IFIs are an important cause of mortality and morbidity in AML patients who are neutropenic due to cytotoxic treatment to induce remission (Gomes, Mulanovich et al. 2014). The prevalence of developing IFI was given as 14–15% up to 2008, and has risen to 58% worldwide in more recent studies (Auberger, Lass-Flörl et al. 2008, Malagola, Peli et al. 2008, Neofytos, Lu et al. 2013, Tang, Kung et al. 2015, Atilla, Çelik et al. 2022). The reason for this increase could be global antimicrobial resistance, which is also observed in fungal pathogens, or due to more potent immunosuppressive agents used in the new regimens (Galgóczy, Nyilasi et al. 2011, Ting, Whitaker et al. 2016, Tavakkoli, Johnston et al. 2020). Similarly, the prevalence of developing IFI in Iran is still high despite PAP with azole anti-fungal agents, especially Fluconazole (Esfahani, Golestannejad et al. 2019, Tavakkoli, Johnston et al. 2020). Therefore, it seems necessary to find a solution for more effective IFI prevention. One implementation strategy is to use existing drugs alongside approved drugs to intensify their antifungal effects. Statins are widely used lipid-lowering drugs that are also known for their benefits beyond the main effect; For example, their anti-inflammatory effects in patients with chronic inflammatory diseases such as those suffering from cardiovascular diseases or chronic renal failure. As with antibacterial and antiviral effects, many in vitro studies have shown the remarkable role of statins against the growth and proliferation of fungal species (Qiao, Kontoyiannis et al. 2007, Galgóczy, Nyilasi et al. 2011, Cabral, Figueroa et al. 2013, Nyilasi, Kocsubé et al. 2014, Ting, Whitaker et al. 2016, Ribeiro, Costa et al. 2017, Esfahani, Golestannejad et al. 2019, Lima, Alves-Nascimento et al. 2019, de Oliveira Neto, Souza et al. 2021, Mahmoud, Faraag et al. 2021). In addition to the synergistic effects of statins with azoles, serious drug-drug interactions or ADR requiring attention in the simultaneous use of these two drug categories have not been reported(Cabral, Figueroa et al. 2013, Ting, Whitaker et al. 2016).
De Oliveira et al mentioned that Atorvastatin can reduce fungal load when used orally or vaginally in experimental models of oral and vulvovaginal candidiasis (de Oliveira Neto, Souza et al. 2021). Eita et al confirmed the previous results in rats (Eita, M. A. Makky et al. 2022). Based on our research, this study is the first interventional study to examine the antifungal effects of statins in humans. For this purpose, due to the high incidence of IFI, AML patients were selected as the study population. This study was conducted in the induction of remission phase and all patients received the same PAP with Fluconazole 400 mg/day. Although most guidelines now favor Posaconazole as antifungal prophylaxis for AML patients (Cornely, Maertens et al. 2007, Cho, Lee et al. 2015), Posaconazole was not available for administration to patients in the study area at the time this study was conducted.
Among 76 patients who involved the study, 14 patients (18%) had proven, and 11 patients (14%) had probable IFI according to criteria. The most frequent IFI in our study was invasive mold infections, which was similar to other studies (Malagola, Peli et al. 2008, Galgóczy, Nyilasi et al. 2011, Perfect, Hachem et al. 2014, Hwang 2020).
In case of choosing the best dose, we reviewed available literature that discussing the Minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC) of Atorvastatin against different fungi spp. The results of those studies have shown that the antifungal effect of statins is directly related to increasing their concentration(Cabral, Figueroa et al. 2013, Nyilasi, Kocsubé et al. 2014, Ribeiro, Costa et al. 2017, Esfahani, Golestannejad et al. 2019, Lima, Alves-Nascimento et al. 2019, de Oliveira Neto, Souza et al. 2021, Mahmoud, Faraag et al. 2021, Eita, M. A. Makky et al. 2022). Nasr Esfahani et al mentioned that The MIC of Atorvastatin is similar to the therapeutic serum level of the drug when used with the dose of 40–80 mg (Esfahani, Golestannejad et al. 2019).Additionally, two reported that Fluvastatin has Fungal inhibitory activity with the concentration that can be provided by taking lipid lowering doses of the drug(Lima, Alves-Nascimento et al. 2019, Tavakkoli, Johnston et al. 2020). However, Due to the lack of clinical studies on the best dose of Atorvastatin for antifungal effects in humans, and respecting the possible drug-drug interaction between anthracyclines and statins, which can increase the concentration of anthracyclines by inhibiting the P-glycoprotein pump(Goard, Mather et al. 2010), we were cautious in giving higher doses and used 40 mg/day. Further studies on the minimum effective concentration for antifungal activity of statins in humans are recommended.
Our study showed that Atorvastatin can reduce the development of IFIs when used as an adjuvant to Fluconazole. This fact confirmed the results of previous animal and in-vitro studies(Qiao, Kontoyiannis et al. 2007, Galgóczy, Nyilasi et al. 2011, Cabral, Figueroa et al. 2013, Nyilasi, Kocsubé et al. 2014, Cho, Lee et al. 2015, Ting, Whitaker et al. 2016, Ribeiro, Costa et al. 2017, Esfahani, Golestannejad et al. 2019, Lima, Alves-Nascimento et al. 2019, de Oliveira Neto, Souza et al. 2021, Mahmoud, Faraag et al. 2021).
Tang et al. have shown that IFI development in the induction phase is an independent predictor of poorer survival (HR 1.536 (1.100-2.141), P = 0.012)(Tang, Kung et al. 2015). In addition, a multivariate analysis of data from AML patients showed that proven IFI is significantly predictive of death (HR 1.7, P = 0.018) (Auberger, Lass-Flörl et al. 2008). Our study demonstrated that atorvastatin can improve IFI-free survival in induction-phase AML patients, accounting for both probable and proven IFI (HR 0.16, P < 0.001 and HR 0.19, P = 0.014). Our study showed no significant difference in the 30-day patients all-cause mortality between the two groups, reminding that factors other than IFI development can also influence patient’s survival and should be considered(Li, Shih et al. 2021).
In case of efficacy, in-vitro studies showed that Atorvastatin can inhibit the growth of Candida spp., azole-resistant Candida spp. except for C. krusei, Cryptococcus gattii, Rhizopus oryzae, Mucor racemosus and Rhizomucor (Roze and Linz 1998, Macreadie, Johnson et al. 2006, Qiao, Kontoyiannis et al. 2007, Galgóczy, Nyilasi et al. 2011, Ting, Whitaker et al. 2016, Ribeiro, Costa et al. 2017, Esfahani, Golestannejad et al. 2019, Naeimi Eshkaleti, Kordbacheh et al. 2019). Given the prevalence pattern of fungi responsible for infections in AML patients, the positive effects of Atorvastatin in our study seem logical. The data regarding the inhibitory effect of statins on Aspergillus spp. growth are conflicting. However, most of them agree about the ineffectiveness of these drugs on the growth of that(Chin, Weitzman et al. 1997, Nash, Burgess et al. 2002, Qiao, Kontoyiannis et al. 2007). We reported four cases of respiratory Aspergillosis in our study; two in each group. This result was in line with in-vitro studies, however, larger sample size in needed to make a decisive decision.
The mechanism of the antifungal action of statins is not only the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and the reduction of ergostrol synthesis, but also the Involvement in fungi’s metabolic pathways. Occurrence of any of these mechanisms, is depended on the type of statin that used. Some of the named mechanisms are include: the impairment of the sterol pool, membrane fluid, gene expression and the protein levels of enzymes from the sterol and non-sterol isoprenoid biosynthetic branches. (Gyetvai, Emri et al. 2006, Westermeyer and Macreadie 2007, Maciejak, Leszczynska et al. 2013). Lima et al mentioned that Atorvastatin can additionally regress farnesol-dependent pathogenicity factors, yeast-to-hyphal transition and biofilm generation in fungi(Lima, Alves-Nascimento et al. 2019).The different mechanism of Statins’ antifungal effect has led these drugs to have synergistic effects when used concomitantly with known antifungal drugs such as Nystatin and azoles (Nyilasi, Kocsubé et al. 2014, Esfahani, Golestannejad et al. 2019).
Limitations:
This study reports results from a time when antifungal prophylaxis was suboptimal due to drug supply problems. In addition, biochemical diagnostic tests such as galactomannan and beta-d-glucan levels were not available.