No abstract

Nontypeable Haemophilus influenzae (NTHi) is one of the most common pathogens in chronic airway infections and exacerbation. The hallmark of chronic respiratory diseases, including cystic fibrosis, diffuse panbronchiolitis and chronic obstructive pulmonary disease, is mucin overproduction. Prolonged macrolide antibiotic therapy at low doses is known to improve clinical outcome in patients with chronic respiratory diseases via anti-inflammatory effects. In this study, we investigated the effects of macrolide therapy on NTHi-induction of the MUC5AC mucin in human airway epithelial cells. A 15-membered macrolide, azithromycin, but not a 14-membered macrolide, clarithromycin, inhibited NTHi-induction of MUC5AC at both the mRNA and protein levels through selective suppression of activation of the transcription factor activator protein-1. Our findings suggest that each macrolide affects MUC5AC production in different ways and that azithromycin is more suitable for the treatment of NTHi-induced respiratory infection.

Many strains of community-acquired meticillin-resistant Staphylococcus aureus (MRSA) have a pore-forming leukotoxin, known as Panton-Valentine leukocidin (PVL), which can cause severe necrotising pneumonia. Linezolid (LZD) is a new antibacterial agent with potent antibacterial activity against MRSA. In this study, a mouse model of haematogenous pulmonary infection was used to compare the efficacies of LZD and vancomycin (VAN) against pulmonary infection caused by PVL-positive S. aureus. Following antibiotic administration for 3 days, the number of viable bacteria (mean+/-standard error of the mean) in the control, VAN and LZD groups was 6.77+/-0.14, 5.29+/-0.27 and 4.25+/-0.33 log colony-forming units/lung, respectively. LZD significantly decreased the number of viable bacteria in the lungs compared with the control and VAN groups (P<0.05). The survival rate at Day 7 post-inoculation was higher in the LZD group (100%) than in the VAN group (50%) or the control group (0%). Histopathological examination and cytokine analysis also showed the beneficial efficacy of LZD compared with VAN. In conclusion, LZD significantly reduced bacterial numbers and inflammation in a mouse model of PVL-positive S. aureus haematogenous infection and improved the survival rate of infected mice compared with VAN. LZD is clinically effective against PVL-positive S. aureus.

No abstract

Clarithromycin is a 14-member lactone ring macrolide with potent activity against Haemophilus influenzae, including ampicillin-resistant strains. We evaluated the in vivo efficacy of clarithromycin at 40 mg/day and 100 mg/day for 3 days in the treatment of a murine model of pneumonia using a macrolide-resistant H. influenzae strain, which was also ampicillin resistant. The MIC of clarithromycin was 64 g/ml. The viable bacterial counts in infected tissues after treatment with 100 mg clarithromycin/kg of body weight were lower than the counts obtained in control and 40-mg/kg clarithromycin-treated mice. The concentrations of macrophage inflammatory protein 2 (MIP-2) and interleukin 1␤ (IL-1␤) in bronchoalveolar lavage fluid (BALF) samples from mice treated at both concentrations were lower than in the control group. Pathologically, following infection, clarithromycin-treated mice, particularly at a dose of 100 mg/kg, showed lower numbers of neutrophils in alveolar walls, and inflammatory changes had apparently improved, whereas large aggregates of inflammatory cells were observed within the alveoli of control mice. In addition, we demonstrated that clarithromycin has bacteriological effects against intracellular bacteria at levels below the MIC. Our results indicate that clarithromycin may be useful in vivo for macrolide-resistant H. influenzae, and this phenomenon may be related to the good penetration of clarithromycin into bronchoepithelial cells. We also believe that conventional drug susceptibility tests may not reflect the in vivo effects of clarithromycin.