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A comparison of the in vitro antimicrobial activity of liposomes containing meropenem and gentamicin

Abstract

The antimicrobial activity of eight cationic, two neutral and three anionic liposome compositions containing meropenem and gentamicin was tested in vitro in broth and serum medium. The cationic formulations showed better antibacterial efficacy against both Gram-positive and Gram-negative bacteria than the anionic and neutral ones, regardless of the encapsulated drug. The most effective formulations were the cationic PC/DOPE/DOTAP 3:4:3 and PC/Chol/DOTAP 3:4:3, as the MICs with meropenem were 2 to 4 times lower than those of the free drug.

Abbreviations

Chol:

cholesterol

DDAB:

dimethyldioctadecylammoniumbromide salt

DMPG:

1,2-dimyristoyl-sn-glycero-3-phosphoglycerol

DOPE:

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

DOTAP:

1,2-dioleoyloxy-3-trimethyl ammonium-propane

DPPC:

1,2-diplamitoyl-sn-glycero-3-phosphocholine

GE:

gentamicin

MEM:

meropenem

MHB:

Mueller Hinton II Broth

MLVs:

the multilamellar vesicles

MIC:

minimum inhibitory concentration

MPS:

the mononuclear phagocytic system

NBS:

normal bovine serum

NCCLS:

National Committee for Clinical Laboratory Standards

OPA:

o-phthaldialdehyde

PBS:

phosphate-buffered solution

PC:

phosphatidylcholine

PI:

phosphatidyl inositiol

SA:

octadecylamine

ULVs:

unilamellar vesicles

References

  1. Mayer, L.D., Bally, M.B., Loughrey, H., Masin, D. and Cullis, P.R. Liposomal vincistine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res. 50 (1990) 575–579.

    PubMed  CAS  Google Scholar 

  2. Mayer, L.D., Bally, M.B., Cullis, P.R., Wilson, S.L. and Emerman, J.T. Comparison of free and liposome encapsulated doxorubicin tumor uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett. 53 (1990) 183–190.

    Article  PubMed  CAS  Google Scholar 

  3. De Marie, S., Janknegt, R. and Bakker-Woudenberg, I.A.J.M. Clinical use of liposomal and lipid complexes amphotericin B. J. Antimicrob. Chemother. 33 (1994) 907–916.

    PubMed  Google Scholar 

  4. Patterson, T.F., and Andrioli, V.T. The role of liposomal amphotericin B in the treatment of systemic fungal infections. Eur. J. Cancer Oncol. 25 (1989) 63–68.

    Google Scholar 

  5. Bakker-Woudenberg, I.A.J.M. Delivery of antimicrobials to infected tissue macrophages. Adv. Drug Deliv. Rev. 17 (1995) 5–20.

    Article  CAS  Google Scholar 

  6. Pinto-Alphandary, H., Andremont, A. and Couvreur, P. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications. Int. J. Antimicrob. Agents 13 (2000) 155–168.

    Article  PubMed  CAS  Google Scholar 

  7. Omri, A., Suntres, Z.E. and Shek, P.N. Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection. Biochem. Pharmacol. 64 (2002) 1407–1413.

    Article  PubMed  CAS  Google Scholar 

  8. Sachetelli, S., Beaulac, C., Riffon, R. and Lagace, J. Evaluation of the pulmonary and systemic immunogenicity of Fluidosomes, a fluid liposomaltobramycin formulation for the treatment of chronic infections in lungs. Biochim. Biophys. Acta 1428 (1999) 334–340.

    PubMed  CAS  Google Scholar 

  9. Schiffelers, R., Storm, G. and Bakker-Woudenberg, I.A.J.M. Host factors influencing the preferential localization of sterically stabilized liposomes in Klebsiella pneumoniae-infected rat lung tissue. Pharmaceutic. Res. 18 (2001) 780–787.

    Article  CAS  Google Scholar 

  10. Schiffelers, R., Storm, G. and Bakker-Woudenberg, I.A.J.M. Liposomeencapsulated aminoglycosides in pre-clinical and clinical studies. J. Antimicrob. Chemother. 48 (2001) 333–344.

    Article  PubMed  CAS  Google Scholar 

  11. Webb, M.S., Boman, N.L., Wiseman, D.J., Saxon, D., Sutton, K., Wong, K.F., Logan, P. and Hope, M.J. Antibacterial efficacy against an in vivo Salmonella typhimurium infection model and pharmacokinetics of a liposomal ciprofloxacin formulation. Antimicrob. Agents Chemother. 42 (1998) 45–52.

    PubMed  CAS  Google Scholar 

  12. Beaulac, C., Clement-Major, S., Hawari, J. and Lagace, J. Eradication of mucoid Pseudomonas aeruginosa with fluid liposome-encapsulated tobramycin in an animal model of chronic pulmonary infection. Antimicrob. Agents Chemother. 40 (1996) 665–669.

    PubMed  CAS  Google Scholar 

  13. Schiffelers, R., Storm, G., Ten Kate, M.T. and Bakker-Woudenberg, I.A.J.M. Therapeutic efficacy of liposome-encapsulated gentamicin in rat Klebsiella pneumoniae pneumonia in relation to impaired host defence and low bacterial susceptibility to gentamicin. Antimicrob. Agents Chemother. 45 (2001) 464–470.

    Article  PubMed  CAS  Google Scholar 

  14. Desai, T.R., Tyrrell, G.J., Ng, T. and Finlay, W.H. In vitro evaluation of nebulization properties, antimicrobial activity, and regional airway surface liquid concentration of liposomal polymyxin B sulfate. Pharmaceutic. Res. 20 (2003) 442–447.

    Article  CAS  Google Scholar 

  15. Deol, P. and Khuller, G.K. Lung specific stealth liposomes: stability, biodistribution and toxicity of liposomal antitubercular drugs in mice. Biochim. Biophys. Acta 1334 (1997) 161–172.

    PubMed  CAS  Google Scholar 

  16. Labana, S., Pandey, R., Sharma, S. and Khuller, G.K. Chemotherapeutic activity against murine tuberculosis of once weekly administered drugs (isoniazid and rifampicin) encapsulated in liposomes. Int. J. Antimicrob. Agents 20 (2002) 301–304.

    Article  PubMed  CAS  Google Scholar 

  17. Mehta, R.T., Keyhani, A., McQueen, T.J., Rosenbaum, B., Rolston, K.V. and Tarrand, J.J. In vitro activities of free and liposomal drugs against Mycobacterium avium-M. intracellulare complex and M. tuberculosis. Antimicrob. Agents Chemother. 37 (1993) 2584–2587.

    PubMed  CAS  Google Scholar 

  18. Duzgunes, N., Flasher, D., Venkata Reddy, M., Luna-Herrera, J., Pattisapu, R. and Gangadharam, J. Treatment of intracellular Mycobacterium avium complex infection by free and liposome-encapsulated sparfloxacin. Antimicrob. Agents Chemother. 40 (1996) 2618–2621.

    PubMed  CAS  Google Scholar 

  19. Cordeiro, C., Wiseman, D.J., Lutwyche, P., Uh, M., Evans, J.C., Finlay, B.B. and Webb, M.S. Antibacterial efficacy of gentamicin encapsulated in pH-sensitive liposomes against an in vivo Salmonella enterica serovar Typhimurium intracellular infection model. Antimicrob. Agents Chemother. 44 (2000) 533–539.

    Article  PubMed  CAS  Google Scholar 

  20. Lutwyche, P., Cordeiro, C., Wiseman, D.J., St-Louis, M., Uh, M., Hope, M.J., Webb, M.S. and Finlay, B.B. Intracellular delivery and antibacterial activity of gentamicin encapsulated in pH-sensitive liposomes. Antimicrob Agents Chemother. 42 (1998) 2511–2520.

    PubMed  CAS  Google Scholar 

  21. Magallanes, M., Dijkstra, J. and Fierer, J. Liposome-incorporated ciprofloxacin in the treatment of murine salmonellosis. Antimicrob. Agents Chemother. 37 (1993) 2293–2297.

    PubMed  CAS  Google Scholar 

  22. Wong, J.P., Yang, H., Blasetti, K.L., Schnell, G., Conley, J. and Schofield, L.N. Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection. J. Control. Release 92 (2003) 265–273.

    Article  PubMed  CAS  Google Scholar 

  23. Bakker-Woudenberg, I.A.J.M, Lokerse, A.F., Roerdink, F.H., Regts, D. and Michel, M.F. Free versus liposome-entrapped ampicillin in treatment of infection due to Listeria monocytogenes in normal and athymic (nude) mice. J. Infect. Dis. 151 (1985) 917–924.

    PubMed  CAS  Google Scholar 

  24. Sanderson, N.M. and Jones, M.N. Interaction of cationic liposomes with skin bacteria. Biochem Soc. Trans. 23 (1995) 561S.

    PubMed  CAS  Google Scholar 

  25. Sanderson, N.M., Guo, B., Jacob, A.E., Handley, P.S., Cunniffe, J.G. and Jones, M.N. The interaction of cationic liposomes with the skin-associated bacterium Staphylococcus epidermidis: effects of ionic strength and temperature. Biochim. Biophys. Acta 1283 (1996) 207–214.

    Article  PubMed  Google Scholar 

  26. Jones, M.N., Francis, S.E., Hutchinson, F.J. and Lyle, I.G. Targeting and delivery of bactericide to adsorbed oral bacteria by use of proteoliposomes. Biochim Biophys. Acta 1147 (1993) 251–261.

    Article  PubMed  CAS  Google Scholar 

  27. Beaulac, C., Clement-Major, S., Hawari, J. and Lagace, J. In vitro kinetics of drug release and pulmonary retention of microencapsulated antibiotic in liposomal formulations in relation to the lipid composition. J. Microencapsul. 14 (1997) 335–348.

    PubMed  CAS  Google Scholar 

  28. Beaulac, C., Sachetelli, S. and Lagace, J. In vitro bactericidal efficacy of sub-MIC concentrations of liposome-encapsulated antibiotic against Gramnegative and Gram-positive bacteria. J. Antimicrob. Chemother. 41 (1998) 35–41.

    Article  PubMed  CAS  Google Scholar 

  29. Furneri, P.M., Fresta, M., Puglisi, G. and Tempera, G. Ofloxacin-loaded liposomes: in vitro activity and drug accumulation in bacteria. Antimicrob. Agents Chemother. 44 (2000) 2458–2464.

    Article  PubMed  CAS  Google Scholar 

  30. Omri, A. and Ravaoarinoro, M. Preparation, properties and the effects of amikacin, netilmicin and tobramycin in free and liposomal formulations on Gram-negative and Gram-positive bacteria. Int. J. Antimicrob. Agents 7 (1996) 9–14.

    Article  CAS  PubMed  Google Scholar 

  31. Puglisi, G., Fresta, M., Mazzone, G., Furneri, P.M. and Tempera, G. Formulation parameters of fluoroquinolone-loaded liposomes and in vitro antimicrobial activity. Int. J. Pharm. 118 (1995) 65–76.

    Article  CAS  Google Scholar 

  32. Sachetelli, S., Khalil, H., Chen, T., Beaulac, C., Senechal, S. and Lagace, J. Demonstration of a fusion mechanism between a fluid bactericidal liposomal formulation and bacterial cells. Biochim. Biophys. Acta 1463 (2000) 254–266.

    Article  PubMed  CAS  Google Scholar 

  33. Stewart, J.C. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal. Biochem. 104 (1980) 10–14.

    Article  PubMed  CAS  Google Scholar 

  34. Dreetz, M., Hamacher, J., Eller J., Bomer, K., Koeppe, P., Schaberg, T. and Lode, H. Serum bactericidal activities and comparative phamakokinetics of meropenem and imipenem-cilastatin. Antimicrob. Agents Chemother. 40 (1996) 105–109.

    PubMed  CAS  Google Scholar 

  35. National Committee for Clinical Laboratory Standards. 2000. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Fifth Edition: Approved Standerd M7-A5. NCCLS, Villanova, Pa, USA.

    Google Scholar 

  36. Gregoriadis, G. Fate of injected liposomes: observations on entrapped solute retention vesicle clearance and tissue distribution in vivo. In: Liposomes as Drug Carriers, Recent Trends and Progress, (Gregoriadis, G., Ed.) John Wiley and Sons, Chichester, 1988, 3–18.

    Google Scholar 

  37. Krieger, J., Childs, S. and Klimberg, I. UTI treatment using liposomal amikacin (MiKasone®). In Program and Abstracts of the Ninth European Congress of Clinical Microbiology and Infectious Diseases, Berlin, 1999. Clinical Microbiology and Infection 5S3, 1999, Abstract P194.

  38. Hernandez-Caselles, T., Vera, A., Crespo, F., Villalain, J. and Gomez-Fernandez, J. C. Treatment of Brucella melitensis infection in mice by use of liposome-encapsulated gentamicin. Am. J. Vet. Res. 50 (1989) 1486–1488.

    PubMed  CAS  Google Scholar 

  39. Vitas, A.I., Diaz, R. and Gamazo, C. Protective effect of liposomal gentamicin against systemic acute murine brucellosis. Chemotherapy 43 (1997) 204–210.

    Article  PubMed  CAS  Google Scholar 

  40. Swenson, C.E., Popescu, M.C. and Ginsberg, R.S. Preparation and use of liposomes in the treatment of microbial infections. Crit. Rev. Microbiol. 15 (1988) 1–31.

    Article  Google Scholar 

  41. Drulis-Kawa Z., Gubemator, J., Kostyn, K., Doroszkiewicz W., and Kozubek, A. Liposome-encapsulated carbapenems. Cell. Mol. Biol. Lett. 7 (2002) 281.

    PubMed  Google Scholar 

  42. Drulis-Kawa Z., Gubernator, J., Dorotkiewicz-Jach, A., Doroszkiewicz W., and Kozubek, A. In vitro antimicrobial activity of liposomal meropenem against Pseudomonas aeruginosa strains. Int. J. Pharm. 315 (2006) 59–66.

    Article  PubMed  CAS  Google Scholar 

  43. Sihorkar, V. and Vyas, S.P. Biofilm consortia on biomedical and biological surfaces: delivery and targeting strategies. Pharmaceutic. Res. 18 (2001) 1247–1254.

    Article  CAS  Google Scholar 

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Correspondence to Zuzanna Drulis-Kawa.

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Drulis-Kawa, Z., Gubernator, J., Dorotkiewicz-Jach, A. et al. A comparison of the in vitro antimicrobial activity of liposomes containing meropenem and gentamicin. Cell Mol Biol Lett 11, 360–375 (2006). https://doi.org/10.2478/s11658-006-0030-6

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