Introduction
Fungi have emerged as an important cause of health-care associated infections (HCAI) in last few decades.1 Factors responsible for the dramatic rise of HCAI mycotic infections include aging populations, advancement in medical technologies, malignancies, intensive myeloablative and antibiotic therapies, ICU stay and solid organ and hematopoietic stem cell transplantation.1
Mycotic HCAI are mostly attributed to Candida spp, Aspergillus spp, Fusarium spp. and Scedosporium spp.2 Candida spp. is the most common cause of invasive fungal infections (IFI) in hospitalized individuals.3 As per National Nosocomial Infection Survey (NNIS), Candida spp. is the fourth most common cause of health-care associated bloodstream infections.1
In an ICU setting, Candida spp. accounts for nearly 10% of all bloodstream infections (BSI) and 25% of all urinary tract infections (UTIs).4 In the United States, Candida spp. is 3rd or 4th common cause of HCAI, surpassing all Gram-negative bacilli.5 Nosocomial Candida infections are usually treatment resistant and are associated with prolonged hospitalization and increased healthcare-cost.4
In recent years, many research studies on Candida infections, have documented a progressive shift from C. albicans to treatment resistant non albicans Candida (NAC) spp.6 As compared to western countries, there is dearth of information regarding health-care associated Candida infection from India. There fore the present study was conducted in a tertiary care teaching hospital with an aim to study species distribution and antifungal susceptibility pattern of Candida isolates from cases of HCAI.
Material and Methods
Study setting
The present study is a part of a Ph.D. thesis carried out in the Department of Microbiology, at Maharao Bhimsingh Hospital, Nayapura, which is affiliated with Government Medical College, Kota, Rajasthan.
Study design and duration
Descriptive cross-sectional study was conducted for a period of one year. Candida isolates from cases of HCAI from medical intensive care unit (MICU) were included. The demographical and clinical features of the patients suspected for HCAI were recorded and analyzed. The protocol of the study was approved by Institutional Ethics Committee.
Species identification and antifungal susceptibility testing
Candida isolates were identified upto species by standard mycological protocol including germ tube test, carbohydrate assimilation test, colony color on HiChrom Candida agar and HiCandida identification Kit. HiChrom Candida agar and HiCandida identification Kit were procured from Himedia Laboratories Pvt Ltd Mumbai.
Antifungal susceptibility testing of Candida isolate was done by Clinical and Laboratory Standard Institute (CLSI) broth microdilution (BMD) method. It testing was performed exactly as outlined in document M27-A3.7 The minimum inhibitory concentration (MIC) of Candida spp was detected for antifungal drugs like amphotericin B, fluconazole, itraconazole and voriconazole. The antifungal drugs were procured from Himedia Laboratories Pvt Ltd Mumbai as a pure standard compound.
MIC values were determined as the lowest concentration of antifungal drug that showed complete inhibition (amphotericin B) or a significant diminution (≥50% inhibition; azoles) of growth compared to the growth of control strain. C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 were used as control strains.
Results
During the study period, a total of 14883 patients were admitted to MICU. Out of these 11197 (75.2%) were having various indwelling medical devices for more than 48 hrs. Urinary catheter was present in 10631 (94.9%) patients. A total of 1384 (12.4%) patients were having central lines whereas 902 (8.1%) patients were on ventilatory support. The month and invasive device wise distribution of patients is shown in Figure 1.
Out of 894 patients with indwelling urinary catheter, a total of 61 developed catheter associated urinary tract infection (CA-UTI) (Table 1). The rate of CA-UTI was 1.3 per 1000 catheter days. Bacterial pathogens were isolated from 45(73.8%) cases whereas Candida was isolated from 16 (26.2%) patients of CA-UTI. The rate of CA-UTI due Candida spp. was 0.3 per 1000 catheter associated days. C. albicans were isolated from 5 cases whereas 11 isolates belonged non albicans Candida spp. (NAC). C. tropicalis was the predominant isolate from NAC spp (Table 2).
A total of 12 (0.9%) patients out of 1384 patients on central line developed catheter related blood stream infection (CR-BSI). The rate of CR-BSI was 2.3 per 1000 catheter associated days (Table 1). Bacterial pathogens were isolated from 7 (58.4%) cases whereas Candida spp. were isolated from 5 (41.6%) patients. The rate of catheter related Candida BSI was 0.9 per 1000 catheter associated days. C. albicans was isolated from 2 (40%) cases whereas C. tropicalis was isolated from 3 (60%) cases of CR-BSI (Table 2).
Ventilator associated pneumonia (VAP) was developed in a total of 9 (0.9%) patients out of 902 on mechanical ventilator support (Table 1). The rate of VAP was 2.3 per 1000 ventilator associated days. All cases of VAP were due to bacterial pathogens (Table 2). In the present study predominance of NAC spp. over C. albicans was noted.
Table 1
Rate of health-care associated infections
Table 2
Pathogens isolated from health-care associated infection
The antifungal susceptibility profile of Candida spp. isolated from HCAI like CAUTI and CR-BSI is shown in Table 3. Fluconazole resistance was significantly high in NAC spp. compared to C. albicans (Chi-square test, P value 0.0001).
All C. krusei isolates were resistant to fluconazole. A total of 20% of C. tropicalis were resistant to fluconazole. Resistance to itraconazole, voriconazole and amphotericin B was not observed in C. albicans. Amphotericin B resistance was observed in 20% of C. tropicalis.
Table 3
Antifungal susceptibility profile of Candida spp.
Discussion
In an any health-care setup, infections are the most common adverse iatrogenic event affecting the safety of the patient. As per definition, healthcare associated infections (HCAI) are infections that are acquired by the patient during the process of receiving health care. These infections are neither present nor incubating at the time of admission to the health-care setup.4 According to the World Health Organisation (WHO), at an any given point of time, more than 1.4 million people worldwide suffer from HCAI and incidence of HCAI is anywhere between 10 to 30%.
Admission to ICU is considered as an important risk factor for acquisition of HCAI. HCAI can lead to complications in 25-50% of patients admitted to ICU.4 In general, ICUs have been described as a factory for creating and disseminating HCAI due to their extremely vulnerable population of seriously ill patients, heavy use of medical devices and invasive procedures, and the frequent usage of broad-spectrum antimicrobials. Indwelling medical devices are cornerstone in management of patients admitted to ICUs.8 In the present study, out a total of 14883 patients admitted to MICU, a total of 11197 (75.2%) were having one or more indwelling medical devices for more than 48 hrs.
In recent years, the upsurge in HCAI, specifically medical device associated infections due to Candida spp., is noted. In the present study, a total of 16 Candida spp., were isolated from cases of CA-UTI. The rate of CA-UTI due Candida spp. was 0.3 per 1000 catheter associated days. Presence of indwelling catheter is one of the important risk factors for candiduria. In the study of Deorukhkar et al. (2016) the rate of CA-UTI due Candida spp. was 1 per 1000 catheter associated days.4
Out 16 Candida isolates from CA-UTI, 11 (68.7%) were NAC spp. As commented by Fisher (2011), the microbiology of candiduria is changing with >50% of isolates now belonging to NAC spp.9 It is considered that chemical composition and pH of urine selectively support the growth of NAC spp 10 As NAC spp. often demonstrated reduced susceptibility to routinely used antifungal drugs, they are difficult to eradicate from urinary tract. C. tropicalis (43.7%) was the predominant isolate from catheter associated candiduria cases. This observation is in accordance to that Jain et al. (2011) and Deorukhkar et al. (2016) who reported C. tropicalis as the predominant cause of candiduria in catheterized ICU patients.4, 11
Hospital acquired BSI are one of the major causes of morbidity and mortality in ICU patients. Iintravascular catheters are inserted in terminally ill patients for the administration of fluids, blood products, medications, nutritional solutions and for hemodynamic monitoring.8 However at times they may act as a source of infections. CR-BSI often originates in emergency rooms and ICU.8 Various researchers have reported, rates of CR-BSI ranging from 2.9 to 11.3 per 1000 catheter days.4 These rates vary as per the types of ICUs and the patient population studied. The prevalence of nosocomial Candida BSI is higher in United States compared to European countries.4 However, the exact prevalence of nosocomial Candida BSI is largely unknown in India. The present study, rate of CR-BSI due to Candida spp. was 0.9 per 1000 catheter associated days.
A total of 05 Candida spp. were isolated from CR-BSI, these included 02 isolates of C. albicans and 03 isolates of C. tropicalis. Many Indian researchers have reported, C. tropicalis as the most common Candida isolate from BSI.4 C. tropicalis is mostly commonly isolated from ICU patients with prolonged indwelling catheters on broad-spectrum antibiotic therapy. Malignancy is also an important risk factor for nosocomial BSI due to C. tropicalis.12
VAP is one of the important complications in ICU patients. Approximately 8-28% patients on mechanical ventilator support suffer from VAP.4 In the present study, VAP was due to bacterial pathogen. No Candida spp. was isolated from VAP cases.4 Other researchers reported similar findings. K. pneumoniae was the predominant isolate from VAP cases.
In the present study, the MIC of Candida spp., was determined by CLSI reference BMD method. The CLSI BMD is internationally recognized standard methodology for antifungal susceptibility testing of Candida spp.7 Azole resistance was significantly high in NAC spp. compared to C. albicans. In contrast to C. albicans, antifungal susceptibility varies significantly in NAC spp. Certain NAC spp. are intrinsically resistant to azoles whereas few can acquire resistance during course of treatment.13 The finding of present study, highlights the importance of antifungal susceptibility in selection of appropriate antifungal drug. It also supports the fact that practice of empirical fluconazole therapy should be stopped or should be limited only in case of emergency. Resistance to amphotericin B was low in the present study.
Conclusion
Health-care associated infection (HCAI) is a significant threat to patient safety. Candida spp. has emerged as an important cause of HCAI particularly medical device associated infections like CA-UTI and CR-BSI. Species identification along with antifungal susceptibility testing plays an important role in selection of antifungal drug and prevention of treatment failure.
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