The ever-evolving landscape of candidaemia in patients with acute leukaemia: non-susceptibility to caspofungin and multidrug resistance are associated with increased mortality.

OBJECTIVES The epidemiology and clinical course of candidaemia in patients with acute leukaemia, a population frequently exposed to antifungals, have not been extensively studied. In the present contemporary series of acute leukaemia patients, we describe patient characteristics, Candida species and MIC distributions and investigate the association between antifungal resistance and all-cause mortality. METHODS We performed a retrospective review of medical records and microbiological data of adult patients with acute leukaemia or high-risk myelodysplastic syndrome with at least one positive blood culture for Candida species at the MD Anderson Cancer Center between January 2008 and October 2012. Susceptibility was defined according to the 2012 epidemiological cut-off values and clinical breakpoints. RESULTS We identified 67 episodes of candidaemia in 65 patients. Almost all episodes (94%) occurred in patients who were receiving antifungal agents, 71% in patients receiving an echinocandin. Almost all isolates (99%) were of non-albicans Candida species [most frequently Candida parapsilosis (32%), Candida tropicalis (23%) and Candida glabrata (20%)]. Caspofungin non-susceptibility was significantly associated with fluconazole resistance (P < 0.001). Non-susceptibility to caspofungin and multidrug resistance were associated with excess 14 day [adjusted HR (aHR) 3.02 (95% CI 1.28-7.09), P = 0.011 and aHR 3.02 (95% CI 1.27-7.14), P = 0.012, respectively] and 30 day [aHR 2.96 (95% CI 1.38-6.37), P = 0.005 and aHR 2.86 (95% CI 1.31-6.21), P = 0.008, respectively] all-cause mortality. CONCLUSIONS In patients with acute leukaemia, a shift in candidaemia epidemiology was noted with a 99% predominance of non-albicans species. Non-susceptibility of Candida strains to caspofungin or multidrug resistance were independent markers of poor outcome in this patient population.

[1]  D. Kontoyiannis,et al.  Emerging Issues With Diagnosis and Management of Fungal Infections in Solid Organ Transplant Recipients , 2015, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  D. Kontoyiannis,et al.  Early initiation of appropriate treatment is associated with increased survival in cancer patients with Candida glabrata fungaemia: a potential benefit from infectious disease consultation. , 2015, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[3]  D. Kontoyiannis,et al.  1446Fungemia due to Uncommon Candida species in Patients with Cancer: Increasing Incidence, Frequent Resistance and High Mortality rates , 2014 .

[4]  D. Kontoyiannis,et al.  Drug-Resistant Candida glabrata Infection in Cancer Patients , 2014, Emerging infectious diseases.

[5]  D. Kontoyiannis,et al.  Efficacy and Tolerability of Micafungin Monotherapy for Candidemia and Deep-Seated Candidiasis in Adults with Cancer , 2014, Antimicrobial Agents and Chemotherapy.

[6]  T. Perl,et al.  Epidemiology of Candida kefyr in Patients with Hematologic Malignancies , 2014, Journal of Clinical Microbiology.

[7]  J. Sohn,et al.  Clinical impact of time to positivity for Candida species on mortality in patients with candidaemia. , 2013, The Journal of antimicrobial chemotherapy.

[8]  Russell E. Lewis,et al.  Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20‐year autopsy study , 2013, Mycoses.

[9]  Anand K. Ramasubramanian,et al.  Antifungal therapy with an emphasis on biofilms. , 2013, Current opinion in pharmacology.

[10]  C. Clancy,et al.  Anidulafungin and Micafungin MIC Breakpoints Are Superior to That of Caspofungin for Identifying FKS Mutant Candida glabrata Strains and Echinocandin Resistance , 2013, Antimicrobial Agents and Chemotherapy.

[11]  M. Castanheira,et al.  Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  C. Clancy,et al.  Caspofungin MICs Correlate with Treatment Outcomes among Patients with Candida glabrata Invasive Candidiasis and Prior Echinocandin Exposure , 2013, Antimicrobial Agents and Chemotherapy.

[13]  L. Ostrosky-Zeichner Candida glabrata and FKS mutations: witnessing the emergence of the true multidrug-resistant Candida. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  J. Garnacho-Montero,et al.  Impact on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections. , 2013, The Journal of antimicrobial chemotherapy.

[15]  M. Ruhnke,et al.  Doxorubicin selects for fluconazole-resistant petite mutants in Candida glabrata isolates. , 2012, International journal of medical microbiology : IJMM.

[16]  M. Pfaller,et al.  Progress in Antifungal Susceptibility Testing of Candida spp. by Use of Clinical and Laboratory Standards Institute Broth Microdilution Methods, 2010 to 2012 , 2012, Journal of Clinical Microbiology.

[17]  J. Heitman,et al.  Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata , 2012, PLoS pathogens.

[18]  J. Sobel,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. , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  Y. Wiener-Well,et al.  Antibiotic Exposure as a Risk Factor for Fluconazole-Resistant Candida Bloodstream Infection , 2012, Antimicrobial Agents and Chemotherapy.

[20]  M. Slavin,et al.  The case for antifungal stewardship , 2012, Current opinion in infectious diseases.

[21]  D. Kontoyiannis,et al.  Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. , 2011, The Journal of infectious diseases.

[22]  B. Alexander,et al.  Fungal infections in transplant and oncology patients. , 2011, Hematology/oncology clinics of North America.

[23]  E. Anaissie,et al.  Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  D. Marriott,et al.  Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death. , 2010, The Journal of antimicrobial chemotherapy.

[25]  Russell E. Lewis,et al.  Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001‐2007) , 2009, Cancer.

[26]  J. Sobel,et al.  Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  T. Chiou,et al.  Candidemia in cancer patients: impact of early removal of non-tunneled central venous catheters on outcome. , 2009, The Journal of infection.

[28]  D. Kontoyiannis,et al.  The changing epidemiology of invasive candidiasis , 2008, Cancer.

[29]  J. Perfect,et al.  Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. , 2007, The New England journal of medicine.

[30]  T. Robak,et al.  Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. , 2006, Current medicinal chemistry.

[31]  L. Pagano,et al.  Design and Methods , 2022 .

[32]  H. Danawi,et al.  Management of central venous catheters in patients with cancer and candidemia. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  J. Mackey,et al.  Nucleoside analogues and nucleobases in cancer treatment. , 2002, The Lancet. Oncology.

[34]  G. Samonis,et al.  Infectious complications of purine analog therapy , 2001, Current opinion in infectious diseases.

[35]  E. Anaissie,et al.  Predictors of adverse outcome in cancer patients with candidemia. , 1998, The American journal of medicine.

[36]  B. Cheson Infectious and immunosuppressive complications of purine analog therapy. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  M. Cheang,et al.  Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen. , 1995, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[38]  R. Wenzel Nosocomial candidemia: risk factors and attributable mortality. , 1995, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.