Peritoneal dialysis (PD) is a well-established renal replacement therapy (RRT) for
end-stage renal failure (ESRF)[1] and offers certain clear advantages over hemodialysis[2].
However, PD is often associated with a high risk of infection of the intraperitoneal
cavity, subcutaneous tunnel and catheter exit site, which may subsequently form microbial
biofilms[1]. Generally, a majority of PD patients suffer from bacterial and fungal
infections and if the infection(s) is diagnosed timely, they can be resolved by appropriate
antibiotic treatment. However, the immune system of ESRF patients continuing on PD
may have been compromised and infections are as frequent as once every 10-15 weeks
necessitating frequent use of conventional antimicrobial drugs, which may cause emergence
of drug resistance. Further as, higher doses of antibiotics are often required for
such infections, this may cause intolerable toxicity. Moreover, infections, if correct
it as “not resolve and sustain” for a week or more, may lead to infectious peritonitis[1],
which severely affects the functioning of the peritoneal membrane, and its resolution
may require hospitalization of the patient.
Clinically, treatment of infectious peritonitis involves rapid resolution of infection
by eradicating the causative organism(s) and the preservation of peritoneal membrane
function. However, in the majority of severe cases, treatment may fail to resolve
the condition even after intravenous and intraperitoneal antibiotics and the patients
are switched to hemodialysis, either temporarily or permanently[1,3]. Switching to
hemodialysis is undesirable because of complications associated with temporary vascular
access, reduced patient autonomy and increased medical costs[1,3]. Infectious peritonitis
is not only the major cause of technique failure, but also the leading cause of mortality
and morbidity in PD patients[1]. Therefore, there is an urgent need to improve the
existing PD technique in terms of its efficacy against infections and in vivo adequacy
during long-term PD; so that, the frequency of PD associated infections could be reduced
during prolonged PD and thereof to reduce the traumatic and life-threatening episodes
of infectious peritonitis[1]. Practically, this can be achieved through developing
infection resistant PD fluid composition which could provide long term protection
against a variety of PD associated infections by bacteria, mycobacteria, fungi or
viruses. The key requisite to develop such an efficient and novel composition is that
the composition should contain some antimicrobial agents with novel mode of action
and multiple molecular targets to tackle microbial resistance. Furthermore, these
antimicrobial agents should preserve their efficacy and adequacy (i.e. biocompatibility
and non-cytotoxicity) during their frequent and long-term use.
Antimicrobial nanoparticles, especially metal (e.g. gold, silver, titanium and bismuth)
and metal oxide (e.g. zinc oxide, titanium oxide, etc.) nanoparticles would be of
immense interest owing to their exclusive antimicrobial activity against a variety
of infections and potential wound healing and anti-inflammatory properties[4–5]. Metallic
nanoparticles have been researched extensively in the past and some of their classes
have been found to be very effective in terms of their antimicrobial and anti-biofilm
properties[2]. Mechanistically, these nanoparticles produce their antimicrobial activity
through affecting multiple pathways[2]. Thus, many concurrent mutations would have
to occur to develop resistance to these nanoparticles[5]. Therefore, antimicrobial
formulations based on these nanoparticles could be administered frequently as required
to manage recurrent and persistent infections during long-term PD with reduced risk
of developing resistance. Studies have demonstrated that naturally occurring bacteria
do not develop antimicrobial resistance against metallic nanoparticles[4]; even some
of their classes have the potential to eradicate multidrug-resistant infections when
these are used in combination with antibiotics[4–5]. Likewise, some classes can limit
biofilm formation either independently or in combination with antibiotics[2]. Owing
to such broad spectral antimicrobial properties and activity against biofilms and
formidable multidrug resistant pathogens, metallic nanoparticles are finding their
potential applications as antimicrobial agents and disinfectants to improve several
biomedical devices, pharmaceutical products and healthcare interventions including
medicines[4–5]. Based on these attributes, the use of metallic nanoparticles can also
be envisaged for developing infection resistant composition of PD fluid (as depicted
in
Fig. 1A
). The particular advantage of employing metal based antimicrobial nanoparticles in
this translational research endeavor is that these can be filter-sterilized and added
directly to the PD fluid for long term storage and prolonged shelf life[2]. Further
more, these can easily withstand temperature variations (ranging from 4°C to 50°C,
which is generally encountered during transportation and storage of medical products),
under which conventional antibiotics may inactivate or degrade. Moreover, the preparation
of nanoparticles is cost-effective and relatively simple compared to antibiotics synthesis[4–7].
Fig. 1
A: Pictorial illustration for developing infection resistant PD fluid composition
through the use antimicrobial nanoparticles (AM-NPs). B: Flowchart denoting the plant-mediated
biological synthesis of nanoparticles. The acronyms AM, NPs, PD, UV, SPR, SEM, TEM,
DLS, and XRD used in (A) and (B) represent, respectively, anti-microbial, nanoparticles,
peritoneal dialysis, ultraviolet, surface plasma resonance, scanning electron microscope,
transmission electron microscope, dynamics light scattering and X-ray diffraction.
Metallic nanoparticles of varying sizes, shapes, and properties can be synthesized
using variety of chemical and physical methods. However, these methods often lead
to the presence of some toxic chemicals adsorbed on the surface and, if are used in
pharmaceutical products or biomedical applications, these could produce intolerable
toxicity and adverse effects to humans[2]. This is not an issue when it comes to biologically
synthesized nanoparticles, i.e. those synthesized from biomaterials derived from micro-organisms
or plant parts following green chemistry approach[6]. Green synthesis of nanoparticles
(using either plant products or microorganisms) is considered as environmentally benign
and cost-effective replacement to the toxic chemical and physical methods.
Compared to plant mediated synthesis, the synthesis of nanoparticles using microorganisms
is relatively more tedious and time consuming process, as it requires more steps in
maintaining cell culture, longer incubation time for intracellular reduction of metal
ions and more steps to purify synthesized nanoparticles. On the other hand, plant
mediated green synthesis of nanoparticles is relatively simple and provides several
clear advantages[2] like (a) extracellular and rapid biosynthesis as water soluble
phytochemicals reduce the metal ions in a much shorter time, (b) no need to maintain
time-consuming microbial cultures and purification steps as required in microbial
mediated biogenic synthesis, (c) preparation is safe to handle and is free from problems
arising due to microbial contamination, (d) cost effectiveness as the use of plant
extracts reduces the cost incurring in maintaining microbial cultures and to isolate
and purify the synthesized nanoparticles in multiple steps, and (e) availability of
broad variability of metabolites that may aid in reduction. The generalized flowchart
for plant mediated nano-biosynthesis is shown in
Fig. 1B
.
Studies have shown that biologically synthesized nanoparticles exhibit better biocompatibility
and less cytotoxicity compared to their counterparts prepared using chemical or physical
methods[2]. Here, I envisage that metal nanoparticles synthesized biologically can
also be used to impart infection resistant properties to peritoneal dialysis fluid
owing to their relatively low in vivo toxicity and higher biocompatibility. A recent
study has shown that zinc oxide nanoparticles synthesized biologically exhibit significantly
higher biocidal activity against various pathogens when compared to chemically synthesized
ZnO nanoparticles[2]. Such preliminary studies suggest that biologically synthesized
nanoparticles have huge potential to address future medical concerns. However, before
putting these nanoparticles into human healthcare actions, the key step is to rule
out their nano-toxicity and adverse effects on long-term exposure. Therefore, efforts
are required to evaluate their pharmacology through conducting dose dependent as well
as time of exposure dependent ex vivo and in vivo studies on human cell lines and
animal models. After successful evaluation of preclinical efficacy and toxicity, nanoparticles
showing favorable in vivo pharmacology response can be envisaged to develop infection
resistant composition of peritoneal dialysis (PD) fluid. Simply, this will be achieved
through adding non-toxic doses of these nanoparticles into different types of PD fluids
widely used in clinics and subsequently, evaluating (a) their efficacy against variety
of healthcare associated infections, (b) in vivo adequacy, and (c) time stability
to ensure their long-term storage and prolonged shelf life. Strategically, a good
start in this direction could be to evaluate the use of nano-sized particles of zinc
oxide (ZnO) which is already listed as “generally recognized as safe (GRAS)” by the
U.S. Food and Drug Administration (21CFR182.8991). Further more, various studies have
shown that ZnO nanoparticles exhibit antimicrobial properties and is also used as
food additive for its long-term preservation[2]. Likewise, the use of other antimicrobial
nanomaterials safe to human beings (e.g. preferably Copper or Silver oxide NPs) can
also be explored in the design of infection resistant PD fluid and further to bring
the resulted composition into clinical use through performing meticulous translational
research. Important to mention here is that the new PD fluid composition containing
non-toxic doses of metallic nanoparticles would be delivered directly into the intraperitoneal
cavity, therefore, intraperitoneal uptake of these nanoparticles to other parts of
the body and thereof non-specific dissemination may lead to unexpected toxicities,
side effects and other complications. Therefore, before putting the new PD fluid composition
in clinical use, it would require careful assessment of its pharmacology and pharmacoknietics.
In this regard, pharmacometabolomics, an emerging application of metabolomics for
deriving early preclinical indications of efficacy and toxicity of pharmaceutical
products, has huge potential to guide the anticipated translational research endeavors.
Different from metal-based nano-particles, the use of nano-scale antimicrobial materials
derived from natural biological substances, including oligo/poly-saccharide based
nanoparticles, liposomes, dendrimers, and etc., can also be envisaged in this translational
research endeavor. Further, the use of promising antimicrobial nanoparticles in conjunction
with novel antibiotic agents can also be explored to manage multidrug resistant pathogens
and formation of biofilms during long-term PD. The antibiotics can be added directly
into the PD fluid containing antimicrobial nanoparticles at the time of intra-peritoneal
instillation. Recently, Dr. Yang's group and their collaborators from IBM Research
have co-developed a biodegradable, biocompatible and cost-effective hydrogel that
can adapt different shapes and can target variety of bacteria and fungi responsible
for healthcare associated infections[8]. The remarkable property of these hydrogels
is their ability to target multidrug-resistant biofilms and to eliminate naturally
by the body owing to their biodegradable nature. Therefore, these hydrogels could
also serve as useful starting material in this endeavor i.e. to evaluate their clinically
safe use for eradicating intraperitoneal, catheter exit-site and subcutaneous tunnel
infections which are often caused by microbial adhesion and subsequent biofilm formation
following episode(s) of infection.
In conclusion, necessity to improve the PD technology for limiting frequent PD associated
infections and possibility to encompass the benefits of antimicrobial nanoparticles
synthesized biologically, have been discussed in a translation research perspective.
Particularly, the biocompatibility and cytotoxicity of metal based antimicrobial nanoparticles
are the key issues to be addressed before putting them into clinical applications.
I foresee that this perspective article would definitely appeal some of the biomedical
researchers to put their conscience efforts in the direction of developing infection
resistant PD fluid composition or nanotechnology based solutions targeting PD related
biofilms for its efficient and long-term management.