Poly( d , l -Lactide-Coglycolide) Particles Containing Gentamicin: Pharmacokinetics and Pharmacodynamics in Brucella melitensis - Infected Mice

Abstract

Drug delivery systems containing gentamicin were studied as a treatment against experimental brucellosis in mice. Micro-and nanoparticles prepared by using poly(D,L-lactide-coglycolide) (PLGA) 502H and microparticles made of PLGA 75:25H were successfully delivered to the liver and the spleen, the target organs for Brucella melitensis. Both polymers have the same molecular weight but have different lactic acid/glycolic acid ratios. Microparticles of PLGA 502H and 75:25H released their contents in a sustained manner, in contrast to PLGA 502H nanoparticles, which were degraded almost completely during the first week postadministration. The values of the pharmacokinetic parameters after administration of a single intravenous dose of 1.5 mg/kg of body weight of loaded gentamicin revealed higher areas under the curve (AUCs) for the liver and the spleen and increased mean retention times (MRTs) compared to those for the free drug, indicating the successful uptake by phagocytic cells in both organs and the controlled release of the antibiotic. Both gentamicin-loaded PLGA 502H and 75:25H microparticles presented similar pharmacokinetic parameter values for the liver, but those made of PLGA 75:25 H were more effective in targeting the antibiotic to the spleen (higher AUCs and MRTs). The administration of three doses of 1.5 mg/kg significantly reduced the load associated with the splenic B. melitensis infection. Thus, the formulation made with the 75:25H polymer was more effective than that made with 502H microspheres (1.45-log and 0.45-log reductions, respectively, at 3 weeks posttreatment). Therefore, both, pharmacokinetic and pharmacodynamic parameters showed the suitability of 75:25H microspheres to reduce the infection of experimentally infected mice with B. melitensis.Brucellosis remains a major zoonosis worldwide (17), and it is among the microorganisms most likely to be used as biological weapons (24). Specific therapy reduces morbidity, shortens the duration of illness, and decreases the incidence of complications (31); however, relapse currently presents a significant problem (27). Long-lasting combined drug treatments are difficult to achieve (27); and also the intracellular location of the pathogen in phagocytic cells, mainly in the liver and the spleen, are involved in therapeutic failure (22). Drug delivery systems containing gentamicin (GEN) have been developed as potential alternatives to classical therapy, and the usefulness of these vectors has been shown (5, 7, 10, 23, 30). Although GEN is effective against the pathogen in vitro (11, 18, 25), it shows a low level of intracellular penetration due to its polar nature; hence, its entrapment in particulate carriers might facilitate the entrance of the drug into the cells. Moreover, sustained drug delivery could avoid long-term treatment, eliminating the toxic systemic levels achieved during classical antibiotic therapy with the free drug. Despite the promising results obtained with GEN-containing liposomes (7,10,30), important drawbacks are attributed to the...

Hydrophobic Gentamicin-Loaded Nanoparticles Are Effective against Brucella melitensis Infection in Mice

“…Brucella melitensis 16 M (ATCC 23456, biotype 1) smooth virulent strain was used for the different studies. Experiments were performed with fresh bacteria incubated in TSB medium at 37°C under shaking to the exponential growth phase (15).…”

“…These drug delivery systems may lead to an improvement in drug cellular accumulation and a reduction of the required dosing frequency which, in turn, will improve patient compliance and the efficacy of the antimicrobial therapy. The aminoglycoside gentamicin is a bactericidal antibiotic with great in vitro activity against clinical isolates of Brucella, and it has already been encapsulated into particulated systems for the treatment of experimental brucellosis with promising results (15,16). However, the low encapsulation efficiency obtained limited the dose of particles that could be administered in vivo.…”

Enhanced Antibacterial Effect of Ceftriaxone Sodium-Loaded Chitosan Nanoparticles Against Intracellular Salmonella typhimurium

“…In addition to the selective delivery to phagocytes, the ingestion of such vehicles may involve macrophage activation, and increasing the immune response of the host (22). Other advantages for antibiotic nanoparticles include enhancement of oral absorption, promotion of intracellular delivery (23)(24)(25)(26), and improvement of the antibacterial effect (27)(28)(29). Nanoparticulate systems that increase the selectivity of antibiotics in phagocytic cells have been reviewed elsewhere (19), most of which were based on biodegradable poly(lactide-co-glycolide polymer (25,28,30,31).…”

Drug delivery systems for potential treatment of intracellular bacterial infections

“…In fact, Lecároz et al showed that when administered in 502H micro or nanoparticles or 752H microparticles, gentamicin was successfully delivered to the liver and the spleen (85,92). Pharmacokinetic parameters illustrated the markedly altered distribution of PLGA-loaded gentamicin compared to the free drug, as higher concentrations of the antibiotic in the spleen and liver were observed when it was administered loaded in microparticles.…”

“…The stimulation of the intracellular ROI may act synergistically with the antibiotic activity to kill intracellular bacteria, thus increasing treatment efficiency. For example, Lecároz et al studied the effect of different PLGA polymers (PLGA 502H and 752H) on the characteristics of gentamicin-containing microparticles (85). The main difference between these two polymers is the lactide/glycolide ratio, being 50:50 for the copolymer 502H and 75:25 for 752H.…”