Christopher C. Kibbler

Epidemiology of Candidaemia in Europe: Results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study

In order to update the epidemiological and mycological profile of candidaemia in Europe, the European Confederation of Medical Mycology conducted a prospective, sequential, hospital population-based study from September 1997 to December 1999. A total of 2,089 cases were documented by 106 institutions in seven European countries. Rates of candidaemia ranging from 0.20 to 0.38 per 1,000 admissions were reported. Candida albicans was identified in 56% of cases. Non-albicans Candida species were most frequently isolated from patients with haematological malignancies (65%). With increasing age, an increasing incidence of Candida glabrata was seen. The 30-day mortality rate was 37.9%. The survey results underline the burden of candidaemia in a wide range of patient populations, confirm the importance of non-albicans species, and provide baseline data for future surveillance studies at a European level.

British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections

Outcomes for invasive fungal infections have greatly improved in the past decade, and several new antifungal drugs have been or will be licensed in the next few years. Early accurate diagnosis and appropriate treatment have major impact on survival. In a 1995 survey of laboratory practice in the UK for mycology, major disparities were seen, with many laboratories not undertaking even simple diagnostic procedures. Delays in processing and inadequate procedures for handling samples, incomplete or delayed reporting of results, or a combination of these, compromise the care of patients. In randomised trials of antifungal chemotherapy, optimum treatments and good alternatives for others have been defined for some infections. High-quality care requires a multidisciplinary approach to diagnosis and management. In this review, we propose microbiology, histopathology, radiology, and clinical auditing standards, with the evidence base for each reviewed. The standards are absolutes, and, therefore, provide a straightforward basis for improving services to patients if they are all implemented.

Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation

Invasive fungal infections are increasing in incidence and now affect as many as 50% of neutropenic/bone marrow transplant patients and 5 to 20% of solid organ transplant recipients. Unfortunately, many of the diagnostic tests available have a low sensitivity. The guidelines presented here have been produced by a working party of the British Society for Medical Mycology in an attempt to optimise the use of these tests. The yield of fungi from blood cultures can be increased by ensuring that at least 20 ml of blood are taken for aerobic culture, by using more than one method of blood culture, and by employing terminal subculture if continuous monitoring systems are used with a five-day incubation protocol. Skin lesions in febrile neutropenic patients should be biopsied and cultured for fungi. The detection of galactomannan in blood or urine is of value in diagnosing invasive aspergillosis only if tests are performed at least twice weekly in highrisk patients. Antigen detection tests for invasive candidiasis are less valuable. Computed tomography scanning is particularly valuable in diagnosing invasive pulmonary fungal infection when the chest radiograph is negative or shows only minimal changes. Bronchoalveolar lavage is most useful in patients with diffuse changes on computed tomography scan. The major advances in the diagnosis of invasive fungal infection in patients with haematological malignancy or solid organ transplantation have been in the use of imaging techniques, rather than in the development of new mycological methods in the routine laboratory.

Toxoplasmosis in bone marrow transplantation: a report of two cases and systematic review of the literature

Toxoplasma infection represents a rare but often fatal complication in bone marrow transplant (BMT) recipients. We report two cases of toxoplasmosis: one of successfully treated cerebral toxoplasmosis after peripheral blood stem cell transplantation, and a fatal case of pulmonary toxoplasmosis in a BMT recipient. We have systematically reviewed the 110 published cases of toxoplasmosis following BMT. We analyzed the pre-transplant and clinical features of BMT recipients developing toxoplasmosis, together with the diagnostic procedures used and treatment given. By univariate and multivariate statistical analysis we analyzed the risk factors for diagnosis (during life vs post-mortem) and Toxoplasma-related mortality. Ante-mortem diagnosis was made in 47% of cases. Site of infection (P = 0.02; odds ratio 10.8), presence of symptoms at onset (P = 0.01) and conditioning regimen (P = 0.04) were factors influencing whether the diagnosis was made before or after death. Overall mortality rate was 80% and that attributed to toxoplasmosis was 66%. Variables influencing outcome were: site of infection (P = 0.02; odds ratio 5.28), day of onset (P = 0.04) and conditioning regimen (P = 0.04). Underlying disease (P = 0.02; odds ratio 9.45), among patients diagnosed before death, was the most significant factor influencing outcome.

Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation

Antifungal prophylaxis for allogeneic haematopoietic stem‐cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open‐label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P < 0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P < 0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment‐related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P < 0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals.

Candida guilliermondii, an Opportunistic Fungal Pathogen with Decreased Susceptibility to Fluconazole: Geographic and Temporal Trends from the ARTEMIS DISK Antifungal Surveillance Program

ABSTRACT Although a rare cause of invasive candidiasis, Candida guilliermondii has been reported to exhibit decreased susceptibility to antifungal agents. Aside from case reports and small surveys, there is little information regarding the epidemiology and antifungal susceptibility profile of C. guilliermondii. We report geographic and temporal trends in the isolation and antifungal susceptibilities of 1,029 C. guilliermondii clinical isolates collected from 127 medical centers as part of the ARTEMIS DISK Antifungal Surveillance Program. In addition, we report the in vitro susceptibility of 132 bloodstream isolates of C. guilliermondii to caspofungin. C. guilliermondii represented 1.4% of the 75,761 isolates collected from 2001 to 2003 and was most common among isolates from Latin America (3.7% versus 0.6 to 1.1%). Decreased susceptibility to fluconazole was noted (75% susceptible; range, 68 to 77% across regions), and voriconazole was more active in vitro against C. guilliermondii than fluconazole (91% susceptible; range, 88 to 93% across regions). Fluconazole was least active against isolates from dermatology (58%) and surgical (69%) services and against isolates associated with skin and soft tissue infection (68%, compared to 85% susceptible for bloodstream isolates). There was no evidence of increasing azole resistance over time among C. guilliermondii isolates tested from 2001 to 2003. Of 132 bloodstream isolates of C. guilliermondii tested against caspofungin, most were inhibited by ≤2 μg/ml (96%; MIC50/MIC90, 0.5/1.0 μg/ml). C. guilliermondii, a species that exhibits reduced susceptibility to fluconazole, is the sixth most frequently isolated Candida species from this large survey and may be an emerging pathogen in Latin America.

Management of Invasive Pulmonary Aspergillosis in Hematology Patients: A Review of 87 Consecutive Cases at a Single Institution

Eighty-seven patients with hematologic malignancies and invasive pulmonary aspergillosis (IPA) were identified between 1982 and 1995. Of these, 39 underwent lung resection on the basis of radiological detection of at least 1 lesion with imaging suggestive of aspergillosis (LISA). IPA was confirmed histologically in 35. The presence of LISA had 90% positive predictive value for IPA. The actuarial survival at 2 years was 36% for 37 patients treated surgically, 20% for 12 patients with unresected LISA but no cultures of Aspergillus species, and 5% for 21 patients diagnosed only by isolation of Aspergillus from respiratory secretions. Analysis by proportional hazard models showed a significant independent negative association between the radiological appearance of LISA and death from all causes. Relapsed hematologic disease was independently significantly associated with death. Age, sex, surgery, previous bone marrow transplantation, or Aspergillus isolation were not independent predictors of death. IPA presenting as LISA carries a relatively good prognosis, possibly explaining the better survival of patients undergoing surgery for such lesions.

Candida rugosa, an Emerging Fungal Pathogen with Resistance to Azoles: Geographic and Temporal Trends from the ARTEMIS DISK Antifungal Surveillance Program

ABSTRACT Candida rugosa is a fungus that appears to be emerging as a cause of infection in some geographic regions. We utilized the extensive database of the ARTEMIS DISK Antifungal Surveillance Program to describe the geographic and temporal trends in the isolation of C. rugosa from clinical specimens and the in vitro susceptibilities of 452 isolates to fluconazole and voriconazole. C. rugosa accounted for 0.4% of 134,715 isolates of Candida, and the frequency of isolation increased from 0.03% to 0.4% over the 6.5-year study period (1997 to 2003). C. rugosa was most common in the Latin American region (2.7% versus 0.1 to 0.4%). Decreased susceptibility to fluconazole (40.5% susceptible) was observed in all geographic regions; however, isolates from Europe and North America were much more susceptible (97 to 100%) to voriconazole than those from other geographic regions (55.8 to 58.8%). C. rugosa was most often isolated from blood and urine in patients hospitalized at the Medical and Surgical inpatient services. Notably, bloodstream isolates were the least susceptible to both fluconazole and voriconazole. C. rugosa should be considered, along with the established pathogens Candida krusei and Candida glabrata, as a species of Candida with reduced susceptibility to the azole antifungal agents.

ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia

Invasive fungal diseases (IFDs) continue to cause considerable morbidity and mortality in patients with haematological malignancy. Diagnosis of IFD is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often reported to be low, which may at least in part be due to sub-optimal sampling or subsequent handling in the routine microbiological laboratory. Therefore, a working group of the European Conference in Infections in Leukaemia was convened in 2009 with the task of reviewing the classical diagnostic procedures and providing recommendations for their optimal use. The recommendations were presented and approved at the ECIL-3 conference in September 2009. Although new serological and molecular tests are examined in separate papers, this review focuses on sample types, microscopy and culture procedures, antifungal susceptibility testing and imaging. The performance and limitations of these procedures are discussed and recommendations are provided on when and how to use them and how to interpret the results.

Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis

BackgroundThe addition of Rituximab (R) to standard chemotherapy (C) has been reported to improve the end of treatment outcome in patients affected by CD-20 positive malignant lymphomas (CD20+ ML). Nevertheless, given the profound and prolonged immunosuppression produced by R there are concerns that severe infections may arise. A systematic review and meta-analysis were performed to determine whether or not the addition of R to C may increase the risk of severe infections in adults undergoing induction therapy for CD20+ ML.MethodsOnly randomised controlled trials comparing R-C to C standard alone in adult patients with CD20+ ML were included. Meta-analysis was performed on overall incidence of severe infection, risk of dying as the consequence of infection, risk of febrile neutropenia, risk of severe leucopenia, risk of severe granulocytopenia and overall response assuming a fixed effect model. Heterogeneity was investigated, if present and I2 >20%, according to several predefined baseline characteristics of the study populations.ResultsSeveral relevant results have emerged. First, the addition of R to standard C does not increase the overall risk of severe infections (RR = 1.00; 95% CI 0.87 to 1.14) nor does it increase the risk of dying as a consequence of infection (RR = 1.60; 95% CI 0.68 to 3.75). Second, we confirmed that the addition of R to standard C increases the proportion of overall response (RR = 1.12; 95% CI 1.09 to 1.15), but it also increases the risk of severe leucopenia (RR = 1.24; 95% CI 1.12 to 1.37) and granulocytopenia (RR = 1.07; 95% CI 1.02 to 1.12).ConclusionsR-C is superior to standard C in terms of overall response and it does not increase the overall incidence of severe infection. However, data on special groups of patients (for example, HIV positive subjects and HBV carriers) are lacking. In our opinion more studies are needed to explore the potential effect of R on silent and chronic viral infections.