ABSTRACT
The entry of an antibiotic into phagocytes is a prerequisite for its intracellular bioactivity against susceptible facultative or obligatory intracellular microorganisms. AF 3013 is a new fluoroquinolone, and its uptake into and elimination from mouse peritoneal macrophages, together with its effects on phagocytic and antimicrobial mechanisms against Klebsiella pneumoniae, were investigated. AF 3013 efficiently penetrated into phagocytic cells at all concentrations tested. The uptake proceeded rapidly and was energy independent, since it was not affected by cell viability, environmental temperature or the addition of a metabolic inhibitor. Therefore, a possible passive transmembrane diffusion mechanism might be proposed. The elution of AF 3013 from macrophages occurred relatively slowly; in fact, 60 min after the removal of extracellular AF 3013, nearly 40% of the drug still remained in the phagocytes. Exposure to 1 MIC of AF 3013 significantly enhanced macrophages phagocytosis and increased intracellular bactericidal activity against K. pneumoniae. Following preexposure of macrophages to 1 MIC of AF 3013, there was a significant increase in both phagocytosis and killing, compared with the controls, indicating the ability of AF 3013 to interact with biological membranes and remain active within phagocytes. Preexposure of Klebsiella to AF 3013 made the bacteria more susceptible to the bactericidal mechanisms of macrophages than untreated organisms.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Fluoroquinolones , Klebsiella pneumoniae/drug effects , Macrophages, Peritoneal/metabolism , Phagocytosis/drug effects , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Infective Agents/pharmacokinetics , Cell Survival , Diffusion , In Vitro Techniques , Macrophages, Peritoneal/drug effects , Mice , Temperature , Time FactorsABSTRACT
The recent increase in the incidence of infections due to Streptococcus pneumoniae resistant to penicillin and other antibiotics, often associated with considerable morbidity and mortality, has been recognized as an alarming problem. From the recent medical literature data it emerges that among beta-lactam antibiotics used as an empiric treatment for infections caused by S. pneumoniae, amoxycillin and amoxycillin/clavulanic acid are the most active oral antibiotics and may be considered as a first-line therapeutic agent for the treatment of these infections. Since the therapeutic result of the treatment of an infection is determined by the combined effect of the antimicrobials and host defenses, we investigated the effect of amoxycillin, with and without clavulanic acid, upon the in vitro interaction between human polymorphonuclear leukocytes (PMNs) and a penicillin-resistant strain of S. pneumoniae. Amoxycillin significantly inhibited the streptococcal uptake by PMNs referred to the control system. Clavulanic acid did not have any significant effect upon the interaction PMNs-S. pneumoniae. The addition of amoxycillin/clavulanic acid to phagocytes and streptococci resulted in a synergystic potentiation of the activity of both drugs upon the PMN functions towards S. pneumoniae in such a manner that the bacteria became more susceptible to either the phagocytosis or the microbicidal activities of phagocytes. These effects came in addition to the intrinsic, excellent antimicrobial properties of this drug combination. Although the clinical significance of the observed enhanced effects of amoxycillin/clavulanate are far from elucidated, the possibility exists that they may play a contributory role, especially in patients with impaired host defense.
