Research code: 0
Ethics code: 0
Clinical trials code: 0
Milad Kashi 
, Yasaman Hariri , Seyede Vania Amiri , Atefeh Mosayebi Dashtaki , Yasaman Shariati , Aref Shariati *
, Yasaman Hariri , Seyede Vania Amiri , Atefeh Mosayebi Dashtaki , Yasaman Shariati , Aref Shariati *
, arefshariati0111@gmail.com
Abstract: (24 Views)
Antibiotic resistance has emerged as one of the major global health challenges of the 21st century, resulting in increased morbidity and mortality (1). The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have recognized antimicrobial resistance as a significant threat to public health (2, 3). In particular, multidrug-resistant (MDR) Gram-negative bacteria play a crucial role in nosocomial infections. This study focuses on investigating new antibiotics and drug combinations that are effective against MDR Gram-negative bacteria. The aim of this research is to provide comprehensive insights into novel drugs and β-lactamase inhibitory compounds in the fight against antibiotic resistance, ultimately helping to improve therapeutic strategies.
The present review indicates that new antibiotics, including ticarcillin/clavulanate, cefepime/zidebactam, cefepime/taniborbactam, ceftazidime/avibactam, imipenem/relebactam, cefiderocol, ceftolozane/tazobactam, meropenem/vaborbactam, and aztreonam/avibactam, represent promising options for the treatment of infections caused by carbapenem-resistant and MDR Gram-negative bacteria. However, a major challenge in the clinical application of these antibiotics is the rapid emergence of resistance against them.
Mechanisms of resistance in Gram-negative bacteria include reduced drug penetration, modification of the drug target, drug inactivation, and drug efflux through efflux pumps (7). Each of these antibiotics demonstrated varying degrees of effectiveness against drug-resistant bacteria. The results for each compound are summarized as follows:
Cefepime/zidebactam is a combination of a fourth-generation cephalosporin and a β-lactamase inhibitor that targets a broad spectrum of resistant bacteria, particularly carbapenem-resistant Enterobacteriaceae and MDR/extensively drug-resistant (XDR) P. aeruginosa (18, 19). In addition to inhibiting β-lactamases, zidebactam enhances bactericidal effect by binding to penicillin-binding protein 2 (PBP2), while cefepime inhibits PBP3, distinguishing this combination from other β-lactamase inhibitors (22). Resistance to this compound seems to arise from multiple mutations in the genes encoding the MexAB-OprM efflux pump and its regulators, as well as in PBP2 and PBP3 (43, 44).
Taniborbactam, a boronic acid β-lactamase inhibitor, has been studied in combination with cefepime against carbapenem-resistant bacteria (46). This combination is effective against class A, C, and D β-lactamases, as well as some class B metallo-β-lactamases (47, 48). In vitro studies have demonstrated that cefepime-taniborbactam exhibits a broad spectrum of antibacterial activity and is effective against strains resistant to other β-lactamase inhibitors (49). Alterations in electrostatic charges within the active-site loops of metallo-β-lactamases, due to single amino acid substitutions, can reduce the binding affinity of taniborbactam (62).
Ceftolozane-tazobactam is an anti-pseudomonal cephalosporin approved for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infection (cIAI) (63). This combination is effective against carbapenem-resistant P. aeruginosa and some Enterobacteriaceae, but it has limited activity against Acinetobacter baumannii and some other Enterobacteriaceae (66, 67). Resistance to this combination is typically associated with increased AmpC expression, mutations in PBP3, and enhanced efflux pump activity (79). Ceftolozane-tazobactam may show reduced efficacy against isolates harboring co-produced class A and D β-lactamases, carbapenemases, and metallo-β-lactamases (87, 88).
Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a β-lactamase inhibitor that is effective against carbapenem-resistant bacteria and P. aeruginosa. While ceftazidime-avibactam has demonstrated efficacy in treating bloodstream infections caused by carbapenem-resistant Enterobacteriaceae, its clinical outcomes may differ in cases of pneumonia or deep-seated infections. This variability is likely attributable to differences in drug penetration and bacterial burden at the infection site (98). Resistance to ceftazidime-avibactam in Enterobacteriaceae is primarily linked to three main mechanisms: enzymatic modifications that inactivate the antibiotic, alterations in the antibiotic target, and reduced cell permeability or increased efflux pump activity (102).
The combination of meropenem with vaborbactam is effective against KPC-producing Enterobacteriaceae and was approved by the Food and Drug Administration (FDA) in 2017 for the treatment of cUTI (136, 137). This combination is particularly effective against carbapenem-resistant bacteria, although its activity against OXA- and metallo-β-lactamase-producing isolates is limited (139). It is capable of penetrating the outer membrane of Klebsiella pneumoniae via the OmpK35 and OmpK36 porins (140). Resistance to this combination is typically linked to reduced membrane permeability and mutations in the OmpK35 and OmpK36 porins, along with increased expression of the blaKPC gene (147–149).
Imipenem-relebactam is used to treat complicated infections. Relebactam acts as a potent inhibitor of class A and C β-lactamases, thereby enhancing the efficacy of imipenem against resistant bacteria (152). Resistance to imipenem-relebactam may arise through various mechanisms, including the overproduction of metallo-β-lactamases, oxacillinases, or other β-lactamases, increased activity of efflux pumps, reduced membrane permeability, and mutations in the OmpK36 and OmpK35 porins (133, 162).
Cefiderocol is a novel antibiotic approved for cUTI and ventilator-associated pneumonia (VAP). It demonstrates high efficacy against MDR bacteria (13). It is transported into bacterial cells through iron uptake systems, where it inhibits PBPs and subsequently disrupts bacterial cell wall synthesis. Although it remains stable against β-lactamases, resistance may develop due to mutations in siderophore receptors and PBP-3 (182).
The combination of aztreonam and avibactam has been demonstrated to enhance the antimicrobial activity of aztreonam and restore its efficacy against MDR bacteria (190). This combination inhibited 99.9% of Enterobacteriaceae at concentrations of ≤ 8 mg/L (192). However, resistance may develop through the production of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, as well as mutations in PBP3 or through the action of efflux pumps (192).
This review demonstrates that although new antibiotics are initially highly effective, resistance to them develops rapidly. This phenomenon limits their clinical use and reduces treatment options, ultimately accelerating the spread of resistant strains. Therefore, effective management and rational use of antibiotics are essential to prevent the spread of resistance and maintain the efficacy of existing treatments. Adhering to the principles of rational antibiotic use, developing alternative compounds and rapid diagnostic tools, and conducting further research in areas with a high prevalence of resistant infections can significantly contribute to reducing resistance rates and enhancing antimicrobial therapies.
The present review indicates that new antibiotics, including ticarcillin/clavulanate, cefepime/zidebactam, cefepime/taniborbactam, ceftazidime/avibactam, imipenem/relebactam, cefiderocol, ceftolozane/tazobactam, meropenem/vaborbactam, and aztreonam/avibactam, represent promising options for the treatment of infections caused by carbapenem-resistant and MDR Gram-negative bacteria. However, a major challenge in the clinical application of these antibiotics is the rapid emergence of resistance against them.
Mechanisms of resistance in Gram-negative bacteria include reduced drug penetration, modification of the drug target, drug inactivation, and drug efflux through efflux pumps (7). Each of these antibiotics demonstrated varying degrees of effectiveness against drug-resistant bacteria. The results for each compound are summarized as follows:
Cefepime/zidebactam is a combination of a fourth-generation cephalosporin and a β-lactamase inhibitor that targets a broad spectrum of resistant bacteria, particularly carbapenem-resistant Enterobacteriaceae and MDR/extensively drug-resistant (XDR) P. aeruginosa (18, 19). In addition to inhibiting β-lactamases, zidebactam enhances bactericidal effect by binding to penicillin-binding protein 2 (PBP2), while cefepime inhibits PBP3, distinguishing this combination from other β-lactamase inhibitors (22). Resistance to this compound seems to arise from multiple mutations in the genes encoding the MexAB-OprM efflux pump and its regulators, as well as in PBP2 and PBP3 (43, 44).
Taniborbactam, a boronic acid β-lactamase inhibitor, has been studied in combination with cefepime against carbapenem-resistant bacteria (46). This combination is effective against class A, C, and D β-lactamases, as well as some class B metallo-β-lactamases (47, 48). In vitro studies have demonstrated that cefepime-taniborbactam exhibits a broad spectrum of antibacterial activity and is effective against strains resistant to other β-lactamase inhibitors (49). Alterations in electrostatic charges within the active-site loops of metallo-β-lactamases, due to single amino acid substitutions, can reduce the binding affinity of taniborbactam (62).
Ceftolozane-tazobactam is an anti-pseudomonal cephalosporin approved for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infection (cIAI) (63). This combination is effective against carbapenem-resistant P. aeruginosa and some Enterobacteriaceae, but it has limited activity against Acinetobacter baumannii and some other Enterobacteriaceae (66, 67). Resistance to this combination is typically associated with increased AmpC expression, mutations in PBP3, and enhanced efflux pump activity (79). Ceftolozane-tazobactam may show reduced efficacy against isolates harboring co-produced class A and D β-lactamases, carbapenemases, and metallo-β-lactamases (87, 88).
Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a β-lactamase inhibitor that is effective against carbapenem-resistant bacteria and P. aeruginosa. While ceftazidime-avibactam has demonstrated efficacy in treating bloodstream infections caused by carbapenem-resistant Enterobacteriaceae, its clinical outcomes may differ in cases of pneumonia or deep-seated infections. This variability is likely attributable to differences in drug penetration and bacterial burden at the infection site (98). Resistance to ceftazidime-avibactam in Enterobacteriaceae is primarily linked to three main mechanisms: enzymatic modifications that inactivate the antibiotic, alterations in the antibiotic target, and reduced cell permeability or increased efflux pump activity (102).
The combination of meropenem with vaborbactam is effective against KPC-producing Enterobacteriaceae and was approved by the Food and Drug Administration (FDA) in 2017 for the treatment of cUTI (136, 137). This combination is particularly effective against carbapenem-resistant bacteria, although its activity against OXA- and metallo-β-lactamase-producing isolates is limited (139). It is capable of penetrating the outer membrane of Klebsiella pneumoniae via the OmpK35 and OmpK36 porins (140). Resistance to this combination is typically linked to reduced membrane permeability and mutations in the OmpK35 and OmpK36 porins, along with increased expression of the blaKPC gene (147–149).
Imipenem-relebactam is used to treat complicated infections. Relebactam acts as a potent inhibitor of class A and C β-lactamases, thereby enhancing the efficacy of imipenem against resistant bacteria (152). Resistance to imipenem-relebactam may arise through various mechanisms, including the overproduction of metallo-β-lactamases, oxacillinases, or other β-lactamases, increased activity of efflux pumps, reduced membrane permeability, and mutations in the OmpK36 and OmpK35 porins (133, 162).
Cefiderocol is a novel antibiotic approved for cUTI and ventilator-associated pneumonia (VAP). It demonstrates high efficacy against MDR bacteria (13). It is transported into bacterial cells through iron uptake systems, where it inhibits PBPs and subsequently disrupts bacterial cell wall synthesis. Although it remains stable against β-lactamases, resistance may develop due to mutations in siderophore receptors and PBP-3 (182).
The combination of aztreonam and avibactam has been demonstrated to enhance the antimicrobial activity of aztreonam and restore its efficacy against MDR bacteria (190). This combination inhibited 99.9% of Enterobacteriaceae at concentrations of ≤ 8 mg/L (192). However, resistance may develop through the production of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, as well as mutations in PBP3 or through the action of efflux pumps (192).
This review demonstrates that although new antibiotics are initially highly effective, resistance to them develops rapidly. This phenomenon limits their clinical use and reduces treatment options, ultimately accelerating the spread of resistant strains. Therefore, effective management and rational use of antibiotics are essential to prevent the spread of resistance and maintain the efficacy of existing treatments. Adhering to the principles of rational antibiotic use, developing alternative compounds and rapid diagnostic tools, and conducting further research in areas with a high prevalence of resistant infections can significantly contribute to reducing resistance rates and enhancing antimicrobial therapies.
Keywords: Antimicrobial resistance, Multidrug-resistant (MDR) bacteria, Carbapenem-resistant, Novel antibiotics, β-lactam/β-lactamase inhibitors.
Type of Study: review article |
Subject:
Microbiology
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