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8/n
…1. Diagnostic implications (cont'd): we realized that ertapenem, which is bulkier, is more affected by porin deficiency than meropenem, whereas both are ~equivalently hydrolyzed by carbapenemases. So we checked, and sure enough, the ratio of ertapenem to meropenem MICs at standard inoculum performs almost as well as the IE at identifying CP-CRE - and since we always measure both erta & mero M
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7/n
…1. Diagnostic implications (cont'd): so what can we do to find CP-CRE better? It turns out meropenem MIC is lousy at distinguishing CP-CRE from non-CP-CRE - almost literally a coin flip, since MIC distributions of CP-CRE and non-CP-CRE cross in the CLSI inoculum range. Measuring the IE does an excellent job at finding CP-CRE, but requires an unacceptable amount of extra work for already-too-b
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4/n
…which means these carbapenemases end up shared with neighbors. (In theory they could be constrained to the periplasm, but at least above a certain cell density, this doesn't seem to be the case: all CP-CRE have a strong IE.
By contrast, porin deficiency, which prevents carbapenems from getting into the periplasm, is a cell-autonomous resistance mechanism that has no effect on neighbors, hence
1 views
5/n
So why is this important? We thought of diagnostic, clinical, and mechanistic implications.
1. Clinical diagnostics: we measure resistance at a certain cell density to guide antibiotic use, so having MICs that vary widely is a problem. The IE is known, so guidance is given on acceptable inoculum range ("CLSI range" in figs) - but even in this range, MICs can vary widely. In fact, 1/3 of CP-CRE
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8/n
…1. Diagnostic implications (cont'd): we realized that ertapenem, which is bulkier, is more affected by porin deficiency than meropenem, whereas both are ~equivalently hydrolyzed by carbapenemases. So we checked, and sure enough, the r…
7/n
…1. Diagnostic implications (cont'd): so what can we do to find CP-CRE better? It turns out meropenem MIC is lousy at distinguishing CP-CRE from non-CP-CRE - almost literally a coin flip, since MIC distributions of CP-CRE and non-CP-CR…
6/n
…1. Diagnostic implications (cont'd): These "unstable" MICs in the approved inoculum range mean that we're most likely to misclassify carbapenemase-producing isolates - just the ones we worry about most, bc they can share carbapenemase…
5/n
So why is this important? We thought of diagnostic, clinical, and mechanistic implications.
1. Clinical diagnostics: we measure resistance at a certain cell density to guide antibiotic use, so having MICs that vary widely is a problem.…
4/n
…which means these carbapenemases end up shared with neighbors. (In theory they could be constrained to the periplasm, but at least above a certain cell density, this doesn't seem to be the case: all CP-CRE have a strong IE.
By contras…
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