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.

A successful aggressive surgical and medical approach to pulmonary artery obstruction due to Mycobacterium abscessus infection post lung transplantation.

Mycobacterium abscessus infection following lung transplantation has historically been associated with poor outcomes. We report a case of bilateral lung retransplantation complicated by obstruction of the right pulmonary artery secondary to M. abscessus mycotic aneurysm. Aggressive surgical management, including reconstruction of the right pulmonary artery, was undertaken with prolonged antimicrobial therapy. Thirty-six months later, antibiotics have been discontinued and the patient has stable soft tissue chest wall disease with good graft function. Mortality and morbidity associated with M. abscessus infection is considerable but this case illustrates that with aggressive early management, outcomes may be favorable.

Dapsone and azole interactions: A clinical perspective.

An understanding of the clinical significance of dapsone-drug interactions is essential for optimal use of this agent. This review aims to provide clinicians with an overview of this topic.

Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: a systematic review and meta-analysis.

BACKGROUND: The clinical utility of bronchoalveolar lavage (BAL) fluid galactomannan (GM) for the early diagnosis of invasive aspergillosis (IA) varies widely across studies mainly due to heterogeneity of the studied populations. METHODS: We conducted a systematic review and meta-analysis of 16 studies involving 783 adults with hematological malignancies to derive summary estimates of the overall accuracy of BAL-GM for diagnosing IA. FINDINGS: Summary estimates of BAL-GM using an optical density (OD) index cutoff value of 1.5 for proven and probable IA were: sensitivity 0.92 (95% CI = 0.48-0.99), specificity 0.98 (95% CI = 0.78-1.00), positive likelihood ratio 53.7 (95% CI = 3.7-771.8), and negative likelihood ratio 0.08 (95% CI = 0.01-0.83). Comparing serum GM and Aspergillus PCR testing on BAL fluid, BAL-GM conferred greater sensitivity, but lower specificity than the serum GM test, and similar specificity as the PCR assay. The use of BAL-GM with serum GM or BAL-PCR tests increased the sensitivity moderately when a positive result was defined by either assay. INTERPRETATION: GM quantification in BAL fluid at an OD index cutoff value of 1.5 has excellent sensitivity and specificity to assist clinical decision-making in confirming or excluding a diagnosis of IA when results are interpreted with clinical findings. Additional research investigating the effects of antifungal agents, optimal timing and processing of BAL sampling are needed to improve the diagnostic accuracy of BAL-GM testing.

The International Society for Heart and Lung Transplantation (ISHLT): 2024 infection definitions for durable and acute mechanical circulatory support devices.

Infections remain a significant concern in patients receiving mechanical circulatory support (MCS), encompassing both durable and acute devices. This consensus manuscript provides updated definitions for infections associated with durable MCS devices and new definitions for infections in acute MCS, integrating a comprehensive review of existing literature and collaborative discussions among multidisciplinary specialists. By establishing consensus definitions, we seek to enhance clinical care, facilitate consistent reporting in research studies, and ultimately improve outcomes for patients receiving MCS.

Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients.

Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r(2) = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients.

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.

Robust immunity to influenza vaccination in haematopoietic stem cell transplant recipients following reconstitution of humoral and adaptive immunity.

Objectives: Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients. Methods: We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls. Results: Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21loCD27+ influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains. Conclusions: Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups.

Invasive aspergillosis in adult patients in Australia and New Zealand: 2017-2020.

Background: New and emerging risks for invasive aspergillosis (IA) bring the need for contemporary analyses of the epidemiology and outcomes of IA, in order to improve clinical practice. Methods: The study was a retrospective, multicenter, cohort design of proven and probable IA in adults from 10 Australasian tertiary centres (January 2017-December 2020). Descriptive analyses were used to report patients' demographics, predisposing factors, mycological characteristics, diagnosis and management. Accelerated failure-time model was employed to determine factor(s) associated with 90-day all-cause mortality (ACM). Findings: Of 382 IA episodes, 221 (in 221 patients) fulfilled inclusion criteria - 53 proven and 168 probable IA. Median patient age was 61 years (IQR 51-69). Patients with haematologic malignancies (HM) comprised 49.8% of cases. Fifteen patients (6.8%) had no pre-specified immunosuppression and eleven patients (5.0%) had no documented comorbidity. Only 30% of patients had neutropenia. Of 170 isolates identified, 40 (23.5%) were identified as non-Aspergillus fumigatus species complex. Azole-resistance was present in 3/46 (6.5%) of A. fumigatus sensu stricto isolates. Ninety-day ACM was 30.3%. HM (HR 1.90; 95% CI 1.04-3.46, p = 0.036) and ICU admission (HR 4.89; 95% CI 2.93-8.17, p < 0.001) but not neutropenia (HR 1.45; 95% CI 0.88-2.39, p = 0.135) were associated with mortality. Chronic kidney disease was also a significant predictor of death in the HM subgroup (HR 3.94; 95% CI 1.15-13.44, p = 0.028). Interpretation: IA is identified in high number of patients with mild/no immunosuppression in our study. The relatively high proportion of non-A. fumigatus species complex isolates and 6.5% azole-resistance rate amongst A. fumigatus sensu stricto necessitates accurate species identification and susceptibility testing for optimal patient outcomes. Funding: This work is unfunded. All authors' financial disclosures are listed in detail at the end of the manuscript.

Dementia-Like Symptoms Associated With Posaconazole.

Posaconazole is widely used in lung transplant recipients as pre-emptive therapy or universal fungal prophylaxis. In this patient group, posaconazole is increasingly used instead of voriconazole due to the concerns of an increased risk of squamous cell carcinoma (SCC) with voriconazole, particularly with its long-term use. Dose dependent toxicity has not been identified for posaconazole in the registration trials of intravenous (IV) and modified-release tablet formulations. This is supported by post-marketing experience. We describe a lung transplant recipient who experienced dementia-like symptoms almost 3 years after commencing posaconazole for treatment of Aspergillus fumigatus complex and Lomentospora prolificans (formerly Scedosporium prolificans) fungal infections. Symptoms resolved upon discontinuation of posaconazole, but recurred when re-challenged at a lower dose more than a year later. To the best of our knowledge, this is the first case reporting a dementia-like state with posaconazole.

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.

Assessment of infection risks prior to lung transplantation.

PURPOSE OF THIS REVIEW: Infections are major causes of morbidity and mortality after lung transplantation. Pretransplant evaluation can identify patients at risk of infectious complications and guide prophylactic strategies post transplantation. This review focuses on studies published from 2006 to the present that relate to the assessment of risk of infection prior to lung transplantation. RECENT FINDINGS: Pretransplant airways colonization with Pseudomonas, Burkholderia, nontuberculosis mycobacteria, Aspergillus and Scedosporium tend to recur after transplantation and cause disease in the lung allograft. Recently, colonization with Pseudomonas and Aspergillus species has been implicated in the subsequent development of allograft dysfunction. B. cenocepacia and Mycobacterium abscessus are particularly associated with poor outcomes after lung transplantation and are considered to be relative contra-indications to lung transplantation in many centers. Tuberculin skin test (TST) has limited value in predicting tuberculosis (TB) reactivation; however, in the absence of a better test, it remains the gold standard for screening patients with latent TB. Serologic screening for histoplasmosis and toxoplasmosis has limited value as these infections rarely occur after lung transplantation. SUMMARY: Recurrence of pretransplant airway infection and reactivation of latent infection are potential sources of infection after lung transplantation. Prospective studies are needed to determine the efficacy of prophylactic antimicrobial strategies.

Dapsone for Pneumocystis jirovecii pneumonia prophylaxis - applying theory to clinical practice with a focus on drug interactions.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that occurs in immunocompromised individuals. The incidence can be as high as 80% in some groups but can be reduced to less than 1% with appropriate prophylaxis. HIV-infected patients with a low CD4 count are at the highest risk of PJP. Others at substantial risk include haematopoietic stem cell and solid organ transplant recipients, those with cancer (particularly haematologic malignancies), and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications. Trimethoprim-sulfamethoxazole is an established first-line line agent for prevention and treatment of PJP. However, in some situations, this medication cannot be used and dapsone is considered a suitable cost-effective second line agent. However, information on potential interactions with drugs commonly used in immunosuppressed patients is lacking or contradictory. In this this article we review the metabolic pathway of dapsone with a focus on interactions and clinical significance particularly in patients with haematological malignancies. An understanding of this process should optimise the use of this agent.

Bloodstream infections in mechanical circulatory support device recipients in the International Society of Heart and Lung Transplantation Mechanically Assisted Circulation Support Registry: Epidemiology, risk factors, and mortality.

BACKGROUND: We used multicenter international data from the International Society of Heart and Lung Transplantation Mechanically Assisted Circulation Support (IMACS) registry to determine bloodstream infection (BSI) event rate, independent risk factors, and association with mortality. METHODS: Included were patients registered in IMACS from January 2013 through December 2015, assessed BSI event rate of mechanical circulatory support (MCS) and non-MCS-related BSIs, and conducted univariate and multivariate analyses between BSI with baseline characteristics and mortality. RESULTS: We documented 1,606 BSIs in 1,231 of 10,171 MCS recipients (12%), with an event rate of 2.43 BSIs/100 patient-months within 3 months after implant (early onset) and 1.03 BSIs/100 patient-months after 3 months (late onset). Of these episodes, 1,378 (85.8%) were non- MCS-related BSI. Increasing body mass index and bilirubin were independent correlates of MCS-related BSI. Independent correlates of non-MCS-related BSI included older age, higher body mass index, previous cardiac surgery, baseline chronic renal disease and dialysis, pre-implant frailty, presence of biventricular assist device, total artificial heart or right ventricular assist device, and Interagency Registry for Mechanically Assisted Circulatory Support category 1. Survival after 3 months after implant of patients who developed early-onset BSI was 56.9% at 24 months vs 77.4% in patients without early-onset BSI (p < 0.001). Early-onset BSI was an independent correlate of mortality at 3 months after implantation (hazard ratio, 2.56; 95% confidence interval, 2.09-3.15; p < 0.001). CONCLUSIONS: Early-onset BSI was associated with significantly increased 24-month mortality. More than 85% of these BSIs were not device related. There is an opportunity for infection prevention practices to decrease the BSI event rate, which may affect 24-month survival. These data can also serve as benchmarking for individual institutions.

Risk and prognosis of bacteremia and fungemia among first-time kidney transplant recipients: a population-based cohort study.

BACKGROUND: Bacterial infections are common complications in kidney transplant recipients (KTRs). Little is known about incidence rates of bacteremia and fungemia (BAF) in KTRs. METHODS: In this population-based cohort study, we used medical and administrative registries to identify episodes of BAF among KTRs in the Central Denmark and North Denmark Regions during 1995-2010. KTRs were followed from the date of their first transplantation to the earliest of BAF, graft loss, death, emigration or 31 December 2010. We calculated incidence rates of first BAF episode overall and stratified by time from transplantation. Potential risk factors were assessed using Cox regression analysis. The Kaplan-Meier analysis was used to estimate 30- and 90-day mortality. RESULTS: Among 612 KTRs, we identified 138 first episodes of bacteremia during 2397 person-years of follow-up (PYFU). The overall incidence rate (IR) was 5.8 BAF episodes per 100 PYFU (95% confidence interval [CI]: 4.9-6.8). The incidence rate declined from 84.0 per 100 PYFU (95% CI: 61.6-114.5) during post-transplant day 0-30 to 2.3 per 100 PYFU (95% CI: 1.7-3.0) from post-transplant day 365 and onwards. Hospital-onset BAF comprised 39% of the episodes of BAF. The most frequently isolated microorganisms were Escherichia coli and Klebsiella species causing 49 (35.5%) and 29 (21.0%) episodes of BAF, respectively. The 30-day mortality was 2.1% (95% CI: 0.7-6.6). CONCLUSIONS: While the risk of BAF in KTRs was high, thirty-day mortality was low. After the first post-transplant year, the IR of bacteremia was substantially lower than in the immediate post-transplant period.