E. Geoffrey Playford

Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials1

Background. Interleukin 2 receptor antagonists (IL-2Ra) are increasingly used to treat renal transplant recipients. This study aims to systematically identify and summarize the effects of using IL-2Ra as induction immunosuppression, as an addition to standard therapy, or as an alternative to other antibody therapy. Methods. Databases, reference lists, and abstracts of conference proceedings were searched extensively to identify relevant randomized controlled trials in all languages. Data were synthesized using the random effects model. Results are expressed as relative risk (RR), with 95% confidence intervals (CI). Results. A total of 117 reports from 38 trials involving 4,893 participants were included. When IL-2Ra were compared with placebo (17 trials; 2,786 patients), graft loss was not significantly different at 1 year (14 trials: RR 0.84; CI 0.64–1.10) or 3 years (4 trials: RR 1.08; CI 0.71–1.64). Acute rejection was significantly reduced at 6 months (12 trials: RR 0.66; CI 0.59–0.74) and at 1 year (10 trials: RR 0.67; CI 0.60–0.75). At 1 year, cytomegalovirus infection (7 trials: RR 0.82; CI 0.65–1.03) and malignancy (9 trials: RR 0.67; CI 0.33–1.36) were not significantly different. When IL-2Ra were compared with other antibody therapy, no significant differences in treatment effects were demonstrated, but IL-2Ra had significantly fewer side effects. Conclusions. Given a 40% risk of rejection, seven patients would need treatment with IL-2Ra in addition to standard therapy, to prevent one patient from undergoing rejection, with no definite improvement in graft or patient survival. There is no apparent difference between basiliximab and daclizumab.

Active surveillance for candidemia, Australia.

This infection has a high death rate and is predominantly associated with healthcare.

Candidemia in nonneutropenic critically ill patients: risk factors for non-albicans Candida spp.

Objective:The objective of this study was to determine the clinical features associated with candidemia caused by non-albicans Candida spp. and with potentially fluconazole-resistant Candida spp. (C. glabrata and C. krusei) among candidemic intensive care unit patients. Design:The authors conducted a nationwide prospective cohort study. Setting:The study was conducted in Australian intensive care units. Patients:All patients with intensive care unit-acquired candidemia over a 3-yr period were included in the study. Measurements:Clinical risk factors occurring up to 30 days before candidemia, Candida spp. associated with candidemia, and outcomes were determined. Risk factors associated with either non-albicans Candida spp. or with potentially fluconazole-resistant Candida spp. (C. glabrata or C. krusei) were assessed using multivariate logistic regression. Main Results:Among 179 episodes of intensive care unit-acquired candidemia, C. albicans accounted for 62%, C. glabrata 18%, C. krusei 4%, and other Candida spp. 16%. Independently significant variables associated with non-albicans Candida bloodstream infection included recent prior gastrointestinal surgery (adjusted odds ratio, 2.87; 95% confidence interval, 1.68–4.91) and recent prior systemic antifungal exposure (4.6; 1.36–15.53). Those associated with potentially fluconazole-resistant candidemia included recent prior gastrointestinal surgery (3.31; 1.79–6.11) and recent prior fluconazole exposure (5.47; 1.23–24.32). No significant differences in outcomes were demonstrated for non-albicans or potentially fluconazole-resistant candidemia. Conclusions:Among candidemic intensive care unit patients, prior gastrointestinal surgery and systemic antifungal exposure were significantly associated with both a non-albicans Candida spp. and a potentially fluconazole-resistant Candida spp. LEARNING OBJECTIVESOn completion of this article, the reader should be able to:List clinical features discriminating between candidemia caused by C. albicans and those caused by other species.Describe predisposing factors that help discriminate between candidemia which are potentially fluconazole-resistant.Use this information in a clinical setting.Dr. Playford has disclosed that he was a consultant/advisor for Pfizer and Merck; was on the advisory board for Schering-Plough; and is a recipient of grant/research funds from Pfizer and Merck. Dr. Marriott has disclosed that she was/is a recipient of grant/research funds from Pfizer; was/is a consultant/advisor for Merck, Sharpe & Dohme and Sanofi-Pasteur; and was/is on the advisory board for Roche. Dr. Nguyen has disclosed that he has no financial relationships with or interests in any commercial companies pertaining to this educational activity. Dr. Chen has disclosed that she was a recipient of grant/research funds from Pfizer; is a recipient of grant/research funds from Gilead Sciences, Inc.; and is on the advisory board for Gilead Sciences, Inc. and Pfizer Australia. Dr. Ellis has disclosed that he was/is a recipient of grant/research funds from Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia; was/is a consultant/advisor for Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia; and was/is on the speakers bureau for Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia. Dr. Slavin has disclosed that she was/is a recipient of grant/research funds from Pfizer Inc., Gilead Sciences, Schering-Plough, and Merck and Co.; and was/is on the advisory board for Pfizer Inc., Gilead Sciences, Schering-Plough, and Merck and Co. Dr. Sorrell has disclosed that she was/is a recipient of grant/research funds from Merck, Sharpe & Dohme Australia, Pfizer, and Gilead; and was/is a consultant/advisor for Pfizer, Merck, Gilead, and Schering-Plough.All faculty and staff in a position to control the content of this CME activity have disclosed that they have no financial relationship with, or financial interests in, any commercial companies pertaining to this educational activity.Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity.Visit the Critical Care Medicine Web Site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy

A 32-year-old woman was treated with long-term voriconazole therapy for recurrent aspergillosis associated with chronic granulomatous disease. A short time after commencement of voriconazole therapy, a severe photosensitivity reaction developed. Continued voriconazole exposure led to the development of multifocal facial squamous cell carcinomas. The photosensitivity reaction resolved after the patient changed therapy to posaconazole.

Antifungal therapy in invasive fungal infections

Early treatment of invasive fungal infections (IFIs) is essential for optimal clinical outcomes. Standard antifungal drugs (polyenes, azoles and echinocandins) are not predictably effective against emerging yeasts and filamentous fungi and may cause undesirable side effects. Species identification can guide antifungal selection for invasive candidiasis, but not less common moulds such as Scedosporium and Fusarium spp. Management strategies targeted to those at highest risk (prophylaxis), those with clinical signs of infection not responsive to antibacterials (empiric therapy) and those with occult infection (asymptomatic but with positive fungal biomarkers) produce better outcomes than therapy predicated on identification of a fungal pathogen, but require comparative evaluation. Appropriate dosing and consideration of pharmacokinetic parameters (including therapeutic drug monitoring) are important with newer triazoles. New therapies such as addition of the iron chelator, deferasirox, in the treatment of zygomycosis in diabetic patients, appear promising but additional agents with new targets of action are urgently needed.

Hendra virus: an emerging paramyxovirus in Australia

Hendra virus, first identified in 1994 in Queensland, is an emerging zoonotic pathogen gaining importance in Australia because a growing number of infections are reported in horses and people. The virus, a member of the family Paramyxoviridae (genus Henipavirus), is transmitted to horses by pteropid bats (fruit bats or flying foxes), with human infection a result of direct contact with infected horses. Case-fatality rate is high in both horses and people, and so far, more than 60 horses and four people have died from Hendra virus infection in Australia. Human infection is characterised by an acute encephalitic syndrome or relapsing encephalitis, for which no effective treatment is currently available. Recent identification of Hendra virus infection in a domestic animal outside the laboratory setting, and the large range of pteropid bats in Australia, underpins the potential of this virus to cause greater morbidity and mortality in both rural and urban populations and its importance to both veterinary and human health. Attempts at treatment with ribavirin and chloroquine have been unsuccessful. Education, hygiene, and infection control measures have hitherto been the mainstay of prevention, while access to monoclonal antibody treatment and development of an animal vaccine offer further opportunities for disease prevention and control.

Determinants of mortality in non-neutropenic ICU patients with candidaemia

IntroductionCandidaemia in critically-ill intensive care unit (ICU) patients is associated with high crude mortality. Determinants of mortality – particularly those amenable to potential modification – are incompletely defined.MethodsA nationwide prospective clinical and microbiological cohort study of all episodes of ICU-acquired candidaemia occurring in non-neutropenic adults was undertaken in Australian ICUs between 2001 and 2004. Multivariate Cox regression analyses were performed to determine independently significant variables associated with mortality.Results183 episodes of ICU-acquired candidaemia occurred in 183 patients during the study period. Of the 179 with microbiological data, Candida albicans accounted for 111 (62%) episodes and Candida glabrata, 32 (18%). Outcome data were available for 173: crude hospital mortality at 30 days was 56%. Host factors (older age, ICU admission diagnosis, mechanical ventilation and ICU admission diagnosis) and failure to receive systemic antifungal therapy were significantly associated with mortality on multivariate analysis. Among the subset who received initial fluconazole therapy (n = 93), the crude mortality was 52%. Host factors (increasing age and haemodialysis receipt), but not organism- (Candida species, fluconazole MIC), pharmacokinetic- (fluconazole dose, time to initiation), or pharmacodynamic-related parameters (fluconazole dose:MIC ratio) were associated with mortality. Process of care measures advocated in recent guidelines were implemented inconsistently: follow-up blood cultures were obtained in 68% of patients, central venous catheters removed within five days in 80% and ophthalmological examination performed in 36%.ConclusionsCrude mortality remains high in Australian ICU patients with candidaemia and is overwhelmingly related to host factors but not treatment variables (the time to initiation of antifungals or fluconazole pharmacokinetic and pharmacodynamic factors). The role and timing of early antifungal intervention in critically-ill ICU patients requires further investigation.

Intradermal versus intramuscular hepatitis B vaccination in hemodialysis patients: a prospective open-label randomized controlled trial in nonresponders to primary vaccination.

BACKGROUND Primary hepatitis B virus (HBV) vaccination through the intramuscular (IM) route is less efficacious in dialysis patients than in the general population. Previous studies suggest improved seroconversion with intradermal (ID) vaccination. STUDY DESIGN Prospective open-label randomized controlled trial. SETTING & PARTICIPANTS Hemodialysis patients nonresponsive to primary HBV vaccination. INTERVENTION Revaccination with either ID (10 microg of vaccine every week for 8 weeks) [DOSAGE ERROR CORRECTED] or IM (40 microg of vaccine at weeks 1 and 8) HBV vaccine . OUTCOMES PRIMARY OUTCOME proportion of patients achieving HBV surface antibody (anti-HBs) titer of 10 IU/L or greater within 2 months of vaccination course. SECONDARY OUTCOMES time to seroconversion, predictors of seroconversion, peak antibody titer, duration of seroprotection, and safety and tolerability of vaccine. MEASUREMENTS Anti-HBs titer to 24 months. RESULTS 59 patients were analyzed. Seroconversion rates were 79% ID versus 40% IM (P = 0.002). The unadjusted odds ratio for seroconversion for ID versus IM was 5.5 (95% confidence interval [CI], 1.6 to 18.4) and increased with adjustment for baseline differences. The only factor predictive of seroconversion was the ID vaccination route. The geometric mean peak antibody titer was significantly greater in the ID versus IM group: 239 IU/L (95% CI, 131 to 434) versus 78 IU/L (95% CI, 36 to 168; P < 0.001). There was a trend toward longer duration of seroprotection with ID vaccination. ID vaccine was safe and well tolerated. LIMITATIONS Inability to distinguish whether the mechanism of the greater efficacy of ID vaccination was the cumulative effect of multiple injections or route of administration; use of anti-HBs as a surrogate marker of protection; lack of evidence of long-term protection. CONCLUSIONS Significantly greater seroconversion rates and peak antibody titers can be achieved with ID compared with IM vaccination in hemodialysis patients nonresponsive to primary vaccination. ID vaccination should become the standard of care in this setting.

Antifungal Therapy and Management of Complications of Cryptococcosis due to Cryptococcus gattii

BACKGROUND We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. METHODS Patient data from culture-confirmed cases (2000-2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. RESULTS Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2-12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. CONCLUSIONS Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.

INTRADERMAL RECOMBINANT HEPATITIS B VACCINE FOR HEALTHCARE WORKERS WHO FAIL TO RESPOND TO INTRAMUSCULAR VACCINE

OBJECTIVE To study the humoral immune responses, safety, and tolerability of intradermal recombinant hepatitis B vaccination in healthcare workers (HCWs) nonresponsive to previous repeated intramuscular vaccination. DESIGN An open, prospective, before-after trial. SETTING A tertiary referral hospital and surrounding district health service in Queensland, Australia. PARTICIPANTS Hospital and community HCWs nonresponsive to previous intramuscular hepatitis B vaccination. METHODS Intradermal recombinant hepatitis B vaccine was administered every second week for a maximum of 4 doses. Hepatitis B surface antibody (anti-HBs) responses were assessed 2 weeks after each dose. RESULTS Protective anti-HBs levels developed in 17 (94%) of 18 study subjects. Three doses resulted in seroconversion of all responding subjects and the highest geometric mean antibody concentration. The vaccine was well tolerated. CONCLUSION More than 90% of previously nonresponsive HCWs responded to intradermal recombinant hepatitis B vaccine with protective anti-HBs levels.