Liposomal targeting of antimicrobial agents of bacterial infections (original) (raw)
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Control of drug-resistant bacteria involved in severe infections acquired in hospital (ICUs) patients are extremely challenging, due to increased levels of antimicrobial resistance presented by microorganism against most antimicrobial agents routinely used. Liposomes are spherical vesicles, with particle sizes ranging from 30 nm to several micrometers, consisting of one or more lipid bilayers surrounding aqueous spaces. Our designed study aimed at knowing the importance of encapsulating antimicrobial drugs into multilamellar liposomes to overcome microbial resistance, when administered as a liposomal formulation by localizing antibiotic to the periplasmic space, allowing it to exert its bactericidal activity. Drug resistant bacteria such as ESBL positive (E. coli, Klebsiella pneumonia), Acinetobacter baumanii, Staph aureus and Methicillin resistant Staph aureus were isolated from around 1750 clinical specimens. The bactericidal activity of drug was tested in vitro by MIC and Disc diffusion. Different antibiotics (Amikacin, Ciprofloxacin, Cloxacillin and Vancomycin) loaded with high efficiency on to these multilamellar vesicles were prepared by the simple thin film hydration method using egg yolk. In vitro antimicrobial activities were determined in comparison to free drug by Inhibition zone using agar well diffusion and were compared with ATCC strains. Antimicrobial activity of polyethylene glycol coated liposomal antibiotics against clinical strains and ATCC strain was compared to free drugs. Further, for Liposomal characterization UV, FTIR, AFM, TEM were used and encapsulation efficiency was also included in this study. Microbiological experiments in vitro was shown to be able to inhibit to a different extent the growth of clinical strain and ATCC strain. Inhibition zone for antibiotic diffusion was as high as 30-40 mm were observed, against clinical isolates used in this study. In comparison, neither the free drug nor liposomes showed any activity against the same bacteria. Moreover, it was noticed that the therapeutic potential of 4 drugs improves by encapsulation in PEG.
Liposomes-A Nanocarrier System for Pulmonary Infection
This review studied the efficacy of liposomal dry powder inhalation for pulmonary infections. The lungs are primary organ of pulmonary system in human and most other animals The lung infection caused by various bacterias, viruses and fungus. The pneumonia is major pulmonary infection caused by some bacterias like Streptococcus pneumoniae, Staphylococcus aureus, Bacillus subtilis, E. coli, etc. The antibiotics can be administered orally, intravenously, or in other ways. On their approach to the infection site and the disease, they travel through numerous layers of tissue. Drugs can fail to perform as intended because of diverse metabolic breakdown. Because they include both hydrophilic and hydrophobic antibiotics, liposomes are amphiphilic. The Liposomes have better features than conventional drug delivery methods, including site-targeting, sustained and regulated release, protection of the drug against degradation and removal, then superior therapeutic effectiveness, and fewer harmful side effects. The size, integrity, and number of charges of liposomes are just a few of the variables that affect their stability. Several polymers are used to prevent liposome leaking.
Nuclear Medicine and Biology, 1998
Liposomes encapsulating both glutathione and deferoxamine were labeled with 99m Tc-HMPAO and 111 In-oxine at the same time. These dual radiolabeled liposomes were intravenously injected in rats with S. aureus infection in thigh. The target-to-background ratio (T/BG) increased from 2.9 at 2 h to 4.4 at 8 h in 99m Tc images. In 111 In images, T/BG of 5.5 at 8 h increased to 10.5 by 48 h. The 24-h spleen uptake of 111 In-and 99m Tc-liposomes was 24.14%ID and 8.91%ID. In femur, 99m Tc-liposomes remained at ϳ10.5%ID, but 111 In-liposomes increased from ϳ11%ID at 4 h to ϳ25.5%ID at 24 h. The simultaneous presence of 99m Tc and 111 In in the liposomes resulted in good early (2-8 h) as well as delayed (24-48 h) images delineating the infection site.
International Journal of Nanomedicine, 2015
Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the overall uptake. In this work, long-circulating and alendronatecoated liposomes containing 99m technetium-radiolabeled ceftizoxime were prepared and their ability to identify infectious foci (osteomyelitis) in animal models was evaluated. The effect of the presence of PEGylated lipids and surface-attached alendronate was evaluated. The bone-targeted long-circulating liposomal 99m technetium-ceftizoxime showed higher uptake in regions of septic inflammation than did the non-long-circulating and/or alendronate-non-coated liposomes, showing that both the presence of PEGylated lipids and alendronate coating are important to optimize the bone targeting. Scintigraphic images of septic or aseptic inflammation-bearing Wistar rats, as well as healthy rats, were acquired at different time intervals after the intravenous administration of these liposomes. The target-to-non-target ratio proved to be significantly higher in the osteomyelitis-bearing animals for all investigated time intervals. Biodistribution studies were also performed after the intravenous administration of the formulation in osteomyelitis-bearing animals. A significant amount of liposomes were taken up by the organs of the mononuclear phagocyte system (liver and spleen). Intense renal excretion was also observed during the entire experiment period. Moreover, the liposome uptake by the infectious focus was significantly high. These results show that long-circulating and alendronate-coated liposomes containing 99m technetium-radiolabeled ceftizoxime have a tropism for infectious foci.
Sterically stabilized liposomes are able to localize at sites of infection and could serve as carriers of antimicrobial agents. For a rational optimization of liposome localization, the blood clearance kinetics and biodistribution of liposomes differing in poly(ethylene glycol) (PEG) density, particle size, bilayer fluidity or surface charge were studied in a rat model of a unilateral pneumonia caused by Klebsiella pneumoniae. It is shown that all liposome preparations studied localize preferentially in the infected lung compared to the contralateral non-infected lung. A reduction of the PEG density or rise in particle size resulted in a higher uptake by the mononuclear phagocyte system, lower blood circulation time and lower infected lung localization. Differences in bilayer fluidity did not affect blood clearance kinetics or localization in the infected lung. Increasing the amount of negatively charged phospholipids in the liposome bilayer did not affect blood clearance kinetics, but did reduce localization of this liposome preparation at the site of lung infection. In conclusion, the degree of localization at the infected site is remarkably independent of the physicochemical characteristics of the PEG liposomes. Substantial selective liposome localization can be achieved provided that certain criteria regarding PEG density, size and inclusion of charged phospholipids are met. These properties seem to be a direct consequence of the presence of the polymer coating operating as a repulsive steric barrier opposing interactions with biological components. ß 1999 Elsevier Science B.V. All rights reserved.
Detecting infection and inflammation with technetium-99m-labeled Stealth (R) liposomes
The performance of ""Tc Stealth* liposomes was investigated in various rat models. Methods: Preformed polyethyleneglycol-containing liposomes with encapsulated reduced glutathione, were radiolabeled using the lipophilic "Tc-HMPAO. The labeled lipo somes were intravenously administered to rats with focal S. aureus or E. coli infection, or turpentine-induced inflammation. For compar ison, Tc-99m-nanocolloid-and ""Tc-labeled nonspecific IgG were tested. In rats with Pneumocystis carinii pneumonia (PCP), Tc-99mliposomes were directly compared to ln-111 labeled nonspecific IgG. Results: Technetium-99m-liposomes accumulated in the in fectious and inflammatory muscle foci over 24 hr (0.59% injected dose per gram tissue (%ID/g) for E. coli; 0.98 %ID/g for S. aureus; 1.18 %ID/g for turpentine). Abscess-to-muscle ratios increased to values as high as 24.0, 41.7 and 44.5 for the respective models at 24 hr postinjection. Technetium-99m-liposomes visualized the foci as early as 1 hr postinjection. Technetium-99m-lgG visualized S. aureus infection, but abscess-to-muscle ratios and abscess uptake at the later time points were significantly lower. Technetium-99mnanocolloid failed to visualize any of the muscle foci. In PCP however, ""Tc-liposomes did not show preferential localization in the infection. The control agent 111ln-lgG showed a significant, twofold increase in lung uptake. Conclusion: Technetium-99m-Stealth® liposomes preferentially accumulated in abscesses, leading to very high target-to-nontarget ratios. This property appears to be related to a process based on uptake of long-circulating particles. In a specific type of infection, i.e. PCP, ""Tc-liposomes did not accumulate in diseased lung tissue, thus mimicking the in vivo behavior of labeled leukocytes.
Sterically stabilized liposomes labeled with indium-111 to image focal infection
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1995
To determine the potential of sterically stabilized liposomes to image infectious and inflammatory foci, the in vivo behavior of 111In-labeled PEGylated (coated with polyethylene glycol) liposomes was studied in a rat model. Indium-111-PEGylated lipsomes were administered intravenously to rats infected with S. aureus in the left calf muscle. The distribution of the radiolabel was studied by gamma counting of dissected tissues and gamma camera imaging for 48 hr. As a reference agent, the preparation of 111In-IgG was included in these studies. Clearance of the PEGylated liposomes from the blood compartment was similar to the clearance of 111In-IgG in this model (t1/2 approximately 20 hr). Uptake of the radiolabel in the abscess with the 111In-liposomes was twice as high as the uptake following injection of 111In-IgG (2.7%ID/g versus 1.1%ID/g at 48 hr postinjection). Tissue counting revealed that abscess-to-muscle ratios reached values up to 20 and 34 (24 and 48 p.i., respectively). As...
Antimicrobial Agents and Chemotherapy, 2001
Long-circulating liposomes (LCL) may be used as targeted antimicrobial drug carriers as they localize at sites of infection. As a result, LCL-encapsulated gentamicin (LE-GEN) has demonstrated superior antibacterial activity over the free drug in a single-dose study of immunocompetent rats with Klebsiella pneumoniae pneumonia. In the present study, the therapeutic efficacy of LE-GEN was evaluated by monitoring rat survival and bacterial counts in blood and lung tissue in clinically relevant models, addressing the issue of impaired host defense and low bacterial antibiotic susceptibility. The results show that in immunocompetent rats infected with the high-GEN-susceptibility K. pneumoniae strain, a single dose of LE-GEN is clearly superior to an equivalent dose of free GEN. Yet complete survival can also be obtained with multiple doses of free GEN. In leukopenic rats infected with the high-GEN-susceptible K. pneumoniae strain, free GEN at the maximum tolerated dose (MTD) was needed to obtain survival. However, with the addition of a single dose of LE-GEN to free-GEN treatment, complete survival can be obtained using a sevenfold-lower cumulative amount of GEN than with free-GEN treatment alone. In leukopenic rats infected with low-GEN-susceptible K. pneumoniae cells, free GEN at the MTD did not result in survival. The use of LE-GEN is needed for therapeutic success.