Clarithromycin Accumulation by Phagocytes and Its Effect on Killing of <i>Aggregatibacter actinomycetemcomitans</i>

Iskandar, Irma; Walters, John D.

doi:10.1902/jop.2010.100221

Cited by 12 publications

(17 citation statements)

References 46 publications

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“…Inhibitors of the P-glycoprotein efflux pump increased the intracellular accumulation of AZM and enhanced the killing of intracellular bacteria. Similarly, PMNs that take up and accumulate CLR exhibit enhanced phagocytic killing of the leukotoxinproducing Y4 strain of A. actinomycetemcomitans (18). Our findings can also be related to a previous study of antibiotic killing of A. actinomycetemcomitans NCTC 9710 within cultured KB epithelial cells (33).…”

Section: Discussionsupporting

confidence: 84%

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Azithromycin Kills Invasive Aggregatibacter actinomycetemcomitans in Gingival Epithelial Cells

Lai

Walters

2013

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 84%

“…Clarithromycin (CLR), a closely related macrolide, is also actively transported and accumulated by human oral epithelial cells, gingival fibroblasts, and PMNs (17,18). PMNs that have taken up CLR exhibit enhanced phagocytic killing of intracellular A. actinomycetemcomitans (18).…”

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confidence: 99%

Azithromycin Kills Invasive Aggregatibacter actinomycetemcomitans in Gingival Epithelial Cells

Lai

Walters

2013

Antimicrob Agents Chemother

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“…A similar study has been conducted with CLR, 21 a macrolide that has a shorter half-life than AZM, is more active against P. gingivalis and Prevotella intermedia , and is comparably effective against A. actinomycetemcomitans . 15,22,32 As with AZM, the most significant differences in killing A. actinomycetemcomitans by control and CLR-loaded neutrophils were observed at a relatively high MOI (100).…”

Section: Discussionmentioning

confidence: 85%

“…However, the transport velocity and the degree of intracellular concentration observed with AZM are lower than those of CLR. 21 In spite of this, the results suggest that neutrophils exposed to 2 μg/mL AZM while migrating through periodontal connective tissue toward the gingival crevice could accumulate an intracellular AZM concentration of ≈10 μg/mL. This is 20-fold higher than its MIC for A. actinomycetemcomitans strain Y4, at least five- to 40-fold higher than its MIC for most other strains of A. actinomycetemcomitans (0.25 to 2.0 μg/mL), and 10- to 80-fold higher than its MIC for most strains of Porphyromonas gingivalis (0.125 to 1.0 μg/mL).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin Enhances Phagocytic Killing of Aggregatibacter actinomycetemcomitans Y4 by Human Neutrophils

Lai

Schibler

Walters

2015

Journal of Periodontology

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Background Aggregatibacter actinomycetemcomitans resists killing by neutrophils and is inhibited by azithromycin (AZM) and amoxicillin (AMX). AZM actively concentrates inside host cells, whereas AMX enters by diffusion. The present study is conducted to determine whether AZM is more effective than AMX at enhancing phagocytic killing of A. actinomycetemcomitans by neutrophils. Methods Killing assays were conducted in the presence of either 2 μg/mL AZM or 16 μg/mL AMX (equipotent against A. actinomycetemcomitans). Neutrophils were loaded by incubation with the appropriate antibiotic. Opsonized A. actinomycetemcomitans strain Y4 was incubated with the indicated antibiotic alone, with loaded neutrophils and antibiotic, or with control neutrophils (without antibiotic) at multiplicities of infection (MOIs) of 30 and 90 bacteria per neutrophil. Results Neutrophil incubation with 2 μg/mL AZM yielded an intracellular concentration of 10 μg/mL. At an MOI of 30, neutrophils loaded with AZM failed to kill significantly more bacteria than control neutrophils during the 60- and 90-minute assay periods. At an MOI of 90, neutrophils loaded with AZM killed significantly more bacteria than either AZM alone or control neutrophils during 60- and 90-minute incubations (P <0.05), and killed significantly more bacteria after 90 minutes than the sum of the killing produced by AZM alone or neutrophils alone. Neutrophils incubated with AMX under identical conditions also killed significantly more bacteria than either AMX alone or control neutrophils, but there was no evidence of synergism between AMX and neutrophils. Conclusions Neutrophils possess a concentrative transport system for AZM that may enhance killing of A. actinomycetemcomitans. Its effects are most pronounced when neutrophils are greatly outnumbered by bacteria.

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“…Moreover, in ventilator-associated pneumonia (VAP) patients with clarithromycin-resistant bacterial infections, combined treatment with clarithromycin was positively correlated with the time of resolution of the infection (4). Although it was proposed that some macrolides could induce degranulation and bacterial killing in polymorphonuclear neutrophils (PMNs), knowledge regarding their role in these cells has been very limited (5,6).…”

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Immunomodulatory Role of Clarithromycin in Acinetobacter baumannii Infection via Formation of Neutrophil Extracellular Traps

Konstantinidis

Kambas

Mitsios

et al. 2016

Antimicrob Agents Chemother

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eMacrolide antibiotics have been shown to act as immunomodulatory molecules in various immune cells. However, their effect on neutrophils has not been extensively investigated. In this study, we investigated the role of macrolide antibiotics in the generation of neutrophil extracellular traps (NETs). By assessing ex vivo and in vivo NET formation, we demonstrated that clarithromycin is able to induce NET generation both in vitro and in vivo. Clarithromycin utilizes autophagy in order to form NETs, and these NETs are decorated with antimicrobial peptide LL-37. Clarithromycin-induced NETs are able to inhibit Acinetobacter baumannii growth and biofilm formation in an LL-37-dependent manner. Additionally, LL-37 antimicrobial function depends on NET scaffold integrity. Collectively, these data expand the knowledge on the immunomodulatory role of macrolide antibiotics via the generation of LL-37-bearing NETs, which demonstrate LL-37-dependent antimicrobial activity and biofilm inhibition against A. baumannii.

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Clarithromycin Accumulation by Phagocytes and Its Effect on Killing of Aggregatibacter actinomycetemcomitans

Cited by 12 publications

References 46 publications

Azithromycin Kills Invasive Aggregatibacter actinomycetemcomitans in Gingival Epithelial Cells

Azithromycin Kills Invasive Aggregatibacter actinomycetemcomitans in Gingival Epithelial Cells

Azithromycin Enhances Phagocytic Killing of Aggregatibacter actinomycetemcomitans Y4 by Human Neutrophils

Immunomodulatory Role of Clarithromycin in Acinetobacter baumannii Infection via Formation of Neutrophil Extracellular Traps

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