This study is the first in Lebanon to analyze the trend of antifungal consumption based on national data recorded between 2004 and 2018. These data indicate an overall increase in antifungal consumption by 18.64%, from 1.18 to 1.4 DDDs per 1000 inhabitants per day. However, a significant increase was measured by the total number of DDDs number which ascended from 1661 thousand to 3120 thousand DDDs. This uptrend is mainly contributed by the overall dominance of azole antifungals (73.57%) generally, and fluconazole (20.99%) specifically. The latter use was amplified by 287.64% between 2004 and 2018.
Results showed an initial slight decline between 2004 and 2006 in antifungal consumption using both measures (DDDs and DDDs per 1000 inhabitants per day). However, this decline was more obvious in the second measure since it was related to the number of current inhabitants during this period. Lebanon was facing political problems during these years. Many citizens left the country so the number of inhabitants decreased as well as the total consumption of drugs including antifungals.
The rates of consumption of antifungals in Lebanon are somehow similar to those in Europe. According to the ESAC reports published between 2010 and 2017, the trend of consumption from 2010 to 2012 showed the same maximum consumption of 3.3 DDDs per 1000 inhabitants per day [19]. This rate increased between 2013 and 2014 to a wider range of 0.36 to 3.8 DDDs per 1000 inhabitants per day [19]. Our study showed a stable consumption, with the lowest value among these years in 2014 (1.37 DDDs/ 1000 inhabitants/ day). Nonetheless, the major discrepancy was the low value of antifungal consumption in Europe during 2017 (0.9 DDDs /1000 inhabitants/ day) in contrast with the maximum value in Lebanon in the same year (1.52 DDDs/1000 inhabitants/ day) [19]. The difference between Lebanon and the European countries in terms of antifungal consumption could be correlated to the social or cultural differences, and variations in the healthcare system, pharmaceutical market, and regulatory systems and resources [20]. Nevertheless, the study findings were similar to the utilization trends of antifungals in Tanzania from 2010 to 2017 which showed a significant increase in the consumption of antiviral antifungal agents [21].
Our study highlighted a rise in antifungal consumption in Lebanon between 2004 and 2018 at 87.76%. Numerous factors contribute to this upward trend. First, similar to antibiotics, a wide range of antifungals is commercially available to the population; in both topical and oral forms (creams, tablets, syrups, etc.) [22]. The market size of antifungal drugs is growing with the increase in over-the-counter (OTC) drugs, especially for dermal use [22]. Second, people usually are self-medicated and can be provided with low-price and prescription-free antifungals from Primary Health Care Centers (PHCCs) [23,24,25]. Third, unspecialized physicians could be prescribing antifungals without proper implementation of guidelines for disease management [24,25,26]. Fourth, pharmacists participate in dispensing medications such as antibiotics without physician prescriptions, and could probably as well dispense antifungals [23,24,25]. Finally, there is no strict and clear implementation of an authorized protocol for antimicrobial sales by the national regularities [23,24,25]. Furthermore, the increase in antifungal consumption can be attributed to the increase in cancer cases. Cancer patients are prescribed antifungal therapy as prophylaxis or as treatment and hence, increased cancer incidences according to CDC statistics will magnify antifungal consumption [27]. In addition, an important reason behind the overall increased use of antifungals could be the increasing number of invasive fungal infections such as chronic pulmonary aspergillosis, cryptococcal meningitis in HIV/AIDs, invasive candidiasis, and Pneumocystis jirovecii pneumonia [28].
Increased incidences of infections were also powered by the increase in global travel that is accompanied by the spread of fungi wherever people go; as well as the climate change dilemma that allowed the variation in the geographical features and rooting of the fungi [29]. As a fact, global warming would significantly affect the distribution of species that are tolerant to heat by favoring conditions needed by some fungi to spread closely into the human population [30].
Among the interesting findings was the 7.87% decrease in antifungal consumption between 2017 and 2018 which is worth elaborating on. During this period and until nowadays, Syrian refugees are returning home as reported by the Ministry of Social Affairs, United Nations Development Program (UNDP), and the United Nations High Commissioner for Refugees (UNHCR) in the Regional Refugee and Resilience Response Plan (3RP), which could implicate a possible decrease in antifungals’ use [31].
The study results were depicted differently between the three routes of administration. Topical drugs were ranked first having 7.22% and 153.492% higher than the consumption of oral and parenteral drugs respectively. This might be related to the fact that topical antifungals are commercially available in a huge number of brands and forms in community pharmacies, such as creams, sprays, shampoos, and nail lacquers, which could be mostly sold as OTC products. Additionally, topical antifungals are less expensive than other dosage forms. Also, parenteral drugs usually require hospitalization so they are not readily available in the community.
Azoles dominated the overall consumption trend. They are mostly used in clinical practice and are readily available in numerous forms and generics/brands and they are the most studied in terms of mode of action, pharmacological characteristics, and resistance profile [32]. The most consumed antifungal agent was fluconazole. Its use was similar to the trend between Lebanon and other nations. This trend is in agreement with other European countries as reported by the European Centre for Disease Prevention and Control (ECDC). The latter also states that Belgium records the highest fluconazole use within Europe (after Greece in 2016) [33]. Moreover, a study conducted in Catalonia on the consumption of systemic antifungals between 2008 and 2013 showed that fluconazole represented 70.3% of antifungals [34]. Similarly, fluconazole had the highest proportion of utilization for antifungals in Tanzania [21]. All of these findings of the high consumption/prescription of fluconazole contributes to the global spread of microbial resistance to it. The point-prevalence study of antimicrobial use in hospitalized neonates and children showed that 20.5% of 146 Candida. glabrata cultures were resistant to fluconazole [8]. In addition, 1846 isolates from 31 countries showed that 11.9% of Candida glabrata and 11.6% of Candida tropicalis were resistant to fluconazole and reported an increase in fluconazole resistance from 9 to 14% between 2001 and 2007 [10]. The Middle East study showed that 38% of Candida isolates were fluconazole-resistant and that 42% of the patients were converted to the second line therapy agents due to decreased responses [2].
Finally, it is worth mentioning the reports of recent studies that severe clinical COVID-19 has increased the risk of invasive fungal infections. COVID-19-associated pulmonary aspergillosis emerged as an important fungal complication in patients with acute respiratory failure. Accordingly, antifungal consumption has increased especially echinocandins, voriconazole, and isavuconazole which may be a contributing factor to antifungal resistance pattern in the upcoming years [35,36,37].
Strengths and limitations
The chief strength of this study is being the first to address antifungal consumption on a national level, and can also be considered the first in the Middle East region. Additionally, the data on antifungal use in the community sector was readily available from the IMS database as a source of surveillance information. Moreover, the consumption figures were recorded over a long period. Furthermore, using the ATC/DDD system adds value to the results obtained on antifungal consumption as it serves as the benchmark of data used for comparison with other countries [11]. However, the study has some limitations. First, missing 2016 data contributes to the major drawback of this study. This is because IMS 2016 data is a mix of hospital and community figures and we couldn’t extract community ones only. Second, the comparison of usage with other countries is dictated by prescribing guidelines that vary from one country or region to another; knowing that Lebanon lacks national ones for such practice. Third, the IMS database is a record of the sales of antifungal agents to community pharmacies without taking into consideration the previously mentioned sources such as PHCCs and free mobile clinics. However, the IMS database is the only available resource to conduct drug utilization studies in Lebanon. Finally, there are no abundant data in the literature available to use the number of DDDs as a standard unit of measurement/comparison with other national and international studies. The majority of the studies report antimicrobial consumption by one of the following: DDDs per number of inhabitants, DDDs per patient days, etc. Using the latter units of measurement is significant for comparison purposes among countries and for effective longitudinal analysis of consumption trends [38]. Using these indicators can be questioned when looking for comparisons or analyses of trends that have an increase in both, consumption rates and population size [38]. For that, reporting most of the data by the number of DDDs is an attenuated limitation by the need for our trend analysis to reflect the changing overall trend with a population number change. The exaggeration depicted by this measure was strengthened as well by the fact that a stable profile was revealed by the DDDs per 1000 inhabitants per day when an actual increase was taking place. Moreover, WHO states that it is impossible to define pediatric DDDs because dose recommendations for use in children vary according to age and body weight.