Norepinephrine in Combination with Antimicrobial Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity [PublishAheadOfPrint]

We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects was coupled to bacterial replication rate, the latter of which was modulated with sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment in vitro infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when administered with a pharmaceutical agent that increases bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was Escherichia coli JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the in vitro infection model, human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] of 6) with and without norepinephrine as a continuous infusion (275 mg/L). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log₁₀ CFU reduction in bacterial density over the first 6-8 hours of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/L). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.

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