A multisite evaluation of antifungal use in critical care: implications for antifungal stewardship.

Background: ICUs are settings of high antifungal consumption. There are few data on prescribing practices in ICUs to guide antifungal stewardship implementation in this setting. Methods: An antifungal therapy (AFT) service evaluation (15 May-19 November 2019) across ICUs at three London hospitals, evaluating consumption, prescribing rationale, post-prescription review, de-escalation and final invasive fungal infection (IFI) diagnostic classification. Results: Overall, 6.4% of ICU admissions (305/4781) received AFT, accounting for 11.41 days of therapy/100 occupied bed days (DOT/100 OBD). The dominant prescribing mode was empirical (41% of consumption), followed by targeted (22%), prophylaxis (18%), pre-emptive (12%) and non-invasive (7%). Echinocandins were the most commonly prescribed drug class (4.59 DOT/100 OBD). In total, 217 patients received AFT for suspected or confirmed IFI; 12%, 10% and 23% were classified as possible, probable or proven IFI, respectively. Hence, in 55%, IFI was unlikely. Proven IFI (n = 50) was mostly invasive candidiasis (92%), of which 48% had been initiated on AFT empirically before yeast identification. Where on-site (1 → 3)-ß-d-glucan (BDG) testing was available (1 day turnaround), in those with suspected but unproven invasive candidiasis, median (IQR) AFT duration was 10 (7-15) days with a positive BDG (≥80 pg/mL) versus 8 (5-9) days with a negative BDG (<80 pg/mL). Post-prescription review occurred in 79% of prescribing episodes (median time to review 1 [0-3] day). Where suspected IFI was not confirmed, 38% episodes were stopped and 4% de-escalated within 5 days. Conclusions: Achieving a better balance between promptly treating IFI patients and avoiding inappropriate antifungal prescribing in the ICU requires timely post-prescription review by specialist multidisciplinary teams and improved, evidence-based-risk prescribing strategies incorporating rapid diagnostics to guide AFT start and stop decisions.

Incidence and outcomes of healthcare-associated COVID-19 infections: significance of delayed diagnosis and correlation with staff absence.

BACKGROUND: The sudden increase in COVID-19 admissions in hospitals during the SARS-CoV-2 pandemic of 2020 led to onward transmissions among vulnerable inpatients. AIMS: This study was performed to evaluate the prevalence and clinical outcomes of healthcare-associated COVID-19 infections (HA-COVID-19) during the 2020 epidemic and study factors which may promote or correlate with its incidence and transmission in a Teaching Hospital NHS Trust in London, UK. METHODS: Electronic laboratory, patient and staff self-reported sickness records were interrogated from 1st March to 18th April 2020. HA-COVID-19 was defined as COVID-19 with symptom onset within >14 days of admission. Test performance of a single combined throat and nose swab (CTNS) for patient placement was calculated. The effect of delayed RNA positivity (DRP, defined as >48 h delay), staff self-reported COVID-19 sickness absence, hospital bed occupancy, and community incidence of COVID-19 was compared for HA-COVID-19. The incidence of other significant hospital-acquired bacterial infections (HAB) was compared with previous years. RESULTS: Fifty-eight HA-COVID-19 (7.1%) cases were identified. When compared with community-acquired admitted cases (CA-COVID-19), significant differences were observed in age (P=0.018), ethnicity (P<0.001) and comorbidity burden (P<0.001) but not in 30-day mortality. CTNS-negative predictive value was 60.3%. DRP was associated with greater mortality (P=0.034) and incidence of HA-COVID-19 correlated positively with DRP (R = 0.7108) and staff sickness absence (R = 0.7815). For the study period HAB rates were similar to the previous 2 years. CONCLUSIONS: Early diagnosis and isolation of COVID-19 patients would help to reduce transmission. A single CTNS has limited value in segregating patients into positive and negative pathways.

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.

Yeasticidal activity of chemical disinfectants and antiseptics against Candida auris.

Candida auris appears to be transmitted readily between patients, yet information regarding the efficacy of environmental disinfection and skin decolonization is lacking. A quantitative suspension test (EN 13624:2013) was used to evaluate the yeasticidal activity of different chemical disinfectants and antiseptics against C. auris and Candida albicans. When tested in suspension, both a chlorine-based disinfectant and iodine-based skin antiseptic were effective against C. auris, suggesting that their use could reduce environmental contamination and skin colonization, respectively, if applied appropriately. Chlorhexidine-based products may also be effective. However, in this study, activity depended on formulation, specifically the presence of isopropyl alcohol.

Sustainable intensive thermal use of the shallow subsurface-a critical view on the status quo.

Thermal use of the shallow subsurface for heat generation, cooling, and thermal energy storage is increasingly gaining importance in reconsideration of future energy supplies. Shallow geothermal energy use is often promoted as being of little or no costs during operation, while simultaneously being environmentally friendly. Hence, the number of installed systems has rapidly risen over the last few decades, especially among newly built houses. While the carbon dioxide reduction potential of this method remains undoubted, concerns about sustainability and potential negative effects on the soil and groundwater due to an intensified use have been raised-even as far back as 25 years ago. Nevertheless, consistent regulation and management schemes for the intensified thermal use of the shallow subsurface are still missing-mainly due to a lack of system understanding and process knowledge. In the meantime, large geothermal applications, for example, residential neighborhoods that are entirely dependent up on shallow geothermal energy use or low enthalpy aquifer heat storage, have been developed throughout Europe. Potential negative effects on the soil and groundwater due to an intensive thermal use of the shallow subsurface as well as the extent of potential system interaction still remain unknown.

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.

An antibiotic formulary for a tertiary care foot clinic: admission avoidance using intramuscular antibiotics for borderline foot infections in people with diabetes.

AIMS: To develop an antibiotic foot formulary for the empirical treatment of diabetes-related foot infections presenting to our service. Subsequently, to asses costs associated with the introduction of our protocol, in particular to assess the effect on admissions avoidance and any cost savings achieved. METHODS: We reviewed several existing antibiotic protocols. We analysed data on costs related to treatment and admission rates prior to and after the introduction of the protocol. RESULTS: We rationalized our antibiotic protocol and adapted the Infectious Disease Society of America guideline by introducing a category of 'moderate infection-borderline admission' to our classification. This enabled the administration of outpatient intramuscular antibiotics. After introducing the rationalized protocol, our average antibiotic prescribing costs for a 3-week course of treatment fell from £17.12 to £16.42. Over 22 months of follow-up, 26 episodes were eligible for treatment with intramuscular antibiotics. Over the same time period, 121 people were admitted directly from the foot clinic. The costs saved as a result of avoided or delayed admission for those 26 episodes was over £76 000. For 12 people who required subsequent admission, their length of hospital stay was significantly shorter than those admitted directly [9.25 days (range 2-25) vs. 16.11 (2-64), P = 0.045]. CONCLUSIONS: By modifying the Infectious Disease Society of America classification and adopting a protocol to administer outpatient oral and intramuscular antibiotics, we have led to substantial cost savings, shorter hospital admissions and also have developed a successful admissions avoidance strategy.

Epidemiology, management and economic impact of febrile neutropenia in oncology patients receiving routine care at a regional UK cancer centre.

BACKGROUND: Febrile neutropenia (FN) is a potentially life-threatening complication following chemotherapy. The incidence and mortality of this condition varies according to cancer type and chemotherapy regimen. The aim of the study was to establish the incidence, risk, outcome, infectious cause and economic cost of FN in solid tumour patients within a routine oncology hospital setting. PATIENTS AND METHODS: All FN solid tumour patients admitted to the oncology unit at a UK regional cancer centre were identified over a 12-month period. Demographic data on age, gender, cancer type, disease burden, chemotherapy regimen, antibiotic treatment, length of hospital stay and outcome was obtained. RESULTS: The annual incidence of FN was 19.4 per 1000 oncology admissions. The most common patient groups were those with breast (27%), lung (16%), ovarian (13%) and oesophageal (13%) cancers. The mean length of stay was 9.2 days with an average cost of £2353 for an FN episode per patient. The attributable mortality rate was 12.5%. The majority (83%) of patients who died were ≥60 years old, presented with hypotension and had a high-risk FN MASCC index compared with those that survived. CONCLUSIONS: This study demonstrates that FN in solid tumour patients continues to be associated with a significant morbidity and mortality during routine cancer care. Early risk classification of FN may help improve the outcome as well as reduce the economic burden.

Standards of care for patients with invasive fungal infections within the United Kingdom: a national audit.

OBJECTIVE: The objective of this study was to audit the compliance and implementation of the British Society for Medical Mycology standards of care for patients with invasive infections in UK hospitals. METHODS: A multidisciplinary audit questionnaire regarding the processing of microbiology and histopathology specimens, radiology imaging and clinical management of patients with invasive fungal infections was distributed to UK hospitals. RESULTS: The study has shown that speciation of Candida and Aspergillus isolates from sterile sites was performed in 42-98% of hospitals. Microscopy of bronchoscopy specimens was not undertaken in 13 of 62 (21%) laboratories. Cryptococcal culture and antigen were undertaken routinely in abnormal CSF in 40-75% and 31-83% of at-risk patients but only in 12% of abnormal CSFs in patients without risk factors. Detailed fungal morphology was provided by <50% of histopathology departments. Most hospitals provided a timely HRCT or MRI on patients suspected to have an invasive fungal infection, but early treatment failed to occur in 15% of hospitals. In patients presenting with candidaemia, central venous catheters (CVC) were not changed routinely within 48h in 15%. CONCLUSION: Improvement in microbiology and histopathology specimen processing as well as rapid interventions such as initiation of anti-fungal therapy or CVC line removal could improve diagnostic rates and clinical outcomes of invasive fungal infections.

A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

OBJECTIVES: To determine the diagnostic accuracy of tests for the rapid diagnosis of bacterial food poisoning in clinical and public health practice and to estimate the cost-effectiveness of these assays in a hypothetical population in order to inform policy on the use of these tests. DATA SOURCES: Studies evaluating diagnostic accuracy of rapid tests were retrieved using electronic databases and handsearching reference lists and key journals. Hospital laboratories and test manufacturers were contacted for cost data, and clinicians involved in the care of patients with food poisoning were invited to discuss the conclusions of this review using the nominal group technique. REVIEW METHODS: A systematic review of the current medical literature on assays used for the rapid diagnosis of bacterial food poisoning was carried out. Specific organisms under review were Salmonella, Campylobacter, Escherichia coli O157, Staphylococcus aureus, Clostridium perfringens and Bacillus cereus. Data extraction was undertaken using standardised data extraction forms. Where a sufficient number of studies evaluating comparable tests were identified, meta-analysis was performed. A decision analytic model was developed, using effectiveness data from the review and cost data from hospitals and manufacturers, which contributed to an assessment of the cost-effectiveness of rapid tests in a hypothetical UK population. Finally, diagnostic accuracy and cost-effectiveness results were presented to a focus group of GPs, microbiologists and consultants in communicable disease control, to assess professional opinion on the use of rapid tests in the diagnosis of food poisoning. RESULTS: Good test performance levels were observed with rapid test methods, especially for polymerase chain reaction (PCR) assays. The estimated levels of diagnostic accuracy using the area under the curve of the summary receiver operating characteristic curve was very high. Indeed, although traditional culture is the natural reference test to use for comparative statistical analysis, on many occasions the rapid test outperforms culture, detecting additional 'truly' positive cases of food-borne illness. The significance of these additional positives requires further investigation. Economic modelling suggests that adoption of rapid tests in combination with routine culture is unlikely to be cost-effective, however, as the cost of rapid technologies decreases; total replacement with rapid technologies may be feasible. CONCLUSIONS: Despite the relatively poor quality of reporting of studies evaluating rapid detection methods, the reviewed evidence shows that PCR for Campylobacter, Salmonella and E. coli O157 is potentially very successful in identifying pathogens, possibly detecting more than the number currently reported using culture. Less is known about the benefits of testing for B. cereus, C. perfringens and S. aureus. Further investigation is needed on how clinical outcomes may be altered if test results are available more quickly and at a greater precision than in the current practice of bacterial culture.

Significant reduction of endemic MRSA acquisition and infection in cardiothoracic patients by means of an enhanced targeted infection control programme.

Due to increasing methicillin-resistant Staphylococcus aureus (MRSA) infection in cardiothoracic patients at St Thomas' Hospital, an enhanced infection control programme was introduced in September 2000. It was based on UK national guidelines on the control of MRSA and targeted additional identified risk factors for surgical site infection (SSI). It included recognition of the problem by senior staff and their taking responsibility for it; intensive support, education and advice from the infection control team; improved ward and theatre hygiene; pre-admission, admission and weekly MRSA screening; isolation and clearance treatment; nursing care pathways for MRSA colonized patients; and teicoplanin plus gentamicin surgical prophylaxis. The effectiveness of the programme was assessed by retrospective analysis of computerized patient data for the 16 months before and after the introduction of the programme. There was no significant change in the number of operations or the proportion of patients admitted with MRSA, although nine patients were cleared of carriage before admission. However, there were significant falls in the proportion of patients acquiring MRSA on the ward [38/1036 to 14/921, P=0.003, RR 2.4 (95%CI 1.32-4.42)] and in the rate of bloodstream MRSA infections [12/1075 to 2/956, P=0.014, RR 5.34 (95%CI 1.20-23.78)]. Sternal and leg wound infections both halved (from 28/1075 to 13/956 and 16/1075 to 7/956, respectively) but this did not reach statistical significance. These results demonstrate that an enhanced, targeted infection control programme based on the UK national guidelines, SSI prevention guidelines and local risk assessment can reduce the incidence of nosocomial MRSA acquisition and invasive infection in cardiothoracic patients in the face of continuing endemic risk.

Candidaemia in a London teaching hospital: analysis of 128 cases over a 7-year period.

In a retrospective analysis of 128 cases of Candida bloodstream infections in a London teaching hospital between 1995 and 2001, the incidence of candidaemia increased from 0.2/1000 admissions in 1995 to 0.5 and 0.4/1000 admissions in 2000 and 2001, respectively. Risk factors for candidaemia included the presence of intravascular (IV) lines (88%), admission to intensive care (51%), parenteral nutrition (35%), multiple antibiotics (74%), corticosteroid therapy (12%), cancer chemotherapy (11%), renal transplantation (5%) and neutropenia (3%). The sources of infection were IV lines (77%), the urinary tract (7%) and the gastrointestinal tract (7%). Serious infective complications (endocarditis, endophthalmitis or brain abscess) were noted in 6% of cases. The most frequently isolated species were Candida albicans (64%), C. glabrata (20%), C. tropicalis (9%) and C. parapsilosis (5%). The overall fluconazole-resistance rate of Candida spp. was 7% (MIC > or = 64 mg l-1). All the C. albicans isolates were sensitive to fluconazole (MIC < or = 8 mg l-1) whereas 20% of non-C. albicans isolates (27% of C. glabrata and 14%C. tropicalis) were resistant. The mortality rate (35%) was lower than in other reports and may be due to the early recognition of candidaemia and the prompt removal of IV lines together with the initiation of appropriate antifungal therapy. Regular surveillance of local Candida species, resistance profiles and risk factors is important in order to identify patients at risk and to develop empirical treatment protocols to reduce the incidence and mortality of candidaemia.

Aspergillus endophthalmitis: an unusual complication of disseminated infection in renal transplant patients.

Endogenous Aspergillus endophthalmitis (AE) is a rare complication of invasive aspergillosis (IA) in transplant patients. In this report, we describe two patients with polycystic kidney disease, who developed AE with cerebral involvement after renal transplantation. Both patients received intense immunosuppression with methyl prednisolone and mycophenolate mofitil (MMF) because of persistent rejection, which rendered them diabetic and vulnerable to opportunistic infections. Endophthalmitis developed within six months of transplantation and was confirmed by microscopy and culture of the vitreous fluid. Patients were treated with combinations of different anti-fungal agents including liposomal amphotericin B, 5-flucytosine, itraconazole, voriconazole and terbinafine. In an electronic MEDLINE review, we found eight further cases of AE in renal transplant patients between 1959 and September 2002. Based on this review, we identified possible risk factors including CMV infection, diabetes mellitus and treatment for rejection with agents such as methyl prednisolone and MMF. In 70% of cases the histology, microscopy or culture of vitreous fluid confirmed the diagnosis. The outcome of AE in renal transplant patients was poor with 70-100% mortality. The review of reported cases and current practice guidelines suggests that vitrectomy and intravitreal amphoterecin B is the treatment of choice. In addition, new antifungal agents with good CSF and ocular penetration such as voriconalzole should be considered for the treatment of invasive cerebral/ocular aspergillosis.

An outbreak of multidrug-resistant Pseudomonas aeruginosa infection associated with contamination of bronchoscopes and an endoscope washer-disinfector.

Over a two-month period, two distinct types of Pseudomonas aeruginosa resistant to ceftazidime and azlocillin were isolated from bronchial specimens of ITU patients who had been previously bronchoscoped. The source of the outbreak was probably a faulty contaminated bronchoscope washer-disinfector which had been purchased a year earlier but not properly maintained. This paper describes the outbreak, the identification and elimination of the source, and the steps taken to prevent recurrence. Several automated, closed washer-disinfectors had been bought by the hospital in response to health and safety concerns about glutaraldehyde disinfection toxicity, but the operation and maintenance of these machines had not been supervised. Several other washer-disinfectors were also found to be faulty. The potential hazards of automated endoscope washer-disinfectors and the importance of controlled professional maintenance, servicing and training is discussed.

Cytokine and chemokine responses following pulmonary challenge with Aspergillus fumigatus: obligatory role of TNF-alpha and GM-CSF in neutrophil recruitment.

Aspergillus fumigatus causes life-threatening invasive pulmonary aspergillosis in the immunocompromised patient. In this study we have used a murine model of intratracheal challenge with A. fumigatus to investigate the recruitment of inflammatory cells in the lung and the expression of proinflammatory cytokines and chemokines. Our results show that A. fumigatus causes an acute pulmonary inflammatory response which is dominated by neutrophils and to a lesser extent macrophages. During the peak of infection, proinflammatory cytokines (TNF-alpha, GM-CSF and IL-1beta) and chemokines (MIP-1alpha, MCP-1 and MIP-2), are induced within the lung. Furthermore, treatment of mice with neutralizing anti-TNF-alpha and anti-GM-CSF mAbs reduced the influx of neutrophils into the lung and delayed fungal clearance. Our observations show that Aspergillus conidia are effective inducers of host chemokine responses both in vitro and in vivo. Furthermore, TNF-alpha and GM-CSF play a central role in the recruitment of neutrophils into the lung in response to this clinically important pathogen.

Binding of host collectins to the pathogenic yeast Cryptococcus neoformans: human surfactant protein D acts as an agglutinin for acapsular yeast cells.

Cryptococcus neoformans is an opportunistic pathogen in AIDS patients causing disseminated disease and lethal meningitis after inhalation of acapsular or sparsely encapsulated yeast cells. In this study we have investigated whether a recently described family of primitive opsonins, termed collectins, contribute to innate resistance against C. neoformans. The pulmonary surfactant proteins SP-A and SP-D as well as the serum collectins mannose-binding protein and CL-43 bound in a calcium-dependent manner to acapsular C. neoformans in vitro. Binding was concentration dependent and abolished by competition with defined mono- and oligosaccharides. In contrast, no binding of the collectins was observed with the encapsulated form of the yeast. Furthermore, binding of purified collectin SP-D, but not SP-A, mannose-binding protein, or CL-43, led to a concentration-dependent agglutination of acapsular C. neoformans. These data indicate that collectins recognize carbohydrate structures in the cell wall of an initial infectious form of C. neoformans and may play a role in early antifungal defenses in the lung.