Abstract
Purpose. We have investigated the efficacy of colistin and ciprofloxacin, free or bound to polyalkylcyanoacrylate nanoparticles, for the targeting and eradication of Salmonella persisting in the organs of the mononuclear phagocyte system.
Methods. A model of persistent S. typhimurium infection was developed in C57BL/6 mice using IV inoculation of the plasmid-cured strain C53.
Results. In vivo and ex vivoexperiments showed that the persisting bacteria seem to evolve to a nongrowing state during experimental salmonellosis. In vivo treatment with free or nanoparticle-bound colistin did not significantly reduce the number of viable Salmonella C53, either in the liver or the spleen of infected mice. In contrast, in vivo treatment with ciprofloxacin led to a significant decrease of bacterial counts in the liver whatever the stage of infection and the form used. However, none of the treatments were able to sterilize the spleen or the liver. In ex vivo experiments, colistin was only active against bacteria recovered during the early phase of infection, whereas ciprofloxacin exerted its activity at all times postinfection.
Conclusions. We suggest that the micro-environment in which the bacterial cells persist in vivo probably causes dramatic changes in their susceptibility to antimicrobial agents.
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REFERENCES
P. Couvreur, E. Fattal, and A. Andremont. Liposomes and nanoparticles in the treatment of intracellular bacterial infections. Pharm. Res. 8:1079–1086 (1991).
E. Fattal, M. Youssef, P. Couvreur, and A. Andremont. Treatment of experimental salmonellosis in mice with ampicillin-bound nanoparticles. Antimicrob. Agents Chemother. 33:1540–1543 (1989).
E. Fattal, J. Rojas, M. Youssef, P. Couvreur, and A. Andremont. Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis. Antimicrob. Agents Chemother. 35:770–772 (1991).
D. R. Storm, K. S. Rosenthal, and P. E. Swanson. Polymyxin and related peptide antibiotics. Ann. Rev. Bioch. 46:723–763 (1977).
B. Becq-Giraudon. Cyclic polypeptides. Sem. Hôp. Paris. 61:2350–2362 (1985).
M. Vaara and T. Vaara. Outer membrane permeability barrier disruption by polymyxin in polymyxin-susceptible and resistant Salmonella typhimurium. Antimicrob. Agents Chemother. 19:578–583 (1981).
M.-E. Page, H. Pinto-Alphandary, E. Chachaty, A. Andremont, and P. Couvreur. Entrapment of Colistin into polyhexylcyanoacrylate nanoparticles: preparation, drug release and tissue distribution in mice. S.T.P. Pharma Sciences. 6:298–301 (1996).
R. H. K. Eng, F. T. Padberg, S. M. Smith, E. N. Tau, and C. E. Cherubin. Bactericidal effect of antibiotics on slowly growing and nongrowing bacteria. Antimicrob. Agents Chemother. 35:1824–1828 (1991).
H. J. Zeiler and K. Grohe. The in vitro and in vivo activity of ciprofloxacin. Eur. J. Clin. Microbiol. 3:339–343 (1984).
H. J. Zeiler. Evaluation of the in vitro bactericidal action of ciprofloxacin on cells of Escherichia coli in the logarithmic and stationary phases of growth. Antimicrob. Agents Chemother. 28:524–527 (1985).
H. J. Zeiler and R. Endermann. Effect of ciprofloxacin on stationary bacteria studied in vivo in a murine granuloma pouch model infected with Escherichia coli. Chemotherapy 32:468–472 (1986).
H. J. Zeiler and W. H. Voigt. Efficacy of ciprofloxacin in stationary-phase bacteria in vivo. Am. J. Med. 82:87–90 (1987).
P. Pardon, M. Y. Popoff, C. Coynault, J. Marly, and I. Miras. Virulence-associated plasmids of Salmonella serovar typhimurium in experimental murine infection. Ann. Inst. Pasteur/Microbiol. 137B:47–60 (1986).
P. A. Gulig and T. J. Doyle. The Salmonella typhimurium virulence plasmid increases the growth rate of Salmonellae in mice. Infect. Immun. 61:504–511 (1993).
National Committee for Clinical Laboratory Standards. Methods for determining bactericidal activity of antimicrobial agents. Document M26-P. National Committee for Clinical Laboratory Standards, Villanova, Pa (1990).
P. Couvreur, M. Roland, and P. Speiser. Biodegradable submicroscopic particles containing a biologically active substance and compositions containing them. U.S. Patent No 4.329.332 (1982).
S. Henry-Michelland, M. J. Alonso, A. Andremont, P. Maincent, J. Sauzières, and P. Couvreur. Attachment of antibiotics to nanoparticles: preparation, drug-release and antimicrobial activity in vitro. Int. J. Pharm. 35:121–127 (1987).
M. Margosis. Quantitative reversed-phase high-performance liquid chromatographic analysis of ampicillin. J. Chromatogr. 236:469–480 (1982).
Z. Budvari-Barany, G. Szasz, K. Takacs-Novak, I. Hermecz, and A. Lore. The pH influence on the HPLC retention of chemotherapeutic fluoroquinolone derivatives. J. Liquid Chromato. 14:3411–3424 (1991).
Y. A. Chabert and H. Boulingre. Modifications pratiques concernant le dosage des antibiotiques en clinique. Rev. Fr. Etud. Clin. Biol. 2:636–640 (1957).
S. P. Gotoff and M. H. Lepper. Assay of colistin in fecal specimens. Antimicrob. Agents Chemother. 447–454 (1962).
N. E. Dunlap, W. H. Benjamin, Jr, R. D. McCall, Jr, A. B. Tilden, and D. E. Briles. A “safe-site” for Salmonella typhimurium is within splenic cells during the early phase of infection in mice. Microbial Pathogenesis 10:297–310 (1991).
D. G. Guiney, S. Libby, F. C. Fang, M. Krause, and J. Fierer. Growth-phase regulation of plasmid virulence genes in Salmonella. Trends in Microbiol. 3:275–279 (1995).
R. Hengge-Aronis. Survival of hunger and stress: the role of rpoS in early stationary phase gene regulation in Escherichia coli. Cell 72:165–168 (1993).
F. Norel, C. Coynault, I. Miras, D. Hermant, and M. Y. Popoff. Cloning and expression of DNA sequences involved in Salmonella serotype Typhimurium virulence. Mol. Microbiol. 3:733–743 (1989).
A. Dalhoff, S. Matutat, and U. Ullmann. Effect of quinolones against slowly growing bacteria. Chemotherapy 41:92–99 (1995).
G. I. McLeod and M. P. Spector. Starvation-and stationary-phaseinduced resistance to the antimicrobial peptide polymyxin B in Salmonella typhimurium is RpoS independent and occurs through both phoP-dependent and-independent pathways. J. Bacteriol. 178:3683–3688 (1996).
M. R. W. Brown and P. Williams. The influence of environment on envelope properties affecting survival of bacteria in infection. Ann. Rev. Microbiol. 39:527–556 (1985).
J. W. Costerton and T. J. Marrie. Role of the bacterial envelope in the survival of bacteria in infection. In C. S. F. Easmon, J. Jeljaszewicz, M. R. W. Brown, and P. A. Lambert (eds.), Medical Microbiology, Acadamic Press, London, 1983, vol. 3, pp. 63–86.
B. D. Hoyle and J. W. Costerton. Bacterial resistance to antibiotics: the role of biofilms. Prog. Drug Res. 37:91–105 (1991).
J. W. Costerton, R. T. Irwin, and K. J. Cheng. The bacterial glycocalyx in nature and disease. Ann. Rev. Microbiol. 35:299–324 (1981).
J. W. Costerton, K. J. Cheng, G. G. Geesey, T. I. Ladd, J. C. Nickel, and M. Dasgupta. Bacterial biofilms in nature and disease. Ann. Rev. Microbiol. 41:435–464 (1987).
P. A. Suci, M. W. Mittelman, F. P. Yu, and G. G. Geesey. Investigation of ciprofloxacin penetration into Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 38:2125–2133 (1994).
N. A. Buchmeier and F. Heffron. Inhibition of macrophage phagosome-lysosome fusion by Salmonella typhimurium. Infect. Immun. 59:2232–2238 (1991).
O. Balland, H. Pinto-Alphandary, A. Viron, E. Puvion, A. Andremont, and P. Couvreur. Intracellular distribution of ampicillin in murine macrophages infected with Salmonella typhimurium and treated with (3H)ampicillin-loaded nanoparticles. J. Antimicrob. Chemother. 37:105–115 (1996).
H. Pinto-Alphandary, O. Balland, M. Laurent, A. Andremont, F. Puisieux, and P. Couvreur. Intracellular visualization of ampicillin-loaded nanoparticles in peritoneal macrophages infected in vitro with Salmonella typhimurium. Pharm. Res. 11:38–45 (1994).
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Page-Clisson, ME., Pinto-Alphandary, H., Chachaty, E. et al. Drug Targeting by Polyalkylcyanoacrylate Nanoparticles Is Not Efficient Against Persistent Salmonella. Pharm Res 15, 544–549 (1998). https://doi.org/10.1023/A:1011921608964
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DOI: https://doi.org/10.1023/A:1011921608964