Moore LSP, Balaji V, Baillon-Plot N. Navigating the Current Treatment Landscape of Metallo-β-Lactamase-Producing Gram-Negative Infections: What are the Limitations? Vol. 13, Infectious Diseases and Therapy. 2024.

Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, et al. Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9).

Pasteran F, Cedano J, Baez M, Albornoz E, Rapoport M, Osteria J, et al. A new twist: The combination of sulbactam/avibactam enhances sulbactam activity against carbapenem-resistant acinetobacter baumannii (crab) isolates. Antibiotics. 2021;10(5).




DOI: https://dx.doi.org/10.21622/AMPDR.2025.05.2.1790

Refbacks

  • There are currently no refbacks.


Copyright (c) 2025 Mohamed Ateeba, Mohammed El-Kholy, Mustafa Alseqely, Eva Edward, Mostafa El-Nakeeb

Advances in Medical, Pharmaceutical and Dental Research

E-ISSN: 2812-4898

P-ISSN: 2812-488X

 

Published by:

Academy Publishing Center (APC)

Arab Academy for Science, Technology and Maritime Transport (AASTMT)

Alexandria, Egypt

ampdr@aast.edu