Novel Method to Maximize Levofloxacin Pharmacodynamics for the Treatment of Systemic Gram Negative Infections Based on the Population Distribution of Patient Demographics at a Community Hospital

Objectives: To develop institution specific LVX dosing guidelines based on the population distribution of patient demographics and the MIC distribution of gram negative bacterial isolates at a community hospital.

Methods: Previously published  pharmacokinetic model incorporating a variety of patient demographics was used in this analysis. Probability of Target Attainment (PTA) at different levels of renal function was established with Monte Carlo Simulation (MCS) for MIC ranges of 0.125 to 1ug/mL. Then, Cumulative Fraction of Response (CFR) was calculated targeting a AUCƮ/MIC ratio of at least 125 for PI recommendations. Additionally,administration of LVX at alternative dosing intervals were evaluated to assess their population PTA. The degree of change in drug accumulation with alternative dosing intervals was estimated to assess for it’smagnitude by comparing the median, 5th and 95th percentiles of Cpmin for 750mg LVX q24 h at CrCl of 51ml/min with the median, 5th and 95th percentiles of Cpmin for the alternative dosing regimens at the respective renal function categories.

Results: PI LVX dosing regimens are expected to achieve suboptimal CFR at all renal function categories from 20 to 120 ml/min. Estimated CFRs showed minimal improvement when LVX regimens with a PTA of 0.9 or more at an MIC of 0.25ug/ml were compared with regimens reaching a PTA of 0.9 or more at an MIC of 0.5 ug/ml.Drug accumulation due to more frequent dosing intervals is expected to be similar or lower in magnitude at all levels of renal function than the estimated Cmin median,5th and 95th percentiles for the 750mg LVX q24 h at CrCl of 51ml/min.

Conclusion: We conclude that for the treatment of gram negative infections to achieve the optimal pharmacodynamic index in our patient population,the PI approved dosing regimens provide insufficient coverage. Moreover, treatment of gram negative infections would require the use of more frequent dosing intervals for isolates with an MIC of 0.5 ug/ml.