Eavan G. Muldoon

Delivering on Antimicrobial Resistance Agenda Not Possible without Improving Fungal Diagnostic Capabilities

Antimicrobial resistance, a major public health concern, largely arises from excess use of antibiotic and antifungal drugs. Lack of routine diagnostic testing for fungal diseases exacerbates the problem of antimicrobial drug empiricism, both antibiotic and antifungal. In support of this contention, we cite 4 common clinical situations that illustrate this problem: 1) inaccurate diagnosis of fungal sepsis in hospitals and intensive care units, resulting in inappropriate use of broad-spectrum antibacterial drugs in patients with invasive candidiasis; 2) failure to diagnose chronic pulmonary aspergillosis in patients with smear-negative pulmonary tuberculosis; 3) misdiagnosis of fungal asthma, resulting in unnecessary treatment with antibacterial drugs instead of antifungal drugs and missed diagnoses of life-threatening invasive aspergillosis in patients with chronic obstructive pulmonary disease; and 4) overtreatment and undertreatment of Pneumocystis pneumonia in HIV-positive patients. All communities should have access to nonculture fungal diagnostics, which can substantially benefit clinical outcome, antimicrobial stewardship, and control of antimicrobial resistance.

Allergic and Noninvasive Infectious Pulmonary Aspergillosis Syndromes

Aspergillus spp are ubiquitous in the environment, and inhalation of Aspergillus spores is unavoidable. An intact immune system, with normal airway function, protects most people from disease. Globally, however, the toll from aspergillosis is high. The literature has largely focused on invasive aspergillosis, yet the burden in terms of chronicity and prevalence is higher for noninvasive Aspergillus conditions. This article discusses allergic aspergilloses and provides an update on the diagnosis and management of allergic bronchopulmonary aspergillosis, including in patients with cystic fibrosis, and an update on severe asthma with fungal sensitization. In addition, the presentation, investigation, and management of noninvasive infectious aspergilloses are reviewed.

Chronic fibrosing pulmonary aspergillosis: a cause of ‘destroyed lung’ syndrome

Abstract Background: Chronic pulmonary aspergillosis (CPA) has substantial impact on quality of life. A subset of patients develops significant pulmonary fibrosis, identified either on biopsy or radiologically. The term chronic fibrosing pulmonary aspergillosis (CFPA) has been suggested. Methods: We describe 11 patients with CFPA referred to our centre. Results: Mean age was 58.5 years and five were male. In nine, fibrosis was already evident on presentation, while in two it developed 3 and 6 years later. The predominant radiological feature was extensive or complete involvement of the entire lung, with minimal contralateral involvement. All patients received prolonged antifungal treatment. Two patients had surgical treatment; both developed post-operative complications. The contralateral lung remained free of significant disease in all but three patients. Conclusions: CFPA is a rare complication of CPA that is usually evident on presentation, but may develop after years in patients not on antifungals. Fibrosis resembles the ‘destroyed lung’ syndrome described after treated tuberculosis.

Editorial Commentary: Prophylactic Echinocandin: Is There a Subgroup of Intensive Care Unit Patients Who Benefit?

Prevention of fungal infection in at-risk patients is an established medical practice. Establishing the optimal combination of antifungal agent with the highest at-risk group has been the subject of hundreds of studies. Given the mortality associated with invasive candidiasis (IC) in the intensive care unit (ICU), a prophylactic approach to antifungal therapy is attractive, but little studied, other than in certain patient subgroups, such as liver transplant recipients and neonates. In general ICU patients, only fluconazole has been studied and probably has a role in those at high risk of developing Candida peritonitis, and by implication those with pancreatitis [1]. In this issue of Clinical Infectious Diseases, Ostrosky-Zeichner et al have authored the first multicenter trial (MSG-01) in a larger group of atrisk patients and utilize the echinocandin caspofungin, a broader-spectrum agent than fluconazole, as antifungal prophylaxis. Overall, their results do not show ab ene fit in these at-risk ICU patients. Based on this study, prophylactic use of caspofungin cannot be recommended for all at-risk ICU patients to prevent IC. Identification of at-risk patients is central to prudent use of antifungal prophylaxis in the ICU. There are some uncertainties in MSG-01 related to the selection of at-risk patients. For example, patients undergoing major cardiovascular surgery are at lower risk of IC than those with abdominal surgery, and yet both groups are lumped together under “major surgery” ;1 4% of the patients had cardiovascular surgery and only 11% had gastrointestinal surgery. Furthermore, the authors use a prediction rule that they had developed previously to identify at-risk patients; this prediction rule excludes solid organ transplant recipients, and yet in the current article corticosteroid therapy is considered a risk categorization and there is no mention of transplantation. In addition, the incidence of IC in patients identified using this prediction rule is lower in both groups (prophylaxis and placebo) than expected. Taken together, these features of the current study make the utility of the findings difficult to translate. The authors utilize the 2008 European

Secondary syphilis presenting with aortitis and coronary ostial occlusion

Aortitis is an established manifestation of tertiary syphilis. We report a rare case of aortitis with ostial occlusion and left ventricular failure in secondary syphilis. Her management required a true multidisciplinary approach from multiple specialities due to complications of concomitant psychosis and a history of anaphylaxis to penicillin. This case illustrates the complexities of diagnosing and managing a rare presentation of this increasingly prevalent infection.

Cerebrospinal fluid HIV viral load may be detectable, despite serum viral load being undetectable, in patients diagnosed with syphilis

With an increasing proportion of male patients co-infected with syphilis and HIV, the management of these patients has become more relevant. HIV and syphilis both enter the central nervous system early in the course of infection, and have been shown to be present at all stages of the disease. Syphilis is reported to increase the serum HIV viral load (VL) in HIV co-infected patients; 1higher CSF HIV VLs …

F508del CFTR Gene Mutation in Patients with Allergic Bronchopulmonary Aspergillosis

ABSTRACT Objective: The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA. Methods: A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing. Results: From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42–98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%. Conclusions: In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.

The impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital

Objectives A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker [serum β-1-3-d-glucan (BDG)] was developed in 2013 by an antifungal stewardship (AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). Methods All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed. Results The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016. Conclusions The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis.

Assessment of posaconazole salvage therapy in chronic pulmonary aspergillosis using predefined response criteria

OBJECTIVES Chronic pulmonary aspergillosis (CPA) is a progressive infection that destroys lung tissue in non-immunocompromised patients. First-line therapies for CPA (itraconazole and/or voriconazole) are often curtailed due to toxicity or the development of drug resistance. Posaconazole is a potential alternative for these patients. METHODS Use of posaconazole was funded by the National Health Service Highly Specialised National Commissioners on an individual basis for patients who failed or did not tolerate first-line therapy; those who met predefined criteria for improvement at 4 and 6 months (weight gain and/or improvement in St Georges Respiratory Questionnaire) continued posaconazole long-term. We recorded response, failure, discontinuation rates, and adverse events. RESULTS Seventy-eight patients received posaconazole as salvage therapy. Thirty-four (44%) achieved targets for continuation of therapy. Fourteen (18%) failed therapy; five (36%) patients did not achieve clinical targets at 4 or 6 months of assessment and nine (64%) developed clinical and/or radiological failure. Twenty-eight (36%) discontinued their trial early; 8 (29%) died and 20 (71%) had significant side effects. One patient was non-compliant and another was lost to follow up. CONCLUSIONS Establishing criteria for therapeutic success offered a clear, safe and sustainable method of identifying patients who benefit from additional therapy, and minimised continuation of ineffective therapy in those who did not.

Varicella infection and the impact of late entry into the Irish healthcare system

We present a case which highlights several areas of concern relating to the prevention and management of varicella in Ireland. We review the pathophysiology of this virus and highlight its greater potential for morbidity in certain groups, most particularly adult males. The experience and opinions with regard to varicella vaccination in the US and other temperate countries is reviewed along with evidence of changing epidemiology of varicella infection. The National Immunisation Advisory Committee (NIAC) guidelines are reviewed in the context of our experience.