Yeni β-laktamaz İnhibitör Kombinasyonları
Özet
β-laktamlar, β-laktamaz aracılı direnç artışı nedeniyle günümüzde etkinliğini yitirmektedir. Bu derleme, klasik tip inhibitörler (klavulanat, sulbaktam, tazobaktam) ile yeni nesil molekülleri (avibaktam, relebaktam, vaborbaktam, durlobaktam, nacubaktam, enmetazobaktam) sınıflandırma, etki mekanizması, antimikrobiyal spektrum, klinik kullanım ve ortaya çıkan direnç mekanizmaları yönünden karşılaştırmaktadır. Yeni nesil inhibitörler özellikle Ambler sınıf A (KPC) ve C (AmpC) için belirgin etkinlik sunarken bazıları sınıf D (OXA-48-benzeri veya Acinetobacter baumannii OXA’ları) üzerinde de etkilidir; metallo- β-laktamazlara (MBL; sınıf B) etkinlik ise sınırlıdır. Fenotipik/Genotipik tanı ile birlikte uygun eş β-laktam seçimi, farmakodinamik optimizasyon ve enfeksiyon kontrolüne entegrasyonu klinik başarının temelidir.
β-lactam antibiotics are progressively losing their effectiveness due to the increasing prevalence of β-lactamase–mediated resistance. This review compares classical inhibitors (clavulanate, sulbactam, tazobactam) and novel compounds (avibactam, relebactam, vaborbactam, durlobactam, nacubactam, enmetazobactam) in terms of their classification, mechanisms of action, antimicrobial spectrum, clinical applications, and emerging resistance mechanisms. New-generation inhibitors show remarkable activity, particularly against Ambler class A (KPC) and class C (AmpC) β-lactamases, while some also demonstrate efficacy against class D enzymes (OXA-48-like and Acinetobacter baumannii OXA variants). However, their activity against metallo-β-lactamases (MBLs; class B) remains limited. Integration of phenotypic/genotypic diagnostic approaches with optimal β-lactam pairing, pharmacodynamic optimization, and infection control measures represents the cornerstone of clinical success.
Referanslar
Naghavi M, Vollset SE, Ikuta KS et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet (London, England) 2024; 404: 1199–226. https://doi.org/ 10.1016/S0140-6736(24)01867-1.
Shankar PR. Book review: tackling drug-resistant infections globally. Arch Pharm Pract 2016; 7: 110. https://doi.org/10.4103/2045-080X. 186181
Neill JO’. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance Chaired 2014. https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20- %20Tackling%20a%20crisis%20for%20the%20health%20and%20wea lth%20of%20nations_1.pdf.
World Health Organization. Prioritization of pathogens to guidediscovery, research and development of new antibiotics for drug-resist-ant bacterial infections, including tuberculosis. 2017. https://www.who.int/ puβLIcations/i/item/WHO-EMP-IAU-2017.12.
World Health Organization. Global antimicrobial resistance and use surveillance system (GLASS) report 2021. 2021. http://www.who.int/ glass/resources/puβLIcations/early-implementation-report-2020/en/.
World Health Organization. WHO puβLIshes list of bacteria for which new antibiotics are urgently needed. 2017. https://www.who.int/news/ item/27-02-2017-who-puβLIshes-list-of-bacteria-for-which-newantibiotics-are-urgently-needed/.
Blair JMA, Webber MA, Baylay AJ et al. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015; 13: 42–51. https://doi.org/10. 1038/nrmicro3380.
Bush K, Bradford PA. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 2019; 17: 295–306. https://doi. org/10.1038/s41579-019-015.
Alarcia-Lacalle A, Canut-Blasco A, Solinís MÁ, Isla A, Rodríguez-Gascón A. Clinical efficacy, safety and pharmacokinetics of novel beta-lactam/beta-lactamase inhibitor combinations: a systematic review. JAC Antimicrob Resist. 2025;7(3):dlaf096. doi: 10.1093/jacamr/dlaf096.
Mojica MF, Rossi M-A, Vila AJ et al. The urgent need for metallo-β-lactamase inhibitors: an unattended global threat. Lancet Infect Dis 2022;22:e28-34. https://doi.org/10.1016/S1473-3099(20) 30868-9.
Bush K, Bradford PA. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 2019;17:295–306. https://doi. org/10.1038/s41579-019-0159-8.
U.S. Department of Health and Human Services. Food and Drug Administration. Avycaz. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2019/206494s005,s006lbl.pdf.
European Medicines Agency. Science Medicines Health. Zavicefta. https://www.ema.europa.eu/en/medicines/human/EPAR/zavicefta.
European Medicines Agency. Science Medicines Health. Emblaveo. https://www.ema.europa.eu/en/documents/product-information/embla veo-epar-product-information_en.pdf.
Bradley JS, Armstrong J, Arrieta A et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime-avibactam in hospitalized pediatric patients. Antimicrob Agents Chemother 2016; 60: 6252–9. https://doi.org/10.1128/AAC. 00862-16.
Lodise TP, O’Donnell JN, Balevic S et al. Pharmacokinetics of ceftazidime-avibactam in combination with aztreonam (COMBINE) in a phase 1, Open-Label Study of Healthy Adults. Antimicrob Agents Chemother 2022;66:e0093622. https://doi.org/10.1128/aac.00936-22
Bensman TJ, Wang J, Jayne J et al. Pharmacokineticpharmacodynamic target attainment analyses to determine optimal dosing of ceftazidime-avibactam for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Antimicrob Agents Chemother 2017;61:e00988-17. https://doi.org/10.1128/AAC.00 988-17
Wang Y, Sholeh M, Yang L, Shakourzadeh MZ, Beig M, Azizian K. Global trends of ceftazidime-avibactam resistance in gram-negative bacteria: systematic review and meta-analysis. Antimicrob Resist Infect Control. 2025;14(1):10. doi: 10.1186/s13756-025-01518-5.
U.S. Department of Health and Human Services. Food and Drug Administration. Recarbrio. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2020/212819s002lbl.pdf.
European Medicines Agency. Science Medicines Health. Recarbrio. https://www.ema.europa.eu/en/medicines/human/EPAR/recarbrio.
Motsch J, Murta de Oliveira C, Stus V et al. RESTORE-IMI 1: a multicenter, randomized, doubleblind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis 2020; 70: 1799–808. https://doi.org/10.1093/cid/ciz530
Boundy K, Liu Y, Bhagunde P et al. Thorough QTc study of a single supratherapeutic dose of relebactam in healthy participants. Clin Pharmacol Drug Dev 2020; 9: 466–75. https://doi.org/10.1002/cpdd.786
Kaye KS, Boucher HW, Brown ML et al. Comparison of treatment outcomes between analysis populations in the RESTORE-IMI 1 phase 3 trial of imipenem-cilastatin-relebactam versus colistin plus imipenem-cilastatin in patients with imipenem-nonsusceptible bacterial infections. Antimicrob Agents Chemother 2020; 64: 1–10. https://doi.org/10.1128/ AAC.02203-19.
Kohno S, Bando H, Yoneyama F et al. The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: a multicenter, open-label, noncomparative phase 3 study. J Infect Chemother 2021; 27: 262–70. https://doi.org/10.1016/j.jiac.2020.09.032
U.S. Department of Health and Human Services. Food and Drug Administration. Xacduro. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216974Orig1s000Correctedlbl.pdf.
Kaye KS, Shorr AF, Wunderink RG 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, noninferiority clinical tri. Lancet Infect Dis 2023; 23: 1072–84. https://doi. org/10.1016/S1473-3099
Lickliter JD, Lawrence K, O’Donnell J et al. Pharmacokinetics, and drug-drug interaction potential of intravenous durlobactam, b-lactamase inhibitor, in healthy subjects. Antimicrob Agents Chemother 2020; 64: e00071-20. https://doi.org/10.1128/AAC.00071-20
McLeod SM, Miller AA, Rana K et al. Clinical outcomes for patients with monomicrobial vs polymicrobial Acinetobacter baumannii calcoaceticus complex infections treated with sulbactam-durlobactam or colistin: a subset analysis from a phase 3 clinical trial. Open Forum Infect Dis 2024; 11: ofae140. https://doi.org/10.1093/ofid/ofae140
O’Donnell J, Maloney K, Steidler M et al. A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects. Clin Transl Sci. 2021;14:1423–30. https://doi.org/10.1111/cts.12991
O’Donnell J, Preston RA, Mamikonyan G et al. Pharmacokinetics, safety, and tolerability of intravenous durlobactam and sulbactam in subjects with renal impairment and healthy matched control subjects. Antimicrob Agents Chemother. 2019; 63: e00794-19. https://doi.org/10. 1128/AAC.00794-19.
Mallalieu NL, Winter E, Fettner S et al. Safety and pharmacokinetic characterization of nacubactam, a novel β-lactamase inhibitor, alone and in combination with meropenem, in healthy volunteers. Antimicrob Agents Chemother 2020; 64: e02229-19. https://doi.org/10.1128/AAC. 02229-19
U.S. Department of Health and Human Services. Food and Drug Administration. Vabomere. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2017/209776lbl.pdf.
European Medicines Agency. Science Medicines Health. Vaborem. https://www.ema.europa.eu/en/medicines/human/EPAR/vaborem.
Bassetti M, Giacobbe DR, Patel N et al. Efficacy and safety of meropenem–vaborbactam versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae infections in patients without prior antimicrobial failure: a post hoc analysis. Adv Ther. 2019;36:1771–7. https://doi.org/10.1007/s12325-019-00981-y
Gaibani P, Giani T, Bovo F, et al. Resistance to Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing. Antibiotics (Basel). 2022;11(5):628. doi: 10.3390/antibiotics11050628.
U.S. Department of Health and Human Services. Food and Drug Administration. Exblifep. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2024/216165s000lbl.pdf.
European Medicines Agency. Science Medicines Health. Exblifep. https://www.ema.europa.eu/en/documents/product-information/ exblifep-epar-product-information_en.pdf.
Das S, Fitzgerald R, Ullah A et al. Intrapulmonary pharmacokinetics of cefepime and enmetazobactam in healthy volunteers: towards new treatments for nosocomial pneumonia. Antimicrob Agents Chemother. 2021;65:e01468-20. https://doi.org/10.1128/AAC.01468-20
Dowell JA, Dickerson D, Henkel T. Safety and pharmacokinetics in human volunteers of taniborbactam (VNRX-5133), a novel intravenous β-lactamase inhibitor. Antimicrob Agents Chemother 2021; 65: e0105321. https://doi.org/10.1128/AAC.01053-21
Preston RA, Mamikonyan G, DeGraff S et al. Single-center evaluation of the pharmacokinetics of WCK 5222 (cefepimezidebactam combination) in subjects with renal impairment. Antimicrob Agents Chemother 2019; 63: e01484-18. https://doi.org/ 10.1128/AAC.01484-18.
Alsenani TA, Viviani SL, Kumar V, et al. Structural Characterization of the D179N and D179Y Variants of KPC-2 beta-Lactamase: omega-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam. Antimicrob Agents Chemother. 2022;66(4):e0241421. doi: 10.1128/aac.02414-21.
Shapiro AB, Moussa SH, Carter Mn, Gao N, Miller AA. Ceftazidime–Avibactam Resistance Mutations V240G, D179Y, and D179Y/T243M in KPC-3 β-Lactamase Do Not Alter Cefpodoxime–ETX1317 Susceptibility. ACS Infectious Diseases. 2020;17(1):79-81.
Winkler ML, Popp WALlace KM, Hujer Am, et al. Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(2):1020–1029. doi: 10.1128/AAC.04238-14.
Tellepgrata C, Ravazi M, Peris PS, Johnson P, Vondracek M, Giske CG. Resistance to aztreonam-avibactam among clinical isolates of E. coli is primarily mediated by altered penicillin binding protein 3 and impermeability. Int J Antimicrob Agents. 2024;64(3):107256. DOI: 10.1016/j.ijantimicag.2024.107256 .
Ma K, McNally A, Zong Z. Struggle To Survive: the Choir of Target Alteration, Hydrolyzing Enzyme, and Plasmid Expression as a Novel Aztreonam-Avibactam Resistance Mechanism. mSystems. 2020;5(6):e00821-20. doi: 10.1128/mSystems.00821-20.
Bella SD, Giacobbe DR, Maraolo AE, et al. Resistance to ceftazidime/avibactam in infections and colonisations by KPC-producing Enterobacterales: a systematic review of observational clinical studies. J Glob Antimicrob Resist. 2021;25:268-281. doi: 10.1016/j.jgar.2021.04.001.
Referanslar
Naghavi M, Vollset SE, Ikuta KS et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet (London, England) 2024; 404: 1199–226. https://doi.org/ 10.1016/S0140-6736(24)01867-1.
Shankar PR. Book review: tackling drug-resistant infections globally. Arch Pharm Pract 2016; 7: 110. https://doi.org/10.4103/2045-080X. 186181
Neill JO’. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance Chaired 2014. https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20- %20Tackling%20a%20crisis%20for%20the%20health%20and%20wea lth%20of%20nations_1.pdf.
World Health Organization. Prioritization of pathogens to guidediscovery, research and development of new antibiotics for drug-resist-ant bacterial infections, including tuberculosis. 2017. https://www.who.int/ puβLIcations/i/item/WHO-EMP-IAU-2017.12.
World Health Organization. Global antimicrobial resistance and use surveillance system (GLASS) report 2021. 2021. http://www.who.int/ glass/resources/puβLIcations/early-implementation-report-2020/en/.
World Health Organization. WHO puβLIshes list of bacteria for which new antibiotics are urgently needed. 2017. https://www.who.int/news/ item/27-02-2017-who-puβLIshes-list-of-bacteria-for-which-newantibiotics-are-urgently-needed/.
Blair JMA, Webber MA, Baylay AJ et al. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015; 13: 42–51. https://doi.org/10. 1038/nrmicro3380.
Bush K, Bradford PA. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 2019; 17: 295–306. https://doi. org/10.1038/s41579-019-015.
Alarcia-Lacalle A, Canut-Blasco A, Solinís MÁ, Isla A, Rodríguez-Gascón A. Clinical efficacy, safety and pharmacokinetics of novel beta-lactam/beta-lactamase inhibitor combinations: a systematic review. JAC Antimicrob Resist. 2025;7(3):dlaf096. doi: 10.1093/jacamr/dlaf096.
Mojica MF, Rossi M-A, Vila AJ et al. The urgent need for metallo-β-lactamase inhibitors: an unattended global threat. Lancet Infect Dis 2022;22:e28-34. https://doi.org/10.1016/S1473-3099(20) 30868-9.
Bush K, Bradford PA. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 2019;17:295–306. https://doi. org/10.1038/s41579-019-0159-8.
U.S. Department of Health and Human Services. Food and Drug Administration. Avycaz. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2019/206494s005,s006lbl.pdf.
European Medicines Agency. Science Medicines Health. Zavicefta. https://www.ema.europa.eu/en/medicines/human/EPAR/zavicefta.
European Medicines Agency. Science Medicines Health. Emblaveo. https://www.ema.europa.eu/en/documents/product-information/embla veo-epar-product-information_en.pdf.
Bradley JS, Armstrong J, Arrieta A et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime-avibactam in hospitalized pediatric patients. Antimicrob Agents Chemother 2016; 60: 6252–9. https://doi.org/10.1128/AAC. 00862-16.
Lodise TP, O’Donnell JN, Balevic S et al. Pharmacokinetics of ceftazidime-avibactam in combination with aztreonam (COMBINE) in a phase 1, Open-Label Study of Healthy Adults. Antimicrob Agents Chemother 2022;66:e0093622. https://doi.org/10.1128/aac.00936-22
Bensman TJ, Wang J, Jayne J et al. Pharmacokineticpharmacodynamic target attainment analyses to determine optimal dosing of ceftazidime-avibactam for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Antimicrob Agents Chemother 2017;61:e00988-17. https://doi.org/10.1128/AAC.00 988-17
Wang Y, Sholeh M, Yang L, Shakourzadeh MZ, Beig M, Azizian K. Global trends of ceftazidime-avibactam resistance in gram-negative bacteria: systematic review and meta-analysis. Antimicrob Resist Infect Control. 2025;14(1):10. doi: 10.1186/s13756-025-01518-5.
U.S. Department of Health and Human Services. Food and Drug Administration. Recarbrio. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2020/212819s002lbl.pdf.
European Medicines Agency. Science Medicines Health. Recarbrio. https://www.ema.europa.eu/en/medicines/human/EPAR/recarbrio.
Motsch J, Murta de Oliveira C, Stus V et al. RESTORE-IMI 1: a multicenter, randomized, doubleblind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis 2020; 70: 1799–808. https://doi.org/10.1093/cid/ciz530
Boundy K, Liu Y, Bhagunde P et al. Thorough QTc study of a single supratherapeutic dose of relebactam in healthy participants. Clin Pharmacol Drug Dev 2020; 9: 466–75. https://doi.org/10.1002/cpdd.786
Kaye KS, Boucher HW, Brown ML et al. Comparison of treatment outcomes between analysis populations in the RESTORE-IMI 1 phase 3 trial of imipenem-cilastatin-relebactam versus colistin plus imipenem-cilastatin in patients with imipenem-nonsusceptible bacterial infections. Antimicrob Agents Chemother 2020; 64: 1–10. https://doi.org/10.1128/ AAC.02203-19.
Kohno S, Bando H, Yoneyama F et al. The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: a multicenter, open-label, noncomparative phase 3 study. J Infect Chemother 2021; 27: 262–70. https://doi.org/10.1016/j.jiac.2020.09.032
U.S. Department of Health and Human Services. Food and Drug Administration. Xacduro. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216974Orig1s000Correctedlbl.pdf.
Kaye KS, Shorr AF, Wunderink RG 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, noninferiority clinical tri. Lancet Infect Dis 2023; 23: 1072–84. https://doi. org/10.1016/S1473-3099
Lickliter JD, Lawrence K, O’Donnell J et al. Pharmacokinetics, and drug-drug interaction potential of intravenous durlobactam, b-lactamase inhibitor, in healthy subjects. Antimicrob Agents Chemother 2020; 64: e00071-20. https://doi.org/10.1128/AAC.00071-20
McLeod SM, Miller AA, Rana K et al. Clinical outcomes for patients with monomicrobial vs polymicrobial Acinetobacter baumannii calcoaceticus complex infections treated with sulbactam-durlobactam or colistin: a subset analysis from a phase 3 clinical trial. Open Forum Infect Dis 2024; 11: ofae140. https://doi.org/10.1093/ofid/ofae140
O’Donnell J, Maloney K, Steidler M et al. A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects. Clin Transl Sci. 2021;14:1423–30. https://doi.org/10.1111/cts.12991
O’Donnell J, Preston RA, Mamikonyan G et al. Pharmacokinetics, safety, and tolerability of intravenous durlobactam and sulbactam in subjects with renal impairment and healthy matched control subjects. Antimicrob Agents Chemother. 2019; 63: e00794-19. https://doi.org/10. 1128/AAC.00794-19.
Mallalieu NL, Winter E, Fettner S et al. Safety and pharmacokinetic characterization of nacubactam, a novel β-lactamase inhibitor, alone and in combination with meropenem, in healthy volunteers. Antimicrob Agents Chemother 2020; 64: e02229-19. https://doi.org/10.1128/AAC. 02229-19
U.S. Department of Health and Human Services. Food and Drug Administration. Vabomere. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2017/209776lbl.pdf.
European Medicines Agency. Science Medicines Health. Vaborem. https://www.ema.europa.eu/en/medicines/human/EPAR/vaborem.
Bassetti M, Giacobbe DR, Patel N et al. Efficacy and safety of meropenem–vaborbactam versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae infections in patients without prior antimicrobial failure: a post hoc analysis. Adv Ther. 2019;36:1771–7. https://doi.org/10.1007/s12325-019-00981-y
Gaibani P, Giani T, Bovo F, et al. Resistance to Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing. Antibiotics (Basel). 2022;11(5):628. doi: 10.3390/antibiotics11050628.
U.S. Department of Health and Human Services. Food and Drug Administration. Exblifep. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2024/216165s000lbl.pdf.
European Medicines Agency. Science Medicines Health. Exblifep. https://www.ema.europa.eu/en/documents/product-information/ exblifep-epar-product-information_en.pdf.
Das S, Fitzgerald R, Ullah A et al. Intrapulmonary pharmacokinetics of cefepime and enmetazobactam in healthy volunteers: towards new treatments for nosocomial pneumonia. Antimicrob Agents Chemother. 2021;65:e01468-20. https://doi.org/10.1128/AAC.01468-20
Dowell JA, Dickerson D, Henkel T. Safety and pharmacokinetics in human volunteers of taniborbactam (VNRX-5133), a novel intravenous β-lactamase inhibitor. Antimicrob Agents Chemother 2021; 65: e0105321. https://doi.org/10.1128/AAC.01053-21
Preston RA, Mamikonyan G, DeGraff S et al. Single-center evaluation of the pharmacokinetics of WCK 5222 (cefepimezidebactam combination) in subjects with renal impairment. Antimicrob Agents Chemother 2019; 63: e01484-18. https://doi.org/ 10.1128/AAC.01484-18.
Alsenani TA, Viviani SL, Kumar V, et al. Structural Characterization of the D179N and D179Y Variants of KPC-2 beta-Lactamase: omega-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam. Antimicrob Agents Chemother. 2022;66(4):e0241421. doi: 10.1128/aac.02414-21.
Shapiro AB, Moussa SH, Carter Mn, Gao N, Miller AA. Ceftazidime–Avibactam Resistance Mutations V240G, D179Y, and D179Y/T243M in KPC-3 β-Lactamase Do Not Alter Cefpodoxime–ETX1317 Susceptibility. ACS Infectious Diseases. 2020;17(1):79-81.
Winkler ML, Popp WALlace KM, Hujer Am, et al. Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(2):1020–1029. doi: 10.1128/AAC.04238-14.
Tellepgrata C, Ravazi M, Peris PS, Johnson P, Vondracek M, Giske CG. Resistance to aztreonam-avibactam among clinical isolates of E. coli is primarily mediated by altered penicillin binding protein 3 and impermeability. Int J Antimicrob Agents. 2024;64(3):107256. DOI: 10.1016/j.ijantimicag.2024.107256 .
Ma K, McNally A, Zong Z. Struggle To Survive: the Choir of Target Alteration, Hydrolyzing Enzyme, and Plasmid Expression as a Novel Aztreonam-Avibactam Resistance Mechanism. mSystems. 2020;5(6):e00821-20. doi: 10.1128/mSystems.00821-20.
Bella SD, Giacobbe DR, Maraolo AE, et al. Resistance to ceftazidime/avibactam in infections and colonisations by KPC-producing Enterobacterales: a systematic review of observational clinical studies. J Glob Antimicrob Resist. 2021;25:268-281. doi: 10.1016/j.jgar.2021.04.001.
