{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T16:04:33Z","timestamp":1697040273659},"reference-count":22,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2001,6,1]],"date-time":"2001-06-01T00:00:00Z","timestamp":991353600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2001,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The emergence of antibiotic resistance in mycobacteria involves the selection of mutant variants within a susceptible bacterial population. However, it is unclear whether antimycobacterial drugs act just as selective agents or can influence the rate of appearance of resistant mutants. The present study was initiated to address this issue by monitoring the effects of antimicrobial agents on the appearance and growth of clarithromycin (CLR)-resistant (CLR\n            <jats:sup>r<\/jats:sup>\n            ) bacilli in broth cultures of\n            <jats:italic>Mycobacterium avium<\/jats:italic>\n            . Preexposure of\n            <jats:italic>M. avium<\/jats:italic>\n            to CLR had a significant dose effect on the emergence of resistance, with concentrations of 4 to 8 \u03bcg\/ml resulting in a maximal (\u223c10\n            <jats:sup>4<\/jats:sup>\n            -fold) increase in the number of CLR\n            <jats:sup>r<\/jats:sup>\n            bacilli after a 4-day incubation. In addition, a dose effect was found with azithromycin. The use of combinations of CLR with either ethambutol (EMB) or rifabutin (RFB) resulted in fewer resistant bacilli compared to the use of CLR alone. The lowest active concentration of EMB (4 \u03bcg\/ml) was equivalent to the EMB MIC (4 to 8 \u03bcg\/ml) for the parental CLR\n            <jats:sup>s<\/jats:sup>\n            strain and the emergent CLR\n            <jats:sup>r<\/jats:sup>\n            variants, and thus, the antiresistance effect was probably the result of the bacteriostatic effect of EMB on CLR\n            <jats:sup>r<\/jats:sup>\n            bacilli. However, RFB was an order of magnitude more active (0.05 \u03bcg\/ml) at reducing resistance than suggested by the MIC of this agent (0.5 to 1 \u03bcg\/ml). These results indicate that the emergence of resistance was not simply the selection of a preexisting subpopulation of resistant bacilli. Further analysis suggested that early events in the emergence of resistance involved organisms (progenitors) that acquired a resistance phenotype. In addition, the progenitors appeared to be in a transient state, able to develop into a stable resistant lineage in the presence of CLR, or able to revert to the wild type in nonselective conditions.\n          <\/jats:p>","DOI":"10.1128\/aac.45.6.1607-1614.2001","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:06:42Z","timestamp":1027764402000},"page":"1607-1614","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Effect of Drug Concentration on Emergence of Macrolide Resistance in\n            <i>Mycobacterium avium<\/i>"],"prefix":"10.1128","volume":"45","author":[{"given":"Kevin A.","family":"Nash","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Childrens Hospital Los Angeles and University of Southern California, Los Angeles, California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/174.6.1218"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1126\/science.8493560","article-title":"Directed mutation.","volume":"260","author":"Cairns J.","year":"1993","unstructured":"Cairns J. Directed mutation. Science 260 1993 1221 1224","journal-title":"Science"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.10.2749"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.7.1756"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.179.5.1550-1554.1997"},{"key":"e_1_3_2_7_2","unstructured":"Hindler\n              J.\n          Antimicrobial susceptibility testing.\n          Clinical microbiology procedures handbook\n              Isenberg\n              H. D.\n          1\n          1992\n          American Society for Microbiology\n          Washington D.C."},{"key":"e_1_3_2_8_2","unstructured":"Inderlied\n              C. B.\n              Salfinger\n              M.\n          Antimicrobial agents and susceptibility tests: mycobacteria\n          Manual of clinical microbiology\n          6th ed.\n              Murray\n              P. R.\n              Baron\n              E. J.\n              Pfaller\n              M. A.\n              Tenover\n              F. C.\n              Yolken\n              R. H.\n          1995\n          1385\n          1404\n          American Society for Microbiology\n          Washington D.C."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.12.3331-3335.2000"},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/BF00132585","article-title":"Spontaneous mutations in bacteria: chance or necessity?","volume":"97","author":"MacPhee D. G.","year":"1996","unstructured":"MacPhee D. G. Ambrose M. Spontaneous mutations in bacteria: chance or necessity? Genetica 97 1996 87 101","journal-title":"Genetica"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.7.1771-1777.2000"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120161797"},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/infdis\/174.2.354","article-title":"Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: observation of multiple 23S rDNA mutations in a clonal population.","volume":"174","author":"Meier A.","year":"1996","unstructured":"Meier A. Heifets L. Wallace R. J. Jr. Zhang Y. Brown B. A. Sander P. B\u00f6ttger E. C. Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: observation of multiple 23S rDNA mutations in a clonal population. J. Infect. Dis. 174 1996 354 360","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.2.381"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.12.2625"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.7.1748"},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1093\/genetics\/144.4.1337","article-title":"Adaptive mutation and slow-growing revertants of an Escherichia coli lacZ amber mutant.","volume":"144","author":"Prival M. J.","year":"1996","unstructured":"Prival M. J. Cebula T. A. Adaptive mutation and slow-growing revertants of an Escherichia coli lacZ amber mutant. 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Methods Enzymol. 164 1988 673 690","journal-title":"Methods Enzymol."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/42701"},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1093\/emboj\/16.11.3303","article-title":"Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.","volume":"16","author":"Torkelson J.","year":"1997","unstructured":"Torkelson J. Harris R. S. Lombardo M. J. Nagendran J. Thulin C. Rosenberg S. M. Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation. 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