Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults

Study objective: To determine the steady-state, extracellular, and intracellular pulmonary disposition of morifloxacin (MXF), levofloxacin (LEVO), and azithromycin (AZI) relative to that of the plasma over a 24-h dosing interval. Design: Randomized, multicenter, open-label investigation. Patients: Forty-seven older adults (mean [± SD] age, 62 ± 13 years) undergoing diagnostic bronchoscopy. Interventions: Oral administration of MXF, 400 mg, LEVO, 500 mg daily for five doses, or AZI, 500 mg for one dose, then 250 mg daily for four doses. BAL and venipuncture were completed at 4, 8, 12, or 24 h following the administration of the last dose. Measurements and results: Steady-state MXF, LEVO, and AZI concentrations were determined in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs). The concentrations of all three agents were greatest in the AMs followed by the ELF compared to the plasma. Plasma concentrations were similar to those previously reported with these agents. The mean ELF concentrations at 4, 8, 12, and 24 h were as follows: MXF, 11.7 ± 11.9, 7.8 ± 5.1, 10.5 ± 3.7, and 5.7 ± 6.3 μg/mL, respectively; LEVO, 15.2 ± 4.5, 10.2 ± 6.7, 6.9 ± 4.4, and 2.9 ± 1.7 μg/mL, respectively; and AZI, 0.6 ± 0.4, 0.7 ± 0.4, 0.9 ± 0.5, and 0.9 ± 0.7 μg/mL, respectively. The AM concentrations at 4, 8, 12, and 24 h were as follows: MXF, 47.7 ± 47.6, 123.3 ± 126.4, 26.2 ± 19.4, and 32.8 ± 16.5 μg/mL, respectively; LEVO, 28.5 ± 30.2, 26.1 ± 15.7, 28.3 ± 12.6, and 8.2 ± 6.1 μg/mL, respectively; and AZI, 71.8 ± 50.1, 73.8 ± 75.3, 155.9 ± 81.3, and 205.2 ± 256.3 μg/mL, respectively. Conclusions: The intrapulmonary concentrations of MXF, LEV, and AZI were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC₉₀) of the common intracellular pathogens (< 1 μg/mL). These data indicate that attainable extracellular concentrations of AZI are insufficient to reliably eradicate Streptococcus pneu-moniae, based on the agent's current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC₉₀ of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 μg/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 μg/mL) throughout the dosing interval.