Indian J Pediatr (November 2014) 81(11):1139–1140 DOI 10.1007/s12098-014-1598-x
EDITORIAL COMMENTARY
Tackling Candidemia in Pediatric Intensive Care Units… A Global Concern! Karthi Nallasamy & Sunit C. Singhi
Received: 26 September 2014 / Accepted: 26 September 2014 / Published online: 12 October 2014 # Dr. K C Chaudhuri Foundation 2014
From being dismissed as ‘non-pathogenic commensals’ once upon a time, Candida spp. are now considered as one of the commonest nosocomial pathogens in intensive care units (ICUs) [1, 2]. Last decade has seen several studies from adult and pediatric intensive care units describing incidence, risk factors, cost and attributable mortality to bloodstream and invasive Candida infections [3–6]. A study by Ağın et al. [7], published in this issue of the Journal, confirms that Turkish ICUs are equally affected by this worldwide trend of increasing incidence of health care associated Candidemia. In this retrospective case–control study that included 53 children with Candidemia admitted to their PICU over a one year period, the authors compared the results of the study-cases with a control group matched for timing of PICU stay. The design is appropriate and quality of data analysis is good. This design has been reported previously by Zaoutis et al. to increase the statistical efficiency of the study since the risk at time of developing Candidemia is an important confounding variable. The paper highlights a change in the disease causing Candida species, from albicans to non-albicans, again a trend that has been observed globally. The steady rise in the number and prevalence of non-albicans candida species is of significance; it could impact therapeutic choices for treating this disease. Studies such as this, from different parts of the world are helpful in defining the geographic and temporal trend of Candida infections. Risk factors identified by Ağın et al. were underlying disease, administration of total parenteral nutrition (TPN), and central venous catheterization. These are similar to K. Nallasamy : S. C. Singhi (*) Department of Pediatrics, Pediatric Emergency and Intensive Care Division, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail: [email protected]
what has been reported and are documented by previous researchers [4, 5, 8]. The study however, falls short in providing additional dimensions to the existing knowledge on Candida infections in PICU. Given the current trend of shifting from albicans to non albicans Candida infections in most intensive care units, identifying specific risk factors for these two groups would have been more relevant in the current scenario. Several authors have attributed this shift to the widespread use of azoles for antifungal therapy or prophylaxis, increased use of indwelling catheters and opportunity for horizontal transmissions in PICU environment [9, 10]. Ağın et al. speculated that the increased rate of Candida parapsilosis infections could have been due to central venous catheterization, a factor that increased the risk of Candidemia by 3.3 times. However, the small sample size of the study is a major limiting factor in carrying out further sub group analysis to confirm this association. Similarly, to study the association between antibacterial use and incidence of Candidemia, both the type and the duration of antibiotic administration are important risk contributors. Broad spectrum antibiotics suppress gastrointestinal bacterial flora which permits unopposed Candida proliferation resulting in overgrowth and eventual tissue invasion. Zaoutis et al. showed that administration of vancomycin or antimicrobials with activity against anerobic organisms for > 3 d independently predicted development of candidemia in PICU [8]. A larger sample size and more specific look into duration of antimicrobial therapy could have brought out distinct relationship between antimicrobial use and Candidemia. The study did not address Candida colonization, the most important postulate in the pathogenesis of invasive Candidiasis in recent literature. Prospective studies in critically ill children have shown strong association between colonization and Candidemia, regardless of site of colonization [11].
1140
Critically ill children are at increased risk of Candidemia from colonization as breakdown of normal mucosal and epithelial barriers and loss of protective immune mechanisms are very common in these children. Recent studies in fact have evaluated colonization scores and indices in adult ICU patients to identify those at risk for developing Candidemia and invasive infections [12]. However, retrospective design is a major limitation for the authors in studying colonization rates or density in the present study. Last and most importantly, Ağın et al. did not report the outcome of children with Candidemia, attributable mortality and risk factors for mortality. There is a paucity of data on outcomes in children with candidemia. Pediatric and adult studies have shown an attributable mortality varying from 10 to 30 % [3, 13]. ICU stay at the time of infection, presence of an arterial catheter, retention of central venous catheters and inadequate fluconazole dosing are identified as some of the risk factors associated with increased mortality. Detecting and further refining these risk factors could be helpful not only to predict outcome but also to identify the susceptible group that can benefit from preventive interventions. The role of central venous catheters (CVC) as a risk factor for occurrence, dissemination and death due to Candidemia in PICU patients is undisputed and hence the clear recommendation to remove CVC when Candidemia is documented [14]. In addition to the recent gain in epidemiological knowledge there has been progress in preventive research as well. Probiotics supplementation has been identified as a promising strategy to reduce Candida colonization in critically ill children receiving broad spectrum antibiotics [15]. Nevertheless, a few questions regarding management still remain unanswered, like whether or not to treat colonization and the role of antifungal prophylaxis in non-oncology children. Further research on these issues is urgently needed to formulate evidence based recommendations for effective prevention and early identification of children at risk of invasive infection. Conflict of Interest None. Source of Funding Departmental and institutional funds.
Indian J Pediatr (November 2014) 81(11):1139–1140
References 1. Raymond J, Aujard Y. Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group. Infect Control Hosp Epidemiol. 2000;21:260–3. 2. Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al; NIAID Mycoses Study Group. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37:634–43. 3. Wenzel RP. Nosocomial candidemia: risk factors and attributable mortality. Clin Infect Dis. 1995;20:1531–4. 4. Paganini H, Rodriguez BT, Santos P, Seu S, Rosanova MT. Risk factors for nosocomial candidaemia: a case control study in children. J Hosp Infect. 2002;52:304–8. 5. Zaoutis TE, Greves HM, Lautenbach E, Bilker WB, Coffin SE. Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J. 2004;23:635–41. 6. Singhi SC, Reddy TC, Chakrabarty A. Candidemia in a pediatric intensive care unit. Pediatr Crit Care Med. 2004;5:369–74. 7. Ağın H, Devrim I, Işgüder R, Karaarslan U, Kanık E, Günay I, et al. Risk factors for candidemia in pediatric intensive care unit patients. Indian J Pediatr. 2014. doi:10.1007/s12098-014-1343-5. 8. Zaoutis TE, Prasad PA, Localio AR, Coffin SE, Bell LM, Walsh TJ, et al. Risk factors and predictors for candidemia in pediatric intensive care unit patients: implications for prevention. Clin Infect Dis. 2010;51:e38–45. 9. Krcmery V, Barnes AJ. Nonalbicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect. 2002;50:243–60. 10. Waggoner-Fountain LA, Walker MW, Hollis RJ, Pfaller MA, Ferguson JE 2nd, Wenzel RP, et al. Vertical and horizontal transmission of unique Candida species to premature newborns. Clin Infect Dis. 1996;22:803–8. 11. Singhi S, Rao DS, Chakrabarti A. Candida colonization and candidemia in a pediatric intensive care unit. Pediatr Crit Care Med. 2008;9:91–5. 12. Leon C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J. Alvarez- Lerma F, et al. A bedside scoring system (‘’Candida score”) for early antifungal treatment in non-neutropenic critically ill patients with Candida colonization. Crit Care Med. 2006;34:730–7. 13. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis. 2005;41:1232–9. 14. Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35. 15. Kumar S, Bansal A, Chakrabarti A, Singhi S. Evaluation of efficacy of probiotics in prevention of Candida colonization in a PICU – a randomized controlled trial. Crit Care Med. 2013;41:565–72.
EDITORIAL COMMENTARY
Tackling Candidemia in Pediatric Intensive Care Units… A Global Concern! Karthi Nallasamy & Sunit C. Singhi
Received: 26 September 2014 / Accepted: 26 September 2014 / Published online: 12 October 2014 # Dr. K C Chaudhuri Foundation 2014
From being dismissed as ‘non-pathogenic commensals’ once upon a time, Candida spp. are now considered as one of the commonest nosocomial pathogens in intensive care units (ICUs) [1, 2]. Last decade has seen several studies from adult and pediatric intensive care units describing incidence, risk factors, cost and attributable mortality to bloodstream and invasive Candida infections [3–6]. A study by Ağın et al. [7], published in this issue of the Journal, confirms that Turkish ICUs are equally affected by this worldwide trend of increasing incidence of health care associated Candidemia. In this retrospective case–control study that included 53 children with Candidemia admitted to their PICU over a one year period, the authors compared the results of the study-cases with a control group matched for timing of PICU stay. The design is appropriate and quality of data analysis is good. This design has been reported previously by Zaoutis et al. to increase the statistical efficiency of the study since the risk at time of developing Candidemia is an important confounding variable. The paper highlights a change in the disease causing Candida species, from albicans to non-albicans, again a trend that has been observed globally. The steady rise in the number and prevalence of non-albicans candida species is of significance; it could impact therapeutic choices for treating this disease. Studies such as this, from different parts of the world are helpful in defining the geographic and temporal trend of Candida infections. Risk factors identified by Ağın et al. were underlying disease, administration of total parenteral nutrition (TPN), and central venous catheterization. These are similar to K. Nallasamy : S. C. Singhi (*) Department of Pediatrics, Pediatric Emergency and Intensive Care Division, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail: [email protected]
what has been reported and are documented by previous researchers [4, 5, 8]. The study however, falls short in providing additional dimensions to the existing knowledge on Candida infections in PICU. Given the current trend of shifting from albicans to non albicans Candida infections in most intensive care units, identifying specific risk factors for these two groups would have been more relevant in the current scenario. Several authors have attributed this shift to the widespread use of azoles for antifungal therapy or prophylaxis, increased use of indwelling catheters and opportunity for horizontal transmissions in PICU environment [9, 10]. Ağın et al. speculated that the increased rate of Candida parapsilosis infections could have been due to central venous catheterization, a factor that increased the risk of Candidemia by 3.3 times. However, the small sample size of the study is a major limiting factor in carrying out further sub group analysis to confirm this association. Similarly, to study the association between antibacterial use and incidence of Candidemia, both the type and the duration of antibiotic administration are important risk contributors. Broad spectrum antibiotics suppress gastrointestinal bacterial flora which permits unopposed Candida proliferation resulting in overgrowth and eventual tissue invasion. Zaoutis et al. showed that administration of vancomycin or antimicrobials with activity against anerobic organisms for > 3 d independently predicted development of candidemia in PICU [8]. A larger sample size and more specific look into duration of antimicrobial therapy could have brought out distinct relationship between antimicrobial use and Candidemia. The study did not address Candida colonization, the most important postulate in the pathogenesis of invasive Candidiasis in recent literature. Prospective studies in critically ill children have shown strong association between colonization and Candidemia, regardless of site of colonization [11].
1140
Critically ill children are at increased risk of Candidemia from colonization as breakdown of normal mucosal and epithelial barriers and loss of protective immune mechanisms are very common in these children. Recent studies in fact have evaluated colonization scores and indices in adult ICU patients to identify those at risk for developing Candidemia and invasive infections [12]. However, retrospective design is a major limitation for the authors in studying colonization rates or density in the present study. Last and most importantly, Ağın et al. did not report the outcome of children with Candidemia, attributable mortality and risk factors for mortality. There is a paucity of data on outcomes in children with candidemia. Pediatric and adult studies have shown an attributable mortality varying from 10 to 30 % [3, 13]. ICU stay at the time of infection, presence of an arterial catheter, retention of central venous catheters and inadequate fluconazole dosing are identified as some of the risk factors associated with increased mortality. Detecting and further refining these risk factors could be helpful not only to predict outcome but also to identify the susceptible group that can benefit from preventive interventions. The role of central venous catheters (CVC) as a risk factor for occurrence, dissemination and death due to Candidemia in PICU patients is undisputed and hence the clear recommendation to remove CVC when Candidemia is documented [14]. In addition to the recent gain in epidemiological knowledge there has been progress in preventive research as well. Probiotics supplementation has been identified as a promising strategy to reduce Candida colonization in critically ill children receiving broad spectrum antibiotics [15]. Nevertheless, a few questions regarding management still remain unanswered, like whether or not to treat colonization and the role of antifungal prophylaxis in non-oncology children. Further research on these issues is urgently needed to formulate evidence based recommendations for effective prevention and early identification of children at risk of invasive infection. Conflict of Interest None. Source of Funding Departmental and institutional funds.
Indian J Pediatr (November 2014) 81(11):1139–1140
References 1. Raymond J, Aujard Y. Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group. Infect Control Hosp Epidemiol. 2000;21:260–3. 2. Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al; NIAID Mycoses Study Group. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37:634–43. 3. Wenzel RP. Nosocomial candidemia: risk factors and attributable mortality. Clin Infect Dis. 1995;20:1531–4. 4. Paganini H, Rodriguez BT, Santos P, Seu S, Rosanova MT. Risk factors for nosocomial candidaemia: a case control study in children. J Hosp Infect. 2002;52:304–8. 5. Zaoutis TE, Greves HM, Lautenbach E, Bilker WB, Coffin SE. Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J. 2004;23:635–41. 6. Singhi SC, Reddy TC, Chakrabarty A. Candidemia in a pediatric intensive care unit. Pediatr Crit Care Med. 2004;5:369–74. 7. Ağın H, Devrim I, Işgüder R, Karaarslan U, Kanık E, Günay I, et al. Risk factors for candidemia in pediatric intensive care unit patients. Indian J Pediatr. 2014. doi:10.1007/s12098-014-1343-5. 8. Zaoutis TE, Prasad PA, Localio AR, Coffin SE, Bell LM, Walsh TJ, et al. Risk factors and predictors for candidemia in pediatric intensive care unit patients: implications for prevention. Clin Infect Dis. 2010;51:e38–45. 9. Krcmery V, Barnes AJ. Nonalbicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect. 2002;50:243–60. 10. Waggoner-Fountain LA, Walker MW, Hollis RJ, Pfaller MA, Ferguson JE 2nd, Wenzel RP, et al. Vertical and horizontal transmission of unique Candida species to premature newborns. Clin Infect Dis. 1996;22:803–8. 11. Singhi S, Rao DS, Chakrabarti A. Candida colonization and candidemia in a pediatric intensive care unit. Pediatr Crit Care Med. 2008;9:91–5. 12. Leon C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J. Alvarez- Lerma F, et al. A bedside scoring system (‘’Candida score”) for early antifungal treatment in non-neutropenic critically ill patients with Candida colonization. Crit Care Med. 2006;34:730–7. 13. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis. 2005;41:1232–9. 14. Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35. 15. Kumar S, Bansal A, Chakrabarti A, Singhi S. Evaluation of efficacy of probiotics in prevention of Candida colonization in a PICU – a randomized controlled trial. Crit Care Med. 2013;41:565–72.
