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452 C. Ginn et al.
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excipients that can encapsulate an anti-infective drug or direct covalent conjugation
of an anti-infective drug to a polymer have been extensively investigated during the
last decades.
Particulate colloidal drug delivery systems are often in the nanometre size range
and are presented as: liposomes, niosomes, solid lipid nanoparticles, polymeric
nanoparticles, polymeric mic elles and polymeric complexes and conjugates. These
nano-sized carriers have been used for the delivery of drugs, imaging agents and
proteins (Soares et al.
2018). Liposomes are uni- or multilamellar bilayer vesicles
composed of phospholipids and cholesterol and encompassing an aqueous core
(80–200 nm). Several liposome-based medicines have been used in the clinic, for
example liposomal amphotericin B (AmBisome
®
). Niosomes are also lipid-based
vesicles composed of cholesterol and a non-ionic surfactant (Chen et al. 2019).
Several polymers have been investigated for the delivery of anti-infective drugs in
the form of drug-polymer conjugates, drug-polymer complexes and polymeric
micelles. A polymer-drug conjugate is defined as the covalent conjugation of a
drug to a polymer via a covalent bond (and are ~5–25 nm). Most anti-infective
drugs are poorly soluble and/or toxic molecules. Water-soluble polymers can be
used to improve the solubility of drugs via covalent or non-covalent bonds. Block
copolymers comprised of hydrophilic-hydrophobic parts are amphi philic and can
self-assemble to form polymeric vesicles. In water, these polymers form
nanoparticles with a hydrophilic shell and hydrophobic core. This is often referred
to as a polymeric micelle and they are 50–200 nm in size. These polymeric micelles
might offer the advantages of improving drug solubility and reducing drug toxicity
(Hwang et al.
2020). A more advanced polymer-based delivery system is made from
dendrimers. Dendrimers are hyperbranched polymers with a large number of chain
end groups, a compact structure and low viscosity which makes them different from
linear polymers. Dendrimers have the advantage of improvi ng drug bioavailability
and can deliver a high drug load or more than one drug due to their branched
structure (Saleem et al.
2019).
More advanced drug delivery systems such as nanotubes have been recently
investigated as carriers of anti-infective drugs. Nanotubes are cylindrical hollow
molecules that are synthesised from inorganic and metallic molecules (Rode et al.
2018). However, the use of nanotubes as nanocarriers has not yet reached the clinical
testing stage.
Nano-delivery systems are complex formulations and the vast majority are
designed to be parenterally administered. The use of these systems in drug delivery
is associated with the following challenges: difficult scalability, ease of sterilisation
and cost. However, these systems provide the possibility of selectively delivering
drugs to specific tissues and the opportunity to deliver drugs intracellularly. The
overall aims of the use of nano-delivery systems are to: (i) increase drug solubility,
(ii) reduce systemic drug toxicity, (iii) enhance drug pharmacokinetics, (iv) increase
drug stability, and (vi) target a drug to a specific site of action to maximise the
efficacy of the drug against the pathogen (Sánchez et al. 2020; Rai et al. 2022).
The rationale for using nano-sized particulate delivery systems to deliver antiinfective drugs are: (i) nanoparticles can be taken up by cells via endocytosis to
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enable cellular internalisation of the drug (Rai et al. 2022), (ii) a targeting ligand can
be associated with the nanoparticles that can, in principle, facilitate the delivery of
the drug to specific tissues and cells (Lin et al. 2015), (iii) the release of the drug from
the nanocarrier to reach the pathogen where it resides in the intracellular compartment, may be modulated, for example by using pH responsive polymers (Maji et al.
2019), and (iv) optimising drug pharmacokinetics to achieve sustained therapeutic
levels resulting in reduced cumulative doses and a reduced frequency of administration, e.g. as is achieved by covalent conjugation of PEG to drugs (Yadav and
Dewangan
In the case of polymeric conjugates, due to their large size, they circulate longer in
the blood without being systemically absorbed. The vasculature at diseased tissue
sites is inflamed due to infection making infected tissue often more permeable than
healthy tissue. This allows for the preferential uptake of polymeric and other nanosized particulates.
There is an unmet medical need for drug delivery systems that can offer optimal
delivery of anti-infective drugs for the treatment of infectious diseases. Six example
diseases are described here where the use of nanomedicine alternatives has had a
positive impact.
2021).
17.2 Visceral Leishmaniasis
17.2.1 Pathology
Leishmaniasis is a complex parasitic disease with various manifestations caused by
more than 20 Leishmania species (kinetoplastid flagellates, Family
Trypansomatidae). It is transmitted by female sandflies (Phlebotomine and
Lutzomyia species) (Burza et al. 2018). There are two main clinical forms of
leishmaniasis, visceral (kalazar) and cutaneous (ulcerative skin lesions), as well as
less common manifestations such as mucocutaneous leishmaniasis (destructive
mucosal inflammation) (Uliana et al. 2018). There are 12 million people in over
90 countries in tropical and subtropical regions affected by leishmaniasis. The
annual incidence of visceral leishmaniasis is 0.9 to 1.6 million with
20,000 to 30,000 deaths per year (Mannan et al. 2021).
Visceral leishmaniasis (VL) is caused primarily by L. donovani in India and East
Africa and Leishmania infantum mainly in the Mediterranean basin, the Middle East,
Central Asia and South America (Burza et al.
to death resulting from opportunistic infections which cause pneumonia and diarrhoea (Henke et al. 2021; Bispo et al. 2020). Clinical symptoms of VL are fever,
weight loss, anaemia, abdominal pain, depression of the immune system and
enlargement of the liver, and spleen. The clinical manifestation of VL can take up
to 4 to 6 months to appear. VL is localised mainly in spleen and liver macrophages,
in addition to macrophages of the bone marrow and lymph nodes (van Griensv en
and Diro
2012).
2018). If VL is not treated, it can lead
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The life cycle of the Leishmania parasite occurs in two hosts: the insect (sandfly)
and the mammalian hosts (Reithinger et al. 2007; Bates 2007; Sadlova et al. 2017).
In the insect, the parasite exists as a uni-flagellated form called promastigote stage. In
the mammalian host, a rounded non-motile form of the parasite is present called the
amastigote stage (Sadlova et al.
2017). Anti-leis hmania chemotherapy targets the
intracellular amastigotes which is the clinically relevant stage. These amastigotes are
present inside the macrophage in a specific cell compartment called the
phagolysosome whic h has an internal pH of 4.5–5.0 (Zilberstein
2021). The acidic
and hydrolytic environment of the lysosome leads to degradation of macromolecules
such as proteins and RNA to lower molecular weight derivatives (amino acids,
nucleoside and phosphate) which are important for parasite nutrition (Burchmore
and Barrett
2001). The uptake of the chemotherapeutic drugs by the phagolysosome
is dependent on their molecular weight, pKa, lipophilicity, and transporters. For the
chemotherapeutic drugs to be efficient in curing leishmaniasis, the drugs should be
able to cross the phagosomal membrane and be taken up by the amastigotes (Roatt
et al.
2020).
17.2.2 Conventional Therapy
The standard treatments for VL are pentavalent antimonials (sodium stibugluconate,
V
) and amphotericin B (AmB). Other drugs available for the treatment of VL are
Sb
pentamidine, miltefosine, and paromomycin (Uliana et al. 2018). Most of these
drugs are toxic, costly and require repeated administration. Sb
the first-line treatment of VL for decades despite its toxicity. The recommended dose
V
for treatment of VL is 20 mg/kg/day for 28–30 days which can be adminis-
of Sb
tered intramuscularly (Sundar and Singh 2018). Intramuscular injections are painful
due to irritation and the administration of large volumes. The drug may also be
administered intravenously, which is less painful but impractical when treating large
numbers of patients. The most recent recommendation by the WHO is to use
liposomal AmB as first treatment choice for VL and Sb
2010). However, liposomal AmB is expensive and not available in many areas
affected by VL which results in Sb
V
use as the first option in some endemic areas.
AmB is a polyene antibiotic which was first isolated from Streptomyces nodosus
in 1955 (Donovick et al.
1955). It is the gold standard for treatment of disseminated
systemic fungal infections such as Candida albicans, Histoplasma capsulatum, and
Aspergillos niger infections (Fernández-García et al. 2017). The anti-leishmanial
activity of AmB was discovered in the1960s (McMill 1960). AmB is currently
recommended as a first-line treatment of VL (especially in immune-competent and
immunocompromised patients) in Europe and the United States (Vigna et al. 2010;
Lagadinou et al. 2013; Sundar and Chakravarty 2010). It is also considered first-line
therapy in India, Nepal, Africa, and Brazil for the treatment of VL due to the
incidence of resistance to antimonials (Sundar and Chakravarty 2010). Incidences
of VL resistance to AmB are rare. However, some recent reports showed that there
V
has been used as
V
as second line (WHO
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might be a risk of Leishmania parasite resistance to AmB and the report explained
how these molecular resistance mechanisms may arise (Ponte-Sucre et al. 2017).
Miltefosine is an oral anti-leishmanial drug which has shown efficacy in treating
VL but its efficacy has declined due to drug resistance (Ponte-Sucre et al.
also it has a teratogenic risk. Paromomycin is an old antibiotic, but it was licensed in
2007 in India for treatment of VL at a dose of 11 mg/kg for 21 days (Davidson et al.
2009) and, has been used in combination with Sb
(Tamiru et al. 2021). A list of drugs used for the treatment of VL is shown in
Table 17.1.
V
for the treatment of VL in Africa
2017) and
17.2.3 Rationale of Using Nano-delivery System
for Anti-leishmanial Drugs
The main barrier to anti-leishmanial drugs is the location of the parasite inside the
phagolysosome of the resident macrophages in different anatomical sites in the body
(Bruni et al.
intracellular parasites. Furthermore, most anti-leishmanial drugs are given intravenously and exhibit systemic toxicity (Bruni et al.
Following systemic administration of anti-leishmanial drugs, a small amount of
the drug reaches the macrophages (Sundar et al. 2019). The main challenge in
drug delivery of anti-leishmanial drugs is modifying the pharmacokinetics and
distribution of the drug to target the macrophages and to reduce the interaction of
the drug with non-target tissues after systemic administration (Sundar et al.
The use of nanocarriers in the delivery of anti-leishmanial drugs can improve
poor solubility, reduce toxicity, modify pharmacokinetics, enhance tissue targeting,
and enhance the therapeutic efficacy of these drugs (Jamshaid et al.
(Table 17.2). Colloidal nanocarriers such as liposomes and nanoparticles may be
internalised by the macrophages in the liver and spleen via phagocytosis
(or endocytosis), releasing the drug inside the macrophages at high concentration
that ultimately kills the parasite (Saleem et al. 2019; Blanco et al. 2015; Shang et al.
2014). This process is called passive targeting and it involves cellular uptake by
invagination of the outside layer of the cell membrane to ‘capture’ a small volume of
extracellular material. Vesicular formation occurs with invagination to allow impermeable extracellular material to be taken up by the cell. Entry into the cytoplasm
then proceeds with extracellular material entrapped within vesicles (e.g. the
endosomes or phagosomes) (Rosales and Uribe-Querol 2017). Cell trafficking
events incl uding fusion with other cytopl asmic vesicles result in a change of the
environment (i.e. decreased pH, increased proteolytic enzymes) within the vesicle
containing the extracellular material resulting in pathogen death and protein
degradation.
Colloidal nanocarriers (particulates) are recognised by phagocytic cells of the
mononuclear phagocytic system (MPS) as an exogenous particle in intact form or
2017). Conventional anti-leishmanial drugs are not able to target these
2017; Jamshaid et al. 2021).
2019).
2021)
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Table 17.1 Chemotherapeutic drugs for the treatment of VL
Drug Chemical nature Mode of action Drawbacks
Pentavalent antimony
compounds (sodium
stiboglucanate SbV,
SSG, meglumine
antimonite)
Miltefosine Alkylphosphocholine 1. Affects ether lipid
Paromomycin
(Aminosidine)
Pentamidine Aromatic diamidine Inhibition of arginine
Amphotericin B Polyene antibiotic Alteration of cell
All the mentioned drugs are administered parenterally except miltefosine (oral administration)
Adapted from (Mohamed-Ahmed et al.
Derivatives of
stibonic acid
Aminoglycoside
antibiotic
2013a)
1. Affect the metabolism of glutathione and
trypanothione (Wyllie
2004)
et al.
2. Killing the parasite
by process of apoptosis through DNA
fragmentation
(Sudhandiran and
2003)
Shaha
metabolism, cellular
signal transduction
(Barratt et al.
2. Induction of apoptosis (Paris et al.
2004)
1. Interaction with
Leishmania ribosome
2.Induction of respiratory dysfunction by
affecting cell metabolism (Davidson et al.
2009)
transport and its effect
on polyamine biosynthesis (Hafiz and
Kyriakopoulos 2022)
membrane integrity. It
interacts with ergosterol in the fungal cell
membrane and ergosterol precursor in
Leishmania parasites
cell membrane. This
interaction increases
the permeability of the
fungal cell or Leish-
mania parasites cells
and results in leakage
of its content causing
its death (Ramos et al.
1996; Cohen 2010)
2009)
Incidences of resistance to SSG and
toxicity (Burza et al.
2018; Ponte-Sucre
et al.
Teratogenicity and
the risk of emergence
of resistance (Burza
et al.
Sucre et al.
Aminoglycoside toxicity (ototoxicity)
(Sundar et al. 2007)
1.Toxicity, diabetes,
nephrotoxicity, and
tachycardia (Piccica
et al.
2. Emergence of
resistant strains in
India
Infusion-related toxicity and nephrotoxicity (Burza et al.
2018)
C. Ginn et al.
2017)
2018; Ponte-
2017)
2021)
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)
Clinical
(L. donovani) at a dose of 1 mg/kg on alter-
nate days for 30 days (total dose of 15 mg/kg)
in India (Sundar et al. 2011; Rodrigo et al.
2018)
Clinical
(L. donovani) at a single dose of 5 mg/kg in
IV Cure rate of 97.5% in VL patients
Pre-
clinical
Pre-
clinical
(continued
L. donovani-infected mice model (Parvez
given at dose of 3 mg/kg x 5 days
et al. 2020)
(49.30 ± 8.47% parasite inhibition) in
Oral Oral administration AmB-paromoycin solid
for 5 days has shown 91.12 ± 2.79% inhibi-
lipid nanoparticles at dose of 20 mg/kg given
tion of the liver parasite burden which is
significantly higher than oral miltefosine
a single bolus injection (20 mg/kg) in BALB/
ance of the parasite from the spleen following
c mice infected with L. infantum. Also, the
parasite DNA was significantly reduced
India (Sundar et al. 2011). A single dose of
89% in VL patients in India (Rodrigo et al.
3.75 mg/kg has achieved a cure rate of over
mal formulation has shown complete clear-
2018)
(41.1%) following administration of liposo-
mal antimoniate compared to unformulated
antimoniate (83.3%) (Reis et al. 2017)
IV The meglumine antimoniate mixed liposo-
AmB: deoxycholate (2:1) IV Cure rate of 93% in VL patients
)
®
(Fungizone
Colloidal dispersion AmB
Delivery system Drug Composition Route Efficacy Status
Table 17.2 Examples of nanocarriers for delivery of anti-leishmanial drugs
Hydrogenated soy phosphatidylcholine:
cholesterol:distearoyl phosphatidylglycerol:
AmB (2:1:0.8:0.4)
)
®
(AmBisome
Liposome AmB
Distearoylphosphatidylethanolamine- poly-
Meglumine
Conventional and
solid nanoparticles (glyceryl monostearate
and soya lecithin). AmB (24%) and
ethylene glycol 2000 (pegylated liposomes)
with 30.6% meglumine antimoniate and
distearoylphosphatidylcholine/cholesterol/
dicetylphosphate (conventional liposomes)
with 20.5% meglumine antimoniate
antimoniate
pegylated liposome
mixture
2-hydroxypropyl-β-cyclodextrin-modified
AmB and
paromomycin
combination
Solid lipid
nanoparticles
paromomycin (10.5%)
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Pre-
clinical
has shown signifi-
cant reduction in liver and spleen parasite
burden in BALB/c mice VL model (Valle
et al. 2019)
nanoparticles (0.4 mg/kg)
Pentamidine Poly(d,l-lactic-co-glycolic) (PLGA) Oral Oral administration of pentamidine-PLGA
Biodegradable poly-
meric nanoparticles
Delivery system Drug Composition Route Efficacy Status
Table 17.2 (continued)
IV intravenous
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opsonised form (Saleem et al. 2019; Bruni et al. 2017; Blanco et al. 2015; Shang
et al. 2014). Both colloidal carriers and the Leishmania parasite are taken up by the
macrophages which might make these carriers ideal delivery systems for antileishmanial drugs.
Active targeting is another stra tegy for delivering anti-leishmanial drugs to the
macrophages; this can be achieved by the inclusion of specific macrophage receptor
ligands in the nanocarrier system (Jamshaid et al. 2021). Macrophages have various
surface receptors such as Fc receptors, complement, fibronectin lipoprotein, and both
mannosyl and galactosyl receptors. These receptors are responsible for controlling
macrophage activities such as activation, recognition, endocytosis and secretion
(Saleem et al. 2019; Ahsan et al. 2002). Several attempts have been made to target
macrophages using liposomes grafted with targe ting ligands such as mannose and
tuftsin (Rathore et al. 2011; Khan 2021). All these techniques have not reached the
clinic because of difficulties in scaling up and their high cost.
Polymeric carriers can passively deliver drugs into macrophages or can be
modified by the attachment of specific macrophage-targeting ligands. Antileishmanial drugs can be attached to a polymeric carrier via a linker that can be
specifically cleaved by lysosomal enzymes or by hydrolysis
(e.g. AmB-(2-hydroxypropyl) methacrylamide (HMPA) conjugates) or can be
non-covalently attached to the polymer (e.g. AmB- poly(α-glutamic acid) complexes) (Mohamed-Ahmed et al.
polymeric carrier with a mannose moiety has been reported to target drug-polymer
conjugates to the macrophages via the mannose receptor. However, in some of the
mannose grafted polymers, for example AmB-HPMA conjugates, there was no
difference between the non-mannosylated and mannosylated conjugate in their
observed in vivo anti-leishmanial activity in BALB/c mice infected with
L. donovani. This was partially explained by the presence of conformational hindrance that prevents interaction of the polymer-bound mannose with the mannose
receptor (Nicoletti et al. 2009).
Biodegradable polymers such as poly-lactic-glycolic acid (PLGA), chitosan and
polycaprolactone have been pre-clinically investigated in the delivery of antileishmanial drugs (Saleem et al. 2019; Jamshaid et al. 2021). These biodegradable
polymeric nanoparticles (e.g. nanospheres and nanocapsules) can release the drug
following polymer enzymatic degradation at the target site or via diffusion of the
drug upon hydration and swelling of the polymeric nanoparticles (Saleem et al.
2019). These polymeric nanoparticles can passively deliver the drug into the mac-
rophages or can be modified via surface attachment o f specific targeting moieties.
For example, AmB loaded on mannan-functionalised PLGA nanospheres has shown
high efficacy against Leishmania parasites (Barros et al. 2015).
Dendrimers have been investigated pre-clinically for the delivery of antileishmanial drugs which can offer the advantages of improving drug bioavailability,
delivering high levels of the drug or delivering more than one drug due their
branched structure (Saleem et al.
have been reported to reduce toxicity and, improve anti-leishmanial effica cy of AmB
in mice infected with L.donovani following IP administration (Jain et al.
2013b, c; Nicoletti et al. 2009). Grafting the
2019). Poly(propylene imine) (PPI) dendrimers
2011). The
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main challenge with the use of dendrimers as a delivery system is high cost of
manufacturing which rendered scalability and commercialisation of these carriers to
not be feasible (Saleem et al. 2019).
Another type of advanced nanocarriers that have shown the potential to be used as
nanocarriers for delivery of anti-leishmanial drugs are nanotubes. For example,
AmB attached to functionalised carbon nanotubes (f-CNTs) has shown higher
anti-leishmanial activity than free AmB in hamsters infected with L. donovani
following IP administration (Prajapati et al.
as nanocarriers have not reached the clinical testing stage yet.
2011). However, the use of nanotubes
17.3 Systemic and Invasive Candidiasis
17.3.1 Pathology
Candidiasis is the most common systemic fungal infection which is associated with a
high rate of mortality (Logan et al. 2020; McCarty et al. 2021). The annual cases of
systemic candidiasis are 400,000 mostly reported in the developing countries
(Chowdhary et al. 2017). C. albicans is still considered the most common cause of
candidiasis, however it constitutes less than 50% of the cases recently. A slight
increase of cases caused by Candida glabrata (~25%), tropicalis (~8–10%),
parapsilosis (~12–17%) and krusei (~2–3%) has been reported (McCarty et al.
2021). A new species that has recently been considered a high risk to cause systemic
candidiasis is C. auris which is highly virulent and multi-drug resistant (Chowdhary
et al.
2017). Candida species are common organisms in the oral, vaginal, and
gastrointestinal tract. Under certain circumstance, these organisms can cause systemic infections which are considered to be very serious and can be fatal.
Invasive candidiasis is a life-threatening infection; it starts with penetration of the
pathogen through the mucosal barrier to the bloodstream and the subsequent spread
of the organism to the body organs (Pappas et al.
disseminated candidiasis, endocarditis, meningitis, endophthalmitis, and other deep
organ infections (McCarty et al. 2021; Pappas et al. 2018). This pathogen causes
necrotic nodules or abscesses resulting in severe damage and failure of the infected
organs (Pappas et al. 2018). There are several risk factors for systemic candidiasis
such as intensive care unit admission, intravascular catheters, surgical implants,
burns, abdominal surgery, solid organ transplants, autoimmune diseases, HIV/AIDS
infections, malnutriti on, and liver disease (Logan et al. 2020; Ostrosky-Zeichner and
Al-Obaidi 2017). The innate immune system especially neutrophils and macrophages are responsible for eliminating systemic fungal infections (Heung 2020;
Gow et al. 2011). Consequently, most of the systemic fungal infections occur in
patients with neutropenia or defects in neutrophils or macrophage function (Heung
2020; Gow et al. 2011).
The ability of Candida spp. to form biofilms might play an important role on its
pathogenesis because: (Croft
2018) biofilms prevent penetration of antifungal agents
2018). It includes candidemia,
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into candida cells and might result in development of resistance to antifungal drugs,
and (Qi et al. 2021) biofilms protect candida cells from host immune systems (Nett
and Andes 2020). Candida can form biofilms on the mucosa, skin or on medical
device surfaces and this can increase the risk of systemic candidiasis (Nett and
Andes
2020; Gulati and Nobile 2016).
17.3.2 Conventional Therapy
The most common treatments for hematogenous and organ candidiasis are intravenous polyene and azole antifungal drugs. Polyene antifungal drugs such as AmB
have been used for the treatment of fungal infections since 1957 (Cavassin et al.
2021). AmB has been a first-line treatment for fungal infections since the 1960s,
because of its broad-spectrum activity and no significant incidence of mycological
resistance (Cavassin et al.
AmB administered intravenous ly in the form of deoxycholate or lipid-based
formulations has been used in the treatment of severe life-threatening fungal infections (Fernández-García et al.
treatment of invasive fungal infections in immunodeficient patients (HIV and
immune-suppressive therapy recipients) (Nivoix et al. 2020). Although AmB is
widely used for the treatment of candidiasis, AmB use is limited by its toxicity.
Several lipid-based formulations have been developed to overcome the problem of
AmB toxicity (Stone et al.
antifungal activity is interaction with fungal cell membranes and formation of
pores that lead to cell death (Anderson et al.
been reported are the formation of AmB extracellular aggregates that extract ergosterol from fungal cell membrane (Anderson et al. 2014), and generation of reactive
oxygen species that damage fungal cells (Kristanc et al.
Azole antifungal drugs such as fluconazole have been used to treat fungal
infections since the 1970s and these compounds are active against most of Candida
species (Pfaller et al. 2010). Intravenous fluconazole is considered to be safe
however its prolonged use at high doses sometimes might cause alopecia, periostitis, and the development of skin cancers (Malani et al. 2015). The main concern with
the use of fluconazole is the presence of some resistant Candida strains (Winston
et al. 2003).
Voriconazole is a second generation of synthetic azoles that have fungicidal
activity against Candida species (Pfaller et al.
2003). It has broad-spectrum antifungal activity and retains activity against
fluconazole-resistant Candida strains (Johnson and Kauffman 2003; Rodrigues
et al. 2017). Side effects associated with voriconazole are a rash, skin photosensitivity, and an increased risk of cutaneous squamous cell carcinoma in lung transplant
patients (Malani et al.
generation synthetic azole which has fungicidal activity similar to voriconazole
(Keating 2005). Both posaconazole and voriconazole are available as oral and
2021).
2017; Pitman et al. 2011). AmB is used for the
2016; Hamill 2013). The main mechanism of AmB
2014). Other mechanisms that have
2019).
2010; Johnson and Kauffman
2015; Hamandi et al.
2018). Posaconazole is a second
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