Deciphering longitudinal optical-density measurements to guide clinical dosing regimen design: A model-based approach

Rapid In Vitro Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology

“…Of course, in addition to the above inherent limitation, secondary issues with optical density instruments may arise from multiple difficulties in the reliable translation of optical density to a number of bacterial cells. Nevertheless, such difficulties, which are expounded on in Section 4 , proved surmountable in the work reported here, a fact that underscores the remarkable robustness of the proposed methodology [ 18 , 19 ] and raises expectations for improvements with the future availability of better optical density instruments.…”

Rapid <em>In Vitro </em>Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology

“…filaments at concentrations close to the MIC) thus inadvertently changing again the optical signature observed. Nevertheless, results show remarkable robustness of the proposed mathematical modeling method based on optical density data [29,30]. Of course, it is also reasonable to expect that improvements in optical density instruments will help improve the applicability of the proposed method.…”

“…In addition to the above inherent limitation, secondary issues with optical density instruments may arise from multiple difficulties in reliably translating optical density to number of bacterial cells. The following examples are representative of systematic error sources: To extend their dynamic range, many optical density instruments change measurement method from scattering to absorption, based on a threshold value of bacterial concentration, thus possibly introducing calibration errors [30]; Dead cells decompose over time, thus changing the optical signature of the cell suspension and making corresponding adjustments necessary; Concentration of cells in suspension used in the instrument may not be uniform, if mixing is not adequate, thus biasing measurements; A number of antibiotics, such as fluoroquinolones, can induce morphological changes to exposed bacteria (e.g. filaments at concentrations close to the MIC) thus inadvertently changing again the optical signature observed.…”

“…The suitability of the proposed model-based methodology to start from optical density time-kill measurements and eventually guide individualized dosing regimen design for clinically relevant pharmacokinetics, was experimentally validated in vitro in [30]. In that study, longitudinal optical density measurements were collected using the same instrument as in section 3.1.…”

“…In both cases drugs were injected every 𝑇𝑇 = 8 h with subsequent exponential decline of concentration from its peak of 𝐶𝐶 max , with corresponding half-life of 𝑑𝑑 1/2 = 2.5 h. Selected for testing in the in vitro HFIM were 𝐶𝐶 max = 60, 150 mg/L for case (a) and 𝐶𝐶 max, ceftazidime /𝐶𝐶 max, amikacin = 40/20 (mg/L)/(mg/L) for case (b) with corresponding probabilities 59%, 38%, and 98%, respectively. Figure reproduced from[30].…”