Candidemia is a life-threatening fungal infection with significant morbidity and mortality among pediatric patients, especially among those subjected to intravenous catheters for a long time, hematopoietic stem cell transplantation, and immunosuppressive therapy or the patients with severe immunodeficiency and cancer . Although Candida albicans is generally the most frequent cause of candidemia, non-albicans Candida species (i.e., C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, C. auris, and C. guilliermondii) have become more frequent and have been recognized as emerging pathogens in cancer patients [1, 2].
Accordingly, the incidence rate of candidemia due to C. guilliermondii ranges from 0.6% in North America to 3.7% in Latin America. In addition, the decreased susceptibility of this pathogenic yeast to fluconazole has been observed in different geographical areas [1-4]. However, the epidemiology of candidemia due to C. guilliermondii has been underestimated so far. Herein, we report the first pediatric case of candidemia due to C. guilliermondii in Iran and present a comprehensive literature review regarding fungemia caused by C. guilliermondii.
Our case was a 4-month-old male infant with neuroblastoma undergoing chemotherapy referred to the Oncology Department of Amirkola Children’s Hospital, Mazandaran, Iran, with fever and neutropenia, without any obvious source of infection. The patient had undergone surgery for neuroblastoma 2 months prior. Laboratory examinations showed the C-reactive protein level of 76 mg/L, white blood cell count of 1.8×103/ μl (i.e., leukopenia), neutrophil count of <500 cell/μl, hemoglobin level of 6.5 g/dl, and platelet count of 134×103/ μl. The blood samples were collected aseptically by arterial puncture in BD BACTEC Plus Aerobic/F culture bottles (Becton Dickinson and Company Spark, MD 21152, Shannon, County Clare, Ireland) and incubated in a BACTEC culture system (Becton Dickinson Microbiology Systems).
The patient was prescribed ciprofloxacin prophylaxis due to mucositis; in addition, empirical therapy with ceftazidime and vancomycin was instituted for up to 7 days; however, his condition deteriorated rapidly. Initial blood cultures were negative for bacteria, whereas two consecutive blood cultures were positive for yeast-like fungi. Positive blood cultures were subcultured on CHROMagar Candida (bioMe´rieux) and resulted in the emergence of smooth colonies with white to cream colors after 24 h in dark. Candida species were initially identified based on conventional assays.
Voucher strains were deposited into the reference culture collection under the accession number IFRC2085. In addition, identification at the species level was performed by using DNA sequencing. Genomic DNA was extracted from 2 to 3-day-old Sabouraud dextrose agar cultures with an UltraClean Microbial DNA Isolation Kit (Mo Bio Laboratories) according to the manufacturer’s protocol, and then stored at -20°C prior to use. The internal transcribed spacer (ITS) was amplified and sequenced using primers ITS5 and ITS4 as previously described .
Briefly, the amplification of ITS rDNA was performed using a cycle of 5 min at 94°C for primary denaturation, followed by 40 cycles at 94°C for 30 sec, 52°C for 30 sec, and 72°C for 80 sec and a final 7-min extension step at 72°C. The sequence data were adjusted using Lasergene SeqMan software (version 9.0.4, DNASTAR) and compared with the data of GenBank through local BLAST with a molecular database maintained for research purposes at the CBS-KNAW Fungal Biodiversity Centre, Utrecht, Netherlands. The DNA sequence of the ITS rDNA region matched that of C. guilliermondii (MH714912) by showing 99.9% similarity with the ex-type strain.
In vitro antifungal susceptibility test was also performed according to the documents M27-A3 and M27-S4 of the Clinical and Laboratories Standards Institute. For the preparation of the microdilution trays, amphotericin B (Sigma, St. Louis, MO, USA), fluconazole (Pfizer, Groton, CT, USA), itraconazole (Janssen research foundation, Beerse, Belgium), voriconazole (Pfizer), and caspofungin (Merck, Whitehouse Station, NJ, USA) were obtained from their respective manufacturers as reagent-grade powders. The minimum inhibitory concentrations for amphotericin B, fluconazole, itraconazole, voriconazole, and caspofungin were obtained as 0.063, 4, 2, 0.25, and 0.5 µg/ml, respectively.
The patient was empirically treated with 0.75 mg/kg/day amphotericin B deoxycholate intravenously, which is a regimen frequently used as standard therapy for candidaemia in Iran. After treatment with amphotericin B for a week, two sequential blood cultures remained negative. The patient was successfully treated and showed no relapse during the two-week follow-up. This report was approved by the Ethics Committee of Mazandaran University of Medical Sciences, Mazandaran, Iran. In line with the principles of research ethics, written informed consent was obtained from the parents of the patient.
Candida guilliermondii complex comprising several species, namely C. guilliermondii, C. fermentati, C. carpophila, and C. xestobii, is an uncommon, newly emerging, and rare agent of candidemia, with low incidence (1-3%), especially in immunocompromised hosts, transplant recipients, and critically ill patients .
Limited cases of invasive candidiasis caused by C. guilliermondii complex have been reported in the past because of its low pathogenicity. However, recently, there is an increasing number of reports regarding the bloodstream infections due to this complex . In addition, due to resistance or decreased susceptibility to antifungal agents, C. guilliermondii complex has been proposed to be a re-emerging pathogen in high-risk patients.
Table 1 summarizes all reported cases of candidemia due to C. guilliermondii in English literature with the patients’ demographic characteristics (e.g., age, gender, source, and location) and clinical data (e.g., underlying condition, risk factors, and outcomes). Most of these patients were adults and had multiple risk factors. The main risk factors were significantly related to cancer patients undergoing chemotherapy, followed by central venous catheter users and ICU patients (Table 1). In the reviewed articles, the mortality rate had a range of 3.4-66.6%. In this regard, this infection had the mortality rates of 11.76-66.6%, 13.6-54%, 16.66-18.8%, 59.25%, and 3.4% in Japan, Spain, Taiwan, United States, and Italy, respectively (Table 1).
Cancer patients suffering from this infection had a high rate of mortality. While the majority of C. guilliermondii fungemia cases have been described in adults with cancer, few cases have been published in pediatric patients. Peman et al. reported seven cases of C. guilliermondii fungemia during a 12-year period, five cases of which occurred in children . In contrast, in a meta-analysis on the epidemiology of candidemia in Iran, C. guilliermondii accounted for 2 (3.8%) cases of infection in adults .
|Number||Year of evaluation||Country||Underlying condition and predisposing factors||Pediatric/ adult||Number 1 /total||Resistant to azoles||Resistant to echinocandins||Mortality rate||Reference|
|2018||Iran||- Cancer- Chemotherapy- Surgery- Neutropenia||4-month-old infant||1||0||0||-||Current case|
|2007-2016||Japan||- Hematological disorder- Surgery- ICU exposure||Adult||17/121||17.6-13.3%||0||11.76%|||
|2008-20142||Japan||- Hematopoietic stem cell transplant recipients||Adult||3/22||NS||NS||66.6%|||
|2006-2015||Turkey||- Cancer- TPN - CVC- ICU exposure- Chemotherapy||Both||141/NS||26.08%3||NS||NS|||
|2007-2014||Spain||- Cancer- Immunosuppressive therapy- Neutropenia- Chemotherapy||Both||22/NS||72%||0||13.6%|||
|2005-2014||USA||- Cancer- ICU exposure- Exposure to steroids||Pediatric||3/192||NS||NS||0|||
|2003-2015||Taiwan||- Cancer- CVC||Both||364||0||4.5-22.7%||16.66%|||
|1998-2013||USA||- Cancer - Neutropenia- TPN- Steroid exposure||Adult||28/795||17-24%||3.7%||59.25%|||
|2002-2007||Brazil||- Hematological disorder||Both||6/67||0||NS||NS|||
|March-April 2012||Spain||- TPN- Steroid exposure- CVC- Surgery- Broad-spectrum antibiotic exposure||Adult||4/13||0||0||54%|||
|2007-2013||Japan||- Cancer- Chemotherapy- CVC- TPN- Neutropenia- Immunosuppressive therapy- ICU exposure||Both||16/66||12.5%||6.2%||18.75%|||
|2009-2012||Taiwan||- Elderly patients- Cancer- Chemotherapy||Adult||2/181||NS||NS||NS|||
|2009-2012||Taiwan||- Cancer- CVC- Neutropenia- Use of steroid - Recent abdominal surgery- Chemotherapy- TPN- Broad-spectrum antibiotic exposure||Adult||2/209||NS||50%||NS|||
|2009-2012||India||- Patients with injuries||NS||4/212||NS||NS||NS|||
|2004-2008||USA||- Cancer- Stem cell transplantation- Chemotherapy||Both||9/2496||0||0||NS|||
|2009-2011||China||- Cancer- CVC- Preterm infants with low birth weight||Both||39/238||NS||NS||NS|||
|2009-2010||France||- Immunosuppressive drugs user- CVC||Both||1/189||NS||NS||NS|||
|1995 to 2006||Spain||- Cancer- CVC- Chemotherapy- ICU stay||Both||7/NS||42.85%||0||28.57%|||
|Table 1. Continued.|
|1983 -2005||Italy||- Cancer- Chemotherapy||NS||29/243||NS||66%||3.4%|||
|1998-2004||Brazil||- Cancer- Prior use of antibiotics- CVC- Use of steroid - Chemotherapy||Both||1/131||0||NS||NS|||
|1Number of C. guilliermondii episodes; 2Breakthrough candidemia was evaluated in this study; 3AFST performed for 46 isolated in this study; 4From January 2003 to September 2015, 4213 episodes of candidemia were identified, 1.9% (79/4213) of which were due to C. guilliermondii (however, only 36 cases were characterized and enrolled in the present study); 5In this study, only candidemia caused by uncommon Candida species were evaluated; ICU: intensive care unit, NS: not specified, TPN: total parenteral nutrition, CVC: central venous catheter|
Our patient was an infant and had a history of chemotherapy and surgery. The epidemiology and antifungal susceptibility testing of C. guilliermondii complex have been poorly studied. This complex is characterized by low susceptibility to azoles and echinocandins. In line with our study demonstrating the susceptibility of C. guilliermondii to amphotericin B and its resistance to fluconazole, numerous studies have demonstrated high MICs for azoles [3-10]. Our literature review showed that the rates of high MICs for azoles and echinocandins were 0-81% and 0-50%, respectively. Although echinocandins therapy is highly effective, emerging drug resistance is a growing threat to successful clinical management.
This is the first report describing candidemia due to C. guilliermondii in a pediatric patient in Iran. Given the high mortality rate of this infection, the early diagnosis and initiation of appropriate antifungal therapy for this infection significantly improve the patients’ survival rate and result in better outcomes. It is highly recommended to monitor the local epidemiology of this life-threatening infection and obtain awareness in this regard.
- Hirano R, Sakamoto Y, Kitazawa J, Yamamoto S, Kayaba H. Epidemiology, practice patterns, and prognostic factors for candidemia; and characteristics of fourteen patients with breakthrough Candida bloodstream infections: a single tertiary hospital experience in Japan. Infect Drug. 2018; 11:821-33.
- Cebeci Guler N, Tosun I, Aydin F. The identification of Meyerozyma guilliermondii from blood cultures and surveillance samples in a university hospital in Northeast Turkey: a ten-year survey. J Mycol Med. 2017; 27(4):506-13.
- Pemán J, Bosch M, Cantón E, Viudes Á, Jarque I, Gómez-García M. Fungemia due to Candida guilliermondii in a pediatric and adult population during a 12-year period. Diagn Microbiol Infect Dis. 2008; 60(1):109-12.
- Marcos-Zambrano LJ, Puig-Asensio M, Perez-Garcia F, Escribano P, Sanchez-Carrillo C, Zaragoza O. Candida guilliermondii complex is characterized by high antifungal resistance but low mortality in 22 cases of Candidemia. Antimicrob Agents Chemother. 2017; 61(7):17.
- Fesharaki SH, Haghani I, Mousavi B, Kargar ML, Boroumand M, Anvari MS. Endocarditis due to a co-infection of Candida albicans and Candida tropicalis in a drug abuser. J Med Microbiol. 2013; 62(Pt 11):1763-7.
- Vaezi A, Fakhim H, Khodavaisy S, Alizadeh A, Nazeri M, Soleimani A. Epidemiological and mycological characteristics of candidemia in Iran: a systematic review and meta-analysis. J Mycol Med. 2017; 27(2):146-52.
- Jung DS, Farmakiotis D, Jiang Y, Tarrand JJ, Kontoyiannis DP. Uncommon Candida species fungemia among cancer patients, Houston, Texas, USA. Emerg Infect Dis. 2015; 21(11):1942-50.
- Kimura M, Araoka H, Yamamoto H, Asano-Mori Y, Nakamura S, Yamagoe S. Clinical and microbiological characteristics of breakthrough Candidemia in allogeneic hematopoietic stem cell transplant recipients in a Japanese Hospital. Antimicrob Agents Chemother. 2017; 61(4):16.
- Harrington R, Kindermann SL, Hou Q, Taylor RJ, Azie N, Horn DL. Candidemia and invasive candidiasis among hospitalized neonates and pediatric patients. Curr Med Res Opin. 2017; 33(10):1803-12.
- Cesaro S, Tridello G, Castagnola E, Calore E, Carraro F, Mariotti I. Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high‐risk pediatric onco-hematological patients. Eur J Haematol. 2017; 99(3):240-8.
- Tseng TY, Chen TC, Ho CM, Lin PC, Chou CH, Tsai CT. Clinical features, antifungal susceptibility, and outcome of Candida guilliermondii fungemia: an experience in a tertiary hospital in mid-Taiwan. J Microbiol Immunol Infect. 2018; 51(4):552-8.
- Liu WL, Lai CC, Li MC, Wu CJ, Ko WC, Hung YL. Clinical manifestations of candidemia caused by uncommon Candida species and antifungal susceptibility of the isolates in a regional hospital in Taiwan, 2007-2014. J Microbiol Immunol Infect. 2017; 17:S1684.
- Neufeld PM, Melhem Mde S, Szeszs MW, Ribeiro MD, Amorim Ede L, da Silva M. Nosocomial candidiasis in Rio de Janeiro State: distribution and fluconazole susceptibility profile. Braz J Microbiol. 2015; 46(2):477-84.
- Asensio A, Munez E, Cantero M, Ramos A. Candida guilliermondii fungemia in hospitalized patients epidemiologically linked to a patient care attendant. Am J Infect Control. 2015; 43(9):1012-4.
- Hirano R, Sakamoto Y, Kudo K, Ohnishi M. Retrospective analysis of mortality and Candida isolates of 75 patients with candidemia: a single hospital experience. Infect Drug Resist. 2015; 8:199-205.
- Tang HJ, Liu WL, Lin HL, Lai CC. Epidemiology and prognostic factors of candidemia in elderly patients. Geriatr Gerontol Int. 2015; 15(6):688-93.
- Hii IM, Chang HL, Lin LC, Lee YL, Liu YM, Liu CE. Changing epidemiology of candidemia in a medical center in middle Taiwan. J Microbiol Immunol Infect. 2015; 48(3):306-15.
- Guinea J, Zaragoza O, Escribano P, Martin-Mazuelos E, Peman J, Sanchez-Reus F. Molecular identification and antifungal susceptibility of yeast isolates causing fungemia collected in a population-based study in Spain in 2010 and 2011. Antimicrob Agents Chemother. 2014; 58(3):1529-37.
- Marcos-Zambrano LJ, Escribano P, Sanchez C, Munoz P, Bouza E, Guinea J. Antifungal resistance to fluconazole and echinocandins is not emerging in yeast isolates causing fungemia in a Spanish tertiary care center. Antimicrob Agents Chemother. 2014; 58(8):4565-72.
- Tak V, Mathur P, Varghese P, Gunjiyal J, Xess I, Misra MC. The epidemiological profile of candidemia at an Indian trauma care center. J Lab Physicians. 2014; 6(2):96-101.
- Oliveira VK, Ruiz Lda S, Oliveira NA, Moreira D, Hahn RC, Melo AS. Fungemia caused by Candida species in a children's public hospital in the city of Sao Paulo, Brazil: study in the period 2007-2010. Rev Inst Med Trop Sao Paulo. 2014; 56(4):301-5.
- Pfaller MA, Andes DR, Diekema DJ, Horn DL, Reboli AC, Rotstein C. 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. PloS One. 2014; 9(7):e101510.
- Wu Z, Liu Y, Feng X, Liu Y, Wang S, Zhu X. Candidemia: incidence rates, type of species, and risk factors at a tertiary care academic hospital in China. Int J Infect Dis. 2014; 22:4-8.
- Parmeland L, Gazon M, Guerin C, Argaud L, Lehot JJ, Bastien O. Candida albicans and non-Candida albicans fungemia in an institutional hospital during a decade. Med Mycol. 2013; 51(1):33-7.
- Chang TP, Ho MW, Yang YL, Lo PC, Lin PS, Wang AH. Distribution and drug susceptibilities of Candida species causing candidemia from a medical center in central Taiwan. J Infect Chemother. 2013; 19(6):1065-71.
- De Carvalho Parahym AM, De Melo LR, De Morais VL, Neves RP. Candidiasis in pediatric patients with cancer interned in a university hospital. Braz J Microbiol. 2009; 40(2):321-4.
- Medeiros EA, Lott TJ, Colombo AL, Godoy P, Coutinho AP, Braga MS. Evidence for a pseudo-outbreak of Candida guilliermondii fungemia in a university hospital in Brazil. J Clin Microbiol. 2007; 45(3):942-7.
- Metwally L, Walker MJ, Coyle PV, Hay RJ, Hedderwick S, McCloskey BV. Trends in candidemia and antifungal susceptibility in a university hospital in Northern Ireland 2001-2006. J Infect. 2007; 55(2):174-8.
- Girmenia C, Pizzarelli G, Cristini F, Barchiesi F, Spreghini E, Scalise G. Candida guilliermondii fungemia in patients with hematologic malignancies. J Clin Microbiol. 2006; 44(7):2458-64.
- Aquino VR, Lunardi LW, Goldani LZ, Barth AL. Prevalence, susceptibility profile for fluconazole and risk factors for candidemia in a tertiary care hospital in southern Brazil. Braz J Infect Dis. 2005; 9(5):411-8.