Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5219_Библиотеки_им_академика_М_И_Перельмана.pdf
384
C. Gupta and S. A. Dar
16.1 Introduction
Aspergillus spp. is a ubiquitous lamentous mold, encompassing a wide spectrum
ranging from saprophytic colonization and allergic syndrome to acute, subacute, or
chronic invasive illnesses, localized or disseminated depending upon the interplay
between host immune response and virulence of pathogen; degree of immunosuppression or hyperactivity; and overlap of syndromes may co-occur or march from
one end to the other end over a period of time (Chakrabarti etal. 2011; Palmieri
etal. 2022). Around 40 species are pathogenic to humans; the most important are
Aspergillus avus and Aspergillus fumigatus, having different geographical distributions and antifungal resistance proles (Geiser 2009). The classical risk factors
for invasive aspergillosis (IA) include inherited or acquired neutrophil defects,
hematological malignancies, solid-organ malignancies with profound neutropenia,
hematopoietic stem cell transplant, solid-organ transplant, prolonged or high-dose
corticosteroids or immunosuppressants, and advance acquired immunodeciency
syndromes (Chakrabarti etal. 2011; Palmieri etal. 2022; Geiser 2009). However,
new risk factors have been identied in the last decade which include reactive airway disease, chronic lung disease, DM, acute or chronic liver disease, and rheumatological conditions (Chakrabarti et al. 2011). Recently, severe viral illnesses,
Inuenza, and COVID-19 have emerged as important risk factors with high mortality (Rijnders etal. 2020; Koehler etal. 2021). More than 250,000 cases of IA occur
annually as per global 2017 estimates, the number is going to increase with the
addition of new risk factors, increasing burden of the immunocompromised host
population (Bongomin etal. 2017). With the increasing complexities of infections,
host immune status, drug, and emerging antifungal resistance, the management of
Aspergillus spp. infections is becoming a challenge. In this chapter, we will discuss
the recent advances in the management of Aspergillus infections.
16.2 Antifungal Agents
Azoles, Amphotericin B (AMB), liposomal AMB (LAMB), and echinocandins are
major antifungal agents available for the treatment of Aspergillus spp. Their mecha-
nism of actions depicted in Fig. 16.1 and major properties are summarized in
Table16.1.
16.2.1 Azoles
Azoles are fungicidal and act by inhibiting 14α-lanosterol demethylation, an essential component of ergosterol biosynthesis in the fungal membrane sterol leading to
cell death (Bennett etal. 2020; Grayson etal. 2018; Panackal etal. 2014a; Jenks and
Hoenigl 2018; Kanaujia etal. 2023; Chen et al. 2020; Ellsworth and OstroskyZeichner 2020) (Fig.16.1). Second-generation triazoles contain three nitrogen rings
in their structure (Fig.16.2). Voriconazole has been recommended for the treatment
Isavuconazole consists of an
16 Recent Advances intheManagement ofAspergillosis
Fig. 16.1 Mechanism of action of antifungal agents. (Adapted from Chen et al. 2020 and
Ellsworth and Ostrosky-Zeichner 2020). Azoles inhibit the conversion of lanosterol to ergosterol,
the most important sterol in fungal cell membranes, inhibiting cell membrane synthesis. Polyenes
(Amphotericin B), binds to ergosterol and forms pores in the cell membranes leading to cell death.
Echinocandins inhibit 1,3 β glucan synthase, inhibiting the synthesis of fungal cell walls
385
of IA (Patterson etal. 2016; Ullmann etal. 2018). Posaconazole and Isavuconazole
are the newer azoles in the armamentarium (Chen et al. 2020; Ellsworth and
Ostrosky-Zeichner 2020).
16.2.2 Posaconazole
Its chemical structure is similar to itraconazole and has uorine in place of chlorine and
a furan ring in place of the dioxolane ring, resulting in an extended spectrum of antifungal activity, and is highly lipophilic (Chen etal. 2020). Recently, in phase 3, randomized,
controlled, non-inferiority trial evaluating posaconazole for primary treatment of IA
against voriconazole, patients with proven, probable, or possible IA from 91 study sites
in 26 countries, was randomized to receive either posaconazole or voriconazole in standard dosages; in the intention-to-treat population with a 10% non-inferiority margin
(Maertens 2021). Posaconazole was non-inferior to voriconazole for all-cause mortality
up until day 42in IIT population (the mortality was 15% in the posaconazole group
compared to 21% in the voriconazole group (p<0.0001) (Maertens 2021).
16.2.3 Isavuconazole
Isavuconazole is a prodrug of water-soluble triazole, isavuconazonium sulfate
which is broken down by plasma esterases to the active component, Isavuconazole.
386
C. Gupta and S. A. Dar
Echinocandins
Non-linear Linear Linear Non-linear Linear
Caspofungin: 0.14L/kg
Micafungin: 0.11L/kg
Anidulafungin: 0.50L/kg
Only IV formulation
kg
Only IV
formulation
by food or
gastric acidity
Increased by fatty meals Not affected
fatty meals
Hepatic
Anidulafungin not
metabolized, degraded into
plasma
Excellent tissue penetration
Not
metabolized
Hepatic
CYP3A4/5
Only by CYP3A
Hepatic Hepatic
Excellent
Excellent
enzymes
Good tissue distribution
Poor in CSF,
except CNS, ocular, renal
tissue
penetration
except urine
tissue
penetration
Poor in CSF, ocular
<0.1% in urine
ocular
<0.2% in urine
Table 16.1 Antifungal agents against Aspergillus spp., their mechanism of action and properties (Bennett etal. 2020; Grayson etal. 2018; Panackal etal.
Voriconazole Itraconazole Posaconazole Isavuconazole LAMB
Non-linear in adults
>58% 99% 98% 98% >90% >95%
Property
Pk Linear in children
Protein
binding
2014b; Jenks and Hoenigl 2018; Kanaujia etal. 2023; Chen etal. 2020; Ellsworth and Ostrosky-Zeichner 2020; Stone etal. 2016; Cavassin etal. 2021;
Mroczyńska and Brillowska-Dąbrowska 2020; Spernovasilis and Kofteridis 2018)
Vd 0.64–21.6L/kg 11L/kg 343–1341L/kg 470L/kg 0.2–1.6L/
Absorption Decreased by fatty meals Increased by
5–6days 2days 7–10days – 3–4days 2–3days
6–12h 15–42h 25–31h 130h 7–10h 9–26h
Steady
states
Half-life t
CYP2C19 (major enzyme)
CYP2C9, CYP3A4 via
N-oxidation
Excellent tissue
Penetration including CSF,
1/2
Metabolism Hepatic
Tissue
distribution
ocular
16 Recent Advances intheManagement ofAspergillosis
Treatment
Micafungin—100mg
Caspofungin—
LD: 70mg then 50mg
Anidulafungin—
LD: 200mg then 100mg
Antifungal prophylaxis –
Micafungin 50mg
Not required for
anidulafungin, micafungin
Caspofungin only in moderate,
no data for severe hepatic
impairment
Not required, no penetration
Adult
IV: 3–5mg/
kg daily
Adult
LD: 200mg
every 8h for
48h
200mg daily
Starting day 3
required
Not
required
Not required
Being
water-soluble,
no SEBCD in
intravenous
drug
387
Adults
LD: 300mg 12 hourly
for 24h, 300mg daily
Starting day 2 approved
for more than 13years
LD:200mg
every 8h for
the rst 2days,
then 200mg
every 12h
starting day 3
(LDs are
required in
LD: 6mg/kg 12 hourly D1,
4mg/kg 12 hourly starting
D2
Children (>2years)
LD: 9mg/kg 12 hourly D1,
MD: 6mg/kg 12 hourly
starting D2
Dosage Adults
Not required Not required Not
severe cases)
No available
data
Mild to moderate hepatic
impairment—Dose
modication
No data for severe hepatic
insufciency or post-liver
transplant
Hepatic
dose
adjustment
Not required for oral
drug,
IV: Modied doses in
moderate to severe renal
impairment due to
SEBCD component
Oral
formulations
complexed
with
hydroxypropyl-
β- cyclodextrin
Carrier, which
is degraded by
Not required for oral IV
formulation complexed with
sulfobutylether
ß-cyclodextrin (SEBCD),
cyclodextrin is nephrotoxic
Modied doses in moderate
to severe renal impairment
due to SEBCD component in
Renal dose
adjustment
amylases in
intestine, not
systemically
absorbed, no
dose
IV formulation
modication
required
Pk pharmacokinetics, Vd volume of distribution, h hourly, mg/kg milligrams per kilograms, IV intravenous, L/kg Liter per kilogram, LD loading doses, D1 day
1, D2 day 2, CNS central nervous system
388
C. Gupta and S. A. Dar
Fig. 16.2 Chemical structure of Azoles. (Adapted from Ellsworth and Ostrosky-Zeichner 2020).
Azoles are cyclic organic molecules, consisting of a core 5- member azole ring with two or three
nitrogen atoms within the azole ring called imidazole and triazole respectively. Voriconazole,
Itraconazole, Posaconazole and Isavuconazole are triazoles. Itraconazole belongs to rst-generation azoles while voriconazole belongs to second-generation azoles. Posaconazole is structurally
similar to itraconazole but has uorine in place of chlorine and a furan ring in place of the dioxolane ring. Isavuconazole is similar to voriconazole and consists of an additional [N-(3-
acetoxypropyl)-N-methylamino]-carboxymethyl group sidearm
[N-(3-acetoxypropyl)-N-methylamino]-carboxymethyl group side arm that orients the molecule to engage the triazole ring to the binding pocket of the fungal
CYP51 protein, conferring activity against some pathogens resistant to itraconazole, voriconazole, and posaconazole (Ellsworth and Ostrosky- Zeichner 2020).
The intravenous formulation contains 200 mg Isavuconazole equivalent to
372.6mg isavuconazonium sulfate powder for solution for infusion, while the
oral capsule contains 100mg isavuconazole (as 186.3mg isavuconazonium sulfate). SECURE trial in Phase 3 randomized double-blind non-inferiority trial
16 Recent Advances intheManagement ofAspergillosis
evaluated treatment outcomes for isavuconazole versus voriconazole in patients
with suspected invasive mold disease (Maertens et al. 2016). A total of 527
patients of probable, proven, or possible IA were randomized to receive either
voriconazole or Isavuconazole in standard dosages. All-cause mortality after
42days was comparable in both groups (19% in the isavuconazole group vs. 20%
in the voriconazole group).
389
16.2.4 SUBA—Itraconazole
A novel formulation SUper BioAvailable (SUBA)–itraconazole (S-ITZ) was developed containing a solid dispersion of itraconazole in a polymeric matrix to enhance
its dissolution and intestinal absorption, with improved bioavailability up to 90%
(Rauseo etal. 2021). The 65-mg capsule S-ITZ formulation achieves bioequivalence to a 100-mg capsule of conventional itraconazole with fewer adverse. Various
studies have shown SUBA itraconazole as a safe and well-tolerated alternative for
primary prophylaxis after transplant (Lindsay etal. 2021; Whitmore etal. 2021).
16.2.5 Nanovoriconazole
Recently, nanotechnology-based drug delivery systems have been used to overcome
limitations of pharmacokinetics and adverse effects. These systems’ results in controlled and sustained release of voriconazole allowing increased permeation and
deposition of voriconazole in target tissues. These nanoparticles include liposomes,
biodegradable polymers, nanoemulsions, and protein carriers and are currently in
phase 2 trials (de Almeida Campos etal. 2023).
16.2.6 Adverse Effects
Overall, posaconazole and isavuconazole are well-tolerated with a favorable side
effect prole compared to other azoles. The most commonly reported side effects of
Posaconazole and Isavuconazole include nausea, vomiting, and diarrhea.
Hepatotoxicity and cardiotoxicity are two major class (azoles) side effects (Chen
et al. 2020; Spernovasilis and Kofteridis 2018). Recently, SECURE trials have
shown a lower frequency of drug-related hepatotoxicity with posaconazole and isavuconazole as compared to the voriconazole group (2% in isavuconazole group vs.
10% in the voriconazole group; 30% for posaconazole and 40% for voriconazole)
(Maertens etal. 2016; Maertens etal. 2021). Even in a study, posaconazole was
safely used for IA as rescue therapy after voriconazole-induced hepatotoxicity
(Martínez-Casanova etal. 2018). In contrast to other triazoles, i.e., voriconazole,
posaconazole, and itraconazole, that cause QTc segment prolongation, isavuconazole leads to dose-dependent QTc shortening. The clinical signicance of QTc
390
C. Gupta and S. A. Dar
interval shortening remains unclear; however, in individuals with familial shortened
QTc syndrome, isavuconazole should be avoided.
16.3 Liposomal Amphotericin B (LAMB)
AMB binds to ergosterol and forms pores in the cell membranes leading to cell
death and is fungicidal in action; in addition, AMB also promotes oxidative killing
inside fungal cells (Cavassin etal. 2021). Conventional AMB is highly nephrotoxic
leading to the innovation of lipid-based formulations or LAMB consisting of unilamellar bilayer liposomes with AMB intercalated within the membrane. The unilamellar liposome structure is comprised of the following lipids: hydrogenated soy
phosphatidylcholine, distearoyl phosphatidylglycerol, and cholesterol (Fig.16.3).
LAMB is sensitive against most Aspergillus spp., except Aspergillus terreus,
Aspergillus nidulans, and Aspergillus ustus which shows intrinsic resistance and
increasing rates of elevated minimum inhibitory concentration (MIC) >2 have been
recently identied in Aspergillus avus (>80% of isolates), while some reports suggest that Aspergillus avus may be intrinsically resistant to LAMB (Bennett etal.
2020; Grayson 2018; Rudramurthy etal. 2019). Although fungicidal in action, due
to adverse effects such as infusion-related reactions, hypokalemia, anemia, and
availability of more potent azoles, LAMB has been placed as second-line or salvage
Fig. 16.3 Structure of Liposomal Amphotericin B. (Adapted from Stone etal. 2016)
16 Recent Advances intheManagement ofAspergillosis
391
therapy for IA ((Patterson etal. 2016; Ullmann etal. 2018). Studies have also shown
intermittent high-dose LAMB (twice or thrice weekly) as effective antifungal prophylaxis in transplant settings (Youngs etal. 2020). Apart from fungicidal action,
LAMB also provides immunomodulatory effects by interaction with Toll-like
receptors 2 and inducing release of proinammatory cytokines (Bellocchio
etal. 2005).
The drug AMB is intercalated in the unilamellar liposomes, which has three
major components, rst is the majority of the lipid bilayer comprises hydrogenated
soy phosphatidylcholine, second is distearoylphosphatidyl glycerol which forms
ionic complex with AMB, and third is cholesterol which binds with AMB.The liposomes preferentially attach to fungal cell membrane forming pores, leading to ion
leakage and cell death.
16.3.1 Echinocandins
Echinocandins inhibit 1,3 β glucan synthase inhibiting fungal cell wall synthesis
and act as fungistatic drugs for Aspergillus spp. blunting hyphal growth. These are
metabolized in the liver with a long half-life permitting once daily dose. All three
echinocandins, such as Caspofungin, Micafungin, and Anidulafungin, are comparable in action and available in intravenous formulation only (Mroczyńska and
Brillowska-Dąbrowska 2020).
16.4 Combination Antifungal Therapy
Combination antifungal therapy (CAFT) is an emerging strategy against IFI
considering high morbidity and mortality. The concept has been derived from
invitro and animal studies demonstrating synergistic or additive effect of caspofungin with voriconazole or LAMB against Aspergillus spp. In a large randomized, multicenter trial at 93 sites including patients with hematological
malignancies or HCT and suspected or documented IA, CAFT with voriconazole and echinocandin was compared to voriconazole monotherapy, mortality
rates at end of therapy (EOT) were comparable in both groups, and however,
subgroup analysis revealed lower mortality at EOT in IA with high galactomannan positivity rate (Marr etal. 2015). A systematic review and meta-analysis
analyzed 16 studies using combination therapy either azoles or AMB with an
echinocandin for IA, this meta-analysis could not nd any support for CAFT as
primary therapy, and only a few observational studies using CAFT as salvage
therapy showed benet over monotherapy (Panackal etal. 2014b). The Infectious
Disease Society of America (IDSA) and European guidelines do not recommend
CAFT over monotherapy. CAFT with azole and echinocandins has been recommended as salvage therapy only in refractory cases; in addition to European
guidelines, it is additionally recommended to use CAFT when MIC is more than
2 (Patterson etal. 2016; Ullmann etal. 2018).
392
C. Gupta and S. A. Dar
16.5 Therapeutic Drug Monitoring (TDM)
The goal of antifungal therapy is to maximize therapeutic efcacy with minimal
adverse effects. In critically ill patients, altered physiology such as hypoalbuminemia, hepatic, or renal failure, renal replacement therapy, or extracorporeal membrane oxygenation may alter the Pk of drugs; further endothelial dysfunction in
sepsis or septic shock leads to capillary leakage, third space loss, and increase Vd,
resulting in suboptimal dosing and therapeutic failure (Myers and Dodds Ashley
2015; Brüggemann etal. 2009). The chances of therapeutic failure or toxicity are
always high due to drug interactions amongst drugs metabolized by cytochrome
P450 (CYP) pathways or variable PK (Baracaldo-Santamaría etal. 2022). IDSA
and European guidelines strongly recommend TDM with serum trough levels, after
achieving a steady state in clinical scenarios with suspected drug interactions, toxicity, prolonged azole exposure, or inappropriate clinical responses (Patterson etal.
2016; Ullmann etal. 2018). The concept of TDM for azoles and ucytosine has
been established, while the data for isavuconazole, echinocandin, or LAMB are
limited (Gómez-López 2020). TDM is strongly recommended for azoles as they
exhibit maximum intra or inter-individual PK variability, while isavuconazole has
predictable PK with no exposure–efcacy relationship, and TDM is not required
(Desai etal. 2017). However, in recent European guidelines, TDM of isavuconazole
is recommended if treating the infection at the sanctuary sites, pathogens with high
MIC, and unexplained toxicity (Ullmann et al. 2018). The recommended target
trough concentrations by the British Society of Medical Mycology and European
guidelines are summarized in Table 16.2. While it is always essential to keep in
mind the method used for measuring TDM, bioassays although simple to use may
measure both the drug and its metabolite, and results are affected by the combination therapies, for instance, it measures both itraconazole free concentration and its
metabolite hydroxyitraconazole (OH-ITC), cutoff may be high (Table16.2), while
mass spectroscopy and liquid chromatography can quantify multiple drugs in a single sample (Myers and Dodds Ashley 2015).
The genetic polymorphism metabolic enzyme (CYP2C19) responsible for voriconazole metabolism also affects bioavailability and clearance. The Clinical
Pharmacogenetics Implementation Consortium (CPIC) categorizes individuals into
ve groups based on their genotype for CYP2C19, ultrarapid metabolizers (UM), or
rapid metabolizers (RM) where the probability of attainment of therapeutic voriconazole levels is low leading to therapeutic failure, while in CYP2C19, poor metabolizers (PM) higher trough levels may be achieved resulting in adverse effects, hence
in UM, RM, and PM; use alternative agents such as POS, ISAVU not affected by
CYP2C19 metabolism may be considered, while CYP2C19 normal metabolizers
and intermediate metabolizers achieve adequate drug levels, and hence, standard
dosages are recommended (Moriyama etal. 2017). The PM phenotype is most common in Asian origin: about 30–40% carry one allele and 10–15% carry both, conferring full PM phenotype, while the UM allele and phenotype are more common in
Caucasians (20–40% and 18–27%) and blacks (33% and 10–26%) (Fricke-Galindo
etal. 2016). Studying genetic polymorphism before the initiation of voriconazole is
16 Recent Advances intheManagement ofAspergillosis
Table 16.2 Therapeutic drug monitoring of antifungals (Ullmann etal. 2018; Ashbee etal. 2014)
Target
Timing of
trough
Drug
Voriconazole 5days after
Posaconazole 7days after
Itraconazole
Metabolite:
Hydroxyitraconazole
(OH-ITC) used
Isavuconazole 5days after
monitoring Indication
initiation of
antifungals
initiation of
antifungals
5–7days
after
initiation of
antifungals
initiation
including
loading
doses
Treatment
IA
Target for
prophylaxis
not clear
Prophylaxis
for invasive
infections
Treatment of
invasive
infections
Treatment of
invasive
infections
Prophylaxis
for invasive
infections
Treatment NA 2–3mg/L
British
Medical
Society
1.0–5.5mg/L 1–5.5mg/L treatment
>0.7mg/L >0.7mg/L
>1mg/L >1mg/L is
1–2μg/mL
(HPCL)
5mg/mL
(Bioassay)
>0.5mg/L >0.5mg/L (measured
Target (European
guidelines, 2018)
and prophylaxis
2–6mg/L
recommended for
severe infections like
CNS infections
multifocal or
disseminated disease,,
infection with
pathogen with
elevated MICs of
2mg/L)
recommended
>1–4 (measured by
HPLC)
>3–17mg/L
(measured by
bioassay)
by HPLC)
>3mg/L (measured
by bioassay)
393
not recommended by any guidelines due to studies with limited sample size, and
personalized decisions can be taken to see polymorphism affecting therapy.
16.5.1 Azole-Resistant Aspergillus Spp.
Currently, the prevalence of azole resistance is not high; however, some pockets of
azole resistance have been identied particularly in European countries, in Dutch
countries, the environmental resistance is more than 10%, and in such cases, it is
recommended to start LAMB or combination of voriconazole and echinocandin as
rst-line therapy (Schauwvlieghe etal. 2018). It is speculated that new azole resistance mechanisms will continue to emerge and expand soon; therefore, periodic