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. 1991 Jul;35(7):1291–1297. doi: 10.1128/aac.35.7.1291

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

L A Mandell 1, M Afnan 1
PMCID: PMC245160  PMID: 1929284

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 ciprofloxacin-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.

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Selected References

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  1. Adam D. Studies on the influence of host defence mechanisms on the antimicrobial effect of chemotherapeutic agents. I. The inluence of serum constituents on the in vitro effect of gentamicin and polymyxin. Int Z Klin Pharmakol Ther Toxikol. 1971 Feb;4(2):175–182. [PubMed] [Google Scholar]
  2. Davis A. T., Estensen R., Quie P. G. Cytochalasin B. 3. Inhibition of human polymorphonuclear leukocyte phagocytosis. Proc Soc Exp Biol Med. 1971 May;137(1):161–164. doi: 10.3181/00379727-137-35535. [DOI] [PubMed] [Google Scholar]
  3. Dutcher B. S., Reynard A. M., Beck M. E., Cunningham R. K. Potentiation of antibiotic bactericidal activity by normal human serum. Antimicrob Agents Chemother. 1978 May;13(5):820–826. doi: 10.1128/aac.13.5.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gemmell C. G., Peterson P. K., Schmeling D., Kim Y., Mathews J., Wannamaker L., Quie P. G. Potentiation of opsonization and phagocytosis of Streptococcus pyogenes following growth in the presence of clindamycin. J Clin Invest. 1981 May;67(5):1249–1256. doi: 10.1172/JCI110152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Goldstein I. M. Neutrophil degranulation. Contemp Top Immunobiol. 1984;14:189–219. doi: 10.1007/978-1-4757-4862-8_7. [DOI] [PubMed] [Google Scholar]
  6. Jit Sud I., Feingold D. S. Detection of agents that alter the bacterial cell surface. Antimicrob Agents Chemother. 1975 Jul;8(1):34–37. doi: 10.1128/aac.8.1.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Leying H., Suerbaum S., Kroll H. P., Karch H., Opferkuch W. Influence of beta-lactam antibiotics and ciprofloxacin on composition and immunogenicity of Escherichia coli outer membrane. Antimicrob Agents Chemother. 1986 Sep;30(3):475–480. doi: 10.1128/aac.30.3.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lobo M. C., Mandell G. L. The effect of antibiotics on Escherichia coli ingested by macrophages. Proc Soc Exp Biol Med. 1973 Mar;142(3):1048–1050. doi: 10.3181/00379727-142-37173. [DOI] [PubMed] [Google Scholar]
  9. Lorain V., Sabath L. D. Penicillins and cephalosporins: differences in morphologic effects on Proteus mirabilis. J Infect Dis. 1972 May;125(5):560–564. doi: 10.1093/infdis/125.5.560. [DOI] [PubMed] [Google Scholar]
  10. Lorian V., Atkinson B. Abnormal forms of bacteria produced by antibiotics. Am J Clin Pathol. 1975 Nov;64(5):678–688. doi: 10.1093/ajcp/64.5.678. [DOI] [PubMed] [Google Scholar]
  11. Lorian V., Atkinson B. Bactericidal effect of polymorphonuclear neutrophils on antibiotic-induced filaments of gram-negative bacilli. J Infect Dis. 1984 May;149(5):719–727. doi: 10.1093/infdis/149.5.719. [DOI] [PubMed] [Google Scholar]
  12. Lorian V., Atkinson B. Effect of serum on gram-positive cocci grown in the presence of penicillin. J Infect Dis. 1978 Dec;138(6):865–871. doi: 10.1093/infdis/138.6.865. [DOI] [PubMed] [Google Scholar]
  13. Lorian V. Some effect of subinbilitory concentrations of penicillin on the structure and division of staphylococci. Antimicrob Agents Chemother. 1975 Jun;7(6):864–867. doi: 10.1128/aac.7.6.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McDonald P. J., Wetherall B. L., Pruul H. Postantibiotic leukocyte enhancement: increased susceptibility of bacteria pretreated with antibiotics to activity of leukocytes. Rev Infect Dis. 1981 Jan-Feb;3(1):38–44. doi: 10.1093/clinids/3.1.38. [DOI] [PubMed] [Google Scholar]
  15. Melby K., Midtvedt T. Effects of some antibacterial agents on the phagocytosis of 32P-labelled Escherichia coli by human polymorphonuclear cells. Acta Pathol Microbiol Scand B. 1980 Apr;88(2):103–106. doi: 10.1111/j.1699-0463.1980.tb02613.x. [DOI] [PubMed] [Google Scholar]
  16. Milatovic D. Antibiotics and phagocytosis. Eur J Clin Microbiol. 1983 Oct;2(5):414–425. doi: 10.1007/BF02013898. [DOI] [PubMed] [Google Scholar]
  17. Perkins R. L., Miller M. A. Scanning electron microscopy of morphological alterations in Proteus mirabilis induced by cephalosporins and semisynthetic penicillins. Can J Microbiol. 1973 Feb;19(2):251–255. doi: 10.1139/m73-038. [DOI] [PubMed] [Google Scholar]
  18. Root R. K., Isturiz R., Molavi A., Metcalf J. A., Malech H. L. Interactions between antibiotics and human neutrophils in the killing of staphylococci. J Clin Invest. 1981 Jan;67(1):247–259. doi: 10.1172/JCI110020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Shah P. M., Heetderks G., Stille W. Activity of amikacin at sub-inhibitory levels. J Antimicrob Chemother. 1976 Mar;2(1):97–100. doi: 10.1093/jac/2.1.97. [DOI] [PubMed] [Google Scholar]
  20. Taylor P. W., Roberts A. P., Gower P. E. Evaluation of a technique for the estimation of serum bactericidal activity against Gram-negative organisms. Med Lab Technol. 1972 Jul;29(3):272–279. [PubMed] [Google Scholar]
  21. Verbrugh H. A., Peters R., Peterson P. K., Verhoef J. Phagocytosis and killing of staphylococci by human polymorphonuclear and mononuclear leucocytes. J Clin Pathol. 1978 Jun;31(6):539–545. doi: 10.1136/jcp.31.6.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Verhoef J., Peterson P. K., Quie P. G. Kinetics of staphylococcal opsonization, attachment, ingestion and killing by human polymorphonuclear leukocytes: a quantitative assay using [3H]thymidine labeled bacteria. J Immunol Methods. 1977;14(3-4):303–311. doi: 10.1016/0022-1759(77)90141-7. [DOI] [PubMed] [Google Scholar]
  23. Zak O., Kradolfer F. Effects of subminimal inhibitory concentrations of antibiotics in experimental infections. Rev Infect Dis. 1979 Sep-Oct;1(5):862–879. doi: 10.1093/clinids/1.5.862. [DOI] [PubMed] [Google Scholar]
  24. Zurier R. B., Hoffstein S., Weissmann G. Cytochalasin B: effect on lysosomal enzyme release from human leukocytes. Proc Natl Acad Sci U S A. 1973 Mar;70(3):844–848. doi: 10.1073/pnas.70.3.844. [DOI] [PMC free article] [PubMed] [Google Scholar]

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