{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:04:35Z","timestamp":1792091075110,"version":"4.4.0"},"reference-count":104,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T00:00:00Z","timestamp":1683331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Aminoglycosides are a family of rapidly bactericidal antibiotics that often remain active against resistant Gram-negative bacterial infections. Over the past decade, their use in critically ill patients has been refined; however, due to their renal and cochleovestibular toxicity, their indications in the treatment of sepsis and septic shock have been gradually reduced. This article reviews the spectrum of activity, mode of action, and methods for optimizing the efficacy of aminoglycosides. We discuss the current indications for aminoglycosides, with an emphasis on multidrug-resistant Gram-negative bacteria, such as extended-spectrum \u03b2-lactamase-producing Enterobacterales, carbapenemase-producing Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Additionally, we review the evidence for the use of nebulized aminoglycosides.<\/jats:p>","DOI":"10.3390\/antibiotics12050860","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T04:04:48Z","timestamp":1683518688000},"page":"860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["Aminoglycosides for the Treatment of Severe Infection Due to Resistant Gram-Negative Pathogens"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9366-505X","authenticated-orcid":false,"given":"Micha\u00ebl","family":"Thy","sequence":"first","affiliation":[{"name":"Assistance Publique H\u00f4pitaux de Paris (AP-HP), Service de M\u00e9decine Intensive et R\u00e9animation Infectieuse, H\u00f4pital Bichat Claude-Bernard, Universit\u00e9 Paris Cit\u00e9, 46 Rue Henri Huchard, 75018 Paris, France"},{"name":"Equipe d\u2019accueil (EA) 7323, Department of Pharmacology and Therapeutic Evaluation in Children and Pregnant Women, Universit\u00e9 Paris Cit\u00e9, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6063-7383","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Timsit","sequence":"additional","affiliation":[{"name":"Assistance Publique H\u00f4pitaux de Paris (AP-HP), Service de M\u00e9decine Intensive et R\u00e9animation Infectieuse, H\u00f4pital Bichat Claude-Bernard, Universit\u00e9 Paris Cit\u00e9, 46 Rue Henri Huchard, 75018 Paris, France"},{"name":"Unit\u00e9 mixte de Recherche (UMR) 1137, Infection, Antimicrobials, Modelization, Epidemiology (IAME), Institut National de la Recherche M\u00e9dicale (INSERM), Universit\u00e9 Paris Cit\u00e9, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"de Montmollin","sequence":"additional","affiliation":[{"name":"Assistance Publique H\u00f4pitaux de Paris (AP-HP), Service de M\u00e9decine Intensive et R\u00e9animation Infectieuse, H\u00f4pital Bichat Claude-Bernard, Universit\u00e9 Paris Cit\u00e9, 46 Rue Henri Huchard, 75018 Paris, France"},{"name":"Unit\u00e9 mixte de Recherche (UMR) 1137, Infection, Antimicrobials, Modelization, Epidemiology (IAME), Institut National de la Recherche M\u00e9dicale (INSERM), Universit\u00e9 Paris Cit\u00e9, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/01.blo.0000175887.98112.fe","article-title":"Streptomycin, a Substance Exhibiting Antibiotic Activity against Gram-Positive and Gram-Negative Bacteria. 1944","volume":"437","author":"Schatz","year":"2005","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_2","first-page":"1","article-title":"Gentamicin, A New Broad-Spectrum Antibiotic Complex","volume":"161","author":"Weinstein","year":"1963","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1128\/AAC.6.4.442","article-title":"Comparative Activity of Tobramycin, Amikacin, and Gentamicin Alone and with Carbenicillin against Pseudomonas Aeruginosa","volume":"6","author":"Kluge","year":"1974","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1136\/bmj.3.5934.778","article-title":"Newer Aminoglycosides\u2014Amikacin and Tobramycin: An in-Vitro Comparison with Kanamycin and Gentamicin","volume":"3","author":"Reynolds","year":"1974","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00236-18","DOI":"10.1128\/AAC.00236-18","article-title":"Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae","volume":"62","author":"Thwaites","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Alfieri, A., Di Franco, S., Donatiello, V., Maffei, V., Fittipaldi, C., Fiore, M., Coppolino, F., Sansone, P., Pace, M.C., and Passavanti, M.B. (2022). Plazomicin against Multidrug-Resistant Bacteria: A Scoping Review. Life, 12.","DOI":"10.3390\/life12121949"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5208","DOI":"10.1128\/AAC.00869-16","article-title":"Association between the Presence of Aminoglycoside-Modifying Enzymes and In Vitro Activity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella Pneumoniae Carbapenemase- and Extended-Spectrum-\u03b2-Lactamase-Producing Enterobacter Species","volume":"60","author":"Haidar","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1021\/cb3005116","article-title":"Aminoglycoside Antibiotics in the 21st Century","volume":"8","author":"Becker","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1128\/AAC.01121-15","article-title":"In Vitro Activities of 21 Antimicrobial Agents Alone and in Combination with Aminoglycosides or Fluoroquinolones against Extended-Spectrum-\u03b2-Lactamase-Producing Escherichia Coli Isolates Causing Bacteremia","volume":"59","author":"Cha","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13613-021-00834-4","article-title":"An International Survey on Aminoglycoside Practices in Critically Ill Patients: The AMINO III Study","volume":"11","author":"Roger","year":"2021","journal-title":"Ann. Intensiv. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1021\/acsinfecdis.6b00176","article-title":"Antimicrobial Activity, AME Resistance, and A-Site Binding Studies of Anthraquinone-Neomycin Conjugates","volume":"3","author":"Degtyareva","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"ref_12","unstructured":"(2023, May 05). Antimicrobial Resistance in the EU\/EEA (EARS-Net). Available online: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/surveillance-antimicrobial-resistance-europe-2021."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1007\/s10096-019-03673-1","article-title":"Resistance Reported from China Antimicrobial Surveillance Network (CHINET) in 2018","volume":"38","author":"Hu","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_14","unstructured":"(2022, October 05). CDC National Infection & Death Estimates for AR, Available online: https:\/\/www.cdc.gov\/drugresistance\/national-estimates.html."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1086\/653120","article-title":"Treatment of Acinetobacter Infections","volume":"51","author":"Fishbain","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Prawang, A., Chanjamlong, N., Rungwara, W., Santimaleeworagun, W., Paiboonvong, T., Manapattanasatein, T., Pitirattanaworranat, P., Kitseree, P., and Kanchanasurakit, S. (2022). Combination Therapy versus Monotherapy in the Treatment of Stenotrophomonas Maltophilia Infections: A Systematic Review and Meta-Analysis. Antibiotics, 11.","DOI":"10.21203\/rs.3.rs-1212986\/v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13613-021-00950-1","article-title":"Effect of Antibiotic Therapy on the Prognosis of Ventilator-Associated Pneumonia Caused by Stenotrophomonas Maltophilia","volume":"11","author":"Puech","year":"2021","journal-title":"Ann. Intensiv. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.cmi.2018.07.020","article-title":"Developing a New Antibiotic for Extensively Drug-Resistant Pathogens: The Case of Plazomicin","volume":"24","author":"Theuretzbacher","year":"2018","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1056\/NEJMc1807634","article-title":"Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae","volume":"380","author":"McKinnell","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106019","DOI":"10.1016\/j.ijantimicag.2020.106019","article-title":"Co-Occurrence of Aminoglycoside and \u03b2-Lactam Resistance Mechanisms in Aminoglycoside- Non-Susceptible Escherichia Coli Isolated in the Zurich Area, Switzerland","volume":"56","author":"Bodendoerfer","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.idc.2016.02.011","article-title":"Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases","volume":"30","author":"Doi","year":"2016","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.drup.2010.08.003","article-title":"Aminoglycoside Modifying Enzymes","volume":"13","author":"Ramirez","year":"2010","journal-title":"Drug Resistance Updates"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.bbapap.2008.10.004","article-title":"Mechanisms of RND Multidrug Efflux Pumps","volume":"1794","author":"Nikaido","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Proteins Proteom."},{"key":"ref_24","first-page":"704","article-title":"Plazomicin: A New Aminoglycoside","volume":"70","author":"Saravolatz","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1086\/533452","article-title":"Federal Funding for the Study of Antimicrobial Resistance in Nosocomial Pathogens: No ESKAPE","volume":"197","author":"Rice","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_26","unstructured":"(2020, June 22). EUCAST: Clinical Breakpoints and Dosing of Antibiotics. Available online: https:\/\/eucast.org\/clinical_breakpoints\/."},{"key":"ref_27","first-page":"1803","article-title":"Difficult-to-Treat Resistance in Gram-Negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-Line Agents","volume":"67","author":"Kadri","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106707","DOI":"10.1016\/j.ijantimicag.2022.106707","article-title":"Geographic Patterns of Carbapenem-Resistant, Multi-Drug-Resistant and Difficult-to-Treat Acinetobacter Baumannii in the Asia-Pacific Region: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) Program, 2020","volume":"61","author":"Chen","year":"2023","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.ijantimicag.2016.01.015","article-title":"Regional Differences and Trends in Antimicrobial Susceptibility of Acinetobacter Baumannii","volume":"47","author":"Lob","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0378-4347(00)00133-X","article-title":"Current Methodologies for the Analysis of Aminoglycosides","volume":"747","author":"Stead","year":"2000","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2174\/1389450023347678","article-title":"Streptogramin Antibiotics: Mode of Action and Resistance","volume":"3","author":"Johnston","year":"2002","journal-title":"Curr. Drug Targets"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1097\/CCM.0b013e3181961bff","article-title":"Pharmacokinetic Issues for Antibiotics in the Critically Ill Patient","volume":"37","author":"Roberts","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1378\/chest.128.2.545","article-title":"Penetration of Gentamicin into the Alveolar Lining Fluid of Critically Ill Patients with Ventilator-Associated Pneumonia","volume":"128","author":"Panidis","year":"2005","journal-title":"Chest"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1097\/01.CCM.0000069734.38738.C8","article-title":"Steady-State Plasma and Intrapulmonary Concentrations of Cefepime Administered in Continuous Infusion in Critically Ill Patients with Severe Nosocomial Pneumonia*","volume":"31","author":"Boselli","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1177\/0091270009355160","article-title":"Permeability and Concentration of Levofloxacin in Epithelial Lining Fluid in Patients with Lower Respiratory Tract Infections","volume":"50","author":"Zhang","year":"2010","journal-title":"J. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/infdis\/155.1.93","article-title":"Clinical Response to Aminoglycoside Therapy: Importance of the Ratio of Peak Concentration to Minimal Inhibitory Concentration","volume":"155","author":"Moore","year":"1987","journal-title":"J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1128\/AAC.43.3.623","article-title":"Optimizing Aminoglycoside Therapy for Nosocomial Pneumonia Caused by Gram-Negative Bacteria","volume":"43","author":"Kashuba","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/jac\/22.1.23","article-title":"Postantibiotic Effect of Aminoglycosides on Gram-Negative Bacteria Evaluated by a New Method","volume":"22","author":"Isaksson","year":"1988","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"377","DOI":"10.2165\/00003088-199427050-00005","article-title":"Pharmacokinetic Contributions to Postantibiotic Effects. Focus on Aminoglycosides","volume":"27","author":"Zhanel","year":"1994","journal-title":"Clin. Pharmacokinet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/bmj.312.7027.338","article-title":"Single or Multiple Daily Doses of Aminoglycosides: A Meta- Analysis","volume":"312","author":"Barza","year":"1996","journal-title":"BMJ"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R53","DOI":"10.1186\/cc8945","article-title":"Revisiting the Loading Dose of Amikacin for Patients with Severe Sepsis and Septic Shock","volume":"14","author":"Taccone","year":"2010","journal-title":"Crit. Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1007\/s00134-014-3276-x","article-title":"Predictors of Insufficient Amikacin Peak Concentration in Critically Ill Patients Receiving a 25 Mg\/Kg Total Body Weight Regimen","volume":"40","author":"Bouadma","year":"2014","journal-title":"Intensiv. Care Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/jac\/dkv291","article-title":"Impact of 30 Mg\/Kg Amikacin and 8 Mg\/Kg Gentamicin on Serum Concentrations in Critically Ill Patients with Severe Sepsis","volume":"71","author":"Roger","year":"2016","journal-title":"JAC"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1002\/phar.2023","article-title":"Comprehensive Guidance for Antibiotic Dosing in Obese Adults","volume":"37","author":"Meng","year":"2017","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Duong, A., Simard, C., Wang, Y.L., Williamson, D., and Marsot, A. (2021). Aminoglycosides in the Intensive Care Unit: What Is New in Population PK Modeling?. Antibiotics, 10.","DOI":"10.20944\/preprints202104.0416.v1"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1128\/AAC.01762-12","article-title":"Gentamicin in Hemodialyzed Critical Care Patients: Early Dialysis after Administration of a High Dose Should Be Considered","volume":"57","author":"Veinstein","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"355","DOI":"10.2215\/CJN.02920707","article-title":"Influence of Hemodialysis on Gentamicin Pharmacokinetics, Removal during Hemodialysis, and Recommended Dosing","volume":"3","author":"Sowinski","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.clinthera.2021.04.015","article-title":"Aminoglycosides in Critically Ill Septic Patients With Acute Kidney Injury Receiving Intermittent Hemodialysis: A Multicenter, Observational Study","volume":"43","author":"Boyer","year":"2021","journal-title":"Clin. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"997","DOI":"10.2165\/00003088-200746120-00003","article-title":"Pharmacokinetic Considerations for Antimicrobial Therapy in Patients Receiving Renal Replacement Therapy","volume":"46","author":"Pea","year":"2007","journal-title":"Clin. Pharmacokinet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.1128\/AAC.00828-16","article-title":"Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy","volume":"60","author":"Roger","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s00134-020-06050-1","article-title":"Antimicrobial Therapeutic Drug Monitoring in Critically Ill Adult Patients: A Position Paper","volume":"46","author":"Alffenaar","year":"2020","journal-title":"Intensiv. Care Med."},{"key":"ref_52","first-page":"223","article-title":"Once-Daily Dosing of Aminoglycosides. A Consensus Document","volume":"35","author":"Anaizi","year":"1997","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e6354","DOI":"10.1136\/bmj.e6354","article-title":"Monitoring Aminoglycoside Level","volume":"345","author":"Banerjee","year":"2012","journal-title":"BMJ"},{"key":"ref_54","first-page":"106","article-title":"In Vitro Activity of Carbapenems Alone and in Combination with Amikacin against KPC-Producing Klebsiella Pneumoniae","volume":"3","author":"Le","year":"2011","journal-title":"J. Clin. Med. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s00134-017-4683-6","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016","volume":"43","author":"Rhodes","year":"2017","journal-title":"Intensive Care Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1097\/01.CCM.0000217961.75225.E9","article-title":"Duration of Hypotension before Initiation of Effective Antimicrobial Therapy Is the Critical Determinant of Survival in Human Septic Shock*","volume":"34","author":"Kumar","year":"2006","journal-title":"Crit. Care Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jinf.2016.11.013","article-title":"Empirical Mono- versus Combination Antibiotic Therapy in Adult Intensive Care Patients with Severe Sepsis\u2014A Systematic Review with Meta-Analysis and Trial Sequential Analysis","volume":"74","author":"Perner","year":"2017","journal-title":"J. Infect."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1128\/CMR.05041-11","article-title":"Combination Therapy for Treatment of Infections with Gram-Negative Bacteria","volume":"25","author":"Tamma","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_59","first-page":"CD003344","article-title":"Beta Lactam Antibiotic Monotherapy versus Beta Lactam-Aminoglycoside Antibiotic Combination Therapy for Sepsis","volume":"2014","author":"Paul","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1097\/CCM.0b013e3181eb3ccd","article-title":"Early Combination Antibiotic Therapy Yields Improved Survival Compared with Monotherapy in Septic Shock: A Propensity-Matched Analysis","volume":"38","author":"Kumar","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1097\/CCM.0b013e3181e96b91","article-title":"A Survival Benefit of Combination Antibiotic Therapy for Serious Infections Associated with Sepsis and Septic Shock Is Contingent Only on the Risk of Death: A Meta-Analytic\/Meta-Regression Study","volume":"38","author":"Kumar","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S1473-3099(17)30228-1","article-title":"Effect of Appropriate Combination Therapy on Mortality of Patients with Bloodstream Infections Due to Carbapenemase-Producing Enterobacteriaceae (INCREMENT): A Retrospective Cohort Study","volume":"17","author":"Salamanca","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00134-021-06506-y","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021","volume":"47","author":"Evans","year":"2021","journal-title":"Intensiv. Care Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.ijantimicag.2016.08.021","article-title":"Colonisation with Extended-Spectrum \u03b2-Lactamase-Producing Enterobacteriaceae and Risk for Infection among Patients with Solid or Haematological Malignancy: A Systematic Review and Meta-Analysis","volume":"48","author":"Alevizakos","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1093\/cid\/civ121","article-title":"Predictive Value of Prior Colonization and Antibiotic Use for Third-Generation Cephalosporin-Resistant Enterobacteriaceae Bacteremia in Patients with Sepsis","volume":"60","author":"Rottier","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.cmi.2018.03.023","article-title":"Development of Diagnostic Prediction Tools for Bacteraemia Caused by Third-Generation Cephalosporin-Resistant Enterobacteria in Suspected Bacterial Infections: A Nested Case-Control Study","volume":"24","author":"Rottier","year":"2018","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e0004521","DOI":"10.1128\/AAC.00045-21","article-title":"Impact of the Inclusion of an Aminoglycoside to the Initial Empirical Antibiotic Therapy for Gram-Negative Bloodstream Infections in Hematological Neutropenic Patients: A Propensity-Matched Cohort Study (AMINOLACTAM Study)","volume":"65","author":"Gudiol","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1128\/AAC.22.5.743","article-title":"Synergism between Aminoglycosides and Cephalosporins with Antipseudomonal Activity: Interaction Index and Killing Curve Method","volume":"22","author":"Hallander","year":"1982","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1128\/AAC.26.4.535","article-title":"Synergism at Clinically Attainable Concentrations of Aminoglycoside and Beta-Lactam Antibiotics","volume":"26","author":"Hooton","year":"1984","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ijantimicag.2010.11.029","article-title":"Clinical Implications of \u03b2-Lactam-Aminoglycoside Synergism: Systematic Review of Randomised Trials","volume":"37","author":"Marcus","year":"2011","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1086\/430912","article-title":"Effect of Aminoglycoside and Beta-Lactam Combination Therapy versus Beta-Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta-Analysis of Randomized, Controlled Trials","volume":"41","author":"Bliziotis","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1086\/497377","article-title":"\u03b2-Lactams with or without Aminoglycosides","volume":"41","author":"Alfandari","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1093\/cid\/ciaa1478","article-title":"Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum \u03b2-Lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas Aeruginosa with Difficult-to-Treat Resistance (DTR- P. Aeruginosa )","volume":"72","author":"Tamma","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cmi.2021.11.025","article-title":"European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines for the Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacilli (Endorsed by European Society of Intensiv. Care Med.icine)","volume":"28","author":"Paul","year":"2022","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e02165-18","DOI":"10.1128\/AAC.02165-18","article-title":"A Systematic Review of Single-Dose Aminoglycoside Therapy for Urinary Tract Infection: Is It Time to Resurrect an Old Strategy?","volume":"63","author":"Goodlet","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12941-016-0155-z","article-title":"In Vitro Potency of Amikacin and Comparators against E. Coli, K. Pneumoniae and P. Aeruginosa Respiratory and Blood Isolates","volume":"15","author":"Sutherland","year":"2016","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e00313-18","DOI":"10.1128\/AAC.00313-18","article-title":"In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes","volume":"62","author":"Castanheira","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_78","first-page":"345","article-title":"Treatment Options for Carbapenem- Resistant Gram-Negative Infections","volume":"115","author":"Fritzenwanker","year":"2018","journal-title":"Dtsch. \u00c4rzteblatt Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1128\/AAC.02638-15","article-title":"Aminoglycosides for Treatment of Bacteremia Due to Carbapenem-Resistant Klebsiella Pneumoniae","volume":"60","author":"Shields","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3389\/fcimb.2019.00422","article-title":"Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella Pneumoniae in Vitro","volume":"9","author":"Yu","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1093\/jac\/dkab122","article-title":"In Vitro and in Vivo Synergistic Effects of Tigecycline Combined with Aminoglycosides on Carbapenem-Resistant Klebsiella Pneumoniae","volume":"76","author":"Ni","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ijantimicag.2018.10.010","article-title":"Combination Therapy with Polymyxin B for Carbapenemase-Producing Klebsiella Pneumoniae Bloodstream Infection","volume":"53","author":"Medeiros","year":"2019","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1128\/AAC.02166-13","article-title":"Carbapenemase-Producing Klebsiella Pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic Combination Schemes and the Role of Carbapenems","volume":"58","author":"Daikos","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1093\/jac\/dkv086","article-title":"Infections Caused by KPC-Producing Klebsiella Pneumoniae: Differences in Therapy and Mortality in a Multicentre Study","volume":"70","author":"Tumbarello","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.cmi.2016.01.016","article-title":"Predictors of Outcome in ICU Patients with Septic Shock Caused by Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae","volume":"22","author":"Falcone","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1093\/cid\/cis588","article-title":"Predictors of Mortality in Bloodstream Infections Caused by Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae: Importance of Combination Therapy","volume":"55","author":"Tumbarello","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s10096-019-03468-4","article-title":"The Role of Therapy with Aminoglycoside in the Outcomes of Kidney Transplant Recipients Infected with Polymyxin- and Carbapenem-Resistant Enterobacteriaceae","volume":"38","author":"Freire","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1093\/jac\/dku495","article-title":"Impact of Therapy and Strain Type on Outcomes in Urinary Tract Infections Caused by Carbapenem-Resistant Klebsiella Pneumoniae","volume":"70","author":"Cober","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/j.1469-0691.2011.03570.x","article-title":"Multidrug-Resistant, Extensively Drug-Resistant and Pandrug-Resistant Bacteria: An International Expert Proposal for Interim Standard Definitions for Acquired Resistance","volume":"18","author":"Magiorakos","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1017\/S095026881200194X","article-title":"Colistin vs. the Combination of Colistin and Rifampicin for the Treatment of Carbapenem-Resistant Acinetobacter Baumannii Ventilator-Associated Pneumonia","volume":"141","author":"Aydemir","year":"2013","journal-title":"Epidemiol. Infect."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/cid\/cit253","article-title":"Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections Due to Extensively Drug-Resistant Acinetobacter Baumannii: A Multicenter, Randomized Clinical Trial","volume":"57","author":"Signoriello","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.1128\/AAC.02435-13","article-title":"Preliminary Study of Colistin versus Colistin plus Fosfomycin for Treatment of Carbapenem-Resistant Acinetobacter Baumannii Infections","volume":"58","author":"Sirijatuphat","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S1473-3099(18)30099-9","article-title":"Colistin Alone versus Colistin plus Meropenem for Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-Negative Bacteria: An Open-Label, Randomised Controlled Trial","volume":"18","author":"Paul","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/jac\/dkw377","article-title":"Polymyxin Monotherapy or in Combination against Carbapenem-Resistant Bacteria: Systematic Review and Meta-Analysis","volume":"72","author":"Zusman","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4103\/ijccm.IJCCM_302_17","article-title":"Colistin versus Colistin Combined with Ampicillin-Sulbactam for Multiresistant Acinetobacter Baumannii Ventilator-Associated Pneumonia Treatment: An Open-Label Prospective Study","volume":"22","author":"Makris","year":"2018","journal-title":"Indian J. Crit. Care Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.ijantimicag.2017.12.020","article-title":"Intravenous Colistin Combination Antimicrobial Treatment vs. Monotherapy: A Systematic Review and Meta-Analysis","volume":"51","author":"Vardakas","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/QCO.0000000000000817","article-title":"How Common Is Ventilator-Associated Pneumonia after Coronavirus Disease 2019?","volume":"35","author":"Wicky","year":"2022","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1186\/s13054-018-2106-x","article-title":"Aerosolized Antibiotics for Ventilator-Associated Pneumonia: A Pairwise and Bayesian Network Meta-Analysis","volume":"22","author":"Xu","year":"2018","journal-title":"Crit. Care"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1038\/s41598-021-86342-8","article-title":"Amikacin Nebulization for the Adjunctive Therapy of Gram-Negative Pneumonia in Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"11","author":"Qin","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S1473-3099(19)30574-2","article-title":"Inhaled Amikacin Adjunctive to Intravenous Standard-of-Care Antibiotics in Mechanically Ventilated Patients with Gram-Negative Pneumonia (INHALE): A Double-Blind, Randomised, Placebo-Controlled, Phase 3, Superiority Trial","volume":"20","author":"Niederman","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.4103\/0366-6999.205846","article-title":"Aerosolized Amikacin as Adjunctive Therapy of Ventilator-Associated Pneumonia Caused by Multidrug-Resistant Gram-Negative Bacteria: A Single-Center Randomized Controlled Trial","volume":"130","author":"Liu","year":"2017","journal-title":"Chin. Med. J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.chest.2016.11.026","article-title":"A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial","volume":"151","author":"Kollef","year":"2017","journal-title":"Chest"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1007\/s00134-019-05914-5","article-title":"Effect of Adjunctive Tobramycin Inhalation versus Placebo on Early Clinical Response in the Treatment of Ventilator-Associated Pneumonia: The VAPORISE Randomized-Controlled Trial","volume":"46","author":"Stokker","year":"2020","journal-title":"Intensiv. Care Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1080\/14787210.2022.2063838","article-title":"Treatment of Ventilator-Associated Pneumonia Due to Carbapenem-Resistant Gram-Negative Bacteria with Novel Agents: A Contemporary, Multidisciplinary ESGCIP Perspective","volume":"20","author":"Giacobbe","year":"2022","journal-title":"Expert Rev. Anti-Infect. 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