a Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam (EMCR), PO Box 1738, 3000 DR Rotterdam; b Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
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Abstract |
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Introduction |
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After the introduction of streptomycin in 1944, aminoglycosides developed into an important class of antibiotics. Their broad antimicrobial activity, post-antibiotic effect, synergy with ß-lactam antibiotics, rapid, concentration-dependent bactericidal activity and low cost contributed to their success, as well as a low frequency of resistance to them.14 However, they require parenteral administration. Moreover, dose-related adverse effects on kidneys and audio-vestibular apparatus make it necessary for the plasma concentrations to be maintained within a narrow range.58 Therefore, aminoglycosides are currently used for the treatment of severe (nosocomial) Gram-negative and Gram- positive infections, especially in immunocompromised patients, and for the treatment of mycobacterial infections.912
A drug delivery system that helps to increase the therapeutic index of the aminoglycosides by increasing the concentration of the drug at the site of infection and/or reducing the nephro- and ototoxicity would attract considerable interest, and liposomal encapsulation of aminoglycosides may provide this.
Liposomes
Liposomes are spherical vesicles, with particle sizes ranging from 30 nm to several micrometres, consisting of one or more lipid bilayers surrounding aqueous spaces.13,14 Hydrophilic drugs, such as aminoglycosides, can be encapsulated in the internal aqueous compartment, whereas hydrophobic drugs may bind to or are incorporated in the lipid bilayer.13,15 The bilayers are usually composed of natural or synthetic phospholipids and cholesterol, but the incorporation of other lipids or their derivatives, as well as proteins, is also possible.1315 The physicochemical characteristics of the liposome, like particle size, surface charge, sensitivity to pH changes and bilayer rigidity, can be manipulated.14 Manipulation of these characteristics can have marked effects on the in vivo behaviour of liposomes and therefore have a major impact on therapeutic success. Liposomes have also been studied as model membranes regarding the interaction of aminoglycosides with phospholipids in relation to aminoglycoside toxicity.1619 The present review will focus exclusively on liposomes as a drug delivery system for aminoglycosides.
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In vitro data |
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The earliest publications on liposome-encapsulated aminoglycosides appeared some 20 years ago. Variable results were reported on the antibacterial activity of liposomal antibiotics against extracellular bacteria. It was generally shown that the concentrations of the liposome-encapsulated aminoglycoside necessary to obtain growth inhibition and killing needed to be substantially higher compared with the free drug.2022 Encapsulation of the antibiotic reduces its antibacterial activity because the bacteria are separated from it by the liposomal bilayer. Variability of the in vitro data is probably the consequence of the variations in the liposome lipid compositions used, resulting in the encapsulated agents having various release profiles.
In contrast to this general observation, Beaulac et al.23 and Sachetelli et al.24 reported that a liposome formulation composed of dipalimitoylphosphatidylcholine and dimyristoylphosphatidylglycerol encapsulating tobramycin showed a considerable antibacterial effect against a range of Gram-positive and Gram-negative bacteria at concentrations below the MIC of the free antibiotic in vitro. They argued that the enhanced antibacterial effect may be due to a fusion mechanism of this liposome formulation with bacteria.24
Intracellular bacteria
In vitro studies using intracellularly infected phagocytic cells demonstrated that the phagocytosis of aminoglycoside-loaded liposomes yielded therapeutic intracellular drug concentrations,25 and consequently enhanced killing of intracellular microorganisms such as Staphylococcus aureus,26,27Escherichia coli,28 Brucella abortus,2931 Brucella canis30 and Mycobacterium avium complex (MAC).3235 A recent report addressed the possibility of further improving liposomal drug efficacy towards infected cells. Liposomes encapsulating gentamicin composed of pH-sensitive bilayers based on dioleoylphosphatidylethanolamine showed an improved antibacterial effect against intracellular Salmonella typhimurium and Listeria monocytogenes in murine macrophage-like J774A cells when compared with non-pH-sensitive liposome formulations.36 It is believed that the pH sensitivity of the liposomes promotes drug release in the acidic environment of the lysosomes after phagocytosis by the infected cells.
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Local application |
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Similar results to those obtained in the ophthalmic studies were reported after the prophylactic local application of aminoglycoside-loaded liposomes in models of soft tissue infection, burn wounds, prosthetic vascular grafts or surgical wound infections,4550 and after intrabronchial/ intratracheal administration of liposomal aminoglycosides in rodents.5154 Following intrabronchial administration, liposome-encapsulated tobramycin was shown to eradicate mucoid Pseudomonas aeruginosa in a model of chronic pulmonary infection.53 Interestingly, treatment results were dependent on the lipid composition of the liposomal formulation. Free tobramycin as well as tobramycin encapsulated in liposomes with rigid lipid bilayers showed no bactericidal effect, whereas tobramycin in liposomes composed of fluid lipid bilayers was able to eliminate the bacteria. These data are in agreement with data from in vitro experiments that have shown that fluid liposomes tend to release encapsulated aminoglycosides faster compared with their rigid counterparts.54
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Intravenous administration |
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Circulation kinetics and tissue distribution. Extensive research on liposome behaviour after iv administration has shown that many liposome types rapidly accumulate in the cells of the mononuclear phagocyte system (MPS), particularly in the liver and spleen.5557 It is believed that the relatively rapid clearance of the liposomes is the result of opsonization in the bloodstream facilitating MPS recognition and uptake.58,59 Such liposomes are generally termed conventional liposomes. The rate at which conventional liposomes are taken up by the MPS can be manipulated by controlling the liposome dose, but also by variation of liposomal characteristics such as charge, size and lipid composition. Generally, large, charged liposomes composed of fluid lipid bilayers tend to accumulate in the MPS more rapidly than small, neutral, rigid liposomes.60 With the objective of reducing the MPS uptake of conventional liposomes, it has been shown that by increasing the liposome dose, the proportion of liposomes that remains in the circulation can be increased because of saturation of MPS uptake.61 However, saturation of the MPS should be avoided as it will impair the body's ability to clear microorganisms from the circulation, which is an important defence mechanism in patients with severe infections.62,63
The pharmacokinetics of intravenously administered conventional liposome-encapsulated aminoglycosides generally show that plasma half-lives are prolonged compared with the free drug.6468 The blood levels reported in some representative studies of (liposomal) aminoglycosides are shown in Figure 1. Free and liposome-encapsulated drug were administered at equivalent doses. It is important to realize that when injected in the free form the aminoglycoside is completely active therapeutically, while after injection of the liposome-encapsulated form only the released portion is expected to show antimicrobial activity. The tissue distribution of aminoglycosides is greatly changed by liposomal encapsulation, as is illustrated in Figure 2
. Free and liposome-encapsulated drug were again administered at equivalent doses. Renal concentrations of aminoglycosides are approximately similar after administration of either the free or the liposome-encapsulated forms, whereas much higher concentrations were observed in the liver and spleen after the injection of the liposome-encapsulated aminoglycosides. The absolute uptake of the liver exceeds that of the spleen when their respective weights are taken into consideration. Swenson et al.66 reported measurable gentamicin levels in the liver and spleen up to 2 and 15 weeks, respectively, after injection of a single liposomal gentamicin dose of 20 mg/kg. Concentrations in other organs achieved with these conventional liposomes are generally insignificant, although a few reports indicated increased concentrations in the lung.65,68 Interestingly, Ladigina & Vladimirsky65 showed that in the lungs of mice infected with Mycobacterium tuberculosis, a six-fold increase was seen in the amount of drug localizing in the infected lungs. However, absolute drug concentrations remained low.
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Safety. Considering the prolonged presence of aminoglycosides in the body, it is unfortunate that studies on nephro- or ototoxicity of conventional liposomal formulations of aminoglycosides are lacking. There are, however, reports comparing the acute toxicity (characterized by convulsions or death as a result of neuromuscular blockade) of free versus liposome-encapsulated aminoglycosides in mice. Without exception all studies showed a substantial reduction in acute toxicity for the liposome-encapsulated drug.67,6971
Therapeutic efficacy. Generally, because of their hydrophilic nature, aminoglycosides are not the drug of choice for treating intracellular infections inside phagocytic cells. However, conventional liposomes readily accumulate in the MPS.7274 Therefore, aminoglycoside-loaded conventional liposomes were initially studied using in vivo models of intracellular infections inside the MPS cells. An overview of treatment results achieved with conventional liposome formulations is presented in Table 1.
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A limited number of reports describe the therapeutic efficacy of conventional liposomes encapsulating aminoglycosides directed against foci of infection outside the cells of the MPS. The prolonged presence of drug in the body after administration of conventional liposomeencapsulated aminoglycosides has been the rationale behind studying their prophylactic activity against extracellular bacterial infections. Swenson et al.66 showed that the dose of liposome-encapsulated gentamicin needed for protection against a lethal ip infection caused by K. pneumoniae or E. coli was substantially lower than for the free drug, when administered from 7 up to 2 days before bacterial inoculation. This result is not surprising, since the free drug is almost completely excreted within 24 h after injection. In a single dose study in a murine model of K. pneumoniae infection, a single dose of liposomeencapsulated gentamicin 20 mg/kg was more effective than an 80 mg/kg dose of free drug.89 The prolonged residence time of gentamicin in the body by liposome-encapsulation is probably responsible for the enhanced efficacy.
Long-circulating liposomes (LCLs)
Circulation kinetics and tissue distribution. To enable the liposomes to reach infectious sites outside the major MPS-organs, such as the liver and spleen, it is necessary to decrease the rate of uptake of the liposomes by the phagocytic cells. One way to achieve this is by preparing small, neutral vesicles with a rigid bilayer. Using this approach, NeXstar Pharmaceuticals (currently Gilead Sciences Inc.) have developed MiKasome, a small (c. 50 nm) unilamellar liposome formulation containing amikacin. This formulation is currently in clinical trials. Another approach to prolonging the circulation time of liposomes is the incorporation of poly(ethylene glycol) (PEG) coupled to phosphatidylethanolamine in the liposome bilayers. It is believed that the hydrophilic PEG provides a layer of steric hindrance around the liposome reducing liposome opsoniza-tion and thereby rapid recognition and uptake by the MPS cells. These liposomes are therefore termed sterically stabilized liposomes (SSLs). The low MPS uptake of the SSLs is to a high degree irrespective of liposome lipid composition, which is an important advantage when tuning the liposome lipid composition for optimal targeting, retention and release.9097 Using this approach in our laboratory, we have developed a long-circulating SSL formulation containing gentamicin.98 Such flexibility in tailoring the liposome characteristics does not apply, for example, to MiKasome, as the lipid composition of MiKasome is restricted to a rigid membrane structure to retain its long half-life.
Studies with aminoglycosides encapsulated in both types of LCL show that drug plasma half-lifes are markedly prolonged. Blood levels obtained for MiKasome and SSLgentamicin are shown in Figure 3. Studies in rats receiving MiKasome 50 mg/kg demonstrated that the AUC in plasma is increased approximately 130-fold compared with the AUC of an equivalent dose of free amikacin.99 Similar findings were also seen in rabbits, dogs, rhesus monkeys and humans.100,101 In man, the mean plasma half-life of MiKasome was 114 h. After 1 week of daily dosing with 2.5 or 5 mg/kg/day mean plasma concentrations were 120 and 215 mg/L, respectively. One week later, plasma concentrations still amounted to 1020 mg/L. Yet, the concentrations of free amikacin released from the liposome never exceeded 4 mg/L. Our experimental studies with SSL-gentamicin showed a similar picture in rats, with 70- to 130-fold increase in AUC compared with the free drug.98
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Safety. Much work has been done on the safety of MiKasome. Parameters tested in a 1 month study with daily or every third day injection of MiKasome in Beagle dogs were based on clinical chemistry, haematology, urine analysis and coagulation together with body weights, clinical observations and vital signs. Gross necropsy and histopathologic examination of tissues was performed at the end of the study period.100 Daily doses of 20 mg/kg or every third day doses of 60 mg/kg were not associated with the occurrence of adverse effects despite mean steady state plasma concentrations above 750 mg/L and pre-dose levels >600 mg/L. Surprisingly, kidney concentrations above 1 mg/g did not lead to elevation of blood urea nitrogen or creatinine concentrations. The study shows that the ratio of cortical to medullary amikacin was substantially reduced by liposome encapsulation compared with the free drug. Therefore, it appears that liposome encapsulation results in a different kidney localization, preventing aminoglycoside-induced nephrotoxicity.100
A clinical study of safety in HIV-positive patients showed that after 1 week of daily dosing of 2.5 or 5 mg/kg, plasma levels were approximately 120 and 215 mg/L, respectively. Plasma amikacin levels of 1020 mg/L persisted for 2 weeks after the last dose. However, no renal or audiovestibular toxicity was noted in any of the subjects participating in the study.100
Administration of gentamicin in rats showed acute toxicity after a single dose of 40 mg/kg, characterized by convulsions. A similar dose of SSL-gentamicin showed no acute toxicity.117
Therapeutic efficacy. Results of the treatment studies with aminoglycosides encapsulated in LCL are shown in Table 2.98,117122 The majority of studies report that the efficacy of LCL-encapsulated aminoglycosides is superior to that of the free aminoglycosides. Most studies relate to the use of MiKasome. The long half-life of LCL in the circulation allows for prolonged dosing intervals or even single dose treatments. A clinical trial in urinary tract infection patients shows that a single dose of MiKasome 40 mg/kg produced a high cure rate and the efficacy was comparable to seven daily infusions of 10 mg/kg.118 In two rabbit models of endocarditis, it was shown that single daily doses of MiKasome improved survival and were as efficient in reducing bacterial numbers as twice daily doses of the free drug, which is probably related to the prolonged residence time in the body of the liposomal formulation.119,120 In contrast, the rate of vegetation sterilization was higher in the animals treated with the free drug, probably as a result of the short-lasting, but high peak-levels of the free drug in the circulation. In the endocarditis models, treatments were combined with suboptimal doses of oxacillin to take advantage of the documented synergy between aminoglycosides and ß-lactams. The studies do not show whether differences in strength of the synergic interaction exist between free amikacin or MiKasome. A recent study reported that liposomal-co-encapsulation of gentamicin and ceftazidime resulted in a synergic interaction of both drugs against a (resistant) K. pneumoniae pneumonia in rats, in contrast to combination of the free drugs.123 This study shows that liposomal formulation does not inhibit and may even promote synergic drug interactions.
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Only one single study failed to show a superior effect of LCL-encapsulated aminoglycoside compared with conventional liposomal drug in the treatment of MAC infection.122 Unfortunately, the preparations used in this study were not characterized with respect to their circulation time as well as their tissue distribution, so the underlying cause of the results cannot be traced.
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Concluding remarks |
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Conventional liposomes are mostly taken up by the MPS after iv administration, the targeted delivery of drugs to MPS cells in the liver and spleen seems to be the most relevant application of this liposome type. Treatment of intracellular infections in the MPS cells may benefit from the high amounts of aminoglycosides that can be delivered intracellularly. By making liposomes pH-sensitive, the therapeutic availability of the liposome-encapsulated drug that is phagocytosed may even be increased. Research is needed on the nephro- and ototoxicity of conventional liposomal aminoglycosides, with respect to their prolonged presence in the body. This research should also include the potential danger of promoting microbial resistance as a result of the prolonged exposure of the resident microbial flora to the drug.
In case the infectious focus is located outside the MPS, conventional liposomes are of limited value. Therefore, research has been aimed at decreasing the MPS uptake of liposomes and consequently increasing their circulation time. LCLs were the result of these efforts. Intravenously administered LCLs potentially offer drug targeting to sites of infection not restricted to the MPS. A number of reports have demonstrated enhanced therapeutic efficacy of LCL-encapsulated aminoglycosides compared with free drugs or conventional liposomes. Unfortunately however, most studies with liposome-encapsulated aminoglycosides have, up to now, been performed in animal models with an intact host defence and infected with bacteria susceptible to the antibiotic. Treatment failure in clinical practice, however, particularly occurs in patients with impaired host defences or in patients infected with bacteria of low susceptibility. A single study addressed both issues in determining the efficacy of SSL-gentamicin.117 These issues should be incorporated more in animal models to demonstrate the value of liposomes in clinically relevant settings. So far, MiKasome has shown an excellent safety profile. Yet, similar to the conventional liposome formulations, the effects that the prolonged tissue drug concentrations have on development of resistance need to be addressed. The results that have been reviewed indicate promising prospects for liposome-encapsulated aminoglycosides and warrant further clinical investigations into the use of these formulations for the treatment of severe infections.
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Acknowledgements |
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Notes |
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References |
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