{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:01:14Z","timestamp":1790805674812,"version":"4.1.0"},"reference-count":31,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,2,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:italic>Mycobacterium abscessus<\/jats:italic>\n            pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate of resistance. Amikacin is critical to treatment, but the development of toxicity, amikacin resistance, and treatment failure are significant challenges. Amikacin has been characterized previously as peak-dependent and extended-interval dosing is commonly used. In our hollow fiber infection model of\n            <jats:italic>M. abscessus<\/jats:italic>\n            , amikacin exhibited time-dependent rather than the expected peak-dependent pharmacodynamics. Humanized amikacin exposures with more frequent, short-interval dosing (continuous infusion or every 12 hours) yielded improved microbiological response compared to extended-interval dosing (every 24 hours or 1\u20133 times per week). Short-interval dosing inhibited growth with a mean (SD) maximum \u0394log\n            <jats:sub>10<\/jats:sub>\n            colony forming units of \u22124.06 (0.52), significantly more than extended-interval dosing (\n            <jats:italic>P<\/jats:italic>\n            = 0.0013) every 24 hours, \u22122.40 (0.58), or 1\u20133 times per week, \u22122.39 (0.38). Growth recovery, an indicator of resistance emergence, occurred at 6.56 (0.70) days with short-interval dosing but was significantly earlier with extended-interval dosing (\n            <jats:italic>P<\/jats:italic>\n            = 0.0032) every 24 hours, 3.88 (0.85) days, and 1\u20133 times per week, 3.27 (1.72) days. Microbiological response correlated best with the pharmacodynamic index of %T &gt; minimum inhibitory concentration (MIC), with an EC\n            <jats:sub>80<\/jats:sub>\n            for growth inhibition of ~40%T &gt; MIC. We used a previously published population model of amikacin to determine the probability of achieving 40%T &gt; MIC and show that current dosing strategies are far below this target, which may partially explain why treatment failure remains so high for these infections. These data support a cautious approach to infrequent amikacin dosing for the treatment of\n            <jats:italic>M. abscessus<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Pulmonary disease caused by\n              <jats:italic>Mycobacterium abscessus<\/jats:italic>\n              complex (MABSC) is increasing worldwide, particularly in patients with cystic fibrosis. MABSC is challenging to treat due to high levels of antibiotic resistance. Treatment requires 2\u20134 antibiotics over more than 12 months and has a significant risk of toxicity but still fails to eradicate infection in over 50% of patients with cystic fibrosis. Antibiotic dosing strategies have been largely informed by common bacteria such as\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              . The \u201cpharmacodynamic\u201d effects of amikacin, a backbone of MABSC treatment, were thought to be related to maximum \u201cpeak\u201d drug concentration, leading to daily or three times weekly dosing. However, we found that amikacin MABSC kill and growth recovery, an indicator of antibiotic resistance, are dependent on how long amikacin concentrations are above the minimum inhibitory concentration, not how high the peak concentration is. Therefore, we recommend a re-evaluation of amikacin dosing to determine if increased frequency can improve efficacy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03222-23","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T14:01:04Z","timestamp":1705586464000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Time-dependent pharmacodynamics of amikacin on\n            <i>Mycobacterium abscessus<\/i>\n            growth and resistance emergence"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-2320","authenticated-orcid":false,"given":"Joy E.","family":"Gibson","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and the Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, Children\u2019s Hospital Los Angeles, Los Angeles, California, USA"},{"name":"Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-7207","authenticated-orcid":false,"given":"Nishant","family":"Nandanwar","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and the Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, Children\u2019s Hospital Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-8276","authenticated-orcid":false,"given":"Michael N.","family":"Neely","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and the Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, Children\u2019s Hospital Los Angeles, Los Angeles, California, USA"},{"name":"Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3201\/2109.141634"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201002-0310OC"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.659997"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201804-236OC"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-0331-1"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207360"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1125"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01977"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01991-2018"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.4.3.479"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0891-5520(03)00057-6"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.08140718"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02282-15"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2020.09.033"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01050-15"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD002009.pub7"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/155.1.93"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-016-0165-5"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccc.2010.11.006"},{"key":"e_1_3_3_22_2","volume-title":"M24-A2 susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes; approved standard","author":"Clinical and Laboratory Standards Institute","year":"2011","unstructured":"Clinical and Laboratory Standards Institute. 2011. 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