Narrative Review of β-Lactam Resistance in Key Bacterial Pathogens: Efficacy and Innovations in Combination Therapies

Background: β-Lactam antibiotics (BLIs) are essential for treating bacterial infections, but resistance is increasing due to β-lactamases, altered penicillin-binding proteins (PBPs), and reduced permeability in pathogens, such as E. coli, K. pneumoniae, P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), A. baumannii, N. gonorrhoeae, and vancomycin-resistant Enterococcus faecium. BLIs aim to restore the effectiveness of these antibiotics, but non-enzymatic resistance remains a challenge. Methods: This narrative review searched databases including PubMed, Scopus, Web of Science, and Google Scholar for articles published between ۲۰۲۰ and ۲۰۲۵. Key search terms included "beta-lactam resistance" and "clustered regularly interspaced short palindromic repeats (CRISPR)-mediated antimicrobial resistance." Out of approximately ۱,۲۰۰ articles, ۸۸ peer-reviewed studies were selected, focusing on resistance mechanisms, prevalence, and innovative therapies for selected pathogens. Results: E. coli and K. pneumoniae exhibit high prevalence rates of extended-spectrum β-lactamases, with Cefotaximase‑Munich (CTX-M) found in ۷۲.۵% of cases and carbapenemase blaKPC-۲ in ۶۶% of K. pneumoniae. Methicillin-resistant Staphylococcus aureus (MRSA) relies on the mecA gene (۳۰% prevalence in burn infections), while A. baumannii shows a prevalence of blaOXA-۲۳ at ۶۸.۹%, and N. gonorrhoeae has blaTEM-۱ in ۸۶.۸۸% of cases. The combination of ceftazidime and avibactam reduces mortality in carbapenem-resistant K. pneumoniae (CRKP) infections by ۵۲%, with additional synergy observed when combined with aztreonam (۸۹% effectiveness). Phage therapy and CRISPR/Cas۹ have shown effectiveness in targeting multidrug-resistant (MDR) strains and restoring susceptibility. Conclusion: Managing β-lactam resistance effectively requires a deep understanding of pathogen-specific mechanisms. While β-lactamase inhibitors (BLIs), such as ceftazidime/avibactam, are useful, their effectiveness is limited by efflux pumps and modifications to penicillin-binding proteins (PBPs). Bacteriophage therapy has proven highly effective in significantly reducing multidrug-resistant (MDR) A. baumannii in vivo, and CRISPR/Cas۹ can precisely target resistance genes such as blaKPC to restore antibiotic sensitivity. Additionally, nanocarrier systems improve drug delivery by overcoming challenges like efflux and biofilm formation. This review synthesizes advancements made since ۲۰۲۰, highlighting innovative strategies involving phage therapy, CRISPR, and nanocarriers, while addressing critical research gaps in understudied pathogens, paving the way for precision antimicrobial therapies. Background: β-Lactam antibiotics (BLIs) are essential for treating bacterial infections, but resistance is increasing due to β-lactamases, altered penicillin-binding proteins (PBPs), and reduced permeability in pathogens, such as E. coli, K. pneumoniae, P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), A. baumannii, N. gonorrhoeae, and vancomycin-resistant Enterococcus faecium. BLIs aim to restore the effectiveness of these antibiotics, but non-enzymatic resistance remains a challenge. Methods: This narrative review searched databases including PubMed, Scopus, Web of Science, and Google Scholar for articles published between ۲۰۲۰ and ۲۰۲۵. Key search terms included "beta-lactam resistance" and "clustered regularly interspaced short palindromic repeats (CRISPR)-mediated antimicrobial resistance." Out of approximately ۱,۲۰۰ articles, ۸۸ peer-reviewed studies were selected, focusing on resistance mechanisms, prevalence, and innovative therapies for selected pathogens. Results: E. coli and K. pneumoniae exhibit high prevalence rates of extended-spectrum β-lactamases, with Cefotaximase‑Munich (CTX-M) found in ۷۲.۵% of cases and carbapenemase blaKPC-۲ in ۶۶% of K. pneumoniae. Methicillin-resistant Staphylococcus aureus (MRSA) relies on the mecA gene (۳۰% prevalence in burn infections), while A. baumannii shows a prevalence of blaOXA-۲۳ at ۶۸.۹%, and N. gonorrhoeae has blaTEM-۱ in ۸۶.۸۸% of cases. The combination of ceftazidime and avibactam reduces mortality in carbapenem-resistant K. pneumoniae (CRKP) infections by ۵۲%, with additional synergy observed when combined with aztreonam (۸۹% effectiveness). Phage therapy and CRISPR/Cas۹ have shown effectiveness in targeting multidrug-resistant (MDR) strains and restoring susceptibility. Conclusion: Managing β-lactam resistance effectively requires a deep understanding of pathogen-specific mechanisms. While β-lactamase inhibitors (BLIs), such as ceftazidime/avibactam, are useful, their effectiveness is limited by efflux pumps and modifications to penicillin-binding proteins (PBPs). Bacteriophage therapy has proven highly effective in significantly reducing multidrug-resistant (MDR) A. baumannii in vivo, and CRISPR/Cas۹ can precisely target resistance genes such as blaKPC to restore antibiotic sensitivity. Additionally, nanocarrier systems improve drug delivery by overcoming challenges like efflux and biofilm formation. This review synthesizes advancements made since ۲۰۲۰, highlighting innovative strategies involving phage therapy, CRISPR, and nanocarriers, while addressing critical research gaps in understudied pathogens, paving the way for precision antimicrobial therapies.

کلیدواژه ها:

Beta-Lactam ، Klebsiella pneumonia ، CRISPR/Cas۹ ، β-Lactamase inhibitors