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Monday, 08 June 2015 16:31

Nanofibers filled with Ciprofloxacin may be the answer in treatment of Pseudomonas aeruginosa and a methicillin-resistant Staphylococcus aureus infections

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Pseudomonas aeruginosa and Staphylococcus aureus causes severe infections, especially in nosocomial environments. The cells are often deeply imbedded in biofilms, which makes treatment of the infections extremely difficult. Cells exposed to antibiotic levels below MIC (minimal inhibitory concentration) may develop resistance. The aim of this study was to develop a drug carrier that would keep antibiotic levels, in this case Ciprofloxacin, well above MIC for the duration of treatment. By electrospinning Ciprofloxacin into a nanofiber scaffold consisting of poly(D,L-lactide) (PDLLA) and poly(ethylene oxide) (PEO), the antibiotic was released within 2 h, killing 99% of P. aeruginosa and 91% of a methicillin-resistant strain of S. aureus in a biofilm. Ciprofloxacin, which remained intact, were released from the nanofibers for 7 days at levels above MIC. The nanofibers were not toxic when tested against MCF-12A breast epithelial cells. Antibiotic-filled nanofibers may be the answer to the eradication of P. aeruginosa and S. aureus biofilms.

Cells in a biofilm are often exposed to sub-lethal concentrations of antibiotics and may develop resistance in a relatively short period. Most antibiotics are released in a “burst”, followed by slow, uncontrolled release below MIC levels. The answer to the problem lies in controlled drug delivery, i.e. reversible binding of antibiotics to an organic or inorganic backbone (scaffold). In previous studies we have reported on the controlled release of antimicrobial peptides (bacteriocins), silver nanoparticles and DHBA (dihydroxybenzoic acid) from polymeric nanofibers (1-6). The nanofibers were constructed from combinations of hydrophobic poly(D,L-lactide) (PDLLA) and hydrophilic poly(ethylene oxide) (PEO). Both polymers are biocompatible and have been approved by the Food and Drug Administration (FDA).

Ciprofloxacin (15 mg) was electrospun into 120 mg PDLLA (Mw 75 kDa - 120 kDa) and 120 mg (w/v) PEO (Mw 200 kDa), suspended into 1 ml 2-chloroethanol. Nanofibers containing Ciprofloxacin were similar in structure and texture to nanofibers without the antibiotic, as recorded with scanning and transmission electron microscopy. No crystal formation was recorded with atomic force microscopy and no diffraction peaks were identified during X-ray diffraction (XRD), suggesting that Ciprofloxacin is completely miscible with PDLLA and PEO and was released in an intact form.

Nanofiber
Most of the antibiotic was released from the nanofibers within 2 h and almost all cells of P. aeruginosa and S. aureus were killed during this period. The remaining cells were killed by the slow and controlled release of the antibiotic from the nanofibers. The high surface-to-volume ratio of nanofibers and the short diffusion distance created a concentration gradient of the encapsulated antibiotic, which enhances the rate of mass transport into mucosal tissue (according to literature). Biofilm formation was inhibited when cells were exposed to nanofibers containing Ciprofloxacin. Diffusion of Ciprofloxacin into the biofilm depended on the net charge of the biofilm. At a neutral pH, the antibiotic exists primarily as a zwitterion. In acidic conditions, Ciprofloxacin is positively charged and entering into bacterial cells is restricted. Thus, under optimal pH conditions, such as physiological pH, penetration of CIP into a biofilm is enhanced and pathogens are eradicated more effectively.

Author: Prof. Leon Dicks, Department of Microbiology, Stellenbosch University.

Journal Reference: Ahire JJ, Neveling DP, Hattingh M, Dicks LMT. 2015. Ciprofloxacin-eluting nanofibers inhibits biofilm formation by Pseudomonas aeruginosa and a methicillin-resistant Staphylococcus aureus. PLoS ONE 10(4): e0123648. DOI:10.1371/journal.pone.0123648.





Further reading:

  1. Ahire JJ, Dicks LMT. 2014. 2,3-Dihydroxybenzoic acid-containing nanofiber wound dressings inhibits biofilm formation by Pseudomonas aeruginosa. Antimicrob Agents Chemother 58(4): 2098–2104.
  2. Ahire JJ, Dicks LMT. 2015. Nisin incorporated with 2,3-dihydroxybenzoic acid in nanofibers inhibits biofilm formation by a methicillin-resistant strain of Staphylococcus aureus. Probiotics & Antimicro Prot 7(1): 52–59.
  3. Ahire JJ, Neppalli R, Heunis TD, van Reenen AJ, Dicks LMT. 2014. 2,3- dihydroxybenzoic acid electrospun into poly (D, L-lactide)(PDLLA)/poly (ethylene oxide)(PEO) nanofibers inhibited the growth of Gram-positive and Gram-negative bacteria. Curr Microbiol 69(5): 587-593.
  4. Ahire JJ, Neveling DP, Dicks LMT. 2015. Co-spinning of silver nanoparticles with nisin increases the antimicrobial spectrum of PDLLA: PEO nanofibers. Curr Microbiol 71: 25-30.
  5. Heunis TDJ, Bshena O, Klumperman B, Dicks LMT. 2011. Release of bacteriocins from nanofibers prepared with combinations of poly(D,L-lactide) (PDLLA) and poly(Ethylene Oxide) (PEO). Int J Mol Sci 12: 2158–2173.
  6. Heunis TDJ, Dicks LMT. 2010. Nanofibers offer alternative ways to the treatment of skin infections. J Biomed Biotechnol 61: 1-10.
  7. Heunis TDJ, Smith C, Dicks LMT. 2013. Evaluation of a nisin-eluting nanofiber scaffold to treat Staphylococcus aureus-induced skin infections in mice. Antimicrob Agents Chemother 57: 3928–3935.

 

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