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 year7.
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 different21.
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 hospitals3.
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 institutions23, 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 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 reference18.
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 use18, 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)10 .
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-14α from lanosterol, resulting in the accumulation of C-14α methylsterols and decreasing the concentration of ergosterol. Thus, the cell membrane of the fungus cannot be maintained, due to lower ergosterol production10, 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 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® 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 Diflucan24, 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 > 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 liver14.
Fluconazole has excellent in vitro activity against Candida albicans and is also effective against some non-albicans species such as C. parapsilosis , C. tropicalis and 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 recommended4, 5.