Synergistic effect of azithromycin on the phagocytic killing ofStaphylococcus aureus by human polymorphonuclear leukocytes

Abstract

Many macrolides have been shown to affect the interaction between bacteria and various immune defense mechanisms, such as chemotaxis, accumulation, and bioactivity within phagocytic cells. The interaction of azithromycin with human polymorphonuclear leukocytes (PMNs) was studied in vitro and compared with the interactions between other macrolides and PMNs. The opsonophagocytic killing of Staphylococcus aureus was synergistically enhanced by azithromycin at concentrations below and above the minimal inhibitory concentration, with a reduction of up to 2.82 log10 cfu/ml with 2 mg/ml of azithromycin. Other macrolides were effective only at subinhibitory concentrations. The beneficial azithromycin-leukocyte interaction may explain azithromycin's efficacy against intracellular pathogens.

Intracellular Penetration and Effects of Antibiotics on Staphylococcus aureus Inside Human Neutrophils: A Comprehensive Review

“…Bacteriostatic effects for macrolides are less pronounced in neutrophils with defective oxidative killing mechanisms. This indicates a synergistic effect with the intrinsic killing mechanisms of neutrophils for this type of antibiotic [62,83,84,86,87,90]. Contrarily, roxithromycin selectively restores functions of defective neutrophils, as low doses increase phagocytosis and intracellular killing of S. aureus [88].…”

“…Inactivation of the antibiotic might occur inside the neutrophil. Some drug molecules are unstable under low pH conditions inside the phagosome, subsequently losing their antibiotic effectivity [75,86]. One or more of the last mechanisms might be the case for macrolide antibiotics like azithromycin, since the intracellular killing seems to be less than expected considering the high C/E ratio [86].…”

“…Some drug molecules are unstable under low pH conditions inside the phagosome, subsequently losing their antibiotic effectivity [75,86]. One or more of the last mechanisms might be the case for macrolide antibiotics like azithromycin, since the intracellular killing seems to be less than expected considering the high C/E ratio [86]. Lastly, although the effect of the antibiotics on neutrophil function did not seem fully responsible for intracellular antibiotic function or the lack thereof, this might be an interesting topic for further research.…”

The Role of Antibiotics in Modulating Virulence in Staphylococcus aureus

“…The authors of that study explained this discrepancy by a reduction in azithromycin's antibacterial activity in the experimental setting, particularly in the acidic lysosome compartment. In addition, Herrera-Insúa et al showed that the bactericidal activity of PMNs was enhanced by sub-MICs of azithromycin, thus contributing to a synergic effect on S. aureus killing (63).…”

Optimal Treatment of Severe Community-Acquired Pneumonia

“…A detailed discussion is beyond the scope of this review but briefly the main hypotheses are: (1) copathogens such as atypical bacteria may be undetected, something serological studies indicate is common in patients with pneumococcal infection [47][48][49]56]; (2) antibiotic synergy is possible although there is little evidence to support this and if anything penicillins and macrolides may be antagonistic [72]; (3) the non-antimicrobial immunomodulatory effects of macrolides which are increasingly being recognized and used therapeutically, especially in panbrochiolitis and cystic fibrosis [73]; (4) other non-antimicrobial effects of macrolides such as impairment of pneumococcal adhesion to epithelia and enhancement of polmorphonuclear cell function [74,75]; (5) antibiotic tolerance being present and leading to misclassification of pneumococci as penicillin sensitive [76]. A detailed discussion is beyond the scope of this review but briefly the main hypotheses are: (1) copathogens such as atypical bacteria may be undetected, something serological studies indicate is common in patients with pneumococcal infection [47][48][49]56]; (2) antibiotic synergy is possible although there is little evidence to support this and if anything penicillins and macrolides may be antagonistic [72]; (3) the non-antimicrobial immunomodulatory effects of macrolides which are increasingly being recognized and used therapeutically, especially in panbrochiolitis and cystic fibrosis [73]; (4) other non-antimicrobial effects of macrolides such as impairment of pneumococcal adhesion to epithelia and enhancement of polmorphonuclear cell function [74,75]; (5) antibiotic tolerance being present and leading to misclassification of pneumococci as penicillin sensitive [76].…”