Impact of cethromycin (ABT-773) therapy on microbiological, histologic, immunologic, and respiratory indices in a murine model of Mycoplasma pneumoniae lower respiratory infection.
Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections. We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were inoculated intranasally once with 10(6) CFU of M. pneumoniae on day 0. Treatment was started 24 h after inoculation. Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice. Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation. Outcome variables included bronchoalveolar lavage (BAL) for M. pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin-1beta [IL-1beta], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1alpha [MIP-1alpha]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively. The cethromycin-treated mice had a greater reduction in M. pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05). HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05). Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-alpha, IFN-gamma, IL-1beta, IL-8, IL-12, MCP-1, and MIP-1alpha) on day 4 (P < 0.05). PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05). In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR.
Ríos
Ana María
AM
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. ana.rios@utsouthwestern.edu
Mejías
Asunción
A
Chávez-Bueno
Susana
S
Fonseca-Aten
Mónica
M
Katz
Kathy
K
Hatfield
Jeanine
J
Gómez
Ana María
AM
Jafri
Hasan S
HS
McCracken
George H
GH
Ramilo
Octavio
O
Hardy
Robert Doug
RD
D000402:Airway Obstruction / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002511:Cephalosporins / Q000627:therapeutic use*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004917:Erythromycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D048628:Ketolides; D008168:Lung / Q000276:immunology; D051379:Mice; D009177:Mycoplasma pneumoniae; D010991:Plethysmography; D011019:Pneumonia, Mycoplasma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015656:Respiratory Mechanics / Q000502:physiology*; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D002511:Cephalosporins; D018925:Chemokines; D016207:Cytokines; D048628:Ketolides; D004917:Erythromycin; C405499:cethromycin