Introduction
Bacterial resistance to fluoroquinolones is a major challenge for researchers who seek to preserve the usefulness of these valuable antibiotics used to treat a large variety of infections. In particular,
P.aeruginosa infections are difficult to overcome owing to the high intrinsic resistance to antibiotics.
Development of new strategies for drug delivery using the concept of mucoadhesion shown to prolong the residence time of dosage forms in the mucosa, allowing sustained drug release remained at a particular target site. That condition allows an intimate contact with the membrane absorption, providing the basis for a high concentration gradient as a driving force for passive drug absorption. Carbomers are synthetic polymer of acrylic acid cross-linked with allylsucrose well established as a good bioadhesive and extensively investigated in the pharmaceutical field. Three carbomers were selected in this work to prepare colloidal aqueous dispersions (hydrogels) with different viscosities and used as carriers of ofloxacin. The aim of this work is to evaluate the effect of the bioadhesive carrier system on antimicrobial properties of ofloxacin by determining MIC values, the bactericidal profiles and bacterial uptake exhibited by hydrogels against fluoroquinolone-sensitive and -resistant P.aeruginosa.
Materials and methods
Hydrogels of carbomer 971, 934 y 940 partially neutralized with ofloxacin (C-OFLO) were prepared
as previously reported (1). P.aeruginosa ATCC 27853 and 3 clinical isolates of Fluoroquinolone resistant P.aeruginosa were used. The MICs of the ofloxacin-containing hydrogels were carried out
by standard two-fold macrodilution technique according to CLSI. The bactericidal activity was
determined in Mueller-Hinton broth in the presence of a wide range of drug concentrations.
Bactericidal indexes (BI) were calculated using data from the bactericidal activity assay (2). The
accumulation of Ofloxacin from C-OFLO was performed by a fluorometric method (3).
Results
The MICs of the ofloxacin-containing hydrogels against P.aeruginosa are similar to or two times lower than those of free drug. No differences were observed between the MICs of the hydrogels prepared with different carbomers. C-OFLO exhibit enhanced bactericidal action against FQ-R P.aeruginosa achieving bacterial eradication in drug concentrations that did not do it ofloxacin. In addition, hydrogels exhibited prolonged effect as compared to that of free drug. These properties were confirmed by the highest Bactericidal Index calculated from bactericidal profiles. The uptake of ofloxacin from hydrogels was higher than that yielded with ofloxacin solution in FQ-R and –S P.aeruginosa. Additionally, the trend of enhanced intracellular accumulation of ofloxacin in the FQ-R strain correlated with the viscosity of the hydrogels as three of them were compared.
Conclusions
The enhanced bactericidal performance of the hydrogels could be important against highly resistant
isolates and the prolonged activity could contribute to reduce the development of persistent cells.
Moreover, these polyelectrolyte-fluoroquinolone reversible complexes promote a higher uptake of
ofloxacin. That behavior could be ascribed to bioadhesive interactions between the complex
polyelectrolyte-fluoroquinolone and the envelopment of bacterial cells. Rheological and bioadhesive
properties of the hydrogels result in prolonged contact time in the site of administration compared
with a solution (5), allowing a sustained drug release at the target site. Hence, hydrogels could be used in the development of a more effective formulation for the topical administration of older
Fluoroquinolones. An improved performance of an old antibiotic can preserve the use of
fluoroquinolones of new generation