Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis.

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI. Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m2). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model. Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88). Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

A case report of typhoidal acute acalculous cholecystitis.

Introduction. Acalculous cholecystitis in the setting of typhoid fever in adults is an infrequent clinical encounter, reported sparsely in the literature. In this case report we review the presentation and management of enteric fever involving the biliary system and consider the literature surrounding this topic. The aim of this case report is to alert clinicians to the potential diagnosis of extraintestinal complications in the setting of typhoid fever in the returned traveller, requiring surgical intervention. Presentation of Case. We report the case of a 23-year-old woman with acalculous cholecystitis secondary to Salmonella Typhi. Discussion. There is scarce evidence surrounding the optimal treatment and prognosis of typhoidal acalculous cholecystitis. In the current case, surgical invention was favoured due to failure of medical management. Conclusion. Clinical judgement dictated surgical intervention in this case of typhoidal acute acalculous cholecystitis, and cholecystectomy was safely performed.

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial.

BACKGROUND: Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients. METHODS: In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered with ClinicalTrial.gov, number NCT00163722. FINDINGS: 240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4-26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20). INTERPRETATION: Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients. FUNDING: Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences.

Use of FDG PET/CT for investigation of febrile neutropenia: evaluation in high-risk cancer patients.

PURPOSE: Febrile neutropenia (FNP) is a frequent complication of cancer care and evaluation often fails to identify a cause. [(18) F]FDG PET/CT has the potential to identify inflammatory and infectious foci, but its potential role as an investigation for persistent FNP has not previously been explored. The aim of this study was to prospectively evaluate the clinical utility of FDG PET/CT in patients with cancer and severe neutropenia and five or more days of persistent fever despite antibiotic therapy. METHODS: Adult patients with a diagnosis of an underlying malignancy and persistent FNP (temperature ≥38°C and neutrophil count <500 cells/µl for 5 days) underwent FDG PET/CT as an adjunct to conventional evaluation and management. RESULTS: The study group comprised 20 patients with FNP who fulfilled the eligibility criteria and underwent FDG PET/CT in addition to conventional evaluation. The median neutrophil count on the day of the FDG PET/CT scan was 30 cells/µl (range 0-730 cells/µl). Conventional evaluation identified 14 distinct sites of infection, 13 (93 %) of which were also identified by FDG PET/CT, including all deep tissue infections. FDG PET/CT identified 9 additional likely infection sites, 8 of which were subsequently confirmed as "true positives" by further investigations. FDG PET/CT was deemed to be of 'high' clinical impact in 15 of the 20 patients (75 %). CONCLUSION: This study supports the utility of FDG PET/CT scanning in severely neutropenic patients with five or more days of fever. Further evaluation of the contribution of FDG PET/CT in the management of FNP across a range of underlying malignancies is required.

Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia.

We describe laboratory-confirmed influenza A pandemic (H1N1) 2009 in 17 hospitalized recipients of a hematopoietic stem cell transplant (HSCT) (8 allogeneic) and in 15 patients with malignancy treated at 6 Australian tertiary centers during winter 2009. Ten (31.3%) patients were admitted to intensive care, and 9 of them were HSCT recipients. All recipients of allogeneic HSCT with infection <100 days posttransplantation or severe graft-versus-host disease were admitted to an intensive care unit. In-hospital mortality rate was 21.9% (7/32). The H275Y neuraminidase mutation, which confers oseltamivir resistance developed in 4 of 7 patients with PCR positive for influenza after > or = 4 days of oseltamivir therapy. Three of these 4 patients were critically ill. Oseltamivir resistance in 4 (13.3%) of 30 patients who were administered oseltamivir highlights the need for ongoing surveillance of such resistance and further research on optimal antiviral therapy in the immunocompromised.

Hospitalised adult patients with pandemic (H1N1) 2009 influenza in Melbourne, Australia.

OBJECTIVE: To describe the case characteristics and outcomes of patients hospitalised with pandemic (H1N1) 2009 influenza infection during the first 2 months of the epidemic. DESIGN, PARTICIPANTS AND SETTING: Prospective case series of 112 patients admitted to seven hospitals in Melbourne with laboratory-confirmed pandemic (H1N1) 2009 influenza between 1 May and 17 July 2009. MAIN OUTCOME MEASURES: Details of case characteristics, risk factors for severe disease, treatment and clinical course. RESULTS: Of 112 hospitalised patients, most presented with cough (88%) and/or fever (82%), but several (4%) had neither symptom. A quarter of female patients (15) were pregnant or in the post-partum period. Patients presenting with multifocal changes on chest x-ray had significantly longer hospital lengths of stay, and were more likely to require intensive care unit admission. Thirty patients required admission to an intensive care unit, and three died during their acute illness. The median length of intensive care admission was 10.5 days (interquartile range, 5-16 days). CONCLUSIONS: This study highlights risk factors for severe disease, particularly pregnancy. Clinical and public health planning for upcoming influenza seasons should take into account the spectrum and severity of clinical infection demonstrated in this report, and the need to concentrate resources effectively in high-risk patient groups.

An Australian case of Streptococcus suis toxic shock syndrome associated with occupational exposure to animal carcasses.

Streptococcus suis is known to cause sporadic infections in people who have occupational exposure to pigs and pig meat. A large outbreak occurred in China in 2005, where there was 62% mortality among those who developed toxic shock syndrome. Despite S. suis being common in pigs, this is the first published report of a human case of S. suis toxic shock syndrome in Australia.