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ABSTRACTThe yeast Candida albicanscauses life-threatening candidemia. A general-purpose genotype (GPG; corresponds to clade 1) causes more infections than other C. albicansgenotypes. To investigate if GPG strains also cause higher mortality, we developed a duplex PCR assay which was 98% accurate in identifying GPG strains in an international collection of strains typed with probe Ca3. We applied the assay to 635 European C. albicanscandidemia isolates. Of these, 18% conformed to the GPG genotype, 4% were of a borderline genotype, and 78% were of a non-GPG genotype, broadly consistent with genotype distributions in earlier studies. The prevalence of GPG strains was increased in females and in younger patients, exceeding 40% in infants aged =1 year. Logistic regression confirmed sex and age as significant determinants of GPG prevalence. Across the entire patient cohort, there was no difference in mortality for patients infected with GPG strains or other strains (36% versus 37%). However, mortality in patients aged =48 years was 33% for infection with GPG strains but only 15% for infection with other strains (ztest; P< 0.01). Mortality rates associated with GPG and non-GPG strains were comparable in older patients (39% versus 46%). A logistic regression analysis confirmed the age-dependent impact of genotype on mortality. Thus, GPG strains may be more virulent than other strains in younger patients. Because candidemia is usually caused by endogenous strains, our PCR assay could potentially be used as a risk assessment tool for identifying younger patients most at risk of death from candidemia.

Objectives: To analyse the clinical features associated with deep Candidainfection (DCI) and the outcome in children with leukaemia, and to evaluate various diagnostic methods. Materials and methods: Serum samples were analysed to determine CandidaIgA, IgM and IgG antibodies and detect free C. albicansglucoprotein antigen and C. enolaseantigen in eight children who had nine episodes of DCI and six with suspected DCI. Results: DCI occurred shortly after the leukaemia diagnosis (median 40 days) or after the leukaemia relapse (median 30 days). Children with DCI had fever (100%), skin lesions/exanthema (45%), oral thrush (45%), oesophagitis (22%) and laryngo‐tracheitis (22%). Candidaendocarditis, arthritis and hepatic candidosis were diagnosed in one patient each. Two children with disseminated candidosis died in leukaemia relapse. In patients with C. albicansinfections serology had a sensitivity of 83%. However, in patients with C. parapsilosisinfection antibody detection was negative. As the patients were cured of their Candidainfection, the IgG antibodies disappeared and the IgM and IgA antibodies fell within the normal range for age. Conclusion: DCI in children occurs shortly after the leukaemia diagnosis or shortly after relapse of leukaemia. The clinical features are many. Candidaserology may help to diagnose or confirm DCI. The dynamics of antibody titres may help to establish the efficacy of antifungal treatment.

Fifteen children who fulfilled the criteria of chronic non-specific diarrhea of infancy were evaluated for intestinal bacterial overgrowth. In 10 of 11 successfully investigated children we found bacterial overgrowth of the small intestine by upper respiratory tract microflora. In 9 of 10 children (group I) treated with trimethoprim-sul-famethoxazole the diarrhea ceased immediately, whereas in all children in group 11 (n = 5; 3 children excluded because of growth of Yersinia enterocolitica) treated with low-lactose diet the diarrhea persisted (p = 0.004). The results indicate that bacterial overgrowth of the small intestine by upper respiratory tract microflora may be a cause of chronic non-specific diarrhea and that this diarrhea may be successfully treated with trimethoprim-sulfamethoxazole.

A prospective randomized multi-center trial was initiated comparing PCR-based preemptive and empirical antifungal therapy with AmBisome in patients after allogeneic stem cell transplantation. A total of 408 patients were randomized at the time of transplant to the antifungal treatment strategy. PCR screening was planned twice weekly during stay in hospital and once weekly after discharge until day 100 post-transplantation. Antifungal prophylaxis consisted of up to 200 mg fluconazole/day. Antifungal therapy was initiated in the PCR group in PCR+ patients with signs of infection and patients with 2 consecutive positive PCR results, and in the empirical treatment group (group B) after 120 hours of febrile neutropenia not responding to broad-spectrum antibacterial therapy. Antifungal treatment consisted of AmBisome at 3 mg/kg for 3 days (loading dose) followed by AmBisome at 1 mg/kg in clinically stable patients, AmBisome at 3 mg/kg was continued in clinically unstable patients. Treatment was stopped according to pre-defined study rules. The two arms were well balanced with regard to age, gender, donor type, underlying disease and stage, and conditioning regimens applied. Out of 403 evaluable patients 196 were randomized to group A and 207 to group B. AmBisome therapy was initiated in 109 patients in group A and in 76 patients in group B (P<0.05). Eleven patients in group A and 16 patients in group B developed proven invasive fungal infections (IFI), overall mortality at 100 and 180 days was not different. Survival curves demonstrated a lower mortality until day 30 post-transplantation for patients receiving PCR-based antifungal therapy with AmBisome (deaths in group A, n=4; group B, n=13; P=0.03). During this early time period when regular PCR-screening was performed, only 1 patient in group A (candidiasis) and 5 patients in group B (invasive aspergillosis, n=1; candidiasis, n=4) succumbed to IFI (P=0.1). This study prospectively compared PCR-based versus empirical antifungal therapy with AmBisome after allogeneic SCT. A reduction in early mortality and a trend for a lower rate of proven invasive fungal infections was documented until day 30 post-transplantation indicating that close fungal PCR monitoring allows to stratify patients at high risk for the subsequent development of invasive fungal infections. Survival at day 100 and 180 post-transplantation was not different.

A prospective randomized multi-center trial was initiated comparing PCR-based preemptive and empirical antifungal therapy with AmBisome in patients after allogeneic stem cell transplantation.