Mechanisms of interaction among subinhibitory concentrations of antibiotics, human polymorphonuclear neutrophils, and gram-negative bacilli

Abstract

Our hypothesis was that pretreatment of bacteria with subinhibitory concentrations (sub-MICs) of antibiotics enhances the susceptibility of the organisms to killing by human polymorphonuclear neutrophils (PMNs). Our purpose was to study a variety of drugs with different mechanisms of action and to determine whether the mechanism and locus of action altered the sub-MIC effect. The following outcome measures were used: ingestion and killing of bacteria by PMNs, bacterial killing in the absence of phagosome formation, and binding requirements of the bacteria to PMNs. The antibiotics used were representative of a variety of classes, including beta-lactams (piperacillin and imipenem) and quinolones (ciprofloxacin). Bacterial uptake and killing were measured by using standard techniques, and results were analyzed by using the analysis-of-variance technique and Dunnett's t test. Pretreatment of Escherichia coli with all drugs showed significantly enhanced killing of bacteria by PMNs, which was independent of ingestion by the phagocytes. Even in the absence of phagosome formation, statistically significant killing persisted with piperacillin-pretreated bacteria but not with imipenem-or ciprofioxacin-pretreated organisms. The opsonization experiments showed that contact between bacteria and PMNs was necessary for killing to occur. The sub-MIC effect appears to be independent of the locus or mechanism of action of the antibiotic. It results in enhanced killing by PMNs which is independent of ingestion and also may persist even in the absence of phagosome formation. Killing is dependent upon specific contact between bacteria and an intact phagocyte.

Pharmacodynamic activity of a cephalosporin, Ro 40-6890, in human skin blister fluid: antibiotic activity in concert with host defense mechanisms

“…Results from our in vitro studies indicate that human blood-derived PMN enhance the killing effect of the cephalosporin against S. aureus. Furthermore, ex vivo, this amplified effect of host defense to the antimicrobial activity of the cephalosporin could be confirmed in the majority of incubations with CCBF Of <MIC for 2 h. Studies by Mandell et al (13) into the mechanisms of interaction among subMICs of different antibiotics, PMN, and an Escherichia coli strain have shown an enhanced killing that was unrelated to any change in uptake by PMN and that contact between bacteria and PMN was essential for killing. Investigations into the mechanism(s) by which cell wall-active antibiotics augment bactericidal susceptibility to killing by PMN suggest that modified surface characteristics of the microorganism play a crucial role in bacterial death (17).…”

Pretreatment of Pseudomonas aeruginosa with a sub-MIC of imipenem enhances bactericidal activity of neutrophils

“…PALE is mainly known to occur with aminoglycosides, macrolides, and carbapenems. In general, it is thought that PALE results from intracellular penetration, causing changes to the surface structures of bacteria (such as hydrophobicity and adhesiveness) or influencing the production or secretion of 2,4,5,15 However, the bacterial characteristics and host defense factors which mediate the presence or absence of PALE with these antibiotics has not been elucidated. In the present study, we compared the PALE of imipenem at sub-MICs against P. aeruginosa with that of ceftazidime, and attempted to investigate the cellular mechanism of PALE.…”

“…2,[4][5][6][7] In vivo, the PAE is considered to be associated with the influence of antimicrobial agents on bacterial structure and metabolism, which causes microorganisms to become more susceptible to killing by humoral and cellular defense factors such as complement, antibodies, and phagocytes. The PAE involving phagocytes is referred to as postantibiotic leucocyte enhancement (PALE).…”

“…However, clinical efficacy is often observed even when an antibiotic is present at a sub-MIC within a site of bacterial infection. [1][2][3] Such in vivo activity is considered to be attributable, not to the direct bactericidal effect of the antibiotic, but rather, to the postantibiotic effect (PAE) that is observed in vitro.…”

Subinhibitory concentrations of cefpodoxime alter membrane protein expression of Actinobacillus actinomycetemcomitans and enhance its susceptibility to killing by neutrophils

“…Growth of bacteria in subinhibitory concentrations of antibiotics can cause changes in bacterial morphology and in the expression of bacterial surface molecules (2,18). These changes may make the bacteria more susceptible to host defense mechanisms including the bactericidal activities of serum and neutrophils (2,7,20,24,34). Rather than leading to treatment failures, subinhibitory concentrations of some antibiotics may be sufficient to clear in vivo infections (1,18,32,37).…”