12.5 Advantages and Successes of Liposomal Antibiotics
It has been more than 40 years since it was suggested that liposomes could become nanocarriers
of antibiotics to drug-resistant pathogens, and research and development has
produced effective liposomal drug delivery systems with multiple advantages over conventional
drug delivery formulations. The goal of any liposome formulation is to improve
drug biodistribution and pharmacokinetics while lowering toxicity. Other aims include
increasing drug uptake by resistant intracellular and extracellular pathogens. The limitations
of conventional antibiotics typically include adverse side effects combined with
limited biodistribution or pharmacokinetics in patients. In addition, there are drawbacks
such as elevated bacterial resistance, low drug permeability levels, and thus interaction
with pathogens. In order to achieve these goals, it is important to characterize the
liposomes for their specific activity by the techniques described in the earlier sections.
Presently, accomplishments in liposomology have been the production of nanocarriers
with reduced toxicity, which not only increase, but also sustain drug levels in the circulation
and at the site of infection (lymph nodes, the lungs) [6,34,146]. These achievements
overwhelmingly promote the utilization of liposomes as carriers in the treatment of fungal
infections, certain cancers, and chronic or resistant lung infections.
12.5.1 Protection from Degradation or Inactivation
At the basic level, liposomes selectively “screen” particular antibiotics for their bacterial
targets. In contrast, for example, β-lactams are broad-spectrum antibiotics that are regularly
used against Gram-positive and Gram-negative pathogens [147]. Due to their popular
clinical use, pathogens like methicillin- or vancomycin-resistant Staphylococcus aureus have
emerged [148]. Their resistance is usually due to β-lactamases, which have prompted the
production of β-lactamase-resistant β-lactams (e.g., meropenem). However, newer forms
of semiresistant mutations of penicillin-binding proteins, or proteins with resistance to
antibiotic compound diffusion across bacterial membranes have developed [149]. Since
liposomes tend to encapsulate compounds which act to mask and protect the internalized
antibiotics, many resistance factors like β-lactamase degradation and poor diffusion
are assumed to be bypassed [147]. As liposomal β-lactam research is only in the formative
stages of in vitro experimentation, in vivo models are lacking [75,82,83]. Schiffelers
et al. explored the synergistic activity of liposome co-encapsulated gentamicin and ceftazidime
in a rat K. pneumoniae infection model [115]. The investigators reported that the
co-encapsulation allowed for a shorter treatment course and a lower dose of antibiotics
compared to the conventional form, warranting further studies.
Opportunistic pathogens that proliferate in the lungs of CF patients reside within biofilms
(an extracellular matrix made up of negatively charged alginate) that are covered with
endotoxins generated by pathogens and patient-excreted polyanionic sputum (a mixture of
DNA and glycoproteins from host neutrophils) [61,150]. Different classes of cationic antibiotics
(e.g., aminoglycosides, polymyxins) with broad-spectrum activity against these pathogens
are inactivated in the presence of polyanions. The aggregation of these factors (owing
to their charges) with antibiotics retards further diffusion through the biofilm matrix, and
hence contact with the pathogens. Liposome entrapment of antibiotics, however, inhibits
the antibiotic–polyanion interaction. We have previously shown this to be true for neutral
liposomes (which do not favor electrostatic interactions) that were loaded with tobramycin
or polymyxin B [60]. While the activity of conventional antibiotics against P. aeruginosa was
inhibited at low concentrations of the factors, liposomal formulations were superior by 2- to
100-fold, dependant on the inhibiting factors. The liposomal formulations also reduced
endogenous bacterial counts in expectorated sputum at a concentration lower than that of
the conventional form, but failed to completely eradicate growth. Further investigations
have shown that the viscous sputum hampers liposomal diffusion, and that recombinant
human DNase and alginate lyase are important components toward the improvement of
conventional or liposomal antibiotic diffusion across this barrier [70,151–153].
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12.5.3 Enhanced Delivery to Intracellular Pathogens
Persistent intracellular pathogens (e.g., Mycobacterium avium complex (MAC), L. monocytogenes,
S. typhimurium) may reside in phagocytic cells (an essential component of the immune system)
after opsonization, hindering any treatment [51,156,157]. The majority of conventional antibiotics
(e.g., aminoglycosides, β-lactams) cannot readily penetrate or diffuse across the phagocyte
membrane, while others (e.g., macrolides, fluoroquinolones) are inactivated by acidic pH
of lysosomes, or do not reach critical bactericidal concentrations [51]. When antibiotics are
loaded within liposomes, these nanocarriers not only show enhanced activity in vitro, but
also improve the clearance of bacterial infections in vivo with greater survival capacities [158].
