Retrospective investigation of combination therapy with clarithromycin and levofloxacin for pulmonary Mycobacterium avium complex disease.

BACKGROUND: Fluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients. METHODS: Pulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate. RESULTS: There were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events. CONCLUSION: The possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.

Serum concentrations of clarithromycin and rifampicin in pulmonary Mycobacterium avium complex disease: long-term changes due to drug interactions and their association with clinical outcomes.

BACKGROUND: Concomitant use of clarithromycin (CAM) and rifampicin (RFP) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease affects the systemic concentrations of both drugs due to CYP3A4-related interactions. To date, however, there has been no report that investigates the long-term relationship between the drug concentrations, CYP3A4 activity, and clinical outcomes. Our aim was to investigate the time course of the drug levels in long-term treatment of subjects with pulmonary MAC disease, and examine the correlation of these concentrations with CYP3A4 activity and clinical outcomes. METHODS: Urine and blood samples from nine outpatients with pulmonary MAC disease were collected on days 1, 15, and 29 (for four subjects, sample collections were continued on days 57, 85, 113, 141, 169, 225, 281, 337, and 365). Serum drug concentrations and urinary levels of endogenous cortisol (F) and 6 beta-hydroxycortisol (6ßOHF), the metabolite of F by CYP3A4, were measured, and evaluated 6ßOHF/F ratio as a CYP3A4 activity marker. In addition, the clinical outcomes of 4 subjects were evaluated based on examination of sputum cultures and chest images. RESULTS: The mean 6ßOHF/F ratio increased from 2.63 ± 0.85 (n = 9) on the first day to 6.96 ± 1.35 on day 15 and maintained a level more than double initial value thereafter. The serum CAM concentration decreased dramatically from an initial 2.28 ± 0.61 µg/mL to 0.73 ± 0.23 µg/mL on day 15. In contrast, the serum concentration of 14-hydroxy-CAM (M-5), the major metabolite of CAM, increased 2.4-fold by day 15. Thereafter, both CAM and M-5 concentrations remained constant until day 365. The explanation for the low levels of serum CAM in pulmonary MAC disease patients is that RFP-mediated CYP3A4 induction reached a maximum by day 15 and remained high thereafter. Sputum cultures of three of four subjects converted to negative, but relapse occurred in all three cases. CONCLUSIONS: Our study demonstrated that serum CAM concentrations in pulmonary MAC disease patients were continuously low because of RFP-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes.

[Effect of osmolality on ion transport in Guinea pig airway epithelial cells].

BACKGROUND: Increased osmolality of the airway surface fluid due to water loss associated with hyperventilation is considered to be a cause of exercise-induced asthma (EIA). AIM: We investigated the influence of changes in osmolality on airway epithelial ion transport in guinea pigs. METHODS: We explored from measuring open circuit potential difference in challenge with hypertonic saline or mannitol. RESULTS: Diphenylamine-2-carboxylate (DPC), amiloride, and disodium cromoglycate (DSCG) prevented an increase of the potential difference (PD) after exposure of tracheal mucosa to 0.9-10.8% hypertonic saline solutions (HSSs) (p < 0.05, p < 0.01, and p < 0.01, respectively on 1.8%). An increase of the PD was observed after a single dose of 1.8% hypertonic saline solution (HSS) was applied to the mucosa, but no increase was observed after a single exposure to a 585 mOsm/kg aqueous mannitol solution (585AMS). The results remained the same when a Cl-free solution was used as the perfusate. The change of airway epithelial cell thickness was only suppressed significantly by DPC (p < 0.01) after 1.8% HSS challenge. CONCLUSIONS: Not only the change of osmolality, but also changes of the Cl- and Na+ concentrations in airway surface fluid seem to have an important influence on the PD. cAMP-dependent Cl- channel may have a role, and the same mechanism may provoke EIA.

Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome.

Serum levels of C-reactive protein (CRP) were measured in 96 consecutive patients with obstructive sleep apnea syndrome (OSAS) before and after nasal continous positive airway pressure treatment. CRP levels only displayed significant correlations with body mass index (BMI) before treatment. No significant changes were observed in BMI and CRP levels after 9 months of treatment. These data suggest that CRP levels in patients with OSAS may be associated with obesity rather than OSAS itself.

Isolated oculomotor nerve palsy in Churg-Strauss syndrome.

A 30-year-old man with bronchial asthma complained of horizontal diplopia. Partial oculomotor nerve palsy with restrictions of elevation and adduction, and mydriasis was observed in the left eye. Cranial magnetic resonance imaging demonstrated an infarct lesion in the territory of the left superior median mesencephalic branch of the posterior cerebral artery. Based on bronchial asthma, hypereosinophilia, mononeuropathy multiplex, pulmonary eosinophilia and positive perinuclear antineutrophil cytoplasmic antibody in the serum, the patient was diagnosed as having Churg-Strauss syndrome. This is the first case of oculomotor nerve palsy due to midbrain infarction associated with Churg-Strauss syndrome.