A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

BACKGROUND: Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide. OBJECTIVES: In this retrospective study we analysed the 'real-world' TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance. METHODS: All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015-17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing. RESULTS: 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence. CONCLUSIONS: Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.

Erratum to: A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

[This corrects the article DOI: 10.1093/jacamr/dlab026.].

Aspergillus fumigatus and aspergillosis: From basics to clinics.

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.

Bronchoalveolar lavage fluid IMMY Sona Aspergillus lateral-flow assay for the diagnosis of invasive pulmonary aspergillosis: a prospective, real life evaluation.

Prompt and reliable diagnosis of invasive pulmonary aspergillosis (IPA) is essential for early initiation of antifungal therapy. We evaluated bronchoalveolar lavage (BAL) fluid IMMY Sona Aspergillus lateral-flow assay (IMMY LFA) in 92 individuals with suspected pulmonary infection. Sensitivity and specificity (vs. host factor but no IPA) of BAL IMMY LFA for diagnosis of IPA in individuals with any European Organisation for Research and Treatment of Cancer-defied "host factor" were 67% and 85%, respectively. Performance appeared better in individuals with renal transplantation (100%, 100%), compared to those with hematological malignancy and/or allogenic stem cell transplantation (70%, 78%). We found BAL IMMY LFA to be a convenient and useful addition to our diagnostic armory for IPA. LAY ABSTRACT: We evaluated a new test for diagnosing invasive pulmonary aspergillosis from bronchoscopy samples. We tested 92 people and found that it was 67% sensitive and 85% specific (compared to diagnosis according to a set of internationally recognised criteria). We found this test convenient and useful.

Posaconazole for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.

OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) can accelerate lung function decline in patients with cystic fibrosis (CF). Antifungal medication can be used in addition to systemic corticosteroid treatment. PATIENTS AND METHODS: We evaluated Aspergillus-specific IgE and the use of therapeutic drug monitoring of triazoles in a retrospective analysis of 32 patients. RESULTS: There was a significant reduction in Aspergillus IgE with posaconazole but not with other triazoles (P = 0.026). Aspergillus IgE levels were inversely correlated with the therapeutic drug level of posaconazole. CONCLUSIONS: These data suggest that posaconazole is better than comparator azoles at decreasing serological response to Aspergillus and that this response was better with therapeutic levels of posaconazole.

Burden of serious fungal infections in Mexico.

Serious fungal infections (SFIs) could be more frequent than are recognised. Estimates of the incidence and prevalence of SFIs are essential in order to identify public health problems. We estimated the rates of SFIs in Mexico, following a methodology similar to that used in prior studies. We obtained information about the general population and populations at risk. A systematic literature search was undertaken to identify epidemiological reports of SFIs in Mexico. When Mexican reports were unavailable, we based our estimates on international literature. The most prevalent SFIs in Mexico are recurrent vulvovaginal candidiasis (5999 per 100,000) followed by allergic bronchopulmonary aspergillosis (60 per 100,000), chronic pulmonary aspergillosis (15.9 per 100,000), fungal keratitis (10.4 per 100,000), invasive candidiasis (8.6 per 100,000) and SFIs in HIV (8.2 per 100,000); coccidioidomycosis (7.6 per 100,000), IA (4.56 per 100,000). These correspond to 2,749,159 people affected in any year (2.45% of the population), probably >10,000 deaths and 7000 blind eyes. SFIs affect immunocompromised and healthy populations. Most are associated with high morbidity and mortality rates. Validation of these estimates with epidemiological studies is required. The burdens indicate that an urgent need to improve medical skills, surveillance, diagnosis, and management of SFIs exists.

Renal allograft recipients fail to increase interferon-γ during invasive fungal diseases.

Invasive fungal diseases are a major cause of death in renal allograft recipients. We previously reported that adjunctive recombinant human interferon-γ therapy has clinical utility for invasive fungal diseases after renal transplantation. We have now developed a rapid peripheral blood-based quantitative real-time PCR assay that enables accurate profiling of cytokine imbalances. Our preliminary studies in renal transplant patients with invasive fungal diseases suggest that they fail to mount an adequate interferon-γ response to the fungal infection. In addition, they have reduced IL-10 and increased TNF-α when compared to stable renal transplant patients. These preliminary cytokine profiling-based observations provide a possible explanation for the therapeutic benefit of adjunctive human interferon-γ therapy in renal allograft recipients with invasive fungal diseases.

A prognostic scoring tool for identification of patients at high and low risk of death from HIV-associated Pneumocystis jirovecii pneumonia.

A prognostic scoring tool (PST) was created to aid prediction of outcome from HIV-associated Pneumocystis jirovecii pneumonia (PCP) using data obtained from 577 episodes of PCP among 540 patients presenting to a specialist HIV treatment centre in London, UK. It used risk factors identifiable at/soon after hospitalization, previously identified as being associated with mortality: repeat episode of PCP, patient's age, haemoglobin (Hb) and oxygen partial pressure (PaO(2)) on admission, presence of medical co-morbidity (Comorb) and of pulmonary Kaposi sarcoma (PKS). The derived PST was 25.5+(age in years/10) + 2 (if a repeat episode of PCP) + 3 (if Comorb present) + 4 (if PKS detected) - PaO(2) (kPa) - Hb (g/dL), and produced scores that ranged between 0 and 19. Patients were divided into five groups according to their prognostic score: 0-3.9 = group 1 (0% mortality), 4-7.9 = group 2 (3% mortality), 8-10.9 = group 3 (9% mortality), 11-14.9 = group 4 (29% mortality) and ≥ 15 = group 5 (52% mortality). This PST facilitates rapid identification of patients early in their hospitalization who have mild or severe HIV-associated PCP and who are at high and low risk of in-hospital death from PCP. The PST may aid assessment of severity of illness and in directing treatment strategies, but requires validation in patient cohorts from other health-care institutions.

Missed opportunities for HIV testing--a costly oversight.

OBJECTIVES: In the UK, one-third of human immunodeficiency virus (HIV)-infected individuals are unaware of their diagnosis, and of those diagnosed a similar proportion have late stage disease. To address this National guidelines have been introduced promoting HIV testing across all medical specialities. We investigated HIV testing patterns in an inner London area with high local HIV prevalence, to identify missed opportunities for HIV testing and its consequences. METHODS: All human immunodeficiency virus (HIV) tests performed in 2008 at Guys and St Thomas' NHS Trust virology department were reviewed. Tests were stratified for location of request. Case-note review was carried out on all hospital HIV-positive diagnoses outside the genitourinary medicine (GUM) or screening settings to establish the circumstances surrounding the test, and missed opportunities for previous HIV testing. RESULTS: A total of 40,883 HIV tests were performed in 36,395 individuals. Three hundred and fifty-four (1%) tested positive. Excluding those from GUM or screening settings, 34 (2.8%) of the 1225 inpatients, 17 (0.3%) of the 5303 outpatients and 68 (1.12%) of the 5746 from primary care tested positive. Nineteen (41%) of 46 evaluable hospital diagnoses had presented to local healthcare services within the previous 12 months, 17 (37%) with an HIV indicator condition, but had not been tested. Of the 5303 outpatient tests conducted, 3148 (59%) were performed by either fertility or renal specialist teams. Other specialties conducted relatively few tests. The mean cost of admission for those diagnosed as an inpatient was £36,625 (range £331-223,000). The total cost for the 12 inpatients, who had presented to services in the preceding year but had not been tested was £439,500. CONCLUSION: Despite large numbers of HIV tests as screening tests in GUM and antenatal settings, relatively few tests occurred elsewhere with profound costs. Missed opportunities to access this high-prevalence HIV population is concerning and urgent engagement of primary, secondary and tertiary healthcare systems to increase HIV testing and prevent late-stage diagnoses is underway.

Novel H1N1 influenza and Panton-Valentine leukocidin Staphylococcus aureus necrotizing pneumonia.

The association between seasonal influenza and staphylococcal pneumonia has long been recognized (Chickering and Park, 1919; Roberts et al, 2008), and both meticillin-resistant Staphylococcus aureus and Panton-Valentine leukocidin S. aureus have been associated with seasonal influenza pandemics (Roberts et al, 2008; Kearns et al, 2009; Murray et al, 2010).

Exogenous interferon-gamma immunotherapy for invasive fungal infections in kidney transplant patients.

The incidence of invasive fungal infections (IFIs) in nonneutropenic solid organ transplant patients is increasing. We report our clinical experience with the use of interferon-gamma (IFN-gamma) immunotherapy in seven renal transplant patients who developed life threatening, disseminated IFIs refractory to conventional antifungal drug therapy. The infections were all microbiologically and histologically proven. The rapid cure of these disseminated infections with exogenous IFN-gamma injections was not associated with impaired kidney allograft function despite the use of liposomal amphotericin B in all cases. No clinical toxicity from the IFN-gamma immunotherapy was seen and no IFI relapsed during long-term follow-up. Our experience is both uncontrolled and in patients with unpredictable fungal infection-related outcomes. However, compared to standard approaches, the accelerated cure of life threatening, disseminated IFIs with 6 weeks of combination antifungal drug therapy and IFN-gamma immunotherapy saved lives, retained allograft function and led to substantial cost savings in this small patient group.