Clinical and epidemiological aspects of Candidemia in eight medical centers in the state of Parana, Brazil: Parana Candidemia Network

Carla Sakuma de Oliveira Arnaldo Lopes Colombo Elaine Cristina Francisco Bernardo de Lima Rinaldo F. Gandra Mariza Cristina Preifz de Carvalho Cláudia Maria Dantas de Maia Carrilho Renan Petinelli Marsilene Pelison Cesar Helbel Gerson Czelusniak Hugo Manuel Paz Morales Jamile Sardi Perozin Rosangela Lameira Pinheiro Regielly Cognialli Giovanni Luis Breda Flávio Queiroz-Telles About the authors

ABSTRACT

Objectives:

Candida spp. has been reported as one of the common agents of nosocomial bloodstream infections and is associated with a high mortality. Therefore, this study evaluated the clinical findings, local epidemiology, and microbiological aspects of candidemia in eight tertiary medical centers in the state of Parana, South of Brazil.

Methods:

In this study, we reported 100 episodes of candidemia in patients admitted to eight different hospitals in five cities of the state of Parana, Brazil, using data collected locally (2016 and 2017) and tabulated online.

Results:

The incidence was found to be 2.7 / 1000 patients / day and 1.2 / 1000 admissions. C. albicans was responsible for 49% of all candidemia episodes. Cancer and surgery were the two most common underlying conditions associated with candidemia. The mortality rate within 30 days was 48%, and removal of the central venous catheter (p = 0.029) as well as empirical or prophylactic exposure to antifungals were both related to improved survival (p = 0.033).

Conclusions:

This study highlights the high burden and mortality rates of candidemia in hospitals from Parana as well as the need to enhance antifungal stewardship program in the enrolled medical centers.

Keywords:
Candida spp.; Epidemiology of candidemia; Antifungal resistance; Echinocandins; Triazoles; Nosocomial infection

Introduction

The incidence of invasive infections by opportunistic fungi has increased significantly in the past few decades. Candida albicans remains the most common species causing candidemia in Latin America11 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:e59373, http://dx.doi.org/10.1371/journal.pone.0059373. Epub 2013/03/26. PubMed PMID: 23527176; PubMed Central PMCID: PMCPMC3601956.
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and in Brazilian hospitals,22 Colombo AL, Nucci M, Park BJ, Nouer 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;44:2816-23, http://dx.doi.org/10.1128/JCM.00773-06. Epub 2006/08/08.PubMed PMID: 16891497; PubMed Central PMCID:PMCPMC1594610.
http://dx.doi.org/10.1128/JCM.00773-06...
,33 Colombo AL, Guimaraes T, Silva LR, de Almeida Monfardini LP, Cunha AK, Rady P, et al. Prospective observational study of candidemia in Sao Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality. Infect Control Hosp Epidemiol. 2007;28:570-6, http://dx.doi.org/10.1086/513615. Epub2007/04/28. PubMed PMID: 17464917.
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including in critically ill patients.44 Girao E, Levin AS, Basso M, Gobara S, Gomes LB, Medeiros EA, et al. Seven-year trend analysis of nosocomial candidemia and antifungal (fluconazole and caspofungin) use in Intensive Care Units at a Brazilian University Hospital. Med Mycol. 2008;46:581-8, http://dx.doi.org/10.1080/13693780802004996. Epub 2009/01/31. PubMed PMID: 19180727.
http://dx.doi.org/10.1080/13693780802004...
,55 Colombo AL, Guimaraes 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 studies sequentially conducted over a 9-year period. Intensive Care Med. 2014;40:1489-98, http://dx.doi.org/10.1007/s00134-014-3400-y. Epub 2014/08/02.PubMed PMID: 25082359; PubMed Central PMCID:PMCPMC4176831.
http://dx.doi.org/10.1007/s00134-014-340...
Incidence of candidemia in Brazil ranges between 2.0–5.4/10.000 patients/day.66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471.,77 Moretti ML, Trabasso P, Lyra L, Fagnani R, Resende MR, de Oliveira Cardoso LG, et al. Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil. Med Mycol. 2013;51:225-30, http://dx.doi.org/10.3109/13693786.2012.708107. Epub2012/08/28. PubMed PMID: 22920712.
http://dx.doi.org/10.3109/13693786.2012....
In our region, mortality rates of candidemia remain very high compared to those of northern hemisphere countries. In fact, crude mortality rates of candidemia in critically ill patients admitted to intensive care units is approximately 70%.33 Colombo AL, Guimaraes T, Silva LR, de Almeida Monfardini LP, Cunha AK, Rady P, et al. Prospective observational study of candidemia in Sao Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality. Infect Control Hosp Epidemiol. 2007;28:570-6, http://dx.doi.org/10.1086/513615. Epub2007/04/28. PubMed PMID: 17464917.
http://dx.doi.org/10.1086/513615...
,44 Girao E, Levin AS, Basso M, Gobara S, Gomes LB, Medeiros EA, et al. Seven-year trend analysis of nosocomial candidemia and antifungal (fluconazole and caspofungin) use in Intensive Care Units at a Brazilian University Hospital. Med Mycol. 2008;46:581-8, http://dx.doi.org/10.1080/13693780802004996. Epub 2009/01/31. PubMed PMID: 19180727.
http://dx.doi.org/10.1080/13693780802004...
An increasing incidence of infections caused by Candida non-albicans, especially C. tropicalis, C. parapsilosis, and C. glabrata, has been reported in Latin America88 da Matta DA, Souza ACR, Colombo AL. Revisiting species distribution and antifungal susceptibility of Candida bloodstream isolates from Latin American Medical Centers. J Fungi (Basel). 2017;3, http://dx.doi.org/10.3390/jof3020024. Epub 2018/01/27. PubMed PMID: 29371542; PubMed Central PMCID: PMCPMC5715916.9
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as well as in Brazil.99 Colombo AL, Guimaraes T, Camargo LF, Richtmann R, Queiroz-Telles F, Salles MJ, et al. Brazilian guidelines for the management of candidiasis - a joint meeting report of three medical societies: Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical. Braz J Infect Dis. 2013;17:283-312, http://dx.doi.org/10.1016/j.bjid.2013.02.001. Epub 2013/05/23.PubMed PMID: 23693017.
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The high prevalence of C. parapsilosis candidemia in our region may be due to the suboptimal central line management as this pathogen is able to adhere to medical devices, causing primary blood stream infections.1010 Sakita KM, Faria DR, Silva EMD, Tobaldini-Valerio FK, Kioshima ES, Svidzinski TIE, et al. Healthcare workers’ hands as a vehicle for the transmission of virulent strains of Candida spp.: a virulence factor approach. Microb Pathog. 2017;113:225-32, http://dx.doi.org/10.1016/j.micpath.2017.10.044. Epub2017/10/28. PubMed PMID: 29074432.
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Concerns about Candida resistance have been discussed worldwide including Brazil, where antimicrobial stewardship strategies in tertiary care hospitals have been recently addressed.1111 Okumura LM, Riveros BS, Gomes-da-Silva MM, Veroneze I. A cost-effectiveness analysis of two different antimicrobial stewardship programs. Braz J Infect Dis. 2016;20:255-61, http://dx.doi.org/10.1016/j.bjid.2016.02.005. Epub 2016/04/21.PubMed PMID: 27094234.
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,1212 Bertollo LG, Lutkemeyer DS, Levin AS. Are antimicrobial stewardship programs effective strategies for preventing antibiotic resistance? A systematic review. Am J Infect Control. 2018;46:824-36, http://dx.doi.org/10.1016/j.ajic.2018.01.002. Epub 2018/02/24.PubMed PMID: 29472107.13
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Therefore, this study evaluated the clinical findings, local epidemiology and microbiological aspects of candidemia in eight tertiary medical centers in the state of Parana, South of Brazil.

Materials and methods

A descriptive, observational study on candidemia was carried out from January 1st 2016 through December 31, 2017 in patients admitted to eight hospitals in five different cities in the state of Parana, Brazil.

Data collection

Clinical and laboratory data of the first 100 sequential episodes of candidemia in patients admitted to the eight included hospitals were collected. Patients with at least one positive blood culture for Candida spp. were eligible for the study and only the first candidemia episode of each patient was included. We used a standard clinical form to collect clinical, epidemiological, and laboratory information of all selected patients under the following variables: demographics, underlying diseases, exposure to risk factors, clinical manifestations, antifungal therapy, and catheter management.

Patients were followed up to 30 days or until mortality, whichever occurred first. All data were recorded in an electronic database, and statistical tests were performed using the SPSS version 25.0.0.0 program. For survival analysis the STATA/SE version 15.1 program was used to compute log-rank test. A p-value < 0.05 was considered statistically significant.

The incidence of candidemia was calculated per 1000 patient/days and per 1000 admissions in all eight medical centers.

Identification of Candida isolates

The isolates were identified by MALDI-TOF MS (MicroFlex LTD, Bruker, Bremen, Germany) using a formic acid extraction method according to described protocols.1313 Zuza-Alves DL, de Medeiros SS, de Souza LB, Silva-Rocha WP, Francisco EC, de Araujo MC, et al. Evaluation of virulence factors in vitro, resistance to osmotic stress and antifungal susceptibility of candida tropicalis isolated from the coastal environment of Northeast Brazil. Front Microbiol. 2016;7:1783, http://dx.doi.org/10.3389/fmicb.2016.01783. Epub 2016/11/30.PubMed PMID: 27895625; PubMed Central PMCID:PMCPMC5108815.
http://dx.doi.org/10.3389/fmicb.2016.017...
,1414 Santos C, Lima N, Sampaio P, Pais C. Matrix-assisted laser desorption/ionization time-of-flight intact cell mass spectrometry to detect emerging pathogenic Candida species. Diagn Microbiol Infect Dis. 2011;71:304-8, http://dx.doi.org/10.1016/j.diagmicrobio.2011.07.002. Epub 2011/08/23. PubMed PMID: 21855250.
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All isolates were tested in triplicates, and only the spot exhibiting the highest probability score of identification was considered. Data analysis was performed using the Biotyper™ 3.1 software (Bruker Daltonics). Log score of ≥ 2 was accepted for species identification according to the manufacturer’s technical specification. Additionally, for isolates exhibiting inconsistent identification results by MALDI-TOF, species identification was carried out by sequencing the internal transcribed spacer (ITS) of rDNA region as published by Merseguel et al.1515 Merseguel KB, Nishikaku AS, Rodrigues AM, Padovan AC, e Ferreira RC, de Azevedo Melo AS, et al. Genetic diversity of medically important and emerging Candida species causing invasive infection. BMC Infect Dis. 2015;15:57, http://dx.doi.org/10.1186/s12879-015-0793-3. Epub 2015/04/19. PubMed PMID: 25887032; PubMed Central PMCID: PMCPMC4339437.
http://dx.doi.org/10.1186/s12879-015-079...

Antifungal susceptibility testing of Candida spp. isolates

Antifungal susceptibility tests for fluconazole (FLU, Sigma, St. Louis, MO, USA), voriconazole (VOR, Sigma), anidulafungin (Pfizer, USA), and amphotericin B (AMB, Sigma) were performed by broth microdilution method using the Clinical and Laboratory Standards Institute (CLSI) 2017 guidelines.1616 CLSI Performance standards for antifungal susceptibility testing of yeast. CLSI Supplement M60. 1st edition Wayne, PA: Clinical and Laboratory Standards Institute; 2017.,1717 CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. Fourth Informational Supplement. CLSI document M27-S4. 4th edition Wayne, PA: Clinical and Laboratory Standards Institute; 2017. The following drug concentration ranges were tested: 0.125–64 µg/mL for fluconazole (FLU) and 0.03–16 µg/mL for voriconazole (VOR), anidulafungin (AND) and amphotericin B (AMB) each. The minimum inhibitory concentration (MIC) values for azoles and echinocandins were interpreted based on clinical breakpoints following the CLSI M60 document,1616 CLSI Performance standards for antifungal susceptibility testing of yeast. CLSI Supplement M60. 1st edition Wayne, PA: Clinical and Laboratory Standards Institute; 2017. while isolates with MIC ≥ 2 µg/mL were considerate resistant for AMB.1818 Nguyen MH, Clancy CJ, Yu VL, Yu YC, Morris AJ, Snydman DR, et al. Do in vitro susceptibility data predict the microbiologic response to amphotericin B? Results of a prospective study of patients with Candida fungemia. J Infect Dis. 1998;177:425-30, http://dx.doi.org/10.1086/514193. Epub 1998/02/18. PubMedPMID: 9466531.
http://dx.doi.org/10.1086/514193...

Statistical analysis

The statistical analyses were carried out using SPSS version 25.0.0.0 program. Continuous and categorical variables were analyzed using the Mann-Whitney and Fisher’s exact tests, when applicable. Pearson’s chi-square test (χ2) or Fischer’s exact test were used to assess the association between quantitative variables. For survival analysis, a log-rank test was computed using the STATA/SE version 15.1 program. The Kaplan-Meier curve was used to measure the effect of central catheter removal and the previous use of antifungals on patient’s survival. This was compared between patients who had their catheters maintained versus patients with catheters removed for up to 30 days (period that patients were observed) and survival was also compared between patients who used previous antifungal versus patients who did not use previous antifungal whether the use was prophylactic, therapeutic or empirical. For analyses, p < 0.05 was considered statistically significant.

Results

The incidence rate of candidemia was 2.7/1000 patient/days, and the overall incidence density was 1.2 per 1000 hospital admissions. As illustrated in Table 1, the study group comprised 70 adults and 30 pediatric patients (age range 0–89 years). The mean age of adults was 40.02 years, with a median age of 46 years. In the pediatric group (<18 years), the mean age was 27.8 months, with a median age of 7.5 months. Half of the patients were in the intensive care unit (ICU) at the time of the candidemia diagnosis (53%). The mean hospitalization period before developing candidemia was 24.6 days ranging from 0 to 176 days. In the pediatric group, four were newborns with a mean gestational age of 28.6 weeks and a mean weight of 891 g. Cancer was the most common underlying condition (N = 44, 44%). In terms of exposure to risk factors, 44(44%) patients had undergone surgeries.

Table 1
Epidemiological, clinical findings and outcome of 100 episodes of candidemia documented in eight medical centers in the State of Parana (2016-2017).

Mechanical ventilation was reported in 58 (58%), parenteral nutrition in 35 (35%) and dialysis in 20 (20%) patients. At the time of diagnosis, fever was present in 74% of patients and 48 required use of vasoactive drugs.

Exposure to vasoactive drugs and corticosteroids, dialysis and mechanical ventilation were found to be associated with increased mortality, reflecting the severity of illness as a predictor of death, especially for ICU patients.

Adults received more antibiotics and histamine H2 antagonists (H2 blockers) than did children (p = 0.043 and 0.001, respectively).

About the clinical management, amphotericin B and echinocandins were the mostly used antifungals in children (p = 0.004) and adults (p = 0.002), respectively.

The distribution of Candida species in each medical center enrolled in our study is shown in Table 2. Etiological agents included eight different Candida spp. that were isolated from 100 episodes of candidemia: C. albicans, C. parapsilosis, C. metapsilosis, C. tropicalis, C. glabrata, C. krusei, C.haemulonii and C. kefyr. Candida albicans was the most common species causing candidemia (49 isolates, 49%), followed by C. parapsilosis (23 isolates, 23%), and C. tropicalis (15 isolates, 15%).

Table 2
Incidence rates of candidemia and species distribution documented in eight different medical centers from Parana.

Table 3 summarizes the antifungal MIC ranges (µg/mL), MIC50 value, MIC90 value, and percentages of isolates considered to be resistant or with intermediate/dose-dependent susceptibility. Of note, all C. albicans, C. parapsilosis and C. tropicalis isolates were classified as susceptible to all antifungals tested. The C. krusei isolates, intrinsically resistant to fluconazole, were susceptible to the other antifungal agents tested. C. glabrata isolates were susceptible to anidulafungin and amphotericin B, but were considered to be dose-dependent susceptible to fluconazole. The 30-day crude mortality rate in our study was 48%. Among 48 patients who died within 30 days of hospitalization, 22 patients had not been treated with antifungal drugs since the results of blood cultures were only available after death. A low diagnostic suspicion of Candida sp as the causative agent of sepsis is illustrated by the 22 patients who did not receive antifungal treatment because of late diagnosis. These data certainly corroborates with the high mortality rate found in this series. The median age of patients who died was 55 years, while the median age of those who survived was 31 years (p = 0.009). Of note, age, admission to ICU, exposure to mechanical ventilation, dialysis, use of vasoactive drugs and corticosteroids were all factors associated with mortality in univariate analysis. The etiology of candidemia had no impact on patient survival.

Table 3
In vitro antifungal susceptibility of 100 Candida spp isolates cultured from patients with candidemia.

About the intravascular catheter (CVC), 93 patients had a CVC in place at the time of diagnosis. Out of the 51 patients who had their device removed, 35 (68.6%) were discharged and 16 (31.4%) died. Among the 41 patients who did not have their catheters removed, 27 (65.8%) progressed to death, and only 14 (34.2%) survived (p = 0.004; OR 4.21). Antifungal agents prior to candidemia was used in 21 patients, including 16 cases of prophylaxis that had an impact on survival (Table 4).

Table 4
Prognostic factors of 100 patients with candidemia documented in eight hospitals from five different cities in the State of Paraná (2016-2017).

The Kaplan–Meier survival curve illustrates the impact of catheter management (Fig. 1A). Patients who had their catheters removed had greater survival compared to patients in whom the catheters were maintained (p = 0.029). Fig. 1B shows that patients who received antifungal drugs (for any reason) had greater survival than those who had not received any antifungal treatment (p = 0.033).

Fig. 1
Kaplan Meier Survival Curve illustrating the impact of catheter management (1A) and previous exposure to antifungals (1B) in patients with candidemia.

Previous use of antifungal drugs (empiric and prophylactic regimens) as well as catheter removal were factors associated with better prognosis (p = 0.033; p = 0.029 respectively) (Fig. 1B).

Discussion

The present study documented an incidence rate of 1.2 candidemic episodes per 1000 hospital admissions. The incidence of candidemia may change substantially from region to region and even among different medical centers. Of the eight hospitals involved in this study, three are university hospitals and one is university hospital and reference for oncology. Three other hospitals are exclusively cancer referral hospitals and one is a general hospital. In this regard, incidence rates in previous studies conducted in Brazil varied from 2.7/10,000 patients/day66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471. to 5.4/10,000 patients/day.77 Moretti ML, Trabasso P, Lyra L, Fagnani R, Resende MR, de Oliveira Cardoso LG, et al. Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil. Med Mycol. 2013;51:225-30, http://dx.doi.org/10.3109/13693786.2012.708107. Epub2012/08/28. PubMed PMID: 22920712.
http://dx.doi.org/10.3109/13693786.2012....
Recently, a large case series enrolling a total of 331 episodes of candidemia found an incidence of 1.30/1000 admissions,1919 Braga PR, Cruz IL, Ortiz I, Barreiros G, Nouer SA, Nucci M. Secular trends of candidemia at a Brazilian tertiary care teaching hospital. Braz J Infect Dis. 2018;22:273-7, http://dx.doi.org/10.1016/j.bjid.2018.07.008. Epub 2018/08/18.PubMed PMID: 30118654.
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a lower rate than previously reported. One previous report from a single center of Parana reported an incidence rate of 1.27/1000 admissions from 100 episodes of candidemia20 concluding that the incidence in Brazilian studies are similar to the rate observed in the present study.

Adults and pediatric populations had similar prevalence rates of comorbidities (with the exception of prematurity) and exposure to risk factors. Pediatric patients had a higher percentage of candidemia caused by C. parapsilosis and a lower mortality rate compared to adults, in line with other reports.2121 Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;civ933, http://dx.doi.org/10.1093/cid/civ933.
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,2222 Blyth CC, Chen SCA, Slavin MA, Serena C, Nguyen Q, Marriott D, et al. Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients. Pediatrics. 2009;123:1360-8, http://dx.doi.org/10.1542/peds.2008-2055.
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C. parapsilosis accounted for a large number (23%) of candidemia episodes in the present series, as found in other Latin American studies.22 Colombo AL, Nucci M, Park BJ, Nouer 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;44:2816-23, http://dx.doi.org/10.1128/JCM.00773-06. Epub 2006/08/08.PubMed PMID: 16891497; PubMed Central PMCID:PMCPMC1594610.
http://dx.doi.org/10.1128/JCM.00773-06...
,55 Colombo AL, Guimaraes 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 studies sequentially conducted over a 9-year period. Intensive Care Med. 2014;40:1489-98, http://dx.doi.org/10.1007/s00134-014-3400-y. Epub 2014/08/02.PubMed PMID: 25082359; PubMed Central PMCID:PMCPMC4176831.
http://dx.doi.org/10.1007/s00134-014-340...
Indeed, C. parapsilosis has been associated with outbreaks in adult and neonate ICUs2323 Pinhati HM, Casulari LA, Souza AC, Siqueira RA, Damasceno CM, Colombo AL. Outbreak of candidemia caused by fluconazole resistant Candida parapsilosis strains in an intensive care unit. BMC Infect Dis. 2016;16:433, http://dx.doi.org/10.1186/s12879-016-1767-9. Epub 2016/08/22.PubMed PMID: 27544427; PubMed Central PMCID:PMCPMC4992558.
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24 Miranda L, Rodrigues EC, Costa SF, van der Heijden IM, Dantas KC, Lobo RD, et al. Candida parapsilosis candidaemia in a neonatal unit over 7 years: a case series study. BMJ Open. 2012;2, http://dx.doi.org/10.1136/bmjopen-2012-000992. Epub2012/08/08. PubMed PMID: 22869093; PubMed Central PMCID:PMCPMC3425904.
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and dialysis units, reinforcing the importance of enhancing our standards for the management of patients with central lines to mitigate the rates of catheter related candidemia in our hospitals.2626 Ourives AP, Goncalves SS, Siqueira RA, Souza AC, Canziani ME, Manfredi SR, et al. High rate of Candida deep-seated infection in patients under chronic hemodialysis with extended central venous catheter use. Rev Iberoam Micol. 2016;33:100-3, http://dx.doi.org/10.1016/j.riam.2015.10.002. Epub 2016/02/15. PubMed PMID: 26874585.
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C. tropicalis is the second or third most common etiological agent of candidemia in Latin America, including Brazil.2727 Bergamasco MD, Garnica M, Colombo AL, Nucci M. Epidemiology of candidemia in patients with hematologic malignancies and solid tumours in Brazil. Mycoses. 2013;56:256-63, http://dx.doi.org/10.1111/myc.12013. Epub 2012/10/10. PubMed PMID: 23043234.
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,2828 Nucci M, Colombo AL. Candidemia due to Candida tropicalis: clinical, epidemiologic, and microbiologic characteristics of 188 episodes occurring in tertiary care hospitals. Diagn Microbiol Infect Dis. 2007;58:77-82, http://dx.doi.org/10.1016/j.diagmicrobio.2006.11.009. Epub2007/03/21. PubMed PMID: 17368800.
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In the US and Europe, this species has been particularly found in patients with hematological malignancies and neutropenia and is usually related to poor prognosis.2929 Kontoyiannis DP, Vaziri I, Hanna HA, Boktour M, Thornby J, Hachem R, et al. Risk Factors for Candida tropicalis fungemia in patients with cancer. Clin Infect Dis. 2001;33:1676-81, http://dx.doi.org/10.1086/323812. Epub 2001/09/25. PubMedPMID: 11568858.
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Most isolates of C. tropicalis in medical centers of Latin America are susceptible to triazoles but some Brazilian centers have reported fluconazole resistance ranging from 7.3% to 25%.3030 Santos ER, Dal Forno CF, Hernandez MG, Kubica TF, Venturini TP, Chassot F, et al. Susceptibility of Candida spp. isolated from blood cultures as evaluated using the M27-A3 and new M27-S4 approved breakpoints. Rev Inst Med Trop Sao Paulo. 2014;56:477-82, http://dx.doi.org/10.1590/s0036-46652014000600004. Epub2014/10/30. PubMed PMID: 25351540; PubMed Central PMCID: PMCPMC4296866.
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,3131 Menezes EA, Mendes LG, Cunha FA. Antifungal resistance of Candida tropicalis isolated in the State of Ceara. Rev Soc Bras Med Trop. 2009;42:354-5, http://dx.doi.org/10.1590/s0037-86822009000300024. Epub2009/08/18. PubMed PMID: 19684991.
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The main concern with increasing rates of non-albicans candidemia is related to the emergence of C. glabrata and C. krusei isolates, which show low susceptibility to fluconazole.3232 da Matta DA, de Almeida LP, Machado AM, Azevedo AC, Kusano EJ, Travassos NF, et al. Antifungal susceptibility of 1000 Candida bloodstream isolates to 5 antifungal drugs: results of a multicenter study conducted in Sao Paulo, Brazil, 1995–2003. Diagn Microbiol Infect Dis. 2007;57:399-404, http://dx.doi.org/10.1016/j.diagmicrobio.2006.10.011. Epub2007/01/24. PubMed PMID: 17240110.
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,3333 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;51:38-44, http://dx.doi.org/10.3109/13693786.2012.698024. Epub2012/07/06. PubMed PMID: 22762208.
http://dx.doi.org/10.3109/13693786.2012....
In the present study, there were few infections caused by C. glabrata, which may be due to the smaller number of patients aged ≥ 60 years and a history of prophylactic exposure to fluconazole. Besides C. glabrata, few episodes of C. krusei, commonly found in patients with malignant diseases and organ transplant recipients and intrinsically resistant to fluconazole3434 Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Nagy E, Dobiasova S, et al. Candida krusei, a multidrug-resistant opportunistic fungal pathogen: geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin Microbiol. 2008;46:515-21, http://dx.doi.org/10.1128/JCM.01915-07. Epub 2007/12/14. PubMed PMID: 18077633; PubMed Central PMCID: PMCPMC2238087.
http://dx.doi.org/10.1128/JCM.01915-07...
were also found.

Three isolates of C. haemulonii were also identified by sequencing ITS region (internal transcribed spacer). These three cases of candidemia occurred in a child (7 yo) with acute myeloid leukemia, in a (47 yo woman) with a solid tumor, and in a 78-year-old man with hematological neoplasia. All cases were diagnosed in different hospitals and had hospital discharge. This rare species of Candida is mostly found in skin and other superficial infections including onychomycosis and vaginal candidiasis.3535 Silva CM, Carvalho-Parahym AM, Macedo DP, Lima-Neto RG, Francisco EC, Melo AS, et al. Neonatal Candidemia caused by Candida haemulonii: case report and review of literature. Mycopathologia. 2015;180:69-73, http://dx.doi.org/10.1007/s11046-015-9872-7. Epub 2015/02/11. PubMed PMID: 25666389.
http://dx.doi.org/10.1007/s11046-015-987...
Recently, this pathogen has been reported from neonatal units and may exhibit resistance to amphotericin B.3636 Muro MD, Motta Fde A, Burger M, Melo AS, Dalla-Costa LM. Echinocandin resistance in two Candida haemulonii isolates from pediatric patients. J Clin Microbiol. 2012;50:3783-5, http://dx.doi.org/10.1128/JCM.01136-12. Epub 2012/08/17.PubMed PMID: 22895037; PubMed Central PMCID:PMCPMC3486200.
http://dx.doi.org/10.1128/JCM.01136-12...
Prompt identification of pathogens, especially those resistant to various antifungals is crucial, as late initiation of appropriate antifungal therapy may increase mortality rates in patients with candidemia.3737 Garnacho-Montero J, Díaz-Martín A, Cantón-Bulnes L, Ramírez P, Sierra R, Arias-Verdú D, et al. Initial antifungal strategy reduces mortality in critically ill patients with candidemia. Crit Care Med. 2018;46:384-93, http://dx.doi.org/10.1097/ccm.0000000000002867.
http://dx.doi.org/10.1097/ccm.0000000000...
,3838 Lausch KR, Søgaard M, Rosenvinge FS, Johansen HK, Boysen T, Røder BL, et al. Treatment of candidemia in a nationwide setting: increased survival with primary echinocandin treatment. Infect Drug Resist. 2018;11:2449-59, http://dx.doi.org/10.2147/idr.s176384.
http://dx.doi.org/10.2147/idr.s176384...

Of note, previous exposure to antifungal drugs in regimens of prophylaxis and empirical therapy was documented mostly in patients infected by non-albicans Candida (75% of patients with previous exposure) when compared with the group infected by C. albicans (25%, p = 0.044). Several other studies have reported that selective pressure of antifungal use may increase the occurrence of non-albicans candidemia, including the emergence of C. glabrata in centers with high consumption of fluconazole.3939 Pasqualotto AC, Zimerman RA, Alves SH, Aquino VR, Branco D, Wiltgen D, et al. Take control over your fluconazole prescriptions: the growing importance of Candida glabrata as an agent of candidemia in Brazil. Infect Control Hosp Epidemiol. 2008;29:898-9, http://dx.doi.org/10.1086/590191 Epub 2008/09/13. PubMed PMID: 18785850.
http://dx.doi.org/10.1086/590191...
Except for C. glabrata and C. krusei, all other Candida spp found in our series were susceptible to the antifungal agents tested. Likewise, other Brazilian authors have reported up to 100% susceptibility of C. albicans isolated from blood to amphotericin B,22 Colombo AL, Nucci M, Park BJ, Nouer 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;44:2816-23, http://dx.doi.org/10.1128/JCM.00773-06. Epub 2006/08/08.PubMed PMID: 16891497; PubMed Central PMCID:PMCPMC1594610.
http://dx.doi.org/10.1128/JCM.00773-06...
,33 Colombo AL, Guimaraes T, Silva LR, de Almeida Monfardini LP, Cunha AK, Rady P, et al. Prospective observational study of candidemia in Sao Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality. Infect Control Hosp Epidemiol. 2007;28:570-6, http://dx.doi.org/10.1086/513615. Epub2007/04/28. PubMed PMID: 17464917.
http://dx.doi.org/10.1086/513615...
fluconazole,33 Colombo AL, Guimaraes T, Silva LR, de Almeida Monfardini LP, Cunha AK, Rady P, et al. Prospective observational study of candidemia in Sao Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality. Infect Control Hosp Epidemiol. 2007;28:570-6, http://dx.doi.org/10.1086/513615. Epub2007/04/28. PubMed PMID: 17464917.
http://dx.doi.org/10.1086/513615...
,66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471. voriconazole,66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471.,2020 Franca JC, Ribeiro CE, Queiroz-Telles F. Candidemia in a Brazilian tertiary care hospital: incidence, frequency of different species, risk factors and antifungal susceptibility. Rev Soc Bras Med Trop. 2008;41:23-8, http://dx.doi.org/10.1590/s0037-86822008000100005. Epub 2008/03/28. PubMed PMID: 18368266.
http://dx.doi.org/10.1590/s0037-86822008...
caspofungin,66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471. and anidulafungin.4040 Doi AM, Pignatari AC, Edmond MB, Marra AR, Camargo LF, Siqueira RA, et al. Epidemiology and microbiologic characterization of nosocomial candidemia from a Brazilian national surveillance program. PLoS One. 2016;11:e0146909, http://dx.doi.org/10.1371/journal.pone.0146909. Epub 2016/01/26. PubMed PMID: 26808778; PubMed Central PMCID: PMCPMC4726651.
http://dx.doi.org/10.1371/journal.pone.0...

Echinocandins have become key players in antifungal treatment of candidemia in different setting of patients; especially when caused by C. glabrata and other fluconazole resistant species2121 Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;civ933, http://dx.doi.org/10.1093/cid/civ933.
http://dx.doi.org/10.1093/cid/civ933...
although only 55% of our patients were treated with this antifungal class. To date, resistance to echinocandins is very rare in Brazil except for the occasional documentation in cases of breakthrough candidemia, especially in those who received prophylaxis with low-dose micafungin.4141 Pfaller MA, Diekema DJ, Turnidge JD, Castanheira M, Jones RN. Twenty years of the SENTRY antifungal surveillance program: results for Candida species from 1997–2016. Open Forum Infect Dis. 2019;6:S79-94, http://dx.doi.org/10.1093/ofid/ofy358. Epub 2019/03/22. PubMed PMID: 30895218; PubMed Central PMCID:PMCPMC6419901.
http://dx.doi.org/10.1093/ofid/ofy358...
,4242 Bizerra FC, Jimenez-Ortigosa C, Souza AC, 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;58:2438-40, http://dx.doi.org/10.1128/AAC.02189-13. Epub 2014 Jan 27. PMID: 24468776; PMCID: PMC4023795.
http://dx.doi.org/10.1128/AAC.02189-13...

The 30-day crude mortality rate in our study (48%) was similar to that reported in other Brazilian studies with rates of 52%,66 Motta AL, Almeida GM, Almeida Junior JN, Burattini MN, Rossi F. Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex. Braz J Infect Dis. 2010;14:441-8. Epub 2011/01/12. PubMed PMID: 21221471. 56%,44 Girao E, Levin AS, Basso M, Gobara S, Gomes LB, Medeiros EA, et al. Seven-year trend analysis of nosocomial candidemia and antifungal (fluconazole and caspofungin) use in Intensive Care Units at a Brazilian University Hospital. Med Mycol. 2008;46:581-8, http://dx.doi.org/10.1080/13693780802004996. Epub 2009/01/31. PubMed PMID: 19180727.
http://dx.doi.org/10.1080/13693780802004...
58.9%,77 Moretti ML, Trabasso P, Lyra L, Fagnani R, Resende MR, de Oliveira Cardoso LG, et al. Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil. Med Mycol. 2013;51:225-30, http://dx.doi.org/10.3109/13693786.2012.708107. Epub2012/08/28. PubMed PMID: 22920712.
http://dx.doi.org/10.3109/13693786.2012....
and 72.2%.1313 Zuza-Alves DL, de Medeiros SS, de Souza LB, Silva-Rocha WP, Francisco EC, de Araujo MC, et al. Evaluation of virulence factors in vitro, resistance to osmotic stress and antifungal susceptibility of candida tropicalis isolated from the coastal environment of Northeast Brazil. Front Microbiol. 2016;7:1783, http://dx.doi.org/10.3389/fmicb.2016.01783. Epub 2016/11/30.PubMed PMID: 27895625; PubMed Central PMCID:PMCPMC5108815.
http://dx.doi.org/10.3389/fmicb.2016.017...
International studies have revealed mortality rates substantially lower in patients with candidemia admitted in the north hemisphere countries. Mortality rates of 35–40% in Europe4343 Koehler P, Stecher M, Cornely OA, Koehler D, Vehreschild MJGT, Bohlius J, et al. Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis. Clin Microbiol Infect. 2019, http://dx.doi.org/10.1016/j.cmi.2019.04.024.
http://dx.doi.org/10.1016/j.cmi.2019.04....
and 25% in United States4444 Toda M, Williams SR, Berkow EL, Farley MM, Harrison LH, Bonner L, et al. Population-based active surveillance for culture-confirmed candidemia — four sites, United States, 2012-2016. MMWR Surveill Summ. 2019;68:1-15, http://dx.doi.org/10.15585/mmwr.ss6808a1.
http://dx.doi.org/10.15585/mmwr.ss6808a1...
have been reported in general hospitals. By checking prognostic factors, we were able to identify several conditions already reported by other authors: age, admission to ICU, mechanical ventilation, and exposure to immunosuppressive drugs.55 Colombo AL, Guimaraes 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 studies sequentially conducted over a 9-year period. Intensive Care Med. 2014;40:1489-98, http://dx.doi.org/10.1007/s00134-014-3400-y. Epub 2014/08/02.PubMed PMID: 25082359; PubMed Central PMCID:PMCPMC4176831.
http://dx.doi.org/10.1007/s00134-014-340...
,2020 Franca JC, Ribeiro CE, Queiroz-Telles F. Candidemia in a Brazilian tertiary care hospital: incidence, frequency of different species, risk factors and antifungal susceptibility. Rev Soc Bras Med Trop. 2008;41:23-8, http://dx.doi.org/10.1590/s0037-86822008000100005. Epub 2008/03/28. PubMed PMID: 18368266.
http://dx.doi.org/10.1590/s0037-86822008...

In addition, we found that catheter removal apparently affected the mortality rate. The relevance of controlling source of infection in terms of mitigating mortality rates has been extensively discussed in the medical literature.4545 Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54:1110-22, http://dx.doi.org/10.1093/cid/cis021. Epub 2012/03/14. PubMed PMID: 22412055.
http://dx.doi.org/10.1093/cid/cis021...
Finally, echinocandins were used to treat the larger number of patients with candidemia our series. This finding is certainly related to the fact that most recent guidelines recommend this class of drugs for first line therapy owing to its efficacy, broad spectrum, and safety.2121 Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;civ933, http://dx.doi.org/10.1093/cid/civ933.
http://dx.doi.org/10.1093/cid/civ933...
,4646 Walsh T, Katragkou A, Chen T, Salvatore C, Roilides E. Invasive Candidiasis in Infants and Children: Recent Advances in Epidemiology, Diagnosis, and Treatment. J Fungi. 2019;5:11, http://dx.doi.org/10.3390/jof5010011.
http://dx.doi.org/10.3390/jof5010011...
Besides adults, the efficacy, safety and tolerability of echinocandins have also been confirmed in children, initially for micafungin4747 Emiroglu M. Micafungin use in children. Expert Rev Anti Infect Ther. 2011;9:821-34, http://dx.doi.org/10.1586/eri.11.91.
http://dx.doi.org/10.1586/eri.11.91...
and more recently for anidulafungin.4848 Roilides E, Carlesse F, Leister-Tebbe H, Conte U, Yan JL, Liu P, et al. A prospective, open-label study to assess the safety, tolerability and efficacy of anidulafungin in the treatment of invasive candidiasis in children 2 to <18 years of age. Pediatr Infect Dis J. 2019;38:275-9, http://dx.doi.org/10.1097/inf.0000000000002237.
http://dx.doi.org/10.1097/inf.0000000000...
,4949 Roilides E, Carlesse F, Tawadrous M, Leister-Tebbe H, Conte U, Raber S, et al. Safety, efficacy and pharmacokinetics of anidulafungin in patients 1 month to <2 years of age with invasive candidiasis, including candidemia. Pediatr Infect Dis J. 2020;39:305-9, http://dx.doi.org/10.1097/inf.0000000000002568.
http://dx.doi.org/10.1097/inf.0000000000...

This study has several limitations including the retrospective collection of data, the lack of information about the time interval between diagnosis of candidemia and removal of CVC, as well as the limited number of hospitals and patients from Parana that were included in our series. Otherwise, we were able to present contemporaneous data on the burden and mortality rates of candidemia from eight medical centers of Parana, including details on susceptible populations, etiologic agents, and prognostic factors. This information may certainly be helpful to support educational programs in the clinical management of candidemia in our region.

Conclusions

The clinical and epidemiological landscape of candidemia in the state of Parana is quite similar to the findings of other national and Latin American studies, including the high mortality rate associated with candidemia. Apparently, antifungal resistance remains rare in most of the medical centers in Parana but continuous surveillance studies on candidemia are certainly needed to detect any early trends in terms of the emergence of resistant pathogens. Finally, we certainly need to incorporate antifungal stewardship program in our hospitals to optimize the clinical standards of care in patients under risk of developing candidemia and other fungal infections.

Acknowledgments

We are very grateful to all the people in the centers involved, FAPESP, the staff of LEMI (Special Mycology Laboratory) of UNIFESP, Pfizer International for the financial incentive to carry out this project, Ademar Dantas da Cunha Junior for the statistical analyses and Fernando Antonio Campello Spencer Netto and Gabriela Donadussi for the English grammatical review.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.bjid.2020.11.006.

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Publication Dates

  • Publication in this collection
    28 Apr 2021
  • Date of issue
    Jan-Feb 2021

History

  • Received
    15 July 2020
  • Accepted
    30 Nov 2020
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