Silke Schelenz

Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors

BACKGROUND The aim of this study was to investigate the epidemiology of oral yeast colonization and infection amongst cancer patients. METHODS Patients with solid tumor, head-neck cancer or hematological malignancy were recruited into the study. Demographic data on age, gender, type of cancer, preceding treatment with antibiotics, anti-fungal agents, chemotherapy, radiation or surgery and presence of dentures were recorded on admission. Oral examination and microbial swabs were obtained and yeast culture, identification and antifungal susceptibility performed. RESULTS Oral yeast colonization was prevalent in 56.8% (227/400) of all cancer patients and 18.9% (43/227) of those had clinical and microbiological evidence of infection. The incidence of oral candidiasis in yeast colonized patients was highest in head neck cancer (29.2%) followed by hematological malignancies (20.5%) and solid tumor (17%) patients. Age and dentures were identified as independent risk factors associated with yeast carriage. Candida albicans was the dominant (74%) species (497.5 per 1000 cancer admissions) followed by C. glabrata (11.5%), C. tropicalis (2.6%), C. krusei (2.6%) and C. parapsilosis (1.9%). The overall resistance to azoles was 28.2% (75/266). Resistance to specific drugs was seen for fluconazole (4.5%), itraconazole (11.7%), ketoconazole (11.3%), voriconazole (0.75%) and caspofungin (41.1%) but none to amphotericin B or nystatin. CONCLUSIONS The highest incidence of oral candidiasis amongst cancer patients was seen in head neck cancers. The majority of infections were caused by C. albicans but almost one third of patients harbored non-C. albicans strains such as C. glabrata which were often more resistant to anti-fungal agents.

Management of candidiasis in the intensive care unit

In the last two decades, Candida has emerged as an important opportunistic pathogen. Patients admitted to the intensive care unit (ICU) are particularly susceptible to this infection because of the severity of their underlying illness and the excess use of medical and surgical interventions. The frequent use of antibiotics, central venous catheters and other intravascular devices as well as poor gut motility or abdominal surgery place these patients at high risk of infection, which contributes to the morbidity and mortality of the already critically ill patient. Early recognition and appropriate management of invasive candidiasis are therefore important. This article addresses important management issues such as the role of screening for Candida colonization, the use of prophylaxis and the choice of antifungal agents for the treatment of presumed and proven invasive candidiasis in the adult ICU setting.

Insidious risk of severe mycobacterium chimaera infection in cardiac surgery patients

Background. An urgent UK investigation was launched to assess risk of invasive Mycobacterium chimaera infection in cardiothoracic surgery and a possible association with cardiopulmonary bypass heater-cooler units following alerts in Switzerland and The Netherlands. Methods. Parallel investigations were pursued: (1) identification of cardiopulmonary bypass–associated M. chimaera infection through national laboratory and hospital admissions data linkage; (2) cohort study to assess patient risk; (3) microbiological and aerobiological investigations of heater-coolers in situ and under controlled laboratory conditions; and (4) whole-genome sequencing of clinical and environmental isolates. Results. Eighteen probable cases of cardiopulmonary bypass–associated M. chimaera infection were identified; all except one occurred in adults. Patients had undergone valve replacement in 11 hospitals between 2007 and 2015, a median of 19 months prior to onset (range, 3 months to 5 years). Risk to patients increased after 2010 from <0.2 to 1.65 per 10000 person-years in 2013, a 9-fold rise for infections within 2 years of surgery (rate ratio, 9.08 [95% CI, 1.81–87.76]). Endocarditis was the most common presentation (n = 11). To date, 9 patients have died. Investigations identified aerosol release through breaches in heater-cooler tanks. Mycobacterium chimaera and other pathogens were recovered from water and air samples. Phylogenetic analysis found close clustering of strains from probable cases. Conclusions. We identified low but escalating risk of severe M. chimaera infection associated with heater-coolers with cases in a quarter of cardiothoracic centers. Our investigations strengthen etiological evidence for the role of heater-coolers in transmission and raise the possibility of an ongoing, international point-source outbreak. Active management of heater-coolers and heightened clinical awareness are imperative given the consequences of infection.

Longitudinal surveillance of bacteraemia in haematology and oncology patients at a UK cancer centre and the impact of ciprofloxacin use on antimicrobial resistance

OBJECTIVES To assess and compare the current trends in bacteraemia and antimicrobial resistance and analyse the impact of ciprofloxacin prescribing on Gram-negative bacterial resistance in haematology and oncology patients. METHODS Information on bacteraemia episodes, causative pathogens, antimicrobial resistance and consumption was compared between haematology and oncology patients at a UK cancer centre in a 14 year longitudinal surveillance study. RESULTS Haematology patients had a 3-fold higher incidence of bacteraemia compared with oncology patients (10.9/1000 versus 3.6/1000 admissions, respectively). Coagulase-negative staphylococci were the most common Gram-positive cause of bacteraemia for both cancer groups, whereas the overall rate of methicillin-resistant Staphylococcus aureus bacteraemia was low (0.16/1000 admissions). Escherichia coli was the most common Gram-negative cause of bacteraemia for both groups, but with a higher incidence in haematology patients (0.92/1000 admissions) compared with oncology patients (0.5/1000 admissions). Pseudomonas spp. formed the second most common Gram-negative infection in haematology patients, with a 4-fold higher bacteraemia incidence compared with oncology patients (0.76 versus 0.16/1000 admissions). Ciprofloxacin resistance of Gram-negative isolates was 22% in haematology and 5% in oncology patients. The rate of ciprofloxacin use measured showed high ciprofloxacin consumption in haematology patients compared with oncology patients (3.6 versus 1.5 defined daily doses/10 admissions, respectively), suggesting that ciprofloxacin may drive resistance. CONCLUSIONS Our longitudinal surveillance highlights the continued importance of Gram-negative bacteraemia, in particular that due to Pseudomonas, in the cancer population and raises concerns regarding increasing ciprofloxacin use and resistance.

The Serum Opsonin L-ficolin Is Detected in Lungs of Human Transplant Recipients Following Fungal Infections and Modulates Inflammation and Killing of Aspergillus fumigatus

BACKGROUND Invasive aspergillosis (IA) is a life-threatening systemic fungal infection in immunocompromised individuals that is caused by Aspergillus fumigatus. The human serum opsonin, L-ficolin, has been observed to recognize A. fumigatus and could participate in fungal defense. METHODS Using lung epithelial cells, primary human monocyte-derived macrophages (MDMs), and neutrophils from healthy donors, we assessed phagocytosis and killing of L-ficolin-opsonized live A. fumigatus conidia by flow cytometry and microscopy. Additionally, cytokines were measured by cytometric bead array, and L-ficolin was measured in bronchoalveolar lavage (BAL) fluid from lung transplant recipients by enzyme-linked immunosorbent assay. RESULTS L-ficolin opsonization increased conidial uptake and enhanced killing of A. fumigatus by MDMs and neutrophils. Opsonization was also shown to manifest an increase in interleukin 8 release from A549 lung epithelial cells but decreased interleukin 1β, interleukin 6, interleukin 8, interleukin 10, and tumor necrosis factor α release from MDMs and neutrophils 24 hours after infection. The concentration of L-ficolin in BAL fluid from patients with fungal infection was significantly higher than that for control subjects (P = .00087), and receiving operating characteristic curve analysis highlighted the diagnostic potential of L-ficolin for lung infection (area under the curve, 0.842; P < .0001). CONCLUSIONS L-ficolin modulates the immune response to A. fumigatus. Additionally, for the first time, L-ficolin has been demonstrated to be present in human lungs.

H‐ficolin binds Aspergillus fumigatus leading to activation of the lectin complement pathway and modulation of lung epithelial immune responses

Aspergillus fumigatus is an opportunistic fungal pathogen that typically infects the lungs of immunocompromised patients leading to a high mortality. H‐Ficolin, an innate immune opsonin, is produced by type II alveolar epithelial cells and could participate in lung defences against infections. Here, we used the human type II alveolar epithelial cell line, A549, to determine the involvement of H‐ficolin in fungal defence. Additionally, we investigated the presence of H‐ficolin in bronchoalveolar lavage fluid from transplant patients during pneumonia. H‐Ficolin exhibited demonstrable binding to A. fumigatus conidia via l‐fucose, d‐mannose and N‐acetylglucosamine residues in a calcium‐ and pH‐dependent manner. Moreover, recognition led to lectin complement pathway activation and enhanced fungal association with A549 cells. Following recognition, H‐ficolin opsonization manifested an increase in interleukin‐8 production from A549 cells, which involved activation of the intracellular signalling pathways mitogen‐activated protein kinase MAPK kinase 1/2, p38 MAPK and c‐Jun N‐terminal kinase. Finally, H‐ficolin concentrations were significantly higher in bronchoalveolar lavage fluid of patients with lung infections compared with control subjects (n = 16; P = 0·00726). Receiver operating characteristics curve analysis further highlighted the potential of H‐ficolin as a diagnostic marker for lung infection (area under the curve = 0·77; P < 0·0001). Hence, H‐ficolin participates in A. fumigatus defence through the activation of the lectin complement pathway, enhanced fungus–host interactions and modulated immune responses.

Role of Ficolin-A and Lectin Complement Pathway in the Innate Defense against Pathogenic Aspergillus Species

ABSTRACT Aspergillus species are saprophytic molds causing life-threatening invasive fungal infections in the immunocompromised host. Innate immune recognition, in particular, the mechanisms of opsonization and complement activation, has been reported to be an integral part of the defense against fungi. We have shown that the complement component ficolin-A significantly binds to Aspergillus conidia and hyphae in a concentration-dependent manner and was inhibited by N-acetylglucosamine and N-acetylgalactosamine. Calcium-independent binding to Aspergillus fumigatus and A. terreus was observed, but binding to A. flavus and A. niger was calcium dependent. Ficolin-A binding to conidia was increased under low-pH conditions, and opsonization led to enhanced binding of conidia to A549 airway epithelial cells. In investigations of the lectin pathway of complement activation, ficolin-A-opsonized conidia did not lead to lectin pathway-specific C4 deposition. In contrast, the collectin mannose binding lectin C (MBL-C) but not MBL-A led to efficient lectin pathway activation on A. fumigatus in the absence of ficolin-A. In addition, ficolin-A opsonization led to a modulation of the proinflammatory cytokine interleukin-8. We conclude that ficolin-A may play an important role in the innate defense against Aspergillus by opsonizing conidia, immobilizing this fungus through enhanced adherence to epithelial cells and modulation of inflammation. However, it appears that other immune pattern recognition molecules, i.e., those of the collectin MBL-C, are involved in the Aspergillus-lectin complement pathway activation rather than ficolin-A.

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

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.

Limitations of caspofungin in the treatment of obstructive pyonephrosis due to Candida glabrata infection

BackgroundCaspofungin is a new antifungal agent with high-level activity against a number of Candida species including those that are resistant to azoles. Its good safety profile and low nephrotoxicity makes it an attractive drug to treat fungal infections in patients with compromised renal function. However, little is known about the clinical efficacy in the treatment of complicated urinary tract infections due to Candida species such as pyonephrosis.Case presentationWe report a case of obstructive pyonephrosis due to an azole (fluconazole and itraconazole) resistant Candida glabrata strain that failed to respond to intravenous treatment with caspofungin. A sustained clinical and microbiological response was only achieved after percutaneous drainage and instillation of amphotericin B deoxycholate into the renal pelvis in combination with intravenous liposomal amphotericin B.ConclusionThis case demonstrates the limitation of intravenous antifungal agents such as caspofungin as the sole treatment of an obstructive upper urinary tract infection due to Candida species. In order to achieve long term sustained cure from an obstructive pyonephrosis, pus and fungal balls should be drained and an anti-fungal agent such as amphotericin B deoxycholate instilled locally. The pharmacokinetics and role of caspofungin in the treatment of complicated Candida urinary tract infection is reviewed.

Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris

Candida auris was first described in 2009, and it has since caused nosocomial outbreaks, invasive infections, and fungaemia across at least 19 countries on five continents. An outbreak of C. auris occurred in a specialized cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak in the UK, involving a total of 72 patients. To understand the genetic epidemiology of C. auris infection both within this hospital and within a global context, we sequenced the outbreak isolate genomes using Oxford Nanopore Technologies and Illumina platforms to detect antifungal resistance alleles and reannotate the C. auris genome. Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin; the outbreak showed similar genetic diversity to that of the entire clade, and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1. These mutations add to a growing body of research on multiple antifungal drug targets in this organism. Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission and implement outbreak control measures.