Kinetic Study of the Inflammatory Response in Streptococcus pneumoniae Experimental Pneumonia Treated with the Ketolide HMR 3004

Abstract

Patients still die from Streptococcus pneumoniae pneumonia after initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing. There is growing evidence that overwhelming inflammation resulting from toxin release contributes to tissue injury, shock, and death. Monitoring host response may help us understand the consequences of antibiotic therapy for the inflammatory processes that occur in bacterial pneumonia. HMR 3004 is a ketolide that displays excellent in vitro activity against S. pneumoniae. In the present experiment, we investigated the chronology of inflammatory events that occur during pneumococcal pneumonia in mice treated with HMR 3004. Infection of mice with 10 7 CFU of living S. pneumoniae resulted in 100% mortality within 5 days. HMR 3004 given at 12.5 mg/kg of body weight/dose twice daily from 48 h postinfection achieved complete bacterial clearance from lungs and blood within 36 h and ensured survival of mice. Recruitment of neutrophils and monocytes from blood to lungs was significantly reduced, and nitric oxide release was totally prevented. Interleukin-6 secretion in lungs and blood became rapidly undetectable after initiation of therapy. Histological examination of lung tissue showed protection of interstitium against edema. By controlling bacterial invasion, HMR 3004 led to rapid and profound modifications of the host response in lungs, which may protect mice from deleterious inflammatory reactions.Streptococcal pneumonia is the most common cause of community-acquired bacterial pneumonia. The worldwide increase in the resistance of Streptococcus pneumoniae to penicillin G and other antimicrobials has dramatically complicated the management of pneumococcal infections (2,16,17,25). HMR 3004 belongs to the ketolide family, which represents a class of 14-membered ring macrolide agents that are characterized by a keto group at position 3 of the macrolactone ring, which replaces the L-cladinose moiety of other members of the macrolide group. Studies with HMR 3004 have indicated that ketolides offer a potential alternative for treating penicillin-and erythromycin-resistant S. pneumoniae strains (1,7,12,20,21). HMR 3004 activity was tested against erythromycin-resistant pneumococci in murine pneumonia models: the bactericidal activity of the drug in the lungs was associated with good pulmonary diffusion and a slightly prolonged half-life compared to those of typical 14-membered ring macrolides (P. Rajagopalan-Levasseur, E. Vallée, C. Agouridas, J. F. Chantot, and J. J. Pocidalo, Abstr. 35th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F173, 1995).Pulmonary phagocytic cell recruitment and inflammatory mediator release also play a pivotal role in the effective killing of respiratory pathogens. However, there is increasing evidence indicating that during acute bacterial pneumonia the combination of bacterial virulence factors and excessive inflammatory reactions from the host together contribute to induce severe lung injury, shock, and death (reviewed in references 3...

Inhibition of T Cells Provides Protection against Early Invasive Pneumococcal Disease

“…In addition, a growing number of S. pneumoniae isolates with resistance to high concentrations of penicillin or multiple classes of antimicrobials has emerged (10,36). There is increasing evidence that the inflammation induced by the bacteria significantly contributes to the high mortality seen with pneumococcal bacteremia and pneumonia (4,12). In accordance with this observation, the case-fatality rate of IPD remains high, despite the general availability of antimicrobials (24,34).…”

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

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Protease Inhibitors Extracted fromCaesalpinia echinataLam. Affect Kinin Release during Lung Inflammation

“…For the lung inflammation model, we used the methodology described by Duong et al, 2001 [25], with some modifications. Male three-month-old Wistar rats, weighing approximately 250 g, were obtained from the Central Biotery at the Universidade Federal de Sao Paulo.…”