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RESEARCH ARTICLE
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Citation: Handa S, Villasis-Keever A, Shenoy M,
Anandan S, Bhrushundi M, Garodia N, et al. (2023)
No evidence of resistance to itraconazole in a
prospective real-world trial of dermatomycosis in
India. PLoS ONE 18(2): e0281514. https://doi.org/
10.1371/journal.pone.0281514
Editor: Felix Bongomin, Gulu University, UGANDA
Received: July 14, 2022
Accepted: December 12, 2022
Published: February 14, 2023
Copyright: © 2023 Handa et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: The data sharing
policy of the study sponsor, Janssen
Pharmaceutical Companies of Johnson & Johnson,
is available at janssen.com/clinical-trials/
transparency. As noted on this site, requests for
access to the study data can be submitted through
Yale Open Data Access (YODA). Others would be
able to access these data in the same manner as
the authors. The authors did not have any special
access privileges that others would not have.
Funding: This study was funded by Janssen
Research & Development, LLC. The funder was
PLOS ONE | https://doi.org/10.1371/journal.pone.0281514 February 14, 2023
No evidence of resistance to itraconazole in a
prospective real-world trial of
dermatomycosis in India
S. Handa1, A. Villasis-Keever2, M. Shenoy3, S. Anandan4, M. Bhrushundi5, N. Garodia6,
D. Fife2, P. De Doncker7, K. Shalayda8, P. Hu8, S. Fonseca2, N. Cure-bolt ID2*
1 Postgraduate Institute of Medical Education & Research, Chandigarh, India, 2 Janssen Research &
Development, LLC, Titusville, New Jersey, United States of America, 3 Yenepoya Medical College Hospital,
Mangalore, Karnataka, India, 4 Sri Ramchandra Hospital, Chennai, Tamil Nadu, India, 5 Lata Mangeshkar
Hospital, Nagpur, Maharashtra, India, 6 Janssen Medical Affairs, Mumbai, Maharashtra, India, 7 Janssen
Infectious Diseases-Diagnostics, Beerse, Belgium, 8 Janssen Research & Development, LLC, Raritan, New
Jersey, United States of America
* ncurebol@its.jnj.com
Abstract
Background
The prevalence of superficial fungal infections in India is believed to have increased sub-
stantially in the past decade. We evaluated the treatment outcomes and risk factors associ-
ated with clinical response to a treatment course of itraconazole for the management of
dermatomycosis in India.
Methods
In this real-world, prospective pilot study (August 2019 to March 2020), adult participants
(18–60 years), diagnosed with T. cruris or T. corporis, received itraconazole 200 mg/day
(any formulation) orally for 7 days, and were followed for an additional 7 days.
Results
The study was terminated early due to the COVID-19 pandemic. Of 40 enrolled participants
(mean [SD] age, 35.5 [12.73] years; {62.5%}] male; 37 received itraconazole and 20 (50%)
completed the study. The median (range) Clinical Evaluation Tool Signs and Symptoms
total score at baseline was 5.5 (2–10). Clinical response of “healed” or “markedly improved”
based on the Investigator Global Evaluation Tool at day 7 (primary objective) was 42.9%
(12/28; 95% CI: 24.53%, 61.19%). Itraconazole minimum inhibitory concentration for identi-
fied microorganisms, T. mentagrophytes species complex (91.7%) and T. rubrum (8.3%),
was within the susceptibility range (0.015–0.25 mcg/mL). At day 14, 8/13 (61.5%) partici-
pants achieved a mycological response, 2/13 participants (15.4%) had a mycological failure
and 90% showed a clinical response.
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PLOS ONE Itraconazole and fungal infections in India

involved in the study design, data collection and Conclusion

analysis, and preparation of the manuscript.
COVID-19 pandemic affected patient recruitment and follow-up, so the findings call for a
Competing interests: S. Handa, M. Shenoy, S.
careful interpretation. Nevertheless, this real-world study reconfirmed the clinical efficacy
Anandan and M. Bhrushundi have nothing to
disclose. D. Fife is a former employee of Janssen and microbial susceptibility to itraconazole for the fungi causing dermatophytosis in India.
Pharmaceutical Company of Johnson & Johnson.
A Villasis-Keever, N. Garodia, P. DeDoncker, K.
Shalayda, P. Hu, S. Fonseca, and N. Cure-bolt are Trial registration
employees of Janssen Pharmaceutical Company of Trial registration number: Clinicaltrials.gov NCT03923010.
Johnson & Johnson that markets a brand of
itraconazole and may own stocks or stock options
in Johnson & Johnson. This does not alter our
adherence to PLOS ONE policies on sharing data
and materials.

Introduction
Superficial cutaneous fungal infections or dermatomycosis/dermatophytosis are one of the
most common dermatoses affecting around 20–25% of the world population [1]. India has a
tropical-like climate with a high prevalence of fungal infections and marked variation reported
across the country ranging from 36.6–78.4% [2]. Although nationwide data is lacking, the
prevalence and severity of the disease have increased at an alarming rate over the last decade as
per physician perception based on the number of cases seen in their outpatient departments.
There are also anecdotal reports of a lack of efficacy with traditionally used topical and sys-
temic antifungals [3–6]. This observed increase in frequency and severity has been attributed
to many factors including the widespread use of high-potency steroids in topical formulations
and misuse of antifungal agents. Host-related factors, abnormal drug pharmacokinetics (PK)
[7, 8], and differences in bioavailability among many itraconazole formulations available in
India [9], have been considered among the factors for treatment failures. To date, there is no
clear evidence that supports these observations.
The clinical presentation of dermatomycosis varies from mild scaling and redness to severe
inflammation [10–13]. Although painless and superficial, these dermatophyte infections have
a significant negative impact on the social, psychological, and occupational life of the individ-
ual and can lead to emotional and financial distress [12, 14–16]. The management armamen-
tarium for treatment of the disease includes topical and oral antifungals. Several newer azoles,
including efinaconazole, luliconazole, sertaconazole, oxaborole, and tavaborole, have either
been introduced or are being studied for topical use [17]. Oral fluconazole, griseofulvin, itraco-
nazole and terbinafine have been used extensively. Itraconazole has remained an important
treatment choice for superficial fungal infections and has shown its clinical value in India due
to increasing resistance to other antifungals [18–20], atypical and unusual presentations of
dermatophytosis [21] and the Trichophyton mentagrophytes pandemic in recent years [4, 22].
Cases of treatment failures have also been reported with itraconazole, though not linked to
anti-fungal resistance [8, 20, 23].
Itraconazole, a triazole antifungal agent, has a broad spectrum of activity against infections
caused by dermatophytes, yeasts, and many other fungi [24–27]. Itraconazole and its main
metabolite, hydroxy-itraconazole both have a prominent affinity to fungal cytochrome P-450
(CYP), which is involved in the biosynthesis of ergosterol from lanosterol [28, 29]. Ergosterol
is a vital cell membrane component in fungi [30] and its specific inhibition by itraconazole
results in drastic inhibition of fungal growth [7].
The objective of this study was to evaluate real-world treatment outcomes and the risk fac-
tors associated with a poor clinical response with the use of a of itraconazole in patients with
dermatomycosis.

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PLOS ONE Itraconazole and fungal infections in India

Methods
Study design
This real-world, prospective, non-randomized, multicenter, interventional, longitudinal study
was conducted in India and consisted of an open-label treatment phase of 7 days followed by a
follow-up phase of 7 days.
The primary objective of the study was to estimate the proportion of participants that
received itraconazole for Tinea cruris (T. cruris) or Tinea corporis (T. corporis) who demon-
strated clinical response after 7 days of treatment. The secondary objectives were to estimate
the proportion of participants with the mycological response after 14 days of follow-up and the
association of clinical response with plasma drug concentrations (itraconazole and hydroxy-
itraconazole) and baseline sensitivity pattern of causative fungi. Other exploratory objectives
included the estimation of the proportion of participants with the clinical response after 14
days of follow-up and the extent to which clinical improvement at Day 7 predicts clinical
improvement at Day 14.
The study is registered with clinicaltrials.gov (NCT03923010). The study protocol,
informed consent forms, and applicable study documents were approved by an independent
ethics committee or institutional review board at each study site. They include Institutional
Ethics Committee, NKP Salve Institute of Medical Science & Lata Mangeshkar Hospital, Nag-
pur, India; Institutional Ethics Committee, Postgraduate Institute of Medical Education and
Research, Chandigarh, India; Institutional Ethics Committee, Sri Ramachandra Hospital,
Chennai, India and Yenepoya Ethics Committee-1, University Road, Deralakatte, Mangalore,
India. Signed informed consent was obtained from all participants at the start of the study.
This study was conducted in accordance with the Declaration of Helsinki and is consistent
with Good Clinical Practices and applicable regulatory requirements. The planned recruitment
time for this study was 4 months. However, the period was extended to 10 months due to the
Coronavirus Disease-2019 (COVID-19) pandemic. The study was eventually discontinued
prematurely for the same reason.

Study population
Adult participants aged �18 to �60 years with a clinical diagnosis of T. cruris or T. corporis
infection, with or without a history of antifungal treatment were enrolled if they were pre-
scribed oral itraconazole 200 mg/day for the management of their dermatophytosis. The par-
ticipants were recruited from clinical practices of dermatologists from four sites (Nagpur,
Chandigarh, Chennai, and Mangalore) in India. Exclusion criteria included the history of ven-
tricular dysfunction, liver or renal insufficiency; contraindications for the use of itraconazole;
known achlorhydria or treatment for gastric acidity; the presence of other dermatoses e.g., pso-
riasis, seborrheic, or atopic dermatitis or infection with an organism with known or estab-
lished resistance to itraconazole; co-existing fungal infection of other body areas, known
allergies or receipt of CYP3A4 substrates or oral itraconazole within 14 days or systemic anti-
fungal or corticosteroid therapy within 30 days or a topical antifungal or corticosteroid therapy
within 14 days before screening.

Treatment
Participants were prescribed locally available itraconazole (either generic or reference). The
dosage was a 200 mg capsule or 2 capsules of 100 mg each, once daily. Participants were
instructed to take their prescribed dose of itraconazole orally each day after a full meal at
home. The recommended duration of treatment was 7 days. The total duration was decided by

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PLOS ONE Itraconazole and fungal infections in India

the treating physician as part of the participant’s clinical care, according to local standards of
practice, and could be extended up to Day 14.

Assessments
Participants’ demographic information was collected at baseline. The clinical assessment of the
disease was evaluated by the treating physicians using two tools. The Clinical Evaluation Tool
Signs and Symptoms (CET SS; total score ranges from 0 to 18) was used in the development
program of itraconazole. It evaluates the presence and severity (absent = 0, mild = 1, moder-
ate = 2, severe = 3) of each of 6 signs and symptoms (desquamation; erythema and pruritus;
exudation or incrustation; infiltration; maceration; vesiculation or pustules). The Investigator
Global Evaluation (IGE) tool was used to classify the clinical response based on the percentage
of clinical improvement from baseline. The CET SS total scores at Day 7 and Day 14 were
compared with baseline scores to assess the percentage of clinical improvement, defined as a
decrease in CET SS total score to 1 or 2, which was further used to classify the clinical efficacy
using the Investigator Global Evaluation (IGE) tool, with scores 1 (absence of signs and symp-
toms) or 2 (� 50% clinical improvement). Clinical response was thus defined as having scores
1 or 2 (considered as “healed” or “markedly improved”) on the IGE tool of clinical improve-
ment while the mycological response was defined as culture negative at Day 14 from partici-
pants positive at baseline.
Pharmacokinetic (PK) assessments were conducted in participants who had at least 1 set of
blood samples drawn at Day 7. Measurement of itraconazole and hydroxyitraconazole concen-
trations in plasma was performed using high performance liquid chromatography with tan-
dem mass spectrometry. Blood samples for PK analysis were collected predose (at 24 hours
(±2 hours) after the previous dose on Day 6) and Day 13 and postdose (at 2 hours and 4.5
hours) after the Day 7 and Day 14 doses. Plasma concentrations of itraconazole and hydroxy-
itraconazole were assessed against clinical outcomes.
Skin scrapings were collected for culture and sensitivity analysis and the baseline resistance
to itraconazole and its association with clinical outcomes was evaluated. Skin specimens were
collected from the edge of lesions using sterile blunt scalpel. The KOH samples were analyzed
locally at each study center and for mycological culture analysis samples were shipped to cen-
tral laboratory (University of Texas—Fungus Testing Lab—San Antonio, Texas). The fungal
pathogens were identified by amplification and Sanger-based (dideoxy-termination) sequenc-
ing as per the Clinical and Laboratory Standards Institute (CLSI) MM18-A guidelines. A
microdilution method, according to the Clinical and Laboratory Standards Institute (CLSI)
M27 guidelines, was used to conduct antifungal sensitivity testing [31]. The minimum inhibi-
tory concentration (MIC) of itraconazole of fungal pathogens from each patient was deter-
mined from the baseline samples, which had been taken before the administration of the study
agent. Further details on culture and sensitivity analysis are provided in the S4 File.
Safety was assessed by monitoring adverse events (AEs) and laboratory parameters.

Statistical analysis
As this was a pilot study, no formal hypothesis was tested. The sample size was not calculated
based on power but rather selected to collect sufficient data to provide a first approximation of
the distribution of efficacy and PK results across the large number of formulations that were
planned to be studied. The target sample size was 50. All analyses were performed on partici-
pants receiving any generic itraconazole and not segregated out by the brand.
Continuous variables were summarized using the number of observations, mean, standard
deviation (SD), coefficient of variation (CV), median, and range as appropriate while the

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PLOS ONE Itraconazole and fungal infections in India

categorical values were described using the number of observations and percentages as appro-
priate. The point estimate and the corresponding 95% confidence intervals (CIs) for the effi-
cacy endpoints were provided. One-Proportion Z-test was used to estimate the 95% CI for the
percentage of participants who had a clinical response. The efficacy analyses were performed
on the treated population that included participants who had the 7-day treatment regimen,
had clinical evaluations at baseline and at Day 7, and completed the study. Missed data at Day
14 follow-up were imputed as “non-responders”. For PK analysis, when an individual concen-
trate value was below the lower limit of quantification (LLOQ), the concentrate value was
assigned a value of 0 for the analysis and presented in tables as below the quantification limit
(BQL). In addition, when greater than 50% of the individual concentration values for a given
time point were below the LLOQ, the mean, minimum, and median values were reported as
BQL, and SD, %CV, and geometric mean were not reported for these analyses. For graphical
analysis, plasma concentration values below the LLOQ were displayed as 0 for the linear plots.
Logistic regression was used to determine the association of clinical response at Day 7 (depen-
dent variable) with the baseline MIC sensitivity pattern (independent regressor) of causative
fungi. SAS version 9.4 was used for calculations.

Results
Demographic and baseline characteristics
The study was conducted from August 2019 to March 2020. Due to COVID-19 related lock-
down, the study was prematurely terminated. Forty participants were enrolled of whom 37
received at least one dose of itraconazole, 12 (32%) received 7 days and 25 (67%) received 14
days of itraconazole. A total of 20 participants completed the study (Fig 1). The mean (SD) age
of the 40 enrolled participants was 35.5 (12.73) years and 25 [62.5%] were male. The median
CET SS total score at baseline was 5.5 (range: 2–10). Of the 11 participants who had taken con-
comitant medications, the majority (n = 9) had antihistamines for systemic use as a prior

Fig 1. Participant disposition.

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PLOS ONE Itraconazole and fungal infections in India

Table 1. Baseline and disease characteristics of participants.

Parameter All participants (N = 40)
Age, years; mean (SD) 35.5 (12.7)
Male, n (%) 25 (62.5%)
BMI, kg/m2; mean (SD) 25.3 (5.04)
2
BSA, m ; mean (SD) 1.733 (0.1565)
CET SS total score, median (range) 5.5 (2–10)
Positive KOH mount, n (%) 37 (92.5%)

BMI, body mass index; BSA, body surface area; CET SS, Clinical Evaluation Tool Signs and Symptoms; KOH,
potassium hydroxide; SD, Standard Deviation.

https://doi.org/10.1371/journal.pone.0281514.t001

medication. The potassium hydroxide (KOH) mount from the skin scrape was negative for 3
and positive for 37 (92.5%) of the 40 participants (Table 1).
A total of 28 (75.6%) participants completed the 7-day treatment phase, and only 20 (50%)
returned for the Day 14 visit and completed the study as per protocol. The most common rea-
sons for discontinuation were COVID-19-related (n = 6; participants did not continue the site
visit due to complete lockdown), personal (n = 6), and patient withdrawal (n = 4). Some partic-
ipants did not return for either day 7 or day 14 visits. Thus, the number of participants avail-
able for clinical response evaluation is less than that on treatment.

Efficacy
Clinical response at day 7. From 28 participants who completed 7 days of treatment and
were evaluable for efficacy, 12 (42.9%; 95% CI: 24.53%, 61.19%) had a clinical response as
“healed” or “markedly improved” based on the IGE Tool assessment.
Clinical response at day 14. Twenty participants completed 14 days of follow-up and
were evaluable for clinical response. Eighteen achieved a score of 1 (absence of signs and symp-
toms) or 2 (�50% clinical improvement), for clinical response of 90% (95% CI: 76.85%,
100%). When all 8 participants that missed the Day 14 follow-up were imputed as “non-
responders”, the estimated proportion of the participants with clinical response was 64.3%
(18/28; 95% CI: 46.54%, 82.03%).

Mycological response
Baseline cultures. A total of 28 fungal cultures were obtained at baseline, 24 (85%) were
positive. T. mentagrophytes species was the most common microorganism isolated (91.7%).
The culture results were presented in Table 2. All isolates were susceptible to itraconazole.
Cultures at day 14. Of the available culture data for 13 participants, 11 participants had
negative cultures, of whom mycological response was achieved by 8 participants (61.5%; 95%
CI: 35.09%, 87.98%). Two participants (15.4%) had mycological failure (T. mentagrophytes spe-
cies complex isolated at baseline and the Day 14 visit (Table 2), with a clinical response score
of 2 (�50% clinical improvement). All isolates were susceptible to itraconazole.

Pharmacokinetics
PK analysis included a total of 28 participants who had samples on Day 7, however, PK results
on Day 14 were not available for 8 participants as they discontinued the study prior to PK sam-
pling on Day 14. Following oral administration of 200 mg (once daily) itraconazole or refer-
ence itraconazole, concentrations of itraconazole and hydroxy-itraconazole were quantifiable

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PLOS ONE Itraconazole and fungal infections in India

Table 2. Participants with microbial culture results and microbial organism identification (efficacy analysis set).
n/N (%)a
Screening 28
Positive 24/28 (85.7%)
Trichophyton rubrum 2/24 (8.3%)
Trichophyton mentagrophytes species complex 22/24 (91.7%)
Negative 4/28 (14.3%)
Day 14 13
Positive 2/13 (15.4%)
Trichophyton mentagrophytes species complex 2/2 (100.0%)
Negative 11/13 (84.6%)
a
Percentages are calculated with respect to the number of participants with available data points at that visit.

https://doi.org/10.1371/journal.pone.0281514.t002

in plasma prior to dosing on Day 7 in 23 of the 26 available samples with an LLOQ of 20 ng/
mL for both the analytes. Of the 3 participants who had plasma concentrations BQL prior to
dosing on Day 7, one participant also had no quantifiable plasma concentrations of itracona-
zole and hydroxy-itraconazole at 2 hours and 4.5 hours postdose. At Day 7, the mean plasma
concentrations for itraconazole and hydroxy-itraconazole in non-responders (participants
with a clinical response score of 3 to 5) was comparable to that of responders (participants
with a clinical response score of 1 or 2 [healed or markedly improved]; Table 3).
Clinical response at Day 7 was not associated with the highest or lowest plasma concentra-
tions of itraconazole or hydroxy-itraconazole. Of the 3 participants with predose plasma con-
centrations BQL on Day 7, two participants were classified as responders (clinical response
score = 2 [markedly improved]) and 1 participant was classified as a nonresponder (clinical
response score = 5 [worse]). All 3 participants had positive fungal cultures for T. mentagro-
phytes species complex at screening. On Day 14, 1 of the 3 participants had a positive fungal

Table 3. Plasma concentrations of itraconazole and hydroxy-itraconazole following oral administration of 200 mg itraconazole once daily or reference itraconazole
(PK analysis set).
Analyte Mean (SD) Plasma Concentrations (ng/mL)
Day 7 Day 14
n 0h 2h 4.5h n 0h 2h 4.5h
Itraconazole
All Participants 28a 167 (141) 208 (215) 311 (255) 20 332 (337) 450 (440) 495 (413)
Non-responders 16b 170 (152) 229 (230) 304 (288) 2 - - -
Responders 12 164 (133) 182 (202) 321 (216) 18 356 (345) 470 (453) 515 (421)
Hydroxy-itraconazole
All Participants 28a 377 (267) 388 (301) 441 (287) 20 579 (444) 621 (509) 650 (447)
Non-responders 16b 387 (274) 417 (316) 450 (319) 2 - - -
Responders 12 364 (271) 353 (290) 429 (250) 18 614 (449) 654 (519) 663 (443)

n = highest observed number of participants across the 3 time points/study day

All Participants = clinical response score 1 to 5, responders = participants with a clinical response score of 1 or 2, non-responders = participants with a clinical response
score of 3 to 5
a
n = 27 for 2h and n = 26 for 0h
b
n = 15 for 2h and n = 14 for 0h
h, hours; PK, pharmacokinetics; SD, standard deviation

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PLOS ONE Itraconazole and fungal infections in India

culture while fungal cultures were not available for the other 2 participants. For most partici-
pants (82% [18/22]), the lowest itraconazole drug concentration on Day 7 was greater than the
MIC by 1.2 to 19.4 times the MIC at baseline.

Safety
The safety set included 37 participants who received at least 1 dose of itraconazole. There were
no safety concerns with itraconazole. Only one treatment-emergent AE (TEAE) of worsening
of T. cruris infection (moderate intensity) was recorded, leading to the withdrawal of the par-
ticipant from the study, although, the investigator considered it to be unrelated to the study
treatment. No serious AEs or deaths were reported during the study and there were no clini-
cally significant changes in vital signs or laboratory parameters.

Discussion
This pilot study was planned to determine the clinical response after a treatment course of 7
days of itraconazole in patients suffering from superficial fungal infection in India. However,
the study was prematurely terminated due to the COVID-19 pandemic, thus calling for a care-
ful interpretation of the results. Nevertheless, the results provide interesting insights regarding
the treatment outcomes and risk factors associated with clinical response in this patient popu-
lation while they received itraconazole as part of their routine clinical care.
Of the 40 participants enrolled in our study, approximately two-thirds were male, and the
mean age was 35.5 years. This is consistent with prior reports showing male preponderance
(2–6 times more than females) and relatively high incidence in the age group of 20–40 years in
India [2]. We used the CET SS tool, which has been used in the prior itraconazole clinical stud-
ies, to assess the presence and severity of signs and symptoms in our study participants and
indicated that the disease severity in our study can be considered as mild to moderate (mean
CET SS score of 5.5).
A dramatic change in the characteristics of dermatophytosis has been reported in India in
recent years and Trichophyton species has emerged as a predominant organism with T.
rubrum, T. mentagrophytes and T. verrucosum are the most commonly identified [32]. The cul-
ture results in our study supported these findings as T. mentagrophytes was the most common
species (~92%) identified followed by T. rubrum (~8%). The MIC for itraconazole was within
the susceptibility range (0.015 to 0.25 mcg/mL) in all isolates both at baseline and after treat-
ment. At Day 7 more than 40% of the participants achieved clinical response (healed or
markedly improved). There was approximately a 2-fold improvement in the clinical response
at Day 14 compared with Day 7 based on the completer analysis. This estimated ratio became
1.5 when participants who missed the Day 14 follow-up were categorized as “non-responders”.
The observed results are similar to those of the pivotal studies of itraconazole where >80%
superficial dermatophytosis healed with the use of 100 mg oral itraconazole for 7 days [33].
The PK properties of itraconazole should also be evaluated while considering the dose and
duration of treatment [8]. Itraconazole has non-linear pharmacokinetics which contributes to
its unpredictable absorption patterns. The observed absolute oral bioavailability of itraconazole
is about 55%; however, gastric conditions (fed vs fasting) and other concomitant medications
affecting gastric acid secretion results in inter-patient variability [9, 34]. On the other hand,
itraconazole is rapidly absorbed after oral administration reaching peak plasma concentrations
within 2–5 hours following an oral capsule dose and steady-state concentrations are reached
by 14–15 days following daily dosing of up to 400 mg [35].
Interestingly, in our study, there was a lack of correlation between PK results and the clini-
cal outcomes observed, along with an absence of itraconazole resistance in the causative

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PLOS ONE Itraconazole and fungal infections in India

organisms. The clinical response at Day 7 was neither associated with the highest or lowest
observed plasma concentrations of itraconazole and hydroxy-itraconazole, nor with the MIC
of the causative fungi. Thus, the treatment failure could not be attributed to either a lack of
drug exposure or elevated MIC values for T. mentagrophytes species complex. This might be
due to the fact that itraconazole accumulates at the infection site, making consistently high
plasma concentrations unnecessary for clinical response [29]. Owing to its high lipophilicity
itraconazole exhibits up to 4-times higher concentrations in skin tissue compared to the
plasma concentration and although the uptake is slower and dependent on the skin areas, peak
concentrations are observed at 7–14 days in the stratum corneum and persist for up to 2–4
weeks after the discontinuation of therapy [36–38].
As per the recommendations of the Expert Consensus on the Management of Dermatophy-
tosis in India (ECTODERM India), itraconazole is the preferred systemic antifungal therapy.
However, in view of the perceived changes in both prevalence and clinical characteristics of
dermatomycosis in India (i.e., more severe and recalcitrant), the ECTODERM expert panel
recommended itraconazole doses are 100–200 mg once a day for 2–4 weeks in treating naïve
cases, and 200–400 mg once a day prolonged periods (>4 weeks) in case of recalcitrant cases
[2].
Anecdotal reports of increased treatment failures with the use of itraconazole in India
should be interpreted with caution. Although this is a small study, our findings suggest that
resistance to itraconazole or PK factors may not be the cause of those reported findings. There
are however other factors that cannot be excluded. One of them is the severity of the disease—
based on our clinical evaluation the cases included in this study were mild. It is possible that in
more severe cases the response to itraconazole would be different. Another factor is adherence
to treatment. It is well known that patients included in clinical trials have better adherence to
treatment. Although this study tried to assess these patients in their regular practice, we
included evaluations that were not part of their regular clinical care and that could have influ-
enced their adherence to therapy and therefore the observed clinical outcomes. There have
been other efforts to understand the epidemic of dermatophytosis in India with similar results
[6, 32, 39, 40].
The conduct of the study was difficult from many perspectives; the COVID-19 pandemic
affected patient recruitment and follow-up and consequently, the study understandably suf-
fered from a significant drop-out rate. Though the small sample size and high discontinuation
rate are important limitations, the study reconfirmed the clinical efficacy and microbial sus-
ceptibility to itraconazole for the fungi causing dermatophytosis in India.

Supporting information
S1 Checklist.
(DOCX)
S1 File.
(PDF)
S2 File.
(PDF)
S3 File.
(PDF)
S4 File.
(DOCX)

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PLOS ONE Itraconazole and fungal infections in India

Acknowledgments
The authors thank Aafrin Khan and Uma Kundu (SIRO Clinpharm Pvt Ltd) for providing
medical writing support and Robert Achenbach (Janssen Global Services, LLC) for providing
editorial assistance.

Author Contributions
Conceptualization: A. Villasis-Keever, N. Garodia, D. Fife, P. De Doncker, K. Shalayda, P.
Hu, S. Fonseca, N. Cure-bolt.
Formal analysis: P. Hu.
Investigation: S. Handa, M. Shenoy, S. Anandan, M. Bhrushundi, K. Shalayda.
Methodology: A. Villasis-Keever, N. Garodia, D. Fife, P. De Doncker, K. Shalayda, P. Hu, S.
Fonseca, N. Cure-bolt.
Supervision: S. Handa, M. Shenoy, S. Anandan, M. Bhrushundi, N. Cure-bolt.
Writing – review & editing: S. Handa, A. Villasis-Keever, M. Shenoy, S. Anandan, M. Bhrush-
undi, N. Garodia, D. Fife, P. De Doncker, K. Shalayda, P. Hu, S. Fonseca, N. Cure-bolt.

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