*3.4. Systemic Candidiasis*

It is recognized that DM predisposes one to systemic candidiasis for several factors [289]. Among these factors, the most important are the microvascular disease progression, the low host defense mechanisms, and the diabetic vasculopathy, which exacerbates hypoperfusion and hyperglycemia and may lead to neutrophil and lymphocyte dysfunction with impaired opsonization [11,42,290–322]. Catheter-associated candiduria is a common clinical finding in hospitalized patients, especially in intensive care units [295], and is intimately related to biofilms. Padawer et al. [295] studied demographic and clinical data at an Israeli hospital between 2011 and 2013 on the prevalence of *Candida* sp. in catheterized in-patients and the medical interventions provided to these patients. Their results showed that candiduria was observed in 146 catheterized in-patients out of the 1408 evaluated and was directly associated with DM. *C. albicans* was present in 69.1% of the subjects, followed by *C. parapsilosis* (9.58%), *C. krusei* (7.53%), *C. tropicalis* (6.16%), *C. glabrata* (4.79%), and other species (2.73%). DM was found to be a significant risk factor of infection by *Candida* sp. In another report, Padawer et al. [295] concluded that *Candida* sp. was the second leading pathogen causing catheter-associated urinary tract infections or asymptomatic colonization. Previously, Tambyah et al. [296], Makin and Tambyah [297], and Sievert et al. [298] found similar results.

Muskett et al. [299] performed a systematic review to identify the most prevalent risk factors, looking at published analyses, risk prediction models, and clinical decision rules for invasive fungal disease (IFD) in critically ill adult patients. The authors found studies that had a significant association of DM and IFD on both univariable and multivariable analyses. Paphitou and colleagues [300] established that patients with any combination of DM, new onset hemodialysis, use of total parenteral nutrition, or receipt of broad-spectrum antibiotics had an invasive candidiasis rate of 16.6% compared to a 5.1% rate in patients lacking these characteristics (*p* = 0.001). Also, Michalopuolos et al. [301], in a univariate regression analysis study between 1997 and 2002, confirmed that DM is a significant candidemia-associated factor and an independent candidemia predictor. *C. albicans* (70%), *C. parapsilosis* (10%), *C. glabrata* (6.7%), *C. tropicalis* (6.7%), and *C. krusei* (6.7%) were isolated in patients with candidemia. *C. albicans* was simultaneously isolated from blood (89.5%) and the central venous catheter tip. Among other factors, the authors found that DM was associated with a high 30-day mortality in candidemia. Candidemia due to *C. parapsilosis* was associated with high rates of survival [11], probably due to the fact that adherence and protein secretion do not correlate with strain pathogenicity in this species as opposed to the other *Candida* sp., as had been discussed [323]. Another retrospective study from 2007 to 2015 of candidemia in hospitalized adults was performed by Khatib et al. Most of the isolates (97.5%) were *C. albicans*. *C. glabrata* was more common in diabetics (52.9% vs. 32.0% in non-diabetics; *p* = 0.004) and in abdominal sources. The findings suggested possible species-related differences in colonization dynamics or pathogenicity [324].

Abad et al. [304] carried out a different study to investigate the susceptibilities of clinical fluconazole-resistant and fluconazole-susceptible dose-dependent to caspofungin of 207 *Candida* sp. in Iranian patients. Results showed that only 9.7% of the isolates were non-sensitive to caspofungin and that these isolates were observed in cancer, DM, and AIDS patients [304]. Wu et al. [305] investigated 238 candidemia hospitalized patients between 2009 and 2011 so as to study the incidence rates of candidemia and identify the differences in risk factors of patients with *C. albicans* and NCACs and with *C. guilliermondii* and non-*C. guilliermondii* candidemia. DM was identified as a significant risk factor in patients with candidemia due to *C. albicans* (35.2%) compared to candidemia related to NCACs (13.2%). Although *C. guilliermondii* is an uncommon cause of candidemia, even in immunocompromised hosts [306–311], it was also found to occur in a significant amount of the hospitalized patients. Over the three year period, the percentage of candidemia due to *C. albicans* decreased, while the percentage of candidemia due to *C. parapsilosis* and *C. guilliermondii* increased in more than 80% of all candidemia cases in 2011 [305].

*Candida* sp. bloodstream infections (CBSI) are the fourth leading cause of nosocomial bloodstream infections in the United States [316,318,325]. CBSIs occur in up to 10% of all bloodstream infections in hospitalized patients [313–315], and the mortality rate is about 40% [316,317]. Normally, this mortality is higher than in bloodstream infections involving bacteria [326,327]. Risk factors for CBSIs include critically ill patients in intensive care units, DM, immunosuppressive states, mechanical ventilation, neutropenia, recent surgical procedures, and prematurity [315,318,319]. In a study by Tumbarello and colleagues [328], it was found that DM is an independent predictor of biofilm-forming *Candida* sp. CBSIs. The use of total parenteral nutrition, hospital mortality, post-CBSI hospital length of stay (LOS), and the costs of antifungal therapy were all significantly greater among patients infected by biofilm-forming isolates when compared to those infected by non-biofilm-forming isolates. It was concluded that biofilm-forming CBSI was significantly related with a high risk of death compared to non-biofilm forming CBSI [328]. Corzo-Leon and colleagues [320] investigated the clinical and epidemiologic characteristics of patients with CBSI in two tertiary care reference medical institutions in Mexico City. Their results showed that CBSIs represented 3.8% of nosocomial bloodstream infections and *C. albicans* was the predominant species (46%), followed by *C. tropicalis* (26%). *C. glabrata* was isolated from 50% of patients with diabetes and elderly patients. Nucci et al. [321] published a paper reporting an incidence of 1.18 episodes of candidemia per 1000 admissions. *C. albicans*, *C. tropicalis*, and *C. parapsilosis* were isolated in 80% of cases and DM was also found in 11% of the total cases. Gupta et al. [322] reviewed the influence of *C. glabrata* candidemia in intensive care unit (ICU) patients between 2006 and 2010. Results showed that this species was the third most isolated, and DM was a risk factor among 50% of the total cases. Also, urine was the most common source of *C. glabrata* candidemia, while the overall mortality rate was 53.8% [322]. In another report, Wang et al. [42] observed no differences in the distribution of *Candida* sp. between elderly and young patients in China, but the resistance to fluconazole and voriconazole for NCAC in the first group was double the amount of the latter. Host-related risk factors included DM, mechanical ventilation, central vascular and urethral catheter placement, and were more common in elderly patients [42].
