Costs associated with invasive Scedosporium and Lomentospora prolificans infections: a case-control study.

BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.

Time-to-positivity in bloodstream infection for Candida species as a prognostic marker for mortality.

Time-to-positivity (TTP) may assist in predicting the outcome of candidaemia. We analysed a candidaemia dataset collected prospectively in Australia over 1 year (2014-2015). TTP was defined as the period from blood culture sampling to the blood culture flagging positive. Of 415 candidaemia episodes, overall, 30-day mortality was 29% (120/415); mortality with Candida albicans was 35% (59/169), C. glabrata complex, 37% (43/115), C. tropicalis, 43% (10/23), Pichia kudriavzevii 25% (3/12), and C. parapsilosis complex 7% (5/71). Each day of increased TTP multiplied the odds ratio (OR) of survival at 30 days by a factor of 1.32 [95% confidence interval (CI) 1.06-1.69]. Shorter TTP was associated with increased mortality, with 1-day TTP associated with 30-day mortality 37% (41/112) (95%CI: 28%-46%) and 5-day TTP 11% (2/18) (95%CI: 2%-36%).

Time-to-positivity is a measure that is available to clinicians when patients are identified as having candida in their bloodstream. Our data support the association of a shorter time to positivity with higher mortality.

An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric ß-lactam therapy.

To determine whether target concentration non-attainment can be anticipated in critically ill patients prior to initiating empiric ß-lactam antibiotic therapy based on readily available clinical factors. Retrospective review of consecutive patients treated with piperacillin or meropenem and who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015 was performed. Predefined subgroups were patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). Potential risk factors were evaluated by correlation with ß-lactam antibiotic trough concentrations (Cmin) lower than or equal to targeted minimum inhibitory concentration (MIC). Only the first drug concentration after initiation of the antibiotic treatment was included to reflect empirical dose selection. A total of n = 249 patients (piperacillin, n = 169; meropenem, n = 80) were investigated. For non-CRRT patients (n = 210), multivariate analysis demonstrated the following: male gender (p = 0.006); younger age (p = 0.015); prescribed daily antibiotic dose less than 1.5 times the product information recommendations (p = 0.004); lack of positive microbiology (p = 0.006); lower overall illness severity (p = 0.005); and estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 (p < 0.001), to be associated with Cmin ≤ MIC. No predictor variable was found to be significantly associated with Cmin ≤ MIC for the CRRT cohort. Evaluating the risk of target concentration non-attainment using simple clinical factors is possible at the bedside for non-CRRT patients prior to empiric antibiotic initiation. Clinicians should be wary of selecting doses based on the product information especially when treating younger male patients with apparently 'normal' renal function.

Cluster of invasive Mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement.

There is a global outbreak of infections due to Mycobacterium chimaera associated with cardiac surgery. The most serious infections involve prosthetic material implantation, and all have followed surgical procedures involving cardiopulmonary bypass. We describe a cluster of four cases following cardiac surgery at a tertiary referral centre in Sydney, Australia. We report novel clinical findings, including haemolysis and kidney rupture possibly related to immune reconstitution inflammatory syndrome. The positive effect of corticosteroids on haemodynamic function in two cases and the failure of currently recommended antimicrobial therapy to sterilise prosthetic valve material in the absence of surgery despite months of treatment are also critically examined. Positron emission tomography was positive in two cases despite normal transoesophageal echocardiograms. The proportion of cases with M. chimaera infection after aortic valve replacement (4/890, 0.45%; 95% confidence interval 0.18-1.15%) was significantly higher than after all other cardiothoracic surgical procedures (0/2433, 0%; 95% confidence interval 0-0.16%).

Too much of a good thing: a retrospective study of ß-lactam concentration-toxicity relationships.

Objectives: To determine the existence of concentration-toxicity relationships for common ß-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely. Patients and methods: Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation. Results: TDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (Cmin) was found in patients diagnosed with neurotoxicity (piperacillin, P < 0.01; meropenem, P = 0.04; flucloxacillin, P = 0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P < 0.01) or meropenem (P < 0.01). Incidence of hepatotoxicity and C. difficile was not related to Cmin. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, Cmin >361.4 mg/L; meropenem, Cmin >64.2 mg/L; flucloxacillin, Cmin >125.1 mg/L) or nephrotoxicity (piperacillin, Cmin >452.65 mg/L; meropenem, Cmin >44.45 mg/L) varied across antibiotics. Conclusions: Our data reveal an association between toxic concentrations for a number of ß-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.

Changing epidemiology of candidaemia in Australia.

Objectives: Knowledge of contemporary epidemiology of candidaemia is essential. We aimed to identify changes since 2004 in incidence, species epidemiology and antifungal susceptibilities of Candida spp. causing candidaemia in Australia. Methods: These data were collected from nationwide active laboratory-based surveillance for candidaemia over 1 year (within 2014-2015). Isolate identification was by MALDI-TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed using Sensititre YeastOne™. Results: A total of 527 candidaemia episodes (yielding 548 isolates) were evaluable. The mean annual incidence was 2.41/105 population. The median patient age was 63 years (56% of cases occurred in males). Of 498 isolates with confirmed species identity, Candida albicans was the most common (44.4%) followed by Candida glabrata complex (26.7%) and Candida parapsilosis complex (16.5%). Uncommon Candida species comprised 25 (5%) isolates. Overall, C. albicans (>99%) and C. parapsilosis (98.8%) were fluconazole susceptible. However, 16.7% (4 of 24) of Candida tropicalis were fluconazole- and voriconazole-resistant and were non-WT to posaconazole. Of C. glabrata isolates, 6.8% were resistant/non-WT to azoles; only one isolate was classed as resistant to caspofungin (MIC of 0.5 mg/L) by CLSI criteria, but was micafungin and anidulafungin susceptible. There was no azole/echinocandin co-resistance. Conclusions: We report an almost 1.7-fold proportional increase in C. glabrata candidaemia (26.7% versus 16% in 2004) in Australia. Antifungal resistance was generally uncommon, but azole resistance (16.7% of isolates) amongst C. tropicalis may be emerging.

Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity.

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.

Economic evaluation of micafungin vs. liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC).

Micafungin was non-inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost-saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost-saving compared with LAmB. Micafungin was associated with cost-saving relative to LAmB in the treatment of candidaemia and IC in Australia.

Invasive Scedosporium and Lomentospora prolificans Infections in Australia: A Multicenter Retrospective Cohort Study.

Background: Management of Scedosporium/Lomentospora prolificans infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including predictors of early (1-month) and late (18-month) all-cause mortality and treatment failure. Methods: We conducted a retrospective Australian-based observational study of proven/probable Scedosporium/L prolificans infections from 2005 to 2021. Data on patient comorbidities, predisposing factors, clinical manifestations, treatment, and outcomes up to 18 months were collected. Treatment responses and death causality were adjudicated. Subgroup analyses, multivariable Cox regression, and logistic regression were performed. Results: Of 61 infection episodes, 37 (60.7%) were attributable to L prolificans. Forty-five of 61 (73.8%) were proven invasive fungal diseases (IFDs), and 29 of 61 (47.5%) were disseminated. Prolonged neutropenia and receipt of immunosuppressant agents were documented in 27 of 61 (44.3%) and 49 of 61 (80.3%) episodes, respectively. Voriconazole/terbinafine was administered in 30 of 31 (96.8%) L prolificans infections, and voriconazole alone was prescribed for 15 of 24 (62.5%) Scedosporium spp infections. Adjunctive surgery was performed in 27 of 61 (44.3%) episodes. Median time to death post-IFD diagnosis was 9.0 days, and only 22 of 61 (36.1%) attained treatment success at 18 months. Those who survived beyond 28 days of antifungal therapy were less immunosuppressed with fewer disseminated infections (both P < .001). Disseminated infection and hematopoietic stem cell transplant were associated with increased early and late mortality rates. Adjunctive surgery was associated with lower early and late mortality rates by 84.0% and 72.0%, respectively, and decreased odds of 1-month treatment failure by 87.0%. Conclusions: Outcomes associated with Scedosporium/L prolificans infections is poor, particularly with L prolificans infections or in the highly immunosuppressed population.

Therapeutic drug monitoring practices of anti-infectives: An Asia-wide cross-sectional survey.

Objectives: The current practice of therapeutic drug monitoring (TDM) in Asia is poorly documented. Our aim was to capture and describe TDM services delivered in hospitals across Asia, including aspects such as assay availability, interpretation of results and clinical decision-making. Methods: An online survey about anti-infective TDM practices, available in English and involving 50 questions, was promoted to people involved in TDM in Asia. The survey was open for responses from September to November 2021. Results: Of 207 responses from participants working in 14 Asian countries, 150 responses from 10 countries could be included. TDM services are available for many anti-infectives, providing assays based on chromatographic assays (100.0%) or immunoassays (39.3%). Clinicians (82.6%) and pharmacists (86.8%) were responsible for ordering and interpreting TDM. Most services provided reference targets and dose recommendations. Interpretative support was available to a varying degree. Assay results were available and clinical decision-making could be completed within 24 h in most hospitals (87.9% and 88.9% respectively). As the turnaround time of assay results decreased, the proportion of clinical decision-making completed within 8 h increased. Barriers to implementation of TDM included lack of funding or equipment (71.1%), lack of clinician interest or cooperation (47.0%), and lack of expertise (42.3%). Lack of expertise was the primary barrier for using precision dosing software (50.5%). Conclusion: There are significant differences and challenges in the development and practice of anti-infective TDM in Asian countries.

Cost-effectiveness analysis of anidulafungin versus fluconazole for the treatment of invasive candidiasis.

BACKGROUND: Anidulafungin was found to be non-inferior to and possibly more efficacious than fluconazole for treatment of invasive candidiasis (IC) in a major randomized clinical trial (RCT). There are no data comparing the cost-effectiveness between azoles and echinocandins in treating IC. This economic analysis investigated the cost-effectiveness of anidulafungin compared with fluconazole for treatment of IC in an Australian setting. METHODS: A decision analytic model was constructed to capture downstream consequences of using either agent for treatment of IC. The main outcomes analysed in the model were treatment success and treatment failure (observed and indeterminate). Outcome probabilities and treatment pathways were derived from a published RCT. Resources used were estimated by an expert panel and cost inputs were derived from the latest Australian resources. The analysis was based on an Australian hospital perspective. Sensitivity analyses were conducted using Monte Carlo simulation. RESULTS: Anidulafungin (AU$74,587) had a higher total cost than fluconazole (AU$60,945) per successfully treated patient, primarily due to its higher acquisition cost. Hospitalization was the main cost driver for both comparators. However, when the rates of mortality in both treatment arms were considered, treatment with anidulafungin was expected to save an additional 0.53 life-years, with an incremental cost-effectiveness ratio (ICER) of AU$25 740 per life-years saved, which was below the implicit ICER threshold value for Australia. The results were robust over a wide range of variables. CONCLUSIONS: This is the first economic evaluation of anidulafungin versus fluconazole in the treatment of IC in Australia. Anidulafungin appears to be a cost-effective option.

Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections.

Nontuberculous mycobacteria can cause minimally symptomatic self-limiting infections to progressive and life-threatening disease of multiple organs. Several factors such as increased testing and prevalence have made this an emerging infectious disease. Multiple guidelines have been published to guide therapy, which remains difficult owing to the complexity of therapy, the potential for acquired resistance, the toxicity of treatment, and a high treatment failure rate. Given the long duration of therapy, complex multi-drug treatment regimens, and the risk of drug toxicity, therapeutic drug monitoring is an excellent method to optimize treatment. However, currently, there is little available guidance on therapeutic drug monitoring for this condition. The aim of this review is to provide information on the pharmacokinetic/pharmacodynamic targets for individual drugs used in the treatment of nontuberculous mycobacteria disease. Lacking data from randomized controlled trials, in vitro, in vivo, and clinical data were aggregated to facilitate recommendations for therapeutic drug monitoring to improve efficacy and reduce toxicity.

Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over-active CD4+ T-cell responses in HIV-positive patients with mycobacterial immune restoration disease.

The role of Treg in patients with late-stage HIV disease, who commence combination antiretroviral therapy (cART) and develop pathogen-specific immunopathology manifesting as immune restoration disease (IRD) remains unclear. We hypothesised that Treg could be defective in either numbers and/or function and therefore unable to ensure the physiological equilibrium of the immune system in patients with IRD. Phenotypic and functional CD4(+) T-cell subsets of eight late-stage HIV patients with nadir CD4 count <50 cells/microL, who developed mycobacterial IRD upon commencing cART were compared with six therapy naive HIV(+) patients (nadir CD4 count <50 cells/microL), who did not develop an IRD after cART. Mycobacterium-avium-specific CD4(+) T cells from IRD patients produced high levels of IFN-gamma and IL-2 compared with controls (p<0.001). Surprisingly, we found a significant expansion of CD127(lo)Foxp3(+)CD25(+) Treg in IRD patients and a higher ratio of Treg to effector/memory subsets (p<0.001). In vitro suppression assays demonstrated reduced functional capacity of suppressor cells and diminished IL-10 secretion in IRD patients. Plasma levels of IL-7 were increased in patients and, interestingly, exogenous IL-7 and other cytokines strongly inhibited Treg suppression. These data suggest that despite substantial Treg expansion in IRD, their ability to induce suppression, and thereby downregulate aberrant immune responses, is compromised.

Therapeutic drug monitoring of commonly used anti-infective agents: A nationwide cross-sectional survey of Australian hospital practices.

When performed according to best-practice principles, therapeutic drug monitoring (TDM) can optimise anti-infective treatment and directly benefit clinical outcomes. We evaluated TDM performance and clinical decision-making for established anti-infective agents amongst Australian hospitals. A nationwide cross-sectional survey was conducted between August and September 2019. The survey consisted of multiple-choice questions regarding TDM of anti-infective agents in general as well as clinical vignettes specific to vancomycin, gentamicin and voriconazole. We sought to survey all Australian hospitals operating both in the public and private health sectors. Responses were captured from 85 unique institutions, from all Australian states and territories. Regarding guidelines, 26% of hospitals did not have endorsed guidelines to advise on the ordering, sampling and interpretation of TDM for any anti-infective agent. Admitting teams were predominantly responsible for ordering TDM (85%) and interpreting results (76%). Only 51% of hospitals had access to dose prediction software, with access generally better amongst principal referral (69%) (P = 0.01) and children's hospitals (100%) (P = 0.04). Whenever a laboratory-derived minimum inhibitory concentration (MIC) was not available to guide dosing decisions, a surrogate target MIC was assumed in 77% of hospitals. This was based on a 'worst-case' scenario infection in 11% of hospitals. The rates of clinical practice consistent with current guideline recommendations across all aspects of TDM were demonstrated to be 0% for vancomycin, 4% for gentamicin and 35% for voriconazole. At present, there is significant institutional variability in the clinical practice of TDM for anti-infective agents in Australia for established TDM drugs.

Managing two decades of visceral leishmaniasis and HIV co-infection: a case report that illustrates the urgent research needs in the field.

Visceral leishmaniasis and HIV co-infection presents diagnostic, monitoring and treatment challenges. This is a report of a co-infected patient who developed multiple complications and treatment side-effects, including renal and liver failure, pancytopenia with recurrent sepsis, along with anal cancer, depression and poor quality-of-life spanning over two decades. Urgent research specific to this cohort is needed.

Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced, HIV-infected individuals: recent data and consensus recommendations.

Recent data from clinical trials investigating the efficacy of enfuvirtide, a fusion inhibitor, in treatment-experienced patients have revealed that the addition of enfuvirtide (ENF) to an active boosted protease inhibitor regimen doubles the rate of virological response. At week 48 of the TORO studies, 55% of patients previously naive to and receiving lopinavir/ritonavir (LPV/r) with ENF achieved a viral load of <400 copies/mL compared with 24% of patients treated with LPV/r alone. At week 24 of the RESIST studies, 70% of previously ENF-naive patients who took both ENF and tipranavir/ritonavir (TPV/r) achieved a >or=1 log10 reduction in viral load compared with 37% of such patients treated with TPV/r alone. Similarly, concomitant use of TMC114/ritonavir (TMC114/r) with ENF, compared with TMC114/r alone, increased the number of patients with <50 copies/mL from 46% to 64% in a combined 24-week analysis from the POWER trials. Data from these trials suggest that combining one agent from a new class with a new agent from a previously exposed class offers a greater chance of achieving full virological control than either type of agent alone. Undetectable viraemia should be the primary objective for treatment-experienced patients requiring a switch in therapy, and the present data support the combination of an active boosted protease inhibitor with an agent from a new class (e.g., ENF) for triple-class-experienced patients.

Skeletal muscle toxicity associated with raltegravir-based combination antiretroviral therapy in HIV-infected adults.

OBJECTIVE/DESIGN: Raltegravir is uncommonly associated with rhabdomyolysis and grade 3-4 creatine kinase (CK) elevation. In this cross-sectional study, we compared the prevalence of skeletal muscle toxicity in HIV-infected adults receiving raltegravir with that of a control group. METHODS: Adults receiving combination antiretroviral therapy were recruited consecutively. Assessments included physical examination, an exercise questionnaire, and blood testing for CK, troponin T, and raltegravir trough levels. The primary endpoint was the prevalence of skeletal muscle toxicity, defined as a composite of any of the following: (1) isolated CK elevation; (2) myalgia; (3) proximal myopathy on examination; or (4) rhabdomyolysis. RESULTS: A total of 318 participants (159 raltegravir, 159 control) were evaluated; 98% were male, 89% white, with median age 51 years, and 91% had HIV-1 RNA <50 copies per milliliter. Mean raltegravir exposure was 28 months. Skeletal muscle toxicity was present in 37% of the raltegravir vs. 19% of the control group (P < 0.001). By component, there were significant respective differences in myalgia (19% vs. 3%, P < 0.001) and proximal myopathy (4% vs. 0%, P = 0.030) but not CK elevation (14% vs. 16%, P = 0.639). No patient had rhabdomyolysis. In multivariate analysis, raltegravir therapy (P < 0.001) and strenuous exercise (P = 0.002) were independently associated with overall muscle toxicity. No component of muscle toxicity was associated with duration of raltegravir or the raltegravir level. CONCLUSIONS: Raltegravir-based therapy is associated with a higher prevalence of symptomatic skeletal muscle toxicity, which does not seem to be concentration or time dependent, nor associated with elevated CK. Proximal myopathy may be an uncommon but significant side effect of raltegravir exposure.