Discussion

This study was conducted to elucidate the complete current epidemiology of candidemia cases in a tertiary-care teaching hospital in Jaipur. Among all blood cultures received from suspected sepsis cases, Candida spp were isolated from 95 (2.8%), with a steady increase in the number of cases from July 2017 to June 2020. Similar prevalence rates have been documented in several studies conducted in different parts of country. ^{Reference Bhatt, Sarangi and Paty12–Reference Xess, Jain, Hasan, Mandal and Banerjee14} The predominance of candidemia in male patients, as observed in the current study, was also observed by Bhattacharjee et al in 2016. ^{Reference Bhattacharjee15}

The prevalence of candidemia was more common in ICUs than in wards, and the difference was statistically significant (P < .001). Patients admitted to an ICU occupy a complex ecological niche that facilitates colonization and subsequent development of invasive candidiasis. These factors include exposure to high-end antibiotic therapy, invasive procedures, presence of indwelling devices, comorbidities, etc. In our study, the most common risk factor associated with candidemia was long-term antibiotic therapy (68%), followed by the presence of a central venous catheter (49%). These results agree with those of other studies by Xess et al, ^{Reference Xess, Jain, Hasan, Mandal and Banerjee14} Giri et al, ^{Reference Giri, Kindo and Kalyani16} and Chowta et al. ^{Reference Chowta, Adhikari, Rajeev and Shenoy17} Prolonged use of broad-spectrum antibiotics alter commensal gut flora, which plays an important role in prevention of fungal overgrowth. The propensity of NAC species to form biofilms on catheters and other prosthetic devices exposes these patients to a further high risk of candidemia.

Isolation of NAC from candidemia cases has been steadily increasing over the past few years. NACs are known to be responsible for higher mortality rates due to increased virulence and reduced susceptibility to antifungal drugs. Our results reflect current trends of C. tropicalis (38%) as the most predominant species, followed by C. parapsilosis (18%). The ARTEMIS antifungal surveillance program also noted a decreasing trend in the isolation of C. albicans and an increase in NACs such as C. tropicalis (from 4.6% in 1997 to 7.5% in 2003) and C. parapsilosis (from 4.2% in 1997 to 7.3% in 2003). ^{Reference Pfaller, Diekema and Rinaldi18} Similar observations have been reported by studies across India. ^{Reference Chander, Singla, Sidhu and Gombar3,Reference Chakrabarti, Chatterjee and Rao5,Reference Giri, Kindo and Kalyani16,Reference Kaur, Singh and Rudramurthy19–Reference Singh, Xess, Mathur, Behera, Gupta and Misra21} The most probable reason for this shift seems to be excessive use of fluconazole, which has led to a survival advantage for resistant species like NAC.

A noteworthy finding in our study is the isolation of C. auris from 10 cases (11%), ranking it the fourth most predominant isolate among all candidemia cases. This finding agrees with another recent study from a tertiary-care hospital in New Delhi where C. auris is the most common isolate, responsible for 39.9% cases. ^{Reference Shastri and Shankarnarayan22} In the study by Rudramurthy et al ^{Reference Rudramurthy, Chakrabarti and Paul9} involving 27 ICUs across India, 74 isolates of C. auris were reported, making it the fifth most common cause of candidemia. ^{Reference Rudramurthy, Chakrabarti and Paul9} The emergence of this fungus is very concerning because it spreads in the hospital rapidly, it is resistant to multiple classes of antifungals, and it causes severe infections in critically ill patients. Another major issue is that the commonly employed phenotypic commercial system cannot identify this fungus accurately. Accurate identification of this yeast is of paramount importance when formulating a therapeutic plan. We hypothesize that this misidentification by conventional techniques could be the reason why only few studies from India have reported C. auris. Nevertheless, there is a need for clinicians to be aware of and prepared for any potential outbreak by this multidrug-resistant fungus. Notably, infection control practices are firmly in place and this situation is closely monitored in our hospital.

With wider and inappropriate use of antifungal drugs, antifungal resistance is likely to continue to increase. This trend will increase treatment costs in resource-poor countries like ours, where healthcare infrastructure is already strained. In our study, although NAC isolates were more resistant to antifungals than was C. albicans, the difference was statistically significant only for amphotericin B (P = .03). Similar findings have been reported in another study from northeastern India by Sabhapandit D et al. ^{Reference Sabhapandit, Lyngdoh, Bora, Prasad, Debnath and Elantamilan23}

Resistance to fluconazole has been observed in 38% of isolates, with NACs being more resistant than C. albicans (36% vs 2%). This finding is of concern because alternative drugs like echinocandins or amphotericin B are more expensive. Kothari et al ^{Reference Kothari and Sagar24} from New Delhi have also reported 36% fluconazole resistance in candidemia isolates. Similar levels of resistance have been reported by other researchers as well. ^{Reference Giri, Kindo and Kalyani16,Reference Adhikary and Joshi20,Reference Gupta, Mittal, Sood, Kumar, Kaur and Mathur25,Reference Verma, Vyas, Sharma and Maheshwari26} Resistance to amphotericin B has been observed in 10.5% isolates. Similar rates of resistance have been reported in other contemporary studies as well. ^{Reference Sabhapandit, Lyngdoh, Bora, Prasad, Debnath and Elantamilan23,Reference Verma, Vyas, Sharma and Maheshwari26} Resistance to amphotericin B was significantly high in NAC isolates in our study.

A ray of hope is that no echinocandin resistance has been observed in our study isolates. Among all antifungals, echinocandins are considered superior because of their broad spectrum of action and fewer side effects. Their high cost and limited availability, however, do not make them an easy choice for resource-constrained countries. Few studies have reported resistance to echinocandins ^{Reference Kaur, Singh and Rudramurthy19} ; hence, they may be considered the drug of choice for azole-resistant isolates.

Among the 95 Candida isolates in our study, resistance to 5-FC was observed in only 4.21%. A wide variation in resistance pattern for 5-FC from various studies in India has been reported, ranging from 11.46% to 37%. ^{Reference Bhatt, Sarangi and Paty12,Reference Vinodkumar, Umakanth, Kalapanavar and Basavarajappa27} This pattern is probably related to difference in usage of this antifungal agent in different settings. Resistance to 5-FC is less likely to develop if it is used in combination with other antifungal drugs.

Amongst the C. auris strains (n = 10), resistance to fluconazole, voriconazole, amphotericin B and 5-FC was observedin 94%, 35%, 35% and 8% isolates respectively (Fig. 3). No resistance was noted for echinocandins. A multicenter study by Chowdhary et al ^{Reference Chowdhary, Prakash and Sharma28} has highlighted ∼90% azole resistance in C. auris isolates. ^{Reference Chowdhary, Prakash and Sharma28} A recent study by Shastri et al ^{Reference Shastri and Shankarnarayan22} also reports ∼97% fluconazole resistance in C. auris isolates. ^{Reference Shastri and Shankarnarayan22}

The study had several limitations. First, the retrospective design of study may have prevented us from identifying all risk factors related to candidemia cases. With the onset of the current coronavirus 2019 (COVID-19) pandemic, the institute was converted into a designated COVID-19 care center. Maximum resources were diverted towards catering to the needs of COVID-19 patients. Therefore, this data may be a slight under representation especially in later one-thirdpart of study period. Nevertheless, our results provide clear insight into the prevalence, epidemiology, and antifungal susceptibility pattern of candidemia in our setting during contemporary times.

Candidemia continues to be a considerable cause of morbidity and mortality. The shift in epidemiology and increasing resistance to antifungals emphasize the need for constant monitoring of these cases. The clinical importance of species-level identification of etiological agents of candidemia cannot be overemphasized. C. auris is an emerging fungal pathogen, and the medical community needs to be on high alert regarding this yeast. The insights obtained from this study will be helpful in guiding clinical management and developing antifungal stewardship guidelines.