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 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 23. Unlike the results of
Siope et al (2020), in the university hospital in France
(2009-2018), which azoles accounted for 54% of total consumption21. 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 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 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 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 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 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<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 consumption8. Vallabhaneni et al., (2016) also identified a 20%
reduction in fluconazole trend in US hospitals, 2006-2012 (p=0.001).
Camargo et al . (2010), in a similar study, obtained values 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 ofC. glabrata and, which often triggers an
excessive and/or inadequate use, thus increasing consumption14.
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 for health
institutions at the time of evaluation and acquisition of the
drug15.