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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThe rapid emergence of antibiotic resistance is a major public health concern [Zhang L et al. \u003Cem\u003EAppl Environ Microbiol\u003C\/em\u003E 2011]. This article discusses five questions of resistant bacteria in the gut: Their possible presence without antibiotic exposure; Whether there is selection of resistant gut bacteria during antimicrobial exposure; Whether there is selection of resistance during systemic treatment for other infections; Whether it is possible to avoid or minimize selection; How optimization of treatment relates to selection of resistance in the gut.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDrug Resistance\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EResistance in the Gut\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EThe rapid emergence of antibiotic resistance is a major public health concern [Zhang L et al. \u003Cem\u003EAppl Environ Microbiol\u003C\/em\u003E 2011]. Johan W. Mouton, MD, Nijmegen Institute for Infection, Inflammation \u0026amp; Immunity, Nijmegen, The Netherlands, discussed five questions of resistant bacteria in the gut:\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n               \u003Cp id=\u0022p-3\u0022\u003ETheir possible presence without antibiotic exposure\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n               \u003Cp id=\u0022p-4\u0022\u003EWhether there is selection of resistant gut bacteria during antimicrobial exposure\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n               \u003Cp id=\u0022p-5\u0022\u003EWhether there is selection of resistance during systemic treatment for other infections\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n               \u003Cp id=\u0022p-6\u0022\u003EWhether it is possible to avoid or minimize selection\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-5\u0022\u003E\n               \u003Cp id=\u0022p-7\u0022\u003EHow optimization of treatment relates to selection of resistance in the gut\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EData suggest that early development of antibiotic resistance in human gut microbiota is independent of an infant\u0027s exposure to antibiotics but is likely to be affected by exposure to maternal and environmental microbes during and after delivery. The population of food-borne antibiotic-resistant bacteria is also significantly amplified within the host, even in the absence of antibiotic-selective pressure [Zhang L et al. \u003Cem\u003EAppl Environ Microbiol\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EProf. Mouton cited a study in which 2 of 20 children with no known antibiotic exposure, living in a very remote Senegalese village, were fecal carriers of a multiresistant \u003Cem\u003EEscherichia coli\u003C\/em\u003E clone that produced CTX-M-15 [Ruppe E et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2009], strongly suggesting that the pC15\u20131a multidrug-resistant region can persist in the intestinal flora in the absence of significant selective pressure, at least that we know of.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EBased on a report by de Smet et al. [\u003Cem\u003ELancet Infect Dis\u003C\/em\u003E 2011], Prof. Mouton justified the widespread use of selective digestive tract decontamination in intensive care units with low levels of antibiotic resistance. Prof. Mouton presented an extensive analysis of an experimental study that looked at the effects and duration of antimicrobial treatment for pneumonia in selecting resistant microorganisms in the gut [Goessens WH et al. \u003Cem\u003EJAC\u003C\/em\u003E 2007]. This showed that the more frequent the dosing regimen, the higher the propensity for selecting resistant bacteria. Emergence of resistance is dependent on dose (inverse U shape), duration of therapy, and dosing regimen. For the first three questions that were posed, Prof. Mouton answered \u201cyes;\u201d \u201cperhaps\u201d to the fourth; and \u201cnot good\u201d to the fifth.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EResistance in a Dynamic Model\u003C\/h2\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EDidier Guillemot, MD, Institut Pasteur\/Univ. Versailles Saint Quentin\/Inserm, Paris, France, discussed the impact of antibiotic dose on resistance selection in the community. His findings were based on a dynamic model of \u003Cem\u003EStreptococcus pneumoniae.\u003C\/em\u003E His presentation covered \u03b2-lactam doses and pneumococci susceptibility, accounting for \u03b2-lactam doses.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EFrom a public health point of view, antibiotics do more to increase the clearance of susceptible bacteria than the acquisition of a new mechanism or resistant strain. Prof. Guillemot noted that much is known about the relation between \u003Cem\u003ES. pneumoniae\u003C\/em\u003E, antibiotics, and resistance, but not at the population level.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EThe mathematical model that he discussed assessed the influence of modifying doses of \u03b2-lactam at the population level to estimate the impact on resistance levels and prevalence in colonized individuals. Questions that were considered using this model included the effects of prescription frequency, prescribed dose, and whether defined daily dose (DDD) is a good indicator to predict the evolution of \u03b2-lactam resistance to \u003Cem\u003ES. pneumoniae.\u003C\/em\u003E Simulations over a 50-year period of fixed- and variable-dose exposure showed a bimodal distribution and that the prevalence of resistance increases with the frequency of exposure. Both findings were consistent with prior epidemiological studies.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EDosing outcomes indicated that higher doses may reduce the prevalence of resistance and increase the minimum inhibitory concentration (MIC) of resistant strains. The model also showed that DDD is not an accurate indicator for predicting pneumococcal resistance to \u03b2-lacams. \u201cDon\u0027t use DDD to anticipate the future of \u003Cem\u003ES. pneumoniae\u003C\/em\u003E dissemination or to analyze the relationship between antibiotic use and \u003Cem\u003ES. pneumoniae\u003C\/em\u003E resistance,\u201d he said.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EWhich Matters More \u2014 Antibiotic Dose or the Bacterium?\u003C\/h2\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EPatrice Courvalin, MD, Institut Pasteur, Paris, France, discussed the relative importance of antibiotic dose or changes in the bacterial genome in causing antibiotic resistance. Bacteria respond to many changes in their environment by sensing small molecules; yet, competence for genetic transformation is transient. In several bacterial species, it depends on achieving a specialized cellular state [Harvarstein LS et al. \u003Cem\u003EProc Natl Acad Sci\u003C\/em\u003E 1995].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EHarvarstein et al. [\u003Cem\u003EProc Natl Acad Sci\u003C\/em\u003E 1995] found that competence-stimulating peptide induced competence in pneumococcal cultures in a dose-response fashion to the synthetic peptide, with the highest yield (about 5% of cells transformed) observed at doses of 30 to 1000 ng\/mL and a monotonic dose response in the intervening region.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EResistance in \u003Cem\u003EAcinetobacter spp.\u003C\/em\u003E, particularly \u003Cem\u003EAcinetobacter baumannii\u003C\/em\u003E, provides another example. \u003Cem\u003EA. baumannii\u003C\/em\u003E possesses two intrinsic \u03b2-lactamase genes, in addition to weak permeability and efflux systems. Together, they confer a natural reduced susceptibility to antibiotics. Numerous acquired mechanisms of resistance and genetic elements, such as resistance islands, have also been identified [Poirel L et al. \u003Cem\u003EIUBMB Life\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EBased on these and other findings, Prof. Courvalin concluded that antibiotics promote evolution of resistance (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/12\/19\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Antibiotics Promote Evolution of Resistance.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1677342309\u0022 data-figure-caption=\u0022Antibiotics Promote Evolution of Resistance.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/12\/19\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/12\/19\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/12\/19\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12449\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-19\u0022 class=\u0022first-child\u0022\u003EAntibiotics Promote Evolution of Resistance.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from P. Courvalin, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EPK-PD and Resistance\u003C\/h2\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EWilliam A. Craig, MD, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA, discussed the use of pharmacodynamics\/pharmacokinetics (PD\/PK) to establish the target that is required to prevent an increase in resistant populations; to identify which PK\/PD indices (C\u003Csub\u003Emax\u003C\/sub\u003E, AUC\/MIC, T\u0026gt;MIC) or other characteristics best prevent the emergence of resistance; and to determine the magnitude of the PK\/PD indices or other characteristics that is required to prevent the development of resistance.\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EWith regard to the mutant prevention concentration (MPC) that stops mutant selection at 10\u003Csup\u003E10\u003C\/sup\u003E organisms, he reported that MPC is usually 2- to 16-fold higher than MIC, with selection of resistance higher if drug concentrations persist in the zone between the two concentrations [Blondeau JM et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2001]. He also pointed out the inverted U-shaped distribution of resistance emergence versus dose intensity [Tam VH et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-22\u0022\u003EDr. Craig discussed aminoglycide dosing to minimize resistance for \u003Cem\u003EEnterobacteriaceae\u003C\/em\u003E and \u003Cem\u003EStaphyloccocus aureus\u003C\/em\u003E (Cmax\/MIC \u0026gt;6 [once-daily dosing]) and the need for a Cmax\/MIC of 30 with twice-daily dosing of gentamicin to prevent emergence of resistance with \u003Cem\u003EP. aeruginosa\u003C\/em\u003E [Tam VH et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2008].\u003C\/p\u003E\n         \u003Cp id=\u0022p-23\u0022\u003EIn addition, he covered PK\/PD indices that are associated with \u003Cem\u003Ein vitro\u003C\/em\u003E enhancement or suppression of fluoroquinolone resistance, including AUC\u003Csub\u003E24\u003C\/sub\u003E\/MIC, AUC\u003Csub\u003E24\u003C\/sub\u003E\/MPC, and Cmax\/MIC, and how doxycycline, combined with moxifloxacin, can reduce emergence of resistant \u003Cem\u003ES. aureus\u003C\/em\u003E [Allen GP, Deshpande LM. \u003Cem\u003EInt J Antimicrob Agents\u003C\/em\u003E 2010]. Dr. Craig concluded that there is a need for more \u003Cem\u003Ein vivo\u003C\/em\u003E studies on optimal dosing and combination therapy to effectively prevent resistance.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/12\/19.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmxdp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmxdp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}