Using Genomics To Investigate an Outbreak of Vancomycin-Resistant Enterococcus faecium ST78 at a Large Tertiary Hospital in Queensland.

To investigate an outbreak of vancomycin-resistant Enterococcus faecium (VREfm) sequence type 78 (ST78) in a large tertiary Australian hospital. A collection of 63 VREfm ST78 isolates, identified during a routine genomic surveillance program, were subjected to genomic epidemiological analysis based on whole-genome sequencing (WGS) data. The population structure was reconstructed using phylogenetic analysis, and a collection of publicly available VREfm ST78 genomes were used to provide global context. Core genome single nucleotide polymorphism (SNP) distances and available clinical metadata were used to characterize outbreak clusters and reconstruct transmission events. In silico genotyping confirmed that all study isolates were vanB-type VREfm carrying virulence characteristics of the hospital-associated E. faecium. Phylogenetic analysis identified two distinct phylogenetic clades, only one of which was responsible for a hospital outbreak. Four outbreak subtypes could be defined with examples of recent transmissions. Inference on transmission trees suggested complex transmission routes with unknown environmental reservoirs mediating the outbreak. WGS-based cluster analysis with publicly available genomes identified closely related Australian ST78 and ST203 isolates, highlighting the capacity for WGS to resolve complex clonal relationships between the VREfm lineages. Whole genome-based analysis has provided a high-resolution description of an outbreak of vanB-type VREfm ST78 in a Queensland hospital. Combined routine genomic surveillance and epidemiological analysis have facilitated better understanding of the local epidemiology of this endemic strain, providing valuable insight for better targeted control of VREfm. IMPORTANCE Vancomycin-resistant Enterococcus faecium (VREfm) is a leading cause of health care-associated infections (HAIs) globally. In Australia, the spread of hospital-adapted VREfm is largely driven by a single clonal group (clonal complex [CC]), CC17, to which the lineage ST78 belongs. While implementing a genomic surveillance program in Queensland, we observed increased incidence of ST78 colonizations and infections among patients. Here, we demonstrate the use of real-time genomic surveillance as a tool to support and enhance infection control (IC) practices. Our results show that real-time whole-genome sequencing (WGS) can efficiently disrupt outbreaks by identifying transmission routes that in turn can be targeted using resource-limited interventions. Additionally, we demonstrate that by placing local outbreaks in a global context, high-risk clones can be identified and targeted prior to them becoming established within clinical environments. Finally, the persistence of these organism within the hospital highlights the need for routine genomic surveillance as a management tool to control VRE transmission.

Identification of genetic markers of resistance to echinocandins, azoles and 5-fluorocytosine in Candida glabrata by next-generation sequencing: a feasibility study.

OBJECTIVES: Multi-antifungal drug resistance in Candida glabrata is increasing. We examined the feasibility of next-generation sequencing (NGS) to investigate the presence of antifungal drug resistance markers in C. glabrata. METHODS: The antifungal susceptibility of 12 clinical isolates and one ATCC strain of C. glabrata was determined using the Sensititre YeastOne® YO10 assay. These included three isolate pairs where the second isolate of each pair had developed a rise in drug MICs. Single nucleotide polymorphisms (SNPs) in genes known to be linked to echinocandin, azole and 5-fluorocytosine resistance were analysed in all isolates through NGS. RESULTS: High-quality non-synonymous SNPs in antifungal resistance genes such as FKS1, FKS2, CgCDR1, CgPDR1 and FCY2 were identified. For two of three isolate pairs, there was a >60-fold rise in MICs to all echinocandins in the second isolate from each pair; one echinocandin-resistant isolate harboured a mutation in FKS1 (S629P) and the other in FKS2 (S663P). Of the third pair, both the 5-fluorocytosine-susceptible, and resistant isolates had a mutation in FCY2 (A237T). SNPs in CgPDR1 were found in pan-azole-resistant isolates. SNPs in other genes linked to azole resistance (CgCDR1, ERG9 and CgFLR1) were present in both azole-susceptible and azole-resistant isolates. SNPs were also identified in Candida adhesin genes EPA1, EPA6, PWP2 and PWP5 but their presence was not associated with higher drug MICs. CONCLUSIONS: Genome-wide analysis of antifungal resistance markers was feasible and simultaneously revealed mutation patterns of genes implicated in resistance to different antifungal drug classes.

First report of monomicrobial Candida parapsilosis necrotizing fasciitis.

Candida parapsilosis is an emerging pathogen worldwide. It commonly causes soft tissue infection; however, to our knowledge there has been no previous report of monomicrobial necrotizing soft tissue infection (NSTI) secondary to C. parapsilosis. We report the first case of NSTI caused by C. parapsilosis in an immunocompromised renal transplant patient, with the diagnosis proven both histologically and microbiologically. Our patient required aggressive surgical intervention and antifungal therapy, with postoperative survival at 90 days.

Supervised self-administration of outpatient parenteral antibiotic therapy: a report from a large tertiary hospital in Australia.

INTRODUCTION: Outpatient parenteral antibiotic therapy (OPAT) has become established as a standard of care in most Australian hospitals to treat a variety of infections. Since 1998, the Alternate Site Infusion Service (ASIS) has provided an OPAT service to five hospitals in southern Brisbane, Queensland, using predominantly a patient or carer administration model (self-administered, S-OPAT). The aim of this study was to evaluate outcomes of our S-OPAT programme. METHODS: Consecutive patients treated by ASIS at the Princess Alexandra Hospital from January 1, 2011 to December 31, 2011 were reviewed. Data on patient demographics, diagnoses, microbiology, antimicrobial therapy, duration, outcome, and complications were sourced from a prospectively collected database and from patient medical records. RESULTS: There were 150 episodes involving 144 patients resulting in 3520 days of OPAT; the median duration on the programme was 22 days (range 4­106 days). Patient or carer administration occurred in the majority of episodes. The most common indication by far was bone or joint infection (47% of patients), followed by infective endocarditis (9%). Staphylococcus aureus was the most frequently treated organism. The overall cure rate was 93%. On multivariate analysis, patients with two or more comorbidities had an increased risk of failure. Line-related complications occurred in 1.4/1000 catheter-days. Rash was the most common drug-related event. Despite the extensive use of broad-spectrum antibiotics there were no cases of Clostridium difficile infection during therapy and for up to 28 days post cessation of intravenous antibiotics. The cost of OPAT per patient excluding drug administration and home visits was approximately A$ 150.00/day, significantly lower than the cost of an inpatient bed, which is estimated to be A$ 500­800/day.5 CONCLUSION: OPAT using a patient or carer administration model is an effective and safe option for the management of selected patients with infection requiring intravenous antibiotics.

Risk factors for urinary catheter associated bloodstream infection.

OBJECTIVES: Urinary catheter associated bloodstream infection (UCABSI) causes significant morbidity, mortality and healthcare costs. We aimed to define the risk factors for UCABSI. METHODS: A case-control study was conducted at two Australian tertiary hospitals. Patients with urinary source bloodstream infection associated with an indwelling urinary catheter (IDC) were compared to controls with an IDC who did not develop urinary source bloodstream infection. RESULTS: There were 491 controls and 67 cases included in the analysis. Independent statistically significant risk factors for the development of UCABSI included insertion of the catheter in operating theatre, chronic kidney disease, age-adjusted Charlson comorbidity index, accurate urinary measurements as reason for IDC insertion and dementia. IDCs were inserted for valid reasons in nearly all patients, however an appropriate indication at 48 h post-insertion was found in only 44% of patients. Initial empiric antibiotics were deemed inappropriate in 23 patients (34%). CONCLUSION: To our knowledge, this is the first study to look specifically at the risk factors for bloodstream infection in urinary catheterised patients. Several risk factors were identified. IDC management and empiric management of UCABSI could be improved and is likely to result in a decreased incidence of infection and its complications.

Infectious diseases consultations at an Australian tertiary hospital: a review of 11,511 inpatient consultations.

BACKGROUND: Infectious diseases (ID) clinicians provide an important service within tertiary hospitals. However, as a largely consultation-based service, their value can be difficult to evaluate. AIMS: A review of 13.5 years of consultations was undertaken to define the scope of the service and any changes over time. METHODS: ID consultations at the Princess Alexandra Hospital are tracked on a database, recording information including the requesting team, indication for and outcome of the consult. Incident formal inpatient consultations between July 1999 and December 2012 were reviewed retrospectively. Phone consultations, repeat consultations and ID admissions were excluded. RESULTS: Eleven thousand five hundred and eleven consultations were identified, with annual consultations increasing significantly during this period. Overall, formal consultations were performed on 1.3% of admissions. Consultations were most commonly requested by orthopaedics (14.3%) and general medicine (11.4%). The two most common syndromes triggering a consult were bloodstream infection (13.9%) and complicated soft tissue infection (7.8%). The final diagnosis was most frequently osteomyelitis (7.9%). Staphylococcus aureus (19.4%) and Pseudomonas aeruginosa (8.3%) were the most commonly identified pathogens. CONCLUSION: The demand for ID consultations has increased over time and there are likely to be many drivers of this increase. Information derived from this audit can enhance the ID service by guiding service delivery, trainee education and informing funding or accreditation applications.

Molecular investigation of bacterial communities on intravascular catheters: no longer just Staphylococcus.

Intravascular catheter-related bloodstream infections (IVC-BSIs) are associated with significant morbidity and mortality. Culture-independent molecular approaches can reveal and capture the composition of complex microbial communities, and are now being used to reveal "new" pathogens as well as the polymicrobial nature of some infections. Patients with concurrently sited arterial and central venous catheters who had clinically suspected IVC-BSIs, were examined by the high-throughput sequencing of microbial 16S rRNA. An average of 100 operational taxonomic units (OTUs, phylotypes) was observed on each IVC, indicating that IVCs were colonised by complex and diverse bacterial communities. Ralstonia (53 % of 16S rRNA sequences), Escherichia group (16 %), Propionibacterium (5 %), Staphylococcus (5 %), and Streptococcus (2 %) were the most abundant genera. There was no statistically significant difference in the bacterial communities examined from arterial and central venous catheters; from those with and without systemic antibiotic treatment; or from conventionally colonised and uncolonised IVCs. The genome of the predominant bacteria, R. pickettii AU12-08, was found to encode resistance to antimicrobial drugs of different classes. In addition, many encoded gene products are involved in quorum sensing and biofilm formation that would further contribute to increased antimicrobial drug resistance. Our results highlight the complex diversity of microbial ecosystems on vascular devices. High-throughput sequencing of 16S rRNA offers an insight into the pathogenesis of IVC-related infections, and opens up the scope for improving diagnosis and patient management.

Development of a risk-adjustment model for antimicrobial utilization data in 21 public hospitals in Queensland, Australia (2006-11).

OBJECTIVES: Making valid comparisons of antimicrobial utilization between hospitals requires risk adjustment for each hospital's case mix. Data on individual patients may be unavailable or difficult to process. Therefore, risk adjustment for antimicrobial usage frequently needs to be based on a hospital's services. This study evaluated such a strategy for hospital antimicrobial utilization. METHODS: Data were obtained on five broad subclasses of antibiotics [carbapenems, ß-lactam/ß-lactamase inhibitor combinations (BLBLIs), fluoroquinolones, glycopeptides and third-generation cephalosporins] from the Queensland pharmacy database (MedTrx) for 21 acute public hospitals (2006-11). Eleven clinical services and a variable for hospitals from the tropical region were employed for risk adjustment. Multivariable regression models were used to identify risk and protective services for these antibiotics. Funnel plots were used to display hospitals' antimicrobial utilization. RESULTS: Total inpatient antibiotic utilization for these antibiotics increased from 130.6 defined daily doses (DDDs)/1000 patient-days in 2006 to 155.8 DDDs/1000 patient-days in 2011 (P < 0.0001). Except for third-generation cephalosporins, the average utilization rate was higher for intensive care, renal/nephrology, cardiac, burns/plastic surgery, neurosurgery, transplant and acute spinal services than for the respective reference group (no service). In addition, oncology, high-activity infectious disease and coronary care services were associated with higher utilization of carbapenems, BLBLIs and glycopeptides. CONCLUSIONS: Our model predicted antimicrobial utilization rates by hospital services. The funnel plots displayed hospital utilization data after adjustment for variation among the hospitals. However, the methodology needs to be validated in other populations, ideally using a larger group of hospitals.

Funnel plots and risk-adjusted count data adverse events. A limitation of indirect standardisation.

Reporting of hospital adverse event data is becoming increasingly mandated and this has motivated work on methods for the analysis and display of these data for groups of institutions. Currently, the method preferred by many workers is the funnel plot. Often, indirect standardisation is employed to produce these plots. It appears that, when used to display binary data such as surgical site infection or mortality data, the method is satisfactory. Increasingly, these data are risk-adjusted. However, risk adjustment of these data usually involves individual patients undergoing the same or similar procedures and the method does not appear to mislead. However, when dealing with count data such as bacteraemias it appears that this method can mislead, particularly where methods for risk adjustment of these data are used. Information about the hospitals or units of interest rather than individual patients is employed. For example, one hospital may have plastic and cardiac surgery units in which bacteraemias occur infrequently whereas another may provide treatment for renal failure (including transplantation) and have a large haematology-oncology unit (also including transplantation), each of which would expect higher bacteraemia rates. Moreover, the hospitals and units within them may differ substantially in size. It is well known that indirect standardisation can give biased results when denominators differ substantially. We illustrate this difficulty with risk-adjusted bacteraemia data from the Queensland Health Centre for Healthcare Infection, Surveillance and Prevention (CHRISP) database.

Increasing incidence of candidaemia: long-term epidemiological trends, Queensland, Australia, 1999-2008.

Given variability in the epidemiology of candidaemia and a relative paucity of contemporary longitudinal data, a passive laboratory-based surveillance study was performed to assess the epidemiology of candidaemia in all public healthcare facilities in Queensland, Australia over the period 1999-2008. Demographic and microbiological data on all candidaemia episodes, together with appropriate denominators (admissions and patient-days), were collected from laboratory and administrative information systems. From 1999 to 2008, 1137 episodes occurred (overall incidence-density: 0.45 per 10 000 patient-days) with a 3.5-fold increase in density (P<0.0001 for trend). Candidaemia episodes originating in traditional high-risk areas either decreased (haemato-oncology and paediatric wards) or remained stable (intensive care units). Episodes on adult medical/surgical wards increased significantly over time, accounting for 60% of the total by 2008. The relative proportion caused by Candida albicans decreased and Candida parapsilosis increased (both P<0.01). The proportion of fluconazole-resistant isolates did not change. The increasing occurrence of candidaemia outside traditional high-risk areas and the emergence of C. parapsilosis present new challenges for preventive and early intervention strategies.

Candidaemia with uncommon Candida species: predisposing factors, outcome, antifungal susceptibility, and implications for management.

The risk factors for and clinical features of bloodstream infection with uncommon Candida spp. (species other than C. albicans, C. glabrata, C. parapsilosis, C. tropicals and C. krusei) are incompletely defined. To identify clinical variables associated with these species that might guide management, 57 cases of candidaemia resulting from uncommon Candida spp. were analysed in comparison with 517 episodes of Candida albicans candidaemia (2001-2004). Infection with uncommon Candida spp. (5.3% of candidaemia cases), as compared with C. albicans candidaemia, was significantly more likely to be outpatient-acquired than inpatient-acquired (15 of 57 vs. 65 of 517 episodes, p 0.01). Prior exposure to fluconazole was uncommon (n=1). Candida dubliniensis was the commonest species (n=22, 39%), followed by Candida guilliermondii (n=11, 19%) and Candida lusitaniae (n=7, 12%).C. dubliniensis candidaemia was independently associated with recent intravenous drug use (p 0.01) and chronic liver disease (p 0.03), and infection with species other than C. dubliniensis was independently associated with age<65 years (p 0.02), male sex (p 0.03) and human immunodeficiency virus infection (p 0.05). Presence of sepsis at diagnosis and crude 30-day mortality rates were similar for C. dubliniensis-related, non-C. dubliniensis-related and C. albicans-related candidaemia. Haematological malignancy was the commonest predisposing factor in C. guilliermondii (n=3, 27%) and C. lusitaniae (n=3, 43%) candidaemia. The 30-day mortality rate of C. lusitaniae candidaemia was higher than the overall death rate for all uncommon Candida spp. (42.9% vs. 25%, p not significant). All isolates were susceptible to amphotericin B, voriconazole, posaconazole, and caspofungin; five strains (9%) had fluconazole MIC values of 16-32 mg/L. Candidaemia due to uncommon Candida spp. is emerging among hospital outpatients; certain clinical variables may assist in recognition of this entity.

Recommendations for the treatment of established fungal infections.

Evidence-based guidelines for the treatment of established fungal infections in the adult haematology/oncology setting were developed by a national consensus working group representing clinicians, pharmacists and microbiologists. These updated guidelines replace the previous guidelines published in the Internal Medicine Journal by Slavin et al. in 2004. The guidelines are pathogen-specific and cover the treatment of the most common fungal infections including candidiasis, aspergillosis, cryptococcosis, zygomycosis, fusariosis, scedosporiosis, and dermatophytosis. Recommendations are provided for management of refractory disease or salvage therapies, and special sites of infections such as the cerebral nervous system and the eye. Because of the widespread use newer broad-spectrum triazoles in prophylaxis and empiric therapy, these guidelines should be implemented in concert with the updated prophylaxis and empiric therapy guidelines published by this group.

Clinician response to Candida organisms in the urine of patients attending hospital.

The epidemiology of 54 episodes of candiduria with respect to clinical risk factors, species of Candida and physician response to the isolation of Candida in urine were studied in an observational survey over 3 months. Candida spp. were isolated from 4.7% of positive urine cultures. Common predisposing conditions included antibiotic use (74.1%), urinary drainage devices (57.4%), surgery (51.9%), intensive care unit (ICU) or high-dependency care unit (HDU) admission (42.6%) and urinary tract (UT) disease (18.5%). Upper UT infection was uncommon (n = 3). Of 65 Candida isolates, C. albicans predominated (85.2%), followed by C. glabrata (27.8%) and other Candida spp. (6.2%). All isolates were susceptible to fluconazole, itraconazole, voriconazole, amphotericin and caspofungin. Indwelling urinary catheters were removed in 76.2% of episodes. Antifungal therapy was initiated in 33.3% of cases independently of patient symptoms, underlying disease or Candida colony count. Patients in ICU/HDUs were significantly more likely to receive antifungal agents than those outside these units (p < 0.001). Fluconazole was the most common drug prescribed (77.8%). Clearance of candiduria occurred independently of antifungal therapy (p = 0.60). Physicians often did not follow up a positive urine result for Candida. Efforts to increase clinician awareness of current recommendations for managing candiduria and further study to elucidate specific risk factors in defined patient populations are warranted.

Carbapenem-resistant Acinetobacter baumannii in intensive care unit patients: risk factors for acquisition, infection and their consequences.

A retrospective case-control study was performed to assess risk factors and the clinical and economic consequences associated with acquisition of carbapenem-resistant Acinetobacter baumannii (CR-AB) in an intensive care unit (ICU) over a 24-month period. CR-AB was acquired by 64 of 1431 ICU admissions; each was matched with two controls. Risk factors associated with CR-AB acquisition included ICU-wide variables, such as 'colonization pressure' (the prevalence of ICU colonized patients) and ICU antibiotic use over the preceding three months, as well as patient-related variables. Among colonized patients, risk factors for CR-AB infection included transfusion and 'colonization density' (the proportion of body sites colonized with CR-AB). CR-AB infection was independently associated with increased hospital mortality [mortality difference: 20%; 95% confidence interval (CI): 1-40%], prolonged ICU stay (median length of stay difference: 15 days; 95% CI: 9-21 days) and prolonged hospital stay (30 days, 11-38 days) compared with matched controls.

Systematic review and meta-analysis of antifungal agents for preventing fungal infections in liver transplant recipients.

A systematic review and meta-analysis was performed to evaluate the benefits and harms of antifungal prophylaxis in liver transplant recipients. Ten randomised trials comparing any prophylactic antifungal regimen with no antifungal agent or with another antifungal regimen were identified from Medline, EMBASE, the Cochrane Library, and other sources. Together, the studies included a total of 1,106 patients. In general, results were consistent across trials despite clinical and methodological heterogeneity. Antifungal prophylaxis did not reduce total mortality (RR 0.84, 95% CI: 0.54-1.3). Fluconazole prophylaxis reduced invasive fungal infections by about 75% (RR 0.28, 95% CI: 0.13-0.57). Although fewer data on prophylactic itraconazole and liposomal amphotericin B were available, indirect comparisons and three direct comparative trials suggested similar efficacy. Fluconazole prophylaxis did not significantly increase colonisation or infection with azole-resistant fungi, although data were limited. A subgroup analysis suggested a dose and duration effect. In conclusion, fluconazole prophylaxis significantly reduces invasive fungal infections in liver transplant recipients and should be instituted in patients at increased risk in the early postoperative period.

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.

BACKGROUND: Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents. OBJECTIVES: This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers. SELECTION CRITERIA: We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients. DATA COLLECTION AND ANALYSIS: Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals. MAIN RESULTS: We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. AUTHORS' CONCLUSIONS: Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

Antifungal agents for preventing fungal infections in solid organ transplant recipients.

BACKGROUND: Invasive fungal infections (IFIs) are important causes of morbidity and mortality in solid organ transplant recipients. OBJECTIVES: This study aims to systematically identify and summarise the effects of antifungal prophylaxis in solid organ transplant recipients. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (Issue 3, 2003), MEDLINE (1966-June 2003), and EMBASE (1980-June 2003) were searched. Reference lists, abstracts of conference proceedings and scientific meetings (1998-2003) were handsearched. Authors of included studies and pharmaceutical manufacturers were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. Differences were resolved by discussion. Data were synthesised using the random effects model and expressed as relative risk (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data. REVIEWERS' CONCLUSIONS: For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered.

Interleukin 2 receptor antagonists for kidney transplant recipients.

BACKGROUND: Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily, with 38% of new kidney transplant recipients in the United States, and 23% in Australasia receiving IL2Ra in 2002. OBJECTIVES: This study aims to systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to other antibody therapy. SEARCH STRATEGY: The Cochrane Renal Group's specialised register (June 2003), the Cochrane Controlled Trials Register (in The Cochrane Library issue 3, 2002), MEDLINE (1966-November 2002) and EMBASE (1980-November 2002). Reference lists and abstracts of conference proceedings and scientific meetings were hand-searched from 1998-2003. Trial groups, authors of included reports and drug manufacturers were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: One hundred and seventeen reports from 38 trials involving 4893 participants were included. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not significantly different at one (RR 0.83, 95% CI 0.66 to 1.04) or three years (RR 0.88, 95% CI 0.64 to 1.22). Acute rejection (AR) was significantly reduced at six months (RR 0.66, 95% CI 0.59 to 0.74) and at one year (RR 0.67, 95% CI 0.60 to 0.75). At one year, cytomegalovirus (CMV) infection (RR 0.82, 95% CI 0.65 to 1.03) and malignancy (RR 0.67, 95% CI 0.33 to 1.36) were not significantly different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but adverse effects strongly favoured IL2Ra. REVIEWER'S CONCLUSIONS: Given a 40% risk of rejection, seven patients would need treatment with IL2Ra to prevent one patient having rejection, with no definite improvement in graft or patient survival. There is no apparent difference between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects

Hypercalcaemia and elevated 1,25(OH)(2)D(3) levels associated with disseminated Mycobacterium avium infection in AIDS.

Hypercalcaemia may complicate granulomatous diseases, such as tuberculosis and sarcoidosis, and various AIDS-related opportunistic infections and malignancies. We report here two patients with AIDS and disseminated Mycobacterium avium infection who developed symptomatic hypercalcaemia several weeks after commencing antimycobacterial chemotherapy, and in whom inappropriately elevated 1,25(OH)(2)D(3)levels were documented. Although vitamin D supplementation may have contributed, no other cause for the hypercalcaemia was found. The biochemical and clinical similarities between these cases and other hypercalcaemic granulomatous diseases suggest a common mechanism related to macrophage activation and dysregulated vitamin D production.

Endemic nosocomial gram-negative bacteraemias resulting from contamination of intravenous heparin infusions.

Following several cases of Gram-negative bacteraemia secondary to intravenous heparin infusion contamination, we retrospectively reviewed nosocomial bacteraemias associated with heparin infusions at our institution. Thirty-one episodes of heparin-infusion related bacteraemia occurred in 30 patients over a 23-month period affecting 2% patients receiving heparin infusions for more than 48 h. Gram-negative bacteria were responsible for all bacteraemias. The care of infusions during clinical use was prospectively surveyed, revealing that approximately 20% of lines and cannulae were left for more than 72 h before replacement, and significant discordance occurred between line replacement and syringe and cannula exchange. We concluded that contamination of the infusions was probably extrinsic and secondary to manipulations of the system during use. Prolonged usage and discordant exchange of infusion components were likely important factors in initial contamination and subsequent bacterial proliferation. The problem resolved following the introduction of a policy for routine and simultaneous replacement of lines and syringes at 24-h intervals and upon cannula exchange.