{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:55:48Z","timestamp":1793404548891,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T00:00:00Z","timestamp":1576540800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>Azithromycin (AZM), the most commonly prescribed antibiotic in the United States, is thought to have no activity against multidrug-resistant Gram-negative pathogens such as <jats:italic toggle=\"yes\">Achromobacter xylosoxidans<\/jats:italic> (AX) per standard minimum inhibitory concentration testing in cation-adjusted Mueller Hinton Broth. Here we provide the first report of AZM bactericidal activity against carbapenem-resistant isolates of AX, with a multifold decrease in minimum inhibitory concentration across 12 clinical isolates when examined under physiologic testing conditions that better recapitulate the in vivo human environment. This pharmaceutical activity, evident in eukaryotic tissue culture media, is associated with enhanced AZM intracellular penetration and synergistic killing with human whole blood, serum, and neutrophils. Additionally, AZM monotherapy inhibited preformed AX biofilm growth in a dose-dependent manner together with a reduction in viable bacteria. In an illustrative case, AZM in combination with piperacillin-tazobactam exerted clear therapeutic effects in a patient with carbapenem-resistant AX mediastinitis, sternal osteomyelitis, and aortic graft infection. Our study reinforces how current antimicrobial testing practices fail to recapitulate the host environment or host-pathogen interactions and may misleadingly declare complete resistance to useful agents, adversely affecting patient outcomes. We conclude that AZM merits further exploration in the treatment of drug-resistant AX infections. Novel approaches to antimicrobial susceptibility testing that better recapitulate the host environment should be considered, especially as infections caused by multidrug-resistant Gram-negative bacterial pathogens are expanding globally with high morbidity and mortality.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/im9.0000000000000014","type":"journal-article","created":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T18:16:04Z","timestamp":1588011364000},"page":"10-17","source":"Crossref","is-referenced-by-count":19,"title":["Azithromycin Exerts Bactericidal Activity and Enhances Innate Immune Mediated Killing of MDR Achromobacter xylosoxidans"],"prefix":"10.1097","volume":"2","author":[{"given":"Erlinda R.","family":"Ulloa","sequence":"first","affiliation":[{"name":"Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Division of Infectious Disease, Children's Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"ERU and AK contributed equally to this study."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Kousha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway"},{"name":"ERU and AK contributed equally to this study."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Tsunemoto","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Pogliano","sequence":"additional","affiliation":[{"name":"Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Licitra","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Orlando Health Medical Group, Orlando, FL 32806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"LiPuma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Sakoulas","sequence":"additional","affiliation":[{"name":"Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[{"name":"Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Kumaraswamy","sequence":"additional","affiliation":[{"name":"Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Infectious Diseases Section, VA San Diego Healthcare System, San Diego, CA 92161, USA"},{"name":"Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,3]]},"reference":[{"issue":"(2)","key":"R3-20230926","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1128\/jcm.11.2.141-145.1980","article-title":"Clinical and laboratory characteristics of Achromobacter xylosoxidans infection","volume":"11","author":"Igra-Siegman","year":"1980","journal-title":"J Clin Microbiol"},{"issue":"(8)","key":"R4-20230926","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1007\/s10096-011-1182-5","article-title":"Achromobacter xylosoxidans respiratory tract infection in cystic fibrosis patients","volume":"30","author":"Lambiase","year":"2011","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"(9)","key":"R5-20230926","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1111\/j.1600-0463.2008.00995.x","article-title":"Achromobacter xylosoxidans respiratory tract infections in cystic fibrosis patients","volume":"116","author":"Raso","year":"2008","journal-title":"APMIS"},{"issue":"(2)","key":"R6-20230926","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1086\/645791","article-title":"Nosocomial Achromobacter xylosoxidans infections","volume":"9","author":"Schoch","year":"1988","journal-title":"Infect Control Hosp Epidemiol"},{"issue":"(2)","key":"R7-20230926","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1513\/AnnalsATS.201406-288FR","article-title":"Achromobacter respiratory infections","volume":"12","author":"Swenson","year":"2015","journal-title":"Ann Am Thorac Soc"},{"issue":"(12)","key":"R8-20230926","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/BF01700563","article-title":"Bacteremia and respiratory involvement by Alcaligenes xylosoxidans in patients infected with the human immunodeficiency virus","volume":"16","author":"Manfredi","year":"1997","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"(9)","key":"R9-20230926","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1002\/cncr.20604","article-title":"Bacteremia caused by Achromobacter and Alcaligenes species in 46 patients with cancer (1989\u20132003)","volume":"101","author":"Aisenberg","year":"2004","journal-title":"Cancer"},{"issue":"(3)","key":"R10-20230926","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1093\/clinids\/23.3.569","article-title":"Achromobacter xylosoxidans bacteremia: report of four cases and review of the literature","volume":"23","author":"Duggan","year":"1996","journal-title":"Clin Infect Dis"},{"issue":"(3)","key":"R11-20230926","first-page":"284","article-title":"Achromobacter xylosoxidans bacteremia in patients with hematologic malignancies","volume":"83","author":"Hernandez","year":"1998","journal-title":"Haematologica"},{"issue":"(2)","key":"R12-20230926","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/clinids\/14.2.479","article-title":"Bacteremia due to Achromobacter xylosoxidans in patients with cancer","volume":"14","author":"Legrand","year":"1992","journal-title":"Clin Infect Dis"},{"issue":"(7)","key":"R13-20230926","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.ebiom.2015.05.021","article-title":"Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens","volume":"2","author":"Lin","year":"2015","journal-title":"EBioMedicine"},{"issue":"(5)","key":"R14-20230926","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/jac\/dkv487","article-title":"Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR Stenotrophomonas maltophilia","volume":"71","author":"Kumaraswamy","year":"2016","journal-title":"J Antimicrob Chemother"},{"issue":"(3)","key":"R15-20230926","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/infdis\/jiz128","article-title":"Avibactam sensitizes carbapenem-resistant NDM-1-producing Klebsiella pneumoniae to innate immune clearance","volume":"220","author":"Ulloa","year":"2019","journal-title":"J Infect Dis"},{"issue":"(2)","key":"R16-20230926","first-page":"e01745","article-title":"Classical beta-lactamase inhibitors potentiate the activity of daptomycin against methicillin-resistant Staphylococcus aureus and colistin against Acinetobacter baumannii","volume":"61","author":"Sakoulas","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"issue":"(11)","key":"R17-20230926","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1128\/AAC.00497-10","article-title":"Synergy testing by Etest, microdilution checkerboard, and time-kill methods for pan-drug-resistant Acinetobacter baumannii","volume":"54","author":"Sopirala","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"issue":"(7)","key":"R20-20230926","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1128\/AAC.01211-10","article-title":"Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus","volume":"55","author":"Haste","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"issue":"(40)","key":"R21-20230926","doi-asserted-by":"crossref","first-page":"16169","DOI":"10.1073\/pnas.1311066110","article-title":"Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules","volume":"110","author":"Nonejuie","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"(4)","key":"R22-20230926","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.phrs.2012.06.001","article-title":"Fluorescently labeled macrolides as a tool for monitoring cellular and tissue distribution of azithromycin","volume":"66","author":"Matijasic","year":"2012","journal-title":"Pharmacol Res"},{"issue":"(2)","key":"R23-20230926","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00109-013-1100-7","article-title":"Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus","volume":"92","author":"Sakoulas","year":"2014","journal-title":"J Mol Med (Berl)"},{"issue":"(3)","key":"R24-20230926","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.ijantimicag.2017.12.032","article-title":"Listeria monocytogenes endocarditis: case report, review of the literature, and laboratory evaluation of potential novel antibiotic synergies","volume":"51","author":"Kumaraswamy","year":"2018","journal-title":"Int J Antimicrob Agents"},{"issue":"(3)","key":"R25-20230926","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3390\/microorganisms4030033","article-title":"Achromobacter Species Isolated from Cystic Fibrosis Patients Reveal Distinctly Different Biofilm Morphotypes","volume":"4","author":"Nielsen","year":"2016","journal-title":"Microorganisms"},{"issue":"(1)","key":"R26-20230926","doi-asserted-by":"crossref","first-page":"E14","DOI":"10.3390\/pathogens8010014","article-title":"Motility, biofilm formation and antimicrobial efflux of sessile and planktonic cells of Achromobacter xylosoxidans","volume":"8","author":"Nielsen","year":"2019","journal-title":"Pathogens"},{"issue":"(9)","key":"R27-20230926","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrmicro.2016.94","article-title":"Biofilms: an emergent form of bacterial life","volume":"14","author":"Flemming","year":"2016","journal-title":"Nat Rev Microbiol"},{"issue":"(3)","key":"R28-20230926","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000239440","article-title":"The influence of azithromycin on the biofilm formation of Pseudomonas aeruginosa in vitro","volume":"42","author":"Ichimiya","year":"1996","journal-title":"Chemotherapy"},{"issue":"(1)","key":"R29-20230926","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1128\/AAC.00607-07","article-title":"Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and diminish established biofilms","volume":"52","author":"Starner","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"issue":"(12)","key":"R30-20230926","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1128\/AAC.05169-11","article-title":"Antibiofilm effects of azithromycin and erythromycin on Porphyromonas gingivalis","volume":"55","author":"Maezono","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"issue":"(6)","key":"R31-20230926","first-page":"737","article-title":"Macrolides as biological response modifiers in cystic fibrosis and bronchiectasis","volume":"24","author":"Bush","year":"2003","journal-title":"Semin Respir Crit Care Med"},{"issue":"(5)","key":"R32-20230926","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00228-011-1161-x","article-title":"Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases","volume":"68","author":"Zarogoulidis","year":"2012","journal-title":"Eur J Clin Pharmacol"},{"issue":"(3)","key":"R33-20230926","first-page":"124","article-title":"The effects of erythromycin on human peripheral neutrophil apoptosis","volume":"38","author":"Inamura","year":"2000","journal-title":"Rhinology"},{"issue":"(3)","key":"R34-20230926","first-page":"501","article-title":"Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells","volume":"104","author":"Matsuoka","year":"1996","journal-title":"Clin Exp Immunol"},{"issue":"(1)","key":"R35-20230926","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1183\/09031936.00.15106200","article-title":"Macrolide antibiotics inhibit nitric oxide generation by rat pulmonary alveolar macrophages","volume":"15","author":"Kohri","year":"2000","journal-title":"Eur Respir J"},{"issue":"(3)","key":"R36-20230926","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1136\/thorax.57.3.212","article-title":"Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial","volume":"57","author":"Wolter","year":"2002","journal-title":"Thorax"},{"issue":"(5)","key":"R37-20230926","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1183\/09031936.04.00084304","article-title":"Azithromycin for cystic fibrosis","volume":"24","author":"Southern","year":"2004","journal-title":"Eur Respir J"},{"issue":"(4)","key":"R38-20230926","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1093\/cid\/cis473","article-title":"Increased susceptibility of Pseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell culture media and biological fluids due to decreased expression of oprM and increased outer-membrane permeability","volume":"55","author":"Buyck","year":"2012","journal-title":"Clin Infect Dis"},{"issue":"(1)","key":"R39-20230926","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/jac\/40.1.13","article-title":"Susceptibility testing of Stenotrophomonas maltophilia to carbapenems","volume":"40","author":"Howe","year":"1997","journal-title":"J Antimicrob Chemother"},{"issue":"(1)","key":"R41-20230926","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1128\/CMR.00036-08","article-title":"AmpC beta-lactamases","volume":"22","author":"Jacoby","year":"2009","journal-title":"Clin Microbiol Rev"},{"issue":"(1)","key":"R42-20230926","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1128\/AAC.27.1.71","article-title":"Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole","volume":"27","author":"Crider","year":"1985","journal-title":"Antimicrob Agents Chemother"},{"key":"R43-20230926","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ebiom.2017.05.026","article-title":"Correcting a fundamental flaw in the paradigm for antimicrobial susceptibility testing","volume":"20","author":"Ersoy","year":"2017","journal-title":"EBioMedicine"}],"container-title":["Infectious Microbes and Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/IM9.0000000000000014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T08:25:09Z","timestamp":1695716709000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/IM9.0000000000000014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,17]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020]]}},"URL":"https:\/\/doi.org\/10.1097\/im9.0000000000000014","relation":{},"ISSN":["2641-5917"],"issn-type":[{"value":"2641-5917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,17]]}}}