Background and objective : Current North American guidelines advocate the use of respiratory fluoroquinolones for the empirical management of community-acquired pneumonia (CAP). While community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a pathogen frequently encountered in skin and skin structure infections, it has also now been recognised as a causative pathogen in CAP. Since fluoroquinolones may be used empirically to treat unsuspected CA-MRSA pneumonia, the objective of this study was to evaluate the antibacterial properties of levofloxacin and moxifloxacin using human simulated drug exposures in epithelial lining fluid (ELF). Methods : An in vitro model was used to simulate the ELF concentrations, previously determined in older adults receiving multiple doses, of levofloxacin 500mg once daily and moxifloxacin 400mg once daily. Four CA-MRSA isolates were studied at a starting inoculum of 10 6 colony-forming units (CFU)/mL; selected isolates were also studied at 10 8 CFU/mL. Bacterial density and resistance were quantitatively assessed over 48 hours. Drug exposure (area under the concentration-time curve [AUC]) was confirmed using validated drug assays. Results : At a standard 10 6 starting inoculum, sustained bacterial kill (3.6–4.5 log) with both fluoroquinolones was noted for CA-MRSA isolates 27 and 44 (AUC/minimum inhibitory concentration [MIC] = 383–3923). Despite an MIC of 8 μg/ mL (AUC/MIC = 25) for isolate 3, levofloxacin displayed a 2.8 log kill, while moxifloxacin (MIC 1 μg/mL) sustained a 4.5 log kill (AUC/MIC = 207) over 48 hours. Against isolate 59, levofloxacin displayed no antibacterial effect (AUC/MIC = 3), while moxifloxacin with an MIC of 8 μg/mL (AUC/MIC = 31) killed 4.6 log. At a high inoculum (108), both fluoroquinolones showed 5.2–5.6 log kill for the susceptible isolate (44), while moxifloxacin showed no antibacterial activity against isolate 59. Drug exposure (AUC/MIC) appeared to correlate well (r 2 = 0.99) with the change in log CFU/mL. Maximal activity was observed for both drugs at an AUC/MIC of approximately 30. Conclusion : When evaluated at human simulated ELF concentrations, both levofloxacin and moxifloxacin appeared to demonstrate sustained antibacterial activity for CA-MRSA isolates with MICs ≤ 8 μg/mL at a starting inoculum of 10 6 . Use of a high inoculum (10 8 ) appeared to compromise the antimicrobial activity of the fluoroquinolones when the MIC was 8 μg/mL, but did not mitigate antibacterial kill for susceptible isolates.
Investments in systems biology approaches by the pharmaceutical industry have not yet yielded the payoffs envisaged by many. In most cases, a plethora of novel drug targets arising from genomics led to many more failed projects in the pipeline, suggesting that target-based drug discovery may not be an optimal strategy for the industry. Before high-throughput “-omics” technologies and computer analysis became commonplace, most drug candidates were laboriously screened in animal systems to identify compounds that produced useful responses. Interestingly, the targets of many of the compounds that became drugs are still uncertain to this day. It is likely that drugs act on multiple targets in concert over time, the identification of which will require not only system level cataloguing and measurements, but next generation multiscale systems modelling. The concept of a “differentiated drug response” — elucidating and integrating responses composed of a range of effects on different tissues and, importantly, different time scales — may eventually prove to be the dominant paradigm of systems biology research. In this article, we explore key relevant concepts and technologies that we believe are critical for the future of systems biology and its place in pharmaceutical research.
Objective: The aim of this study was to investigate the extent of variations in lamotrigine serum concentrations between two immediate-release tablet formulations. Data were compared with in vitro difference and similarity tests on dissolution profiles of the two formulations. Methods: Dissolution characteristics of formulations A (reference) and B (test) were evaluated at three points spanning the physiologic pH range (pH 1.2, pH 4.5, pH 6.8). A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. A clinical study was performed with 16 patients who were divided into two groups — one group received formulation A (n=9) and the other received formulation B (n=7). Lamotrigine steady-state concentrations were determined by high-performance liquid chromatography on a reverse-phase column. Results: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97±4.1 μg/mL; formulation B: 5.78±2.7 μg/mL). Dissolution profiles of the two formulations were similar in the pH 1.2 dissolution medium; however, the dissolution profiles of formulation B were outside the dissolution limit (≥85% at 15 minutes) in the pH 4.5 and 6.8 dissolution media. Conclusions: No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations. There is no evidence to suggest that the differences in dissolution profiles at pH 4.5 and pH 6.8 affect the therapeutic efficacy of the formulations. It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study. This investigation was a pilot study and thus further investigations with a larger sample size are necessary to determine if there is a connection between dissolution profiles and the therapeutic effect of investigated formulations.
