We focused on candidemia patients and found that C. albicans was the most prevalent of the candidemia episodes (43.8%). Among the NAC species, C. glabrata was the predominant species, followed by C. parapsilosis, C. tropicalis, and C. lusitaniae. In most previous studies around the world, C. albicans was the most common species isolated from candidemia, which is consistent with our study [13]. Despite this, in a systematic review, C. parapsilosis (30.8%) was the leading agent of candidemia in Iran [23]. Similar to previous studies, C. glabrata is the most common NAC species in this study [24–26]. However, in other studies, C. parapsilosis has been the most prevalent NAC species [27–30]. Moreover, the increasing mortality rate associated with the increased frequency of NAC might be linked to the failure in clinical cure rate resulting from either acquired or intrinsic resistance to the few antifungal drugs available to treat candidemia. For example, echinocandins are regarded as the first-line drug for the treatment of C. glabrata BSI. However, the increasing reports on BSI caused by C. glabrata isolates resistant to both fluconazole and the echinocandins are alarming. It has been shown that C. lusitaniae can rapidly acquire multidrug resistance traits (MDR) during the course of antifungal treatment with fluconazole, amphotericin B, and caspofungin [31]. C. kefyr can cause serious infection in patients with hematologic malignancies and recently, resistance to amphotericin B have been reported in C. kefyr isolates [32]. C. norvegensis, is also shown to be azole resistant [33]. While 12.5% of the NAC species in this study were fluconazole-resistant, only 4.2% of the C. albicans species were resistant to fluconazole. Our study confirmed that primary fluconazole resistance is uncommon in C. albicans. The majority of C. albicans are sensitive to amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and echinocandins in vitro, especially in patients without a history of exposure to antifungal agents [34]. A recent study looked at the impact of the new CLSI breakpoints and demonstrated that applying revised fluconazole breakpoints increased the rate of fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis [35]. The occurrence of fluconazole resistance in C. tropicalis has been previously reported as 5.0–7.2% from two reports from the ARTEMIS study over 12 years [36, 37]. The high rate of azole non-susceptible C. tropicalis in this study was similar to other studies from Asia [38, 39]. Also among the fluconazole-resistant C. tropicalis isolates in our study, six were resistant to voriconazole. Many candidemia studies revealed a significant increase in azole-resistant C. tropicalis blood isolates and some reported pan-azole and amphotericin B resistant isolates [40]. An extensive candidemia study in India showed that C. tropicalis and C. auris isolates also carry MDR trait [41]. The susceptible dose-dependent (SDD) C. glabrata isolate is defined as fluconazole MIC ≤ 32 mg/l, since 2012. Overall, 96.7% of C. glabrata isolates were categorized as SDD (MIC50 = 16 mg/l, MIC90 = 32 mg/l) that is consistent with studies from the Asian-Pacific region [42]. As demonstrated in the current study, no resistance to any of the antifungal agents was observed in C. guiliermondii, C. lusitaniae, C. kefyr, and C. krusei (except for the intrinsic fluconazole resistance in C. krusei). Furthermore, resistance to echinocandins was very low, except for C. parapsilosis, which exhibited higher MICs than those of other Candida species.
The increased frequency of NAC may also be attributable to the improved diagnostic technique, allowing NAC species to be characterized with methods that are more sensitive. In this study, all Candida isolates were identified using the DNA sequencing method to assess the exact epidemiological pattern of species distribution. The mean age of the patients in this study was 49.6 years. Most of these patients were over forty years old (68.5%). The Mean age in other studies varies from 40 to 65 years. Candidemia patients (usually with underlying conditions, such as diabetes, cancer, pulmonary and heart complications) mostly are admitted to ICUs. The overall crude mortality of 47.2% in our study is similar to that reported by other investigators from Iran [43–45] but considerably higher than the 26% quoted by Chen et al. [46]. Sixty patients took at least one antifungal drug and the mortality rate for these patients was 38.3% (23/60; 38.3%). However, the mortality rate among patients who did not receive antifungal drugs was 65.5% (19/29; 65.5%). This suggests that early diagnosis and timely antifungal administration can dramatically reduce the rate of mortality. We found that mortality was highest among ICU patients (65.7%) which is unsurprising, given the severity of underlying illness in this population. Evidence supports the fact that patients admitted in the ICU have higher mortality rates than those in other wards [47]. The major underlying diseases were malignancy, sepsis, renal failure/dialysis, and HTN. Diabetes mellitus, cardiovascular diseases, and pulmonary disorders were other underlying diseases. Consistently, similar underlying condition were documented in studies conducted in Turkey [48], China [9], and Australia [49]. Multivariate analyses of risk factors for BSIs caused by C. albicans and NAC species showed that malignancy was an independent risk factor for candidemia (P = 0.013). In the multivariate analyses of risk factors for BSIs mortality, intubation (P = 0.001) and urinary catheterization (P = 0.03) were independent risk factors for mortality. In a prospective study performed in the ICU of a tertiary care hospital in Athens, the authors noted that the administration of glucocorticoids, presence of CVCs, and candiduria were independent risk factors for candidemia caused by NAC species [50].
The current study had some limitations. First, in this study, two main medical centers in the capital of Iran had been selected; however, information from other centers has not been included in this study to obtain insights into the epidemiological status of candidemia in Tehran. Second, the results of the multivariate analyses might be influenced by the sample size and the number of variables included in the models.
In conclusion, Candidemia, with a shift in species distribution towards non-albicans Candida species, remains a lethal disease. The results of this study provide important information regarding the distribution of Candida spp in patients with candidemia in Tehran, the capital of Iran for which there is a paucity of data regarding the epidemiology, risk factors, and antifungal susceptibility patterns of these species. Accurate knowledge of predisposing factors and epidemiological patterns can be an effective step in disease management. In this study, C. albicans is reported to be the most common species causing candidemia; however, an increasing frequency of NAC species could pose a serious challenge to treatment due to different antifungal susceptibility patterns. This report shows that candidemia is a significant source of morbidity in Tehran.