Abstract
BackgroundNonencapsulated and nontypeable Haemophilus influenzae (NTHi) is a major cause of human respiratory tract infections. Some strains of NTHi can cause invasive diseases such as septicemia and meningitis, even if H. influenzae is not generally considered to be an intracellular pathogen. There have been very few reports about the therapeutic efficacy of antibiotics against respiratory tract infection caused by NTHi in mice because it is difficult for H. influenzae to infect mice. Therefore, we evaluated the efficacy of antibiotics against NTHi in both a cell culture model and a mouse model of infection.MethodsWe used six strains of NTHi isolated from adult patients with chronic otitis media, namely three β-lactamase-negative ampicillin (AMP)-resistant (BLNAR) strains and three β-lactamase-negative AMP-susceptible (BLNAS) strains, to evaluate the efficacy of AMP, cefcapene (CFPN), levofloxacin (LVX), clarithromycin (CLR), and azithromycin (AZM) in both a cell culture infection model and a mouse infection model. In the cell culture infection model, strains that invade A549 human alveolar epithelial cells were treated with each antibiotic (1 μg/ml). In the mouse infection model, female C57BL/6 mice were intraperitoneally injected with cyclophosphamide (200 mg/kg) three days before intranasal infection with 1 × 109 colony-forming units (CFU) of NTHi and on the day of infection. After infection, the mice were orally administered each antibiotic three times daily for three days, except for AZM, which was administered once daily for three days, at a dose of 100 mg/kg/day.ResultsIn the cell culture infection model, it was found that two BLNAR strains were able to enter the cell monolayers by the process of macropinocytosis, and treatment with LVX yielded good bactericidal activity against both strains inside the cells. In the mouse infection model, no bacteria were detected by means of plating the lung homogenates of LVX-treated mice at day 4 after infection, while more than 105 CFU of bacteria per tissue sample were detected in nontreated mice.ConclusionOur findings show the outcome and rich benefits of fluoroquinolone treatment of respiratory infections caused by either invasive or noninvasive BLNAR strains of NTHi.
Highlights
Nonencapsulated and nontypeable Haemophilus influenzae (NTHi) is a major cause of human respiratory tract infections
It has been reported that NTHi can pass through viable cell layers of the human lung epithelial cell line NCI-H292 by paracytosis, requiring bacterial protein synthesis, even though the passage time is dependent on the growth rate, which is influenced by the bacterial strains [4]
The minimum inhibitory concentration (MIC) ranges of the antibiotics tested against the three β-lactamase-negative AMP-resistant Haemophilus influenzae (BLNAR) and the three β-lactamase-negative AMP-susceptible Haemophilus influenzae (BLNAS) strains were as follows: BLNAR, AMP 1–4 mg/l; AZM 0.25–8 mg/l; CLR ≥ 8 mg/l; CFPN 1 mg/l; LVX ≤ 0.125 mg/l; and GEN 4 mg/l; BLNAS, AMP 0.25–0.5 mg/l; AZM 4–8 mg/l; CLR 8–16 mg/l; CFPN 0.063–0.125 mg/l; LVX ≤ 0.125 mg/l; and GEN 2– 4 mg/l
Summary
Nonencapsulated and nontypeable Haemophilus influenzae (NTHi) is a major cause of human respiratory tract infections. There have been very few reports about the therapeutic efficacy of antibiotics against respiratory tract infection caused by NTHi in mice because it is difficult for H. influenzae to infect mice. Nonencapsulated and nontypeable H. influenzae (NTHi) are consistently over 1,000 times more invasive than Hib [2]. Some strains of NTHi can cause invasive diseases such as septicemia and meningitis, which suggests that the bacteria can pass through the cell layers and survive within both epithelial and endothelial cells [3]. NTHi is a major cause of human infections at present, to the best of our knowledge only one comparative evaluation of antibiotics using an NTHi infection model in mice has been reported [5]. As a matter of fact, mouse models of infection are not typical for H. influenzae because it is difficult for this bacterium to infect mice via the respiratory route
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