Candidemia is a growing problem in hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%. We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstream infections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7% of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the reference laboratory for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64% SDD. All of them were susceptible to anidulafungin and amphotericin B. We observed that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil.
Mortality rates remain increasingly higher than that observed in the Northern Hemisphere countries, emphasizing the need for improving local practices of clinical management of candidemia, including early diagnosis, source control and precise antifungal therapy.
Citation: Doi AM, Pignatari ACC, Edmond MB, Marra AR, Camargo LFA, Siqueira RA, et al. (2016) Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program. PLoS ONE 11(1): e0146909. doi:10.1371/journal.pone.0146909
Editor: Anuradha Chowdhary, V.P.Chest Institute, INDIA
Received: May 1, 2015; Accepted: December 23, 2015; Published: January 25, 2016
Copyright: © 2016 Doi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: The study was funded in part by an independent medical grant provided by Pfizer, Inc. Great part was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2010/13533-9. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The study was funded in part by an independent medical grant provided by Pfizer, Inc. This does not alter the author's adherence to all the PLOS ONE policies on sharing data and materials.
Candidemia is a growing problem in tertiary care hospitals all over the world. It is a cause of late sepsis and risk factors include broad-spectrum antibiotic therapy, ICU stay for more than 72 hours, immunosuppressive therapy, parenteral nutrition, and multiple invasive medical procedures [1,2,3,4]. A recent study conducted in 183 US medical centers showed that Candida ranked as the most common cause of bloodstream infections .
Despite advances in the medical support of critically ill patients, hematogenous candidiasis is still considered difficult to diagnose, leads to prolonged hospitalization, has a mortality rate of around 50% and is a financial burden to health care systems [2,6,7].
The incidence of candidemia may vary substantially from region to region, but numbers appears to be stable or increasing in most series [7–11]. Although C. albicans is still considered the major pathogen associated with candidemia, infections due to non-albicans species are increasing and may present resistance to some antifungal agents [1,12–18].
Recent studies have documented increasing rates of fluconazole and echinocandin resistance in the US and European countries [18–20]. Indeed, in addition to C. glabrata and C. krusei, fluconazole resistance has also been documented among C. tropicalis and C. parapsilosis strains in different regions [15,20–22].
The epidemiology of candidemia has been extensively studied in the United States and Europe, but not in Latin America, and there is a lack of data on echinocandin resistance in Latin America [5,6,13]. Recently, Bizerra et al  published the first case of echinocandin resistance in Brazil illustrating the relevance of conducting continuous surveillance activities to identify changes in incidence rates, susceptible populations, etiologic agents, and antifungal resistance in our region.
We conducted a multicenter surveillance study in 16 hospitals geographically distributed across five regions of Brazil to assess the incidence, species distribution, frequency of antifungal resistance, and risk factors for bloodstream infections due to Candida species.
Materials and Methods
Brazilian Surveillance and Control of Pathogens of Epidemiologic Importance (BrSCOPE), involved 16 participating public and private hospitals throughout the five regions in Brazil (North, Northeast, Middle-East, Southeast and South). The study was approved by the Institutional Review Board (IRB) at each participating site and it was submitted to the final approval of the IRB from Universidade Federal de Sao Paulo. The requirements for informed consent was waived by the IRB of Universidade Federal de Sao Paulo in accordance with the Code of Federal Regulations and Privacy Rule.
The participating centers in this study were: Hospital Israelita Albert Einstein, Universidade Federal de Sao Paulo (UNIFESP), Hospital 9 de Julho, Santa Casa de Porto Alegre, Hospital Conceição, Hospital de Base de Brasiília, Hospital Walter Cantidio, Hospital de Diadema, Instituto de Oncologia Pediatrica-IOP/GRAAC, Santa Casa do Pará, Hospital Espanhol, de Salvador, Hospital do Coração de Natal, Hospital da UNIMED de Natal, Hospital das Clinicas de Goiânia, Hospital do Rim e Hipertensão and Universidade Federal do Triangulo Mineiro.
The Brazilian SCOPE (BrSCOPE) was a surveillance project based at Universidade Federal de São Paulo Brazil that included 16 hospitals geographically distributed across five regions of Brazil. Clinical data and microbiological features of the first episode of nosocomial bloodstream infection from 12 June 2007 to 31 March 2010 were collected and analyzed.
A nosocomial BSI was diagnosed if 1 or more cultures of blood sampled at least 48 h after admission yielded a pathogenic organism. If the bloodstream isolate was a potential skin contaminant (e.g., diphtheroid, Propionibacterium spp., Bacillus spp., coagulase-negative staphylococci, or micrococci), the presence of an intravascular catheter and the initiation of targeted antimicrobial therapy were required for the diagnosis, as well as at least 1 of the following findings: temperature of >38.0°C or <36°C, chills, and/or systolic blood pressure of <90 mm Hg. BSI episodes that represented relapses were excluded . In this study, we are only analyzing the infections due to Candida spp.
Clinical data were concurrently collected by local infection control practitioners using a standardized case report form and forwarded to the coordinating center, along with all eligible episodes of BSI caused by yeasts. The data that were routinely collected included the patient’s gender, location at the onset of BSI (ICU versus non-ICU ward), clinical service at the onset of BSI, and predisposing clinical conditions, as well as the identifications and antimicrobial susceptibilities of the causative pathogens and status at discharge. Predisposing clinical conditions that were routinely recorded included neutropenia (defined as an absolute neutrophil count of <1,000/mL), peritoneal dialysis or hemodialysis, and presence of intravascular catheters (i.e., central lines, arterial catheters, or peripheral intravenous catheters).
Blood cultures were processed at the participating hospitals using automated systems. The identification of blood isolates was performed by routine methods in use at the affiliated laboratories as API-ID32 (Biomerieux, Marcy l’Étoile France) or automated systems (Vitek 2 Biomerieux). All affiliated laboratories were Brazilian Society of Clinical Pathologists certified, and all microbiological methods used were consistent with current Clinical and Laboratory Standards Institute (CLSI) recommendations. The yeast isolates were sent to the reference laboratory, the Special Laboratory of Mycology at Universidade Federal de São Paulo, for confirmation of species identification and antifungal susceptibility testing.
All identifications were confirmed by MALDI-TOF using the Microflex LT (Bruker Daltonics, Bremen Germany) and the software Biotyper 3.0. according to the manufacturer’s recommendations. Antifungal susceptibility testing was performed using the broth microdilution method according to CLSI document M27-A3, using current CLSI MIC interpretative criteria (CLSI, M27-S4) [24,25]. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were used as quality controls.
The antimicrobial agents tested were all provided by the manufacturers as pure powder for analysis: fluconazole (Pfizer Incorporated, New York, NY, USA), voriconazole (Pfizer Incorporated, New York, NY, USA), anidulafungin (Pfizer Incorporated, New York, NY, USA) and amphotericin B (Sigma-Aldrich, St Louis, MO, USA).
Statistical analysis. Distribution Analysis of continuous variables with median and mean determinations was performed. Differences in proportions were compared using a chi- square test or Fisher’s exact test, as appropriate. All tests of significance were 2 tailed; p-value was set at 0.05. All statistical analyses were done using SPSS software (SPSS version 21).
From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes with 2,688 microorganisms reported by the 16 participant centers. Candida spp. was the 7th most prevalent agent, accounting for 137 monomicrobial BSIs and one polymicrobial BSI.
Characteristics of the 137 patients with nBSIs caused by Candida spp. at the 16 Brazilian hospitals are demonstrated in Table 1. Most of the patients were male, with a median age of 56 years. Most of patients needed intensive care support (64.2%) and 46.7% were in the ICU when candidemia occurred.
Concerning predisposing factors, 68 patients (49.6%) were mechanically ventilated, 8 were receiving hemodialysis and 121 (88.3%) had central venous catheters at the time of the diagnosis of candidemia.
The mean time between admission and first nBSI caused by Candida spp. was 29 days.
Malignancies were the most common underlying condition, but neutropenia was rare (<1%).
The crude mortality of candidemia patients during the hospital admission was 72% (53% for non-ICU and 85% for ICU patients (p<0,01), Table 2.
Of the 137 Candida isolates causing monomicrobial nBSI, non-albicans species accounted for 65.7%. The rank order of the major Candida spp. isolated was C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%), Candida glabrata (10.2%), Candida krusei (1.5%), Candida pelliculosa (1.5%), Candida lusitaniae (0.7%), Candida famata (0.7%), and Candida guilliermondii (0.7%).
Only 47 out of 137 Candida isolates were sent to the reference laboratory (LEMI) for further confirmation of species and antifungal susceptibility testing.
The identification at species level was correct for all isolates tested by the sentinel centers and 6 strains initially identified as Candida spp. were determined to be C. tropicalis (4), C. glabrata (1) and C. albicans (1). Consequently, C. tropicalis accounted for 18% of all 137 candidemia episodes.
The 36 C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 4 antifungal drugs tested.
Among 11 C. glabrata isolates, 4 isolates were resistant to fluconazole, and 7 fluconazole susceptible dose-dependent (SDD). All were susceptible to anidulafungin and amphotericin-B (see Table 3).
Few multicenter studies have been published in Brazil addressing the incidence of candidemia, susceptible populations, crude mortality rates, etiology and rates of in vitro antifungal resistance [10,11,26,27].
In our series, Candida spp. was the 7th most prevalent cause (5.6%) of nosocomial bloodstream infection among all pathogens studied in SCOPE Brazil where 137 monomicrobial Candida nBSI were characterized .
It is important to emphasize that the incidence of candidemia is probably underestimated in the present study considering that: 1) we excluded putative patients who could develop candidemia after bacteremia since we have evaluated only the first episode of bloodstream infection reported after hospital admission and 2) automated blood culture is far more sensitive for the detection of bacteremia than fungemia.
It is also important to highlight that we included in this study a total of 16 tertiary care hospitals serving high complexity patients with good clinical practices for treating septic patients, including the collection of blood cultures for all patients with suspicion of sepsis. In addition, according to the SCOPE study methodology, all investigators were asked to select for the study only the first episode of nosocomial BSI. Therefore, subsequent episodes of BSIs were not considered. Consequently, it is expected that a substantial number of patients that could further develop candidemia after bacteremia were censored. This could explain the low number of blood cultures recorded per year.
A similar epidemiologic study, SCOPE USA, revealed that Candida spp. were the 4th most prevalent agent (4% of the total) . Data recently reported by a national point prevalence survey conducted in 183 centers in the US revealed that Candida has become the most common microorganism causing BSI. This finding is probably related to the substantial reduction of primary bacteremia due to implementation of bundles to reduce BSI .
Another multicenter study showed that C. glabrata is now emerging as a relevant pathogen in Brazil, accounting for 10% of all episodes.  Corroborating this finding, C. glabrata accounted for 10% of all candidemia episodes in the present series. Otherwise, C. tropicalis and C. parapsilosis strains remain the non-albicans Candida species more prevalent among candidemia episodes. [6,12,15]
Of note, differently from series in the US and Europe, C. tropicalis was highly prevalent also among non-cancer patients. This finding had already been noted in previous series published in our region [2,8,11].
The reasons for the emergence of non-albicans species are not completely understood, but some risk factors may include the presence of central vascular catheters, total parenteral nutrition, cancer, neutropenia and antifungal selective pressure [4,11,29].
As reported in previous Brazilian series [10,11,13], cancer was the most common underlying condition followed by gastrointestinal and neurologic diseases. Vascular catheters were the most important risk factors in our patients]. ICU admissions at the onset of candidemia was 46.7%, a rate that is also similar to other series. In this scenario, discrepancies of mortality documented in the present series in contrast to previous publications may be partially explained by differences in the median ages of the populations evaluated. The median age of the patients in our study was 56 years, higher than that reported by Nucci et al and Colombo et al, (41 and 36 years old, respectively [2,13].
Indeed, according to other published series, mortality rates of candidemia in Brazil are very high, usually exceeding 50% [2,11]. Several factors may explain this phenomenon including: severity of underlying conditions (32.1% had malignancy as the principal underlying condition), high APACHE score at the time of diagnosis (47% patients requiring ICU care at the onset of candidemia), late diagnosis of fungemia, and suboptimal management of candidemia by the clinical staff.
In addition, we cannot exclude the possibility that the diagnosis was made at a late stage of disease when patients are less likely to respond to antifungal therapy. Another hypothesis to be considered is the suboptimal treatment of sepsis by Candida either by the overuse of fluconazole in critically ill patients instead of echinocandins, as well inadequate source control of the fungal infection. 
Considering our hypothesis that higher mortality rates could be partially related to the aging of the susceptible population, in the present series only 16% of the patients were under 12 years old, a finding that is completely differently from other multicenter series published in which 32% (Colombo et al) and 40% (Nucci et al) of candidemic patients were children [8,11].
Regarding the rate of antifungal resistance, we were able to test only 47 of 137 isolates. Despite this limitation, our data is consistent with previous Brazilian series where fluconazole resistance is basically confined to C. glabrata and C. krusei strains. Finally, Candida resistance to echinocandins and amphotericin B remains rare in Brazil and Latin America [11–13].
In summary, we observed that Candida spp. is one of the most important pathogens causing nosocomial BSI where C. glabrata is emerging as a major player among non-albicans Candida spp, a reality different than we observed a decade earlier.
Mortality rates remain higher than that observed in the Northern Hemisphere countries, emphasizing the importance of early diagnosis, appropriate control of the infectious source, and appropriate antifungal therapy.
The members of the Brazilian SCOPE Study Group are: Fabiane Carlesse (Instituto de Oncologia Pediatrica), Soraya Andrade (Universidade Federal de São Paulo (UNIFESP)), Marinês Dalla Vale Martino (Hospital Israelita Albert Einstein), Antônia Maria de Oliveira Machado (Universidade Federal de São Paulo (UNIFESP)), Paulo Bispo (Universidade Federal de São Paulo (UNIFESP)), Sérgio Barsanti Wey (Universidade Federal de São Paulo (UNIFESP)), Rodrigo Molina (Universidade Federal do Triangulo Mineiro), Luciana Scheidt Puga (Hospital Conceição), Gabriela Medeiros Dantas (Hospital da UNIMED), Andrea Moura (Santa Casa do Pará).
Conceived and designed the experiments: AMD RAS ACCP ALC. Performed the experiments: AMD RAS. Analyzed the data: AMD RAS ARM ACCP ALC. Contributed reagents/materials/analysis tools: AMD RAS ARM ACCP ALC. Wrote the paper: AMD ACCP MBE ARM LFAC RAS VPM ALC.
- 1. Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Meis JF, Gould IM, et al. Global Antifungal Surveillance Study. Results from the ARTEMIS DISK Global Antifungal Surveillance study, 1997 to 2005: an 8.5-year analysis of susceptibilities of Candida species and other yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol. 2007; 45(6): 1735–45.
- 2. Colombo AL, Guimarães T, Sukienik T, Pasqualotto AC, Andreotti R, Queiroz-Telles F, et al. Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter centers sequentially conducted over a 9-year Period. M. Intensive Care Med. 2014; 40(10): 1489–98
- 3. Ahmed A, Azim A, Baronia AK, Marak KRSK, Gurjar M. Risk prediction for invasive candidiasis. Indian J Crit Care Med. 2014; 18(10): 682–688.
- 4. Delaloye J, Calandra T. Invasive candidiasis as a cause of sepsis in the critically ill patient. Virulence. 2014; 5(1):161–9. doi: 10.4161/viru.26187. pmid:24157707
- 5. Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Emerging infections program healthcare-associated infections and antimicrobial use prevalence survey team. 2014 Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 370(13):1198–208. doi: 10.1056/NEJMoa1306801. pmid:24670166
- 6. Lortholary O, Renaudat C, Sitbon K, Madec Y, Denoeud-Ndam L, Wolff M, et al. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med. 2014; 40(9): 1303–12. doi: 10.1007/s00134-014-3408-3. pmid:25097069
- 7. Bassetti M, Righi E, Ansaldi F, Merelli M, Trucchi C, De Pascale G, et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med. 2014; 40(6):839–45. doi: 10.1007/s00134-014-3310-z. pmid:24807083
- 8. Nucci M, Queiroz-Telles F, Alvarado-Matute T, Tiraboschi IN, Cortes J, Zurita J, et al. Epidemiology of candidemia in Latin America: a laboratory-based survey. PLOS One 2013; 8(3):e59373. doi: 10.1371/journal.pone.0059373. pmid:23527176
- 9. Chen PY, Chuang YC, Wang JT, Sheng WH, Yu CJ, Che CC, et al. Comparison of epidemiology and treatment outcome of patients with candidemia at a teaching hospital in Northern Taiwan, in 2002 and 2010. J Microbiol Immunol Infect. 2014; 47(2):95–103. doi: 10.1016/j.jmii.2012.08.025. pmid:23063082
- 10. Wille MP, Guimarães T, Furtado GHC, Colombo AL. Historical trends in the epidemiology of candidemia: analysis of an 11-year period in a tertiary care hospital in Brazil. Mem Inst Oswaldo Cruz, Rio de Janeiro. 2013; 108(3): 288–292.
- 11. Colombo AL, Nucci M, Park BJ, Nouér SA, Arthington-Skaggs B, da Matta DA, et al. Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in eleven medical centers. J Clin Microbiol. 2006; 44(8): 2816–23. pmid:16891497
- 12. Colombo AL, Garnica M, Aranha Camargo LF, Da Cunha CA, Bandeira AC, Borghi D, et al. Candida glabrata: an emerging pathogen in Brazilian tertiary care hospitals. Med Mycol. 2013; 51(1):38–44. doi: 10.3109/13693786.2012.698024. pmid:22762208
- 13. Nucci M, Queiroz-Telles F, Tobon AM, Restrepo A, Colombo AL. Epidemiology of opportunistic fungal infections in Latin America. Clin. Infect. Dis. 2010; 51: 561–570). doi: 10.1086/655683. pmid:20658942
- 14. Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S. The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis. 1997; 24:1122–1128. pmid:9195068
- 15. Pfaller MA, Andes DR, Diekema DJ, Horn DL, Reboli AC, Rotstein C, et al. Epidemiology and Outcomes of Invasive Candidiasis Due to Non-albicans Species of Candida in 2,496 Patients: Data from the Prospective Antifungal Therapy (PATH) Registry 2004–2008. 2014; PLOS ONE 9(7): e101510. doi: 10.1371/journal.pone.0101510. pmid:24991967
- 16. Chowdhary A, Kumar VA, Sharma C, Prakash A, Agarwal K, Dinesh KR, et al. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur J Clin Microbiol Infect Dis. 2014; 33:919–926. doi: 10.1007/s10096-013-2027-1. pmid:24357342
- 17. Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN. Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008–2009). Diagn Microbiol Infect Dis. 2010; 68(3):278–83. doi: 10.1016/j.diagmicrobio.2010.06.015. pmid:20846808
- 18. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Monzon A, Buitrago MJ, Rodriguez-Tudela JL. Activity profile in vitro of micafungin against Spanish clinical isolates of common and emerging species of yeasts and molds. Antimicrob Agents Chemother 2009; 53(1):2192–2195.
- 19. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009). J. Clin. Microbiol. 2011; 49:396–399. doi: 10.1128/JCM.01398-10. pmid:21068282
- 20. Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis. 2014; 27(6): 484–92. doi: 10.1097/QCO.0000000000000111. pmid:25304391
- 21. Souza AC, Fuchs BB, Pinhati HM, Siqueira RA, Hagen F, Meis JF, et al. Candida parapsilosis Resistance to fluconazole: molecular mechanisms and in vitro impact in infected Galleria mellonella larvae. Antimicrob Agents Chemother. 2015; 59(10):6581–7. doi: 10.1128/AAC.01177-15. pmid:26259795
- 22. Castanheira M, Messer SA, Jones RN, Farrell DJ, Pfaller MA. Activity of echinocandins and triazoles against a contemporary (2012) worldwide collection of yeast and moulds collected from invasive infections. Int J Antimicrob Agents. 2014; 44(4):320–6.
- 23. Bizerra FC, Jimenez-Ortigosa C, Souza ACR, Breda GL, Queiroz-Telles F, Perlin DS, et al. Breakthrough Candidemia Due to Multidrug-Resistant Candida glabrata during Prophylaxis with a Low Dose of Micafungin. Antimicrob. Agents Chemother. 2014; 58(4):2438–40. doi: 10.1128/AAC.02189-13. pmid:24468776
- 24. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard 3rd ed. CLSI document M27-A3. 2008; Clinical and Laboratory Standards Institute, Wayne, PA.
- 25. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts; fourth informational supplement. CLSI document M27-S4. 2012; Clinical and Laboratory Standards Institute, Wayne, PA.
- 26. Marra AR, Camargo LFA, Pignatari ACC, Sukiennik T, Behar PRP, Medeiros EAS, et al. Nosocomial Bloodstream Infections in Brazilian Hospitals: Analysis of 2,563 Cases from a Prospective Nationwide Surveillance Study. J Clin Microbiol. 2011; 49(5): 1866–1871. doi: 10.1128/JCM.00376-11. pmid:21411591
- 27. Brito LR, Guimaraes T, Nucci M, Rosas RC, Paula Almeida L, Da Matta DA, et al. Clinical and microbiological aspects of candidemia due to Candida parapsilosis in Brazilian tertiary care hospitals. Med Mycol. 2006; 44:261–266. pmid:16702106
- 28. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial Bloodstream Infections in US Hospitals: Analysis of 24,179 Cases from a Prospective Nationwide Surveillance Study. Clin Infect Dis. 2004; 39(3): 309–317. pmid:15306996
- 29. Kullberg BJ, Arendrup MC. Invasive Candidiasis. N Engl J Med. 2015; 373;15
- 30. Wisplinghoff H, Ebbers J, Geurtz L, Stefanik D, Major Y, Edmond MB, et al. Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities. Int J Antimicrob Agents 2014; 43:78–81. doi: 10.1016/j.ijantimicag.2013.09.005. pmid:24182454
- 31. Nucci M, Thompson-Moya LO, Guzman-Blanco M, Tiraboschi IN, Cortes JA, Echevarria J, et al. Recommendations for the management of candidemia in adults in Latin America. Latin America Mycosis Network. Rev Iberoam Micol. 2013; 30(3):179–88.