Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.

https://www.mdpi.com/2309-608X/3/4/57/pdf/1

Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision

The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals. To avoid a global collapse in our ability to control fungal infections and to avoid critical failures in medicine and food security, we must improve our stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.

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Worldwide emergence of resistance to antifungal drugs challenges human health and food security

Candidiasis, which includes both superficial infections and invasive disease, is the most common cause of fungal infection worldwide. Candida bloodstream infections (BSI) cause significant mortality and elicit a major threat to intensive care unit (ICU) patients [1]. The annual global burden of Candida spp. BSIs is about 400,000 cases, with most cases reported from the developed world. Although Candida albicans remains the most frequently isolated Candida species in the clinical setting, in some countries, a marked shift towards species of Candida that have increased resistance to azoles such as fluconazole (FLU), the standard antifungal drug of choice in many countries, and to the recently introduced antifungals known as echinocandins, is reported. Several species of non-albicans Candida, such as C. tropicalis, C. glabrata, and C. parapsilosis, are well-recognized pathogens in BSIs in different geographic locations. More recently, Candida auris, a multidrug-resistant (MDR) yeast that exhibits resistance to FLU and markedly variable susceptibility to other azoles, amphotericin B (AMB), and echinocandins, has globally emerged as a nosocomial pathogen (Fig 1) [2–20]. Alarmingly, in a span of only 7 years, this yeast, which is difficult to treat and displays clonal interand intra-hospital transmission, has become widespread across several countries, causing a broad range of healthcare-associated invasive infections [4, 5, 10, 12, 21, 22].

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Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally.

Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence.

Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment

The emerging pathogen Candida auris has been associated with nosocomial outbreaks on five continents. Genetic analysis indicates the simultaneous emergence of separate clades of this organism in different geographical locations. Invasive infection and colonization have been detected predominantly in patients in high-dependency settings and have garnered attention due to variable antifungal resistance profiles and transmission within units instituting a range of infection prevention and control measures. Issues with the identification of C. auris using both phenotypic and molecular techniques have raised concerns about detecting the true scale of the problem. This review considers the literature available on C. auris and highlights the key unknowns, which will provide direction for further work in this field.

Candida auris: a Review of the Literature.

Candida auris is a globally emerging multidrug resistant fungal pathogen causing nosocomial transmission. We report an ongoing outbreak of C. auris in a London cardio-thoracic center between April 2015 and July 2016. This is the first report of C. auris in Europe and the largest outbreak so far. We describe the identification, investigation and implementation of control measures. Data on C. auris case demographics, environmental screening, implementation of infection prevention/control measures, and antifungal susceptibility of patient isolates were prospectively recorded then analysed retrospectively. Speciation of C. auris was performed by MALDI-TOF and typing of outbreak isolates performed by amplified fragment length polymorphism (AFLP). This report describes an ongoing outbreak of 50 C. auris cases over the first 16 month (April 2015 to July 2016) within a single Hospital Trust in London. A total of 44 % (n = 22/50) patients developed possible or proven C. auris infection with a candidaemia rate of 18 % (n = 9/50). Environmental sampling showed persistent presence of the yeast around bed space areas. Implementation of strict infection and prevention control measures included: isolation of cases and their contacts, wearing of personal protective clothing by health care workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chorine based reagents and hydrogen peroxide vapour. Genotyping with AFLP demonstrated that C. auris isolates from the same geographic region clustered. This ongoing outbreak with genotypically closely related C. auris highlights the importance of appropriate species identification and rapid detection of cases in order to contain hospital acquired transmission.

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First hospital outbreak of the globally emerging Candida auris in a European hospital

Summary
Candida auris has caused nosocomial infections and transmissions within hospital settings. As little is known about the efficacy of skin and environmental decontamination products to kill C. auris, this study investigated the in vitro activity of chlorine, chlorhexidine, iodine povidone and vaporised hydrogen peroxide products against C. auris. H2O2 vapour showed 96.6%-100% effective killing of C. auris. All isolates were inhibited by chlorhexidine gluconate concentrations at 0.125%-1.5% and for iodinated povidone at 0.07%-1.25%. Other species of Candida were also killed at 1000 ppm chlorine except C. parapsilosis which failed to be killed at 3 minutes contact time. We conclude that chlorhexidine gluconate, iodinated povidone, chlorine and H2O2 vapour demonstrate effective killing activity against C. auris at concentrations used in clinical practice.

Lisa Ryan

Papers

First hospital outbreak of the globally emerging Candida auris in a European hospital

In vitro efficacy of disinfectants utilised for skin decolonisation and environmental decontamination during a hospital outbreak with Candida auris