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\begin{document}

\title{Trend of consumption of the antifungal agents fluconazole, voriconazole
and itraconazole in an adult ICU from 2009 to 2020 in a university
hospital in Salvador-Bahia}



\author[1]{FABIO FERREIRA}%
\author[2]{Federico Marilia  Marilia  Pinto}%
\author[1]{Aníbal de Freitas  Júnior}%
\affil[1]{UNEB}%
\affil[2]{Universidade Estadual de Feira de Santana}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Invasive fungal infections have a high morbidity and mortality rate in
Brazil. In this aspect, antifungal agents used in hospital units
represent the only treatment alternative. This work aims to to analyze
the trend of antifungal consumption in an Intensive Care Unit (ICU) for
adults, in a university hospital, in Salvador-Bahia. Retrospective
descriptive study, which evaluated the trend of consumption of
antifungal agents in the adult ICU based on the consumption records of
standardized systemic antifungals that were dispensed to patients over
the period and expressed in Defined Daily Dose (DDD)/100 patients -day.
The most consumed antifungals, in descending order were: Fluconazole
(91.58\%; p= 0.1726) voriconazole (7.2\%; p=0.9356) and itraconazole
(0.45\%). Antifungals were widely used in the adult ICU of the
university hospital and the growing consumption trend demonstrates that
it is necessary to monitor and promote the rational use of these drugs,
since the inadequate and/or excessive use, in addition to burdening the
health system , can increase fungal resistance to the only agents
available to fight fungal infections.%
\end{abstract}%



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\textbf{Trend of consumption of the antifungal agents fluconazole,
voriconazole and itraconazole in an adult Intensive Care Unit (ICU) from
2009 to 2020 in a university hospital in Salvador-Bahia}

Fabio Ferreira dos Santos\textsuperscript{1}, An\selectlanguage{ngerman}íbal de Freitas Santos
Junior\textsuperscript{2}, Marilia Pinto Federico\textsuperscript{3}

\textbf{Affiliations}

1. Fabio Ferreira dos santos Master's Degree in Pharmaceutical Sciences
at the University of the State of Bahia.
E-mail:fabiobilac\_farma@yahoo.com.br

2. Aníbal de Freitas coordinator and Permanent Professor of the Stricto
Sensu Postgraduate Program in Pharmaceutical Sciences (PPGFARMA) of the
Department of Life Sciences, Pharmaceutical Sciences, Faculty of
Pharmacy, State University of Bahia -UNEB-BAHIA(BA), BRAZIL.

3. Marilia Pinto Doctorate in Science (Infectology) from the Federal
University of São Paulo (UNIFESP). Master's Degree in Public Health from
the State University of Feira de Santana (UEFS).

\textbf{Corresponding author:}

Fabio Ferreira, Department of Life Sciences

Master of the Stricto Sensu Postgraduate Program in Pharmaceutical
Sciences (PPGFARMA), State University of Bahia, Bahia-salvador

E-mail: Fabiobilac\_farma@yahoo.com.br

\textbf{Word count:}

4000 Words

\textbf{Trend of consumption of the antifungal agents in an adult ICU
from 2009 to 2020 in a university hospital.}

Fabio Ferreira dos Santos, Aníbal de Freitas Santos Junior, Marilia
Pinto Federico

ABSTRACT

\emph{\textbf{Background}. Invasive fungal infections have a high
morbidity and mortality rate in Brazil. In this aspect, the antifungal
agents used in hospital units represent a single treatment
alternative.\textbf{Objectives}. This study aims to analyze the trend in
antifungal consumption in an Intensive Care Unit (ICU) for adults, in a
university hospital, in Salvador-Bahia. \textbf{Methods}. Retrospective
descriptive study, which evaluated the trend of consumption of
antifungal agents in the adult ICU based on the consumption records of
standardized systemic antifungals that were dispensed for patients over
the period and expressed in Defined Daily Dose (DDD) / 100 patients-day.
The most consumed antifungals, in descending order, were: fluconazole
(91.58\%; p=0.1726) voriconazole (7.2\%; p= 0.9356) and itraconazole
(0.45\%).\textbf{Conclusions} Antifungals were widely used in the adult
ICU of the university hospital and the growing consumption trend
demonstrates that it is necessary to monitor and promote the rational
use of these drugs, since the inadequate and/or excessive use, in
addition to burdening the health system, can increase fungal resistance
to the only agents available to fight fungal infections}

\textbf{Keywords:} antifungals; intensive care unit; trend of
consumption

What is already known about this subject:

Antifungal drugs are costly to the health system, belong to a small
therapeutic class, are used empirically, prophylactically and
therapeutically in invasive fungal infections.

What this study adds:

This study brought unprecedented data on the use of the main antifungal
drugs used in the adult ICU of a Brazilian university hospital, scarce
information in the literature and little discussed in
pharmacoepidemiology

\textbf{Introduction}

Systemic fungal infections represent an emerging problem in current
clinical practice. In Brazil, it is rare and difficult to obtain
statistical data on the incidence rates of such infections. What is
known are the causes that contribute to the increase in this rate. The
intensive use of broad-spectrum antibiotics, conditions associated with
immunosuppression (transplantation, cancer, chemotherapy treatment, and
Acquired Immunodeficiency Syndrome) and currently, in a pandemic
context, severe cases of COVID19. All of this has contributed to the
increase in invasive fungal infections and to the emergence of outbreaks
of infections across the country. It is estimated that nearly 4 million
people must have fungal infections in Brazil each
year\textsuperscript{7}.

One of the main concerns regarding the rational use of medications is
related to the use of antibacterials, which often leave antifungal
agents in the background of control. However, the increase in resistance
to various agents is a global reality and causes difficulties in the
therapeutic management of these infections, in addition to contributing
to the increase in treatment costs in the public and private health
system. In developing countries, few resources are used in actions
related to the rational use of antifungals. Furthermore, there are
limited data on the use of these agents in hospitals, and the Brazilian
scenario is no different\textsuperscript{21}.

In this context, antimicrobials are among the groups of drugs most used
in the hospital environment, with the aim of reducing nosocomial
infection rates, but their excessive use can lead to the emergence of
resistant strains. Antifungals in this aspect are highlighted, as they
are drugs used in the treatment of fungal infections in many public
hospitals\textsuperscript{3}.

The study of antifungal consumption in public hospitals is a
pharmaco-epidemiological practice, developed and based on studies of
drug use. This practice gained uniformity and internationalization with
the creation and implementation of the Anatomical-Therapeutic-Chemical
classification system and defined daily dose - ATC/DDD (Anatomical
Therapeutic Chemical/Defined Daily Dose), a tool that categorizes drugs
according to the acting sites. This made it possible to standardize the
studies in such a way that without this information previously defined
and outlined, it would not be possible to conceive or study the
consumption and consumption trend of this type of medicine in Heath
institutions\textsuperscript{23, 1}.

Therefore, studies on the use of these drugs become important to draw a
profile of their use in different contexts, with a view to promoting
rational use and measuring hospital costs. For, a significant increase
in use implies higher costs \textsuperscript{17, 1}.

Thus, the trend study can be used to understand how drug consumption
varies over a given period, in order to manage care practices and
protocols, whether in national or international institutions, as well as
to make comparisons between hospital units and establish parameter and
usage reference\textsuperscript{18}.

Therefore, studying, knowing and measuring data on the temporal
evolution of antifungal consumption, over 12 years in an adult Intensive
Care Unit (ICU), in a University Hospital, in Salvador-Bahia, gains even
more importance within the patient safety context and rational use of
medications. In this intensive care environment, hospital costs are
higher, adverse reactions and drug interactions are potentially more
frequent. Therefore, factors such as these, which directly influence
patient care, must be monitored with accurate information, to infer
measures and strategies, in the management of these drugs, in costs, in
the management and monitoring of therapy with a focus on rational
use\textsuperscript{18, 17, 1}.

Within the pharmacological universe, there are many antifungal agents
that are divided according to their origin and can be natural or
synthetic. Natural drugs are polyenes and echinocandins; the synthetic
ones are represented by the azoles (Fluconazole, Voriconazole and
Itraconazole)\textsuperscript{10} \textbf{.}

They are drugs for systemic use, which differ according to their
chemical structure. Ketoconazole and miconazole belong to the group of
imidazoles; fluconazole, itraconazole and voriconazole to the triazole
group. The azoles act on the fungal cytochrome P450 enzymes, inhibiting
the demethylation of C-14\selectlanguage{greek}α \selectlanguage{english}from lanosterol, resulting in the
accumulation of C-14\selectlanguage{greek}α \selectlanguage{english}methylsterols and decreasing the concentration of
ergosterol. Thus, the cell membrane of the fungus cannot be maintained,
due to lower ergosterol production\textsuperscript{10, 11, 13}.

Among the Azoles, the highlight is for the triazoles, which is a
pharmacological group with an excellent safety profile, used in the
treatment of invasive fungal infections. Since 1979, several newer
azoles (the triazoles) have been commercialized \textsuperscript{10}.

Fluconazole, one of the most commonly used antifungal agents, was the
first antifungal of a new subclass of synthetic triazole antifungals,
developed by the Pfizer\selectlanguage{ngerman}® laboratory in Sandwich, England, in 1970, being
approved by the Food and Drugs Administration (FDA) and introduced in
the United States of America (USA), in 1990 under the name of
Diflucan\textsuperscript{24, 3}.

All azoles are lipophilic and can be administered orally, with
satisfactory bioavailability. Itraconazole is highly protein bound and
therefore achieves high concentrations in adipose tissue and low
concentrations in Cerebrospinal Fluid (CSF). Fluconazole and
voriconazole are minimally protein bound (voriconazole \textgreater{}
fluconazole) and therefore can reach high concentrations in the CSF.
With the exception of fluconazole, which is metabolized and excreted
almost unchanged in the urine, all azoles are metabolized by the
liver\textsuperscript{14}.

Fluconazole has excellent in vitro activity against Candida albicans and
is also effective against some non-albicans species such as \emph{C.
parapsilosis} , \emph{C. tropicalis} and \emph{C. glabrata,} although
high doses of the drug are required for these species. Itraconazole is a
broad-spectrum triazole antifungal agent with antiangiogenic properties,
indicated for the treatment of endemic mycoses (histoplasmosis,
coccidioidomycosis, blastomycosis, onychomycosis) and for rescue
treatment for aspergillosis. It has variable bioavailability, with
significant differences between capsule and solution formulations, as
well as fasting versus feeding administration. The efficacy of
itraconazole was associated with the drug's serum concentrations and due
to its erratic absorption, therapeutic monitoring is
recommended\textsuperscript{4, 5}.

\textbf{MATERIALS AND METHODS}

The research was a study of antifungal consumption trends using
retrospective data at a University Hospital in Salvador, Bahia, Brazil.
The study was carried out in the Intensive Care Unit for adult patients
at HUPES, linked to the Federal University of Bahia (UFBA). It is
certified as a Teaching Hospital. The HUPES ICU has 20 active beds and
receives patients with some type of comorbidity (hypertension, diabetes,
heart disease, kidney failure, cancer, autoimmune disease), who have
suffered hemodynamic instability and need 24-hour monitoring. The
consumption of antifungal agents for the period from January 1, 2009 to
December 31, 2020 was measured, totaling 12 years. Information on
antifungal consumption was obtained through annual consumption reports,
provided by the hospital's Material Management System. These reports
were processed based on daily records of drug dispensing, carried out by
the Hospital Pharmacy Service and generated month by month,
corresponding to the study period, the database was consolidated in
Microsoft® Excel® version 2010.

Data regarding the number of patient-days were obtained through hospital
reports, prepared by the Hospital Center for Epidemiology (NHE) of
HUPES, the sector that prepares epidemiological indicators and
disseminates these reports to the entire internal (HUPES intranet) and
external community . This information was stored in file folders and
cataloged by year. This study included antifungals from the HUPES
standardized azole class, namely: fluconazole, itraconazole and
voriconazole defined as antiinfectives for systemic use, according to
the Anatomical Therapeutic and Chemical (ATC) classification system of
drugs, from the WHO Collaborating Center for Drug Statistics
Methodology. Topical antifungals, those dispensed outside the study
period or to other units (other than the adult general ICU) were
excluded, in addition to non-standardized hospital antifungals.

To calculate the presumed consumption of antifungal agents, the annual
consumption of each drug was considered, based on the amount dispensed
to the adult ICU by the Hospital Pharmacy Service of HUPES, expressed by
consumption density in DDD/100 patient-days (pd).

The next step took place through the process of converting the quantity
of dispensed units to the quantity in grams of the active ingredient.
The absolute consumption of each drug obtained per year was multiplied
by the amount of active ingredient, corresponding to each standardized
pharmaceutical presentation, the result being expressed in grams.

The DDD value of the fluconazole, voriconazole and itraconazole was
obtained from the ATC/DDD indexhttps://www.whocc.no/atc\_ddd\_index and
are respectively (J02AC01) 0.2g, (J02AC03)0.4g and (J02AC02)0.2g. Data
were subjected to statistical treatment of descriptive pattern and to
obtain relevant results. To calculate the trend, the Mann-Kendall
statistical method was used. In this study, a significance level
(p\textless{}0.05) and a 95\% confidence interval (95\%CI) were adopted.

\textbf{DECLARATION OF ETHICS}

The authors confirm that the journal's ethical policies, as noted on the
journal's author guidelines page, have been respected. No ethical
approval was required, as the research used in its entirety statistical
data and hospital indicators to carry out the work.

\textbf{RESULTS AND DISCUSSION}

Fluconazole, Voriconazole and Itraconazole belong to the class of
triazole azoles; however, the first two are the most frequent
medications used for fungal infections, due to their safety and
tolerability profile, in relation to the imidazole azoles that present
greater toxicity.

According to Figure 1, it was possible to observe an initial growth of
75.75\% (16.99DDD/100pd to 29.86DDD/100pd) in the consumption of this
class, expressed in DDD/100pd. Over the subsequent years, consumption
decreased by 48.19\% (2011-2016). Based on this oscillation, the
consumption of azoles proved to be non-linear and highly variable, with
an average of 42.13 DDD/100pd. Vallabhaneni \emph{et al} (2016)
evaluated the trend of use of antifungals in intensive care hospitals in
the United States of America (USA) (2006-2012) and azoles accounted for
80\% of all antifungals used \textsuperscript{23}. Unlike the results of
Siope \emph{et al} (2020), in the university hospital in France
(2009-2018), which azoles accounted for 54\% of total
consumption\textsuperscript{21}. In the survey, the results were
different from both previous studies and represented 62.76\% of the ATF
used.

Data regarding the consumption of azoles in the ICU were also obtained
from the studies by \textsuperscript{6}. This research found an average
of 12.54 DDD/100 pd in the ICU of hospitals in Catalonia, Spain, much
lower than that found in this study(42.12DDD/10pd).

It can be seen by looking at Figure 2 that, of this group, itraconazole
was the agent with the lowest consumption in DDD/100 pd in the study. It
was also observed that in the first four years, there was practically no
use of itraconazole in the ICU and, over the period, the growth was
small, with the highest consumption being 0.58 DDD/100pd in 2015.
Similar data were obtained by Fondevilla (2015) who presented a low
density of itraconazole consumption (0.18 DDD/100pd) in relation to
other azoles, however, studies by katja \emph{et al} (2005) and other
collaborators (2005) that evaluated the density of antifungal
consumption in five hospitals in Germany from 2001 to 2003, obtained
results (mean 2.5 DDD/100pd) very different from the one found in the
Research \textsuperscript{25}. According to Figure 2, this drug had a
low consumption in the study, compared to the others, for the same
period. The trend was up, however little expressive in relation to other
antifungals. As the value of p=0.400 (95\% CI), it did not present
statistically significant relevance.

Itraconazole is recommended for endemic fungal infections such as
Histoplasmosis and paracoccidioidomycosis, in addition to being widely
used for prophylaxis in transplant patients. This can justify the low
consumption, since patients with this profile have a low incidence in
the ICU, which shows the low use of the drug.

As for voriconazole, a second-generation triazole, in the first year
(2009), there was an increase of 136.7\% (0.79 DDD/100pd to 1.87),
followed by a very significant reduction of 68 .44\% (2011). It is
noteworthy that in three years (2016-2018), the growth was 46.4\%,
showing a growing consumption curve. Overall, it grew by 243\% in the
period studied, going from 0.79 DDD/100pd in 2009 to 2.71 DDD/100pd in
2020. Thus, the trend was upwards, but it was not statistically
significant. significant (p=0.372). Similar results were obtained in the
studies by Lai \emph{et al} (2012), that evaluated the consumption of
antifungal agents at the medical center in Taiwan (2000-2010).
Voriconazole showed an increasing trend in the 10 years of study with a
mean of 5.69 DDD/100 pd and a significant consumption variation
(p=0.001).

Of all the triazoles, fluconazole was the most consumed drug in the
adult ICU, in all years, compared to voriconazole and itraconazole. The
most prominent years were: 2010 (24.7 DDD/100pd); 2011 (29.17
DDD/100pd), 2012 (25.6 DDD/100pd); 2014 (23.78 DDD/100pd) and 2017
(24.31 DDD/100pd) (Table 1)

Such results, referring to the increase in consumption, were consistent
with the studies by Hidalgo (2008) carried out in the ICU of a hospital
in São Paulo, which assessed the profile of antimicrobial consumption.
In this study by Hidalgo, fluconazole showed a statistically significant
(p=0.001) growth of 3100\% (0.2 DDD/100pd to 6.4 DDD/100pd) in the
period (1995-2006).

And they were consistent with studies by Oberoi \emph{et al} . (2012) in
a tertiary hospital in New Delhi, India, which analyzed the change in
the epidemiology of candidemia and the use of antifungals, identified
that fluconazole was the most frequently prescribed antifungal and
represented an increase of 25 \% between 2000-2008(r²= 0.971,
p\textless{}0.001).

Contrary to the data regarding the consumption trend presented in the
studies of Hidalgo (2008), which was high, the trend of triazoles in the
research obtained a reduction of 16.7\%, showing a statistically
significant difference (p=0.0163) year after years in
consumption\textsuperscript{8}. Vallabhaneni et al., (2016) also
identified a 20\% reduction in fluconazole trend in US hospitals,
2006-2012 (p=0.001).

Camargo \emph{et al} . (2010), in a similar study, obtained values \selectlanguage{english}\selectlanguage{english}of
63.3 DDD/100 pd in the use of fluconazole in an ICU and Salci (2011)
found 12.5 DDD/100 pd in 2017, 19.8 DDD/100 pd in 2008 and 22.6
DDD/100pd in 2009, at a large University Hospital in southern Brazil.
Studies of susceptibility and consumption of antifungals in intensive
care in hospitals in France carried out by {[}18{]} obtained a
percentage of fluconazole consumption of 84.3\% in relation to other
antifungals. These evidences, confirmed through the studies and the
results presented, support the assertions that fluconazole, despite
being a first-generation drug with 21 years of existence on the market,
is still routinely used in clinical practice in ICUs around the world.

Some factors justify this expressive number in the consumption of this
medication and one of them is the form of use in the ICU. According to
Salci (2011), 42.6\% of the use of this medication was empirical,
against 51.1\% therapeutic. Studies have shown that the time taken to
start treatment for fungal infections was important for therapeutic
success and, especially, for reducing morbidity and mortality.

As for empiricism in treatment, there is a consensus among researchers
on the need for this practice, but this form should be reserved for
patients at high risk of developing invasive fungal infection. Long
exposure to repeated fluconazole therapies is also another important
factor that is associated with reduced susceptibility to antifungals as
occurs with strains of\emph{C. glabrata} and, which often triggers an
excessive and/or inadequate use, thus increasing
consumption\textsuperscript{14}.

Furthermore, the studies by Salci (2011) also showed that patients
treated based on microbiological evidence of fungal infection had longer
survival (60\%), when compared to individuals treated empirically
(50\%). Risk factors for developing IFI, such as the use of invasive
devices such as central and indwelling venous catheters, in addition to
previous therapies are interfering that can contribute to the increase
of this medication in the ICU.

Another highlight that may be related to the consumption of fluconazole
in the adult ICU is the affordable price of this drug compared to other
antifungals. According to the federal government's price panel, the
average purchase price of fluconazole is R\$14.26 for intravenous and
R\$5.32 for oral therapy. Although the work did not assess the cost of
ATF, it is worth emphasizing the importance of these values \selectlanguage{english}\selectlanguage{english}for health
institutions at the time of evaluation and acquisition of the
drug\textsuperscript{15}.

\textbf{CONCLUSION}

In general, in hospitals in Brazil there are specific circumstances that
interfere in the variation in the consumption of antifungal agents in
the ICU, such as the profile of strains' sensitivity to antifungal
agents, the prescription practices and the epidemiology of the IFIs,
which despite not being included in this study, influence the
consumption of these agents. The vast majority of studies greatly
reinforce the pattern of consumption of antimicrobials, emphasizing
antibacterials, and this limits the number of studies that serve to
counteract the results for systemic antifungal agents. Therefore,
observing the variation in the consumption of these drugs helps to
better assess the dispensing process and, consequently, their rational
use. This pharmacoepidemiology practice, widely used in Europe in drug
use studies, it is important not only for the knowledge and monitoring
of adverse reactions and consumption, but also for the rationing of
hospital expenses. According to the data, fluconazole showed a smaller
growth trend in relation to the other studies compared, but it was still
considered the most consumed drug in the analyzed period, different from
itraconazole, which, with a reduced consumption density, was not very
expressive in terms of use in the ICU, and voriconazole presented a
growing scale of consumption, which shows its use in fungal infections
in this sector.

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