Effect of community active case-finding strategies for detection of tuberculosis in Cambodia: study protocol for a pragmatic cluster randomized controlled trial.

BACKGROUND: Cambodia has made notable progress in the fight against tuberculosis (TB). However, these gains are impeded by a significant proportion of undiagnosed cases. To effectively reach people with TB, active case-finding (ACF) strategies have been adopted by countries affected by the epidemic, including Cambodia, alongside passive case finding (PCF). Despite increased efforts to improve case detection, approximately 40% of TB cases in Cambodia remained undiagnosed in 2018. In Cambodia, several community-based TB ACF modalities have been implemented, but their effectiveness has yet to be systematically assessed. METHODS: This pragmatic cluster randomized controlled trial will be conducted between December 2019 and June 2021. We will randomize eight operational districts (clusters) in seven provinces (Kampong Cham, Kampong Thom, Prey Veng, Thbong Khmum, Kampong Chhnang, Kandal, and Kampong Speu) to either the control group (PCF) or the intervention groups (ACF using a seed-and-recruit model, ACF targeting household and neighborhood contacts, and ACF targeting persons aged ≥ 55 years using mobile screening units). The primary endpoints will be TB case notification rates, additionality, and cumulative yield of TB cases. The secondary endpoints include treatment outcomes, the number needed to screen to find one TB case, and cost-effectiveness outcome measures. We will analyze the primary and secondary endpoints by intention to treat. We will compare cluster and individual-level characteristics using Student's t test and hierarchical or mixed-effect models to estimate the ratio of these means. The incremental cost-effectiveness ratio per disability-adjusted life year averted will also be considered as a benchmark to determine whether the interventions are cost-effective. DISCUSSION: This study will build an evidence base to inform future scale-up, implementation, and sustainability of ACF strategies in Cambodia and other similar settings. Implementation of this study will also complement TB control strategies in Cambodia by conducting ACF in operational districts without active interventions to find TB cases currently. Those who are ill and might have TB will be promptly screened, diagnosed, and linked to care. Early diagnosis and treatment initiation will also benefit their community by interrupting transmission and prevent further infections. The experience gained from this project will inform future attempts in conducting pragmatic trials in low-resource settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04094350. Registered on 18 September 2019.

Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.

Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections around the world, with attendant high rates of morbidity and mortality. Progressive reduction in potency of antibiotics capable of treating MDR K. pneumoniae infections - including lung infection - as a consequence of escalating drug resistance provides the motivation to develop drug candidates targeting MDR K. pneumoniae. We recently reported degradable broad-spectrum antimicrobial guanidinium-functionalized polycarbonates with unique antimicrobial mechanism - membrane translocation followed by precipitation of cytosolic materials. These polymers exhibited high potency against bacteria with negligible toxicity. The polymer with ethyl spacer between the quanidinium group and the polymer backbone (pEt_20) showed excellent in vivo efficacy for treating MDR K. pneumoniae-caused peritonitis in mice. In this study, the structures of the polymers were optimized for the treatment of MDR Klebsiella pneumoniae lung infection. Specifically, in vitro antimicrobial activity and selectivity of guanidinium-functionalized polycarbonates containing the same number of guanidinium groups but of a shorter chain length and a structural analogue containing a thiouronium moiety as the pendent cationic group were evaluated. The polymers with optimal compositions and varying hydrophobicity were assessed against 25 clinically isolated K. pneumonia strains for antimicrobial activity and killing kinetics. The results showed that the polymers killed the bacteria more efficiently than clinically used antibiotics, and repeated use of the polymers did not cause drug resistance in K. pneumonia. Particularly, the polymer with butyl spacer (pBut_20) self-assembled into micelles at high concentrations, where the hydrophobic component was shielded in the micellar core, preventing interacting with mammalian cells. A subtle change in the hydrophobicity increased the antimicrobial activity while reducing in vivo toxicity. The in vivo efficacy studies showed that pBut_20 alleviated K. pneumonia lung infection without inducing damage to major organs. Taken together, pBut_20 is promising for treating MDR Klebsiella pneumoniae lung infection in vivo. STATEMENT OF SIGNIFICANCE: Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections, with attendant high rates of morbidity and mortality. The progressive reduction in antibiotics capable of treating MDR K. pneumoniae infections - including lung infection - as a consequence of escalating drug resistance rates provides the motivation to develop drug candidates. In this study, we report a degradable guanidinium-functionalized polycarbonate with unexpected antimicrobial activity and selectivity towards MDR Klebsiella pneumoniae. A subtle change in polymer hydrophobicity increases antimicrobial activity while reducing in vivo toxicity due to self-assembly at high concentrations. The polymer with optimal composition alleviates Klebsiella pneumonia lung infection without inducing damage to major organs. The polymer is promising for treating MDR Klebsiella pneumoniae lung infection in vivo.

Investigation of a cluster of multi-drug resistant tuberculosis in a high-rise apartment block in Singapore.

OBJECTIVE: Between February 2012 and May 2016, six residents of an 11-storey apartment block were diagnosed with MDR-TB. Based on initial tests, all isolates had similar genotypic profiles, although there were no identifiable epidemiological transmission patterns between three cases. We present findings from the cluster investigation and results of a mass screening exercise. DESIGN: Free voluntary TB screening was offered to past and current residents of the apartment block, comprising an interview, Chest X-Ray, and Interferon Gamma Release Assay or Tuberculin skin test. Expected latent TB proportions were calculated using a reference population, and whole genome sequencing (WGS) was performed. RESULTS: The index case was involved in a separate gaming centre outbreak involving five patrons. 241 current (67.9% of 355 residents) and 18 past residents were screened. The latent TB proportion was 19.9%, which was at the higher end of the expected range. WGS confirmed relatedness of cases' MDR-TB isolates- eight of 10 isolates were genetically identical, while the remaining two were one Single Nucleotide Polymorphism apart. CONCLUSION: With WGS, TB clusters not apparent through regular activity-based contact tracing may be detected. Mass screening may help inform the extent of transmission, but is limited by participation and difficulties in interpretation.

Prevalence of Healthcare-Associated Infections and Antimicrobial Use Among Adult Inpatients in Singapore Acute-Care Hospitals: Results From the First National Point Prevalence Survey.

BACKGROUND: We conducted a national point prevalence survey (PPS) to determine the prevalence of healthcare-associated infections (HAIs) and antimicrobial use (AMU) in Singapore acute-care hospitals. METHODS: Trained personnel collected HAI, AMU, and baseline hospital- and patient-level data of adult inpatients from 13 private and public acute-care hospitals between July 2015 and February 2016, using the PPS methodology developed by the European Centre for Disease Prevention and Control. Factors independently associated with HAIs were determined using multivariable regression. RESULTS: Of the 5415 patients surveyed, there were 646 patients (11.9%; 95% confidence interval [CI], 11.1%-12.8%) with 727 distinct HAIs, of which 331 (45.5%) were culture positive. The most common HAIs were unspecified clinical sepsis (25.5%) and pneumonia (24.8%). Staphylococcus aureus (12.9%) and Pseudomonas aeruginosa (11.5%) were the most common pathogens implicated in HAIs. Carbapenem nonsusceptibility rates were highest in Acinetobacter species (71.9%) and P. aeruginosa (23.6%). Male sex, increasing age, surgery during current hospitalization, and presence of central venous or urinary catheters were independently associated with HAIs. A total of 2762 (51.0%; 95% CI, 49.7%-52.3%) patients were on 3611 systemic antimicrobial agents; 462 (12.8%) were prescribed for surgical prophylaxis and 2997 (83.0%) were prescribed for treatment. Amoxicillin/clavulanate was the most frequently prescribed (24.6%) antimicrobial agent. CONCLUSIONS: This survey suggested a high prevalence of HAIs and AMU in Singapore's acute-care hospitals. While further research is necessary to understand the causes and costs of HAIs and AMU in Singapore, repeated PPSs over the next decade will be useful to gauge progress at controlling HAIs and AMU.

Clinical and Molecular Epidemiology of Carbapenem-Resistant Enterobacteriaceae Among Adult Inpatients in Singapore.

BACKGROUND: Since 2010, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) has been increasing in Singapore. We analyzed the clinical and molecular epidemiology of CRE among adult inpatients in Singapore. METHODS: Quarterly incidence of unique subjects (per 100000 patient-days) with positive clinical and surveillance cultures for CRE were estimated based on mandatory data submitted to the National Public Health Laboratory by public hospitals between 2010 and 2015. CRE-positive adult inpatients were prospectively recruited from 6 public sector hospitals between December 2013 and April 2015. Subjects answered a standardized epidemiologic questionnaire and provided samples for this study. Further clinical information was extracted from subjects' electronic medical records. Whole-genome sequencing was performed on study isolates to determine transmission clusters. RESULTS: Incidence of CRE clinical cultures among adult inpatients plateaued from 2013 (range: 7.73 to 10.32 per 100000 patient-days) following an initial increase between 2010 and end-2012. We prospectively recruited 249 subjects. Their median age was 65 years, 108 (43%) were female, and 161 (64.7%) had carbapenemase-producing Enterobacteriaceae (CPE). On multivariate analysis, prior carbapenem exposure (OR: 3.23; 95% CI: 1.67-6.25) and hematological malignancies (OR: 2.85; 95% CI: 1.10-7.41) were associated with non-carbapenemase-producing CRE (NCPE) (n = 88) compared with CPE (n = 161) subjects. Among 430 CRE isolates from the 249 subjects, 307(71.3%) were CPE, of which 154(50.2%) were blaKPC-positive, 97(31.6%) blaNDM-positive, and 42 (13.7%) blaOXA-positive. Klebsiella pneumoniae (n = 180, 41.9%), Escherichia coli (n = 129, 30.0%) and Enterobacter cloacae (n = 62, 14.4%) were the main Enterobacteriaceae species. WGS (n = 206) revealed diverse bacterial strain type (STs). The predominant blaKPC-positive plasmid was pHS102707 (n = 62, 55.4%) and the predominant blaNDM-positive plasmid was pNDM-ECS01 (n = 46, 48.9%). Five transmission clusters involving 13 subjects were detected. CONCLUSIONS: Clinical CRE trend among adult inpatients showed stabilization following a rapid rise since introduction in 2010 potentially due to infection prevention measures and antimicrobial stewardship. More work is needed on understanding CPE transmission dynamics.

Using an Adenosine Triphosphate Bioluminescent Assay to Determine Effective Antibiotic Combinations against Carbapenem-Resistant Gram Negative Bacteria within 24 Hours.

BACKGROUND: Current in vitro combination testing methods involve enumeration by bacterial plating, which is labor-intensive and time-consuming. Measurement of bioluminescence, released when bacterial adenosine triphosphate binds to firefly luciferin-luciferase, has been proposed as a surrogate for bacterial counts. We developed an ATP bioluminescent combination testing assay with a rapid turnaround time of 24h to determine effective antibiotic combinations. METHODS: 100 strains of carbapenem-resistant (CR) GNB [30 Acinetobacter baumannii (AB), 30 Pseudomonas aeruginosa (PA) and 40 Klebsiella pneumoniae (KP)] were used. Bacterial suspensions (105 CFU/ml) were added to 96-well plates containing clinically achievable concentrations of multiple single and two-antibiotic combinations. At 24h, the luminescence intensity of each well was measured. Receiver operator characteristic curves were plotted to determine optimal luminescence threshold (TRLU) to discriminate between inhibitory/non-inhibitory combinations when compared to viable plating. The unweighted accuracy (UA) [(sensitivity + specificity)/2] of TRLU values was determined. External validation was further done using 50 additional CR-GNB. RESULTS: Predictive accuracies of TRLU were high for when all antibiotic combinations and species were collectively analyzed (TRLU = 0.81, UA = 89%). When individual thresholds for each species were determined, UA remained high. Predictive accuracy was highest for KP (TRLU = 0.81, UA = 91%), and lowest for AB (TRLU = 0.83, UA = 87%). Upon external validation, high overall accuracy (91%) was observed. The assay distinguished inhibitory/non-inhibitory combinations with UA of 80%, 94% and 93% for AB, PA and KP respectively. CONCLUSION: We developed an assay that is robust at identifying useful combinations with a rapid turn-around time of 24h, and may be employed to guide the timely selection of effective antibiotic combinations.

Risk factors for febrile respiratory illness and mono-viral infections in a semi-closed military environment: a case-control study.

BACKGROUND: Febrile respiratory illness (FRI) results in substantial burden in semi-closed environments. Tackling risk factors may reduce transmission and infection. However, risk factors involved in one setting may not be generalizable in all settings due to differences in climate, residential environment, population genetic and cultural backgrounds. This study aims to identify risk factors of FRI and mono-viral infections in a tropical military environment. METHODS: From year 2009 to 2012, military personnel with temperature ≥37.5 °C, cough and/or sore throat, and personnel with no fever or no respiratory symptoms were recruited as cases and controls, respectively. Subjects provided nasal wash specimens and answered a standardized questionnaire. Resplex assays were used to determine the viral etiologies. Descriptive, univariate and multivariate analyses of the variables were performed using appropriate descriptive tests and logistic regression modelling, respectively, with R program. RESULTS: A total of 7,743 FRI cases and 1,247 non-FRI study controls were recruited. Increasing age [adjusted odds ratio (AOR) = 1.03; 95 % confidence interval (CI) = 1.01-1.05], recruit camp (AOR = 4.67; 95 % CI = 3.99-5.46) and smoker (AOR = 1.31; 95 % CI = 1.13-1.52) were independent risk factors of FRI. Malay ethnicity was positively associated with influenza A(H1N1)pdm09 (AOR = 1.50; 95 % CI = 1.04-2.15) and coxsackie/echovirus (AOR = 1.67; 95 % CI = 1.19-2.36) mono-infection. Significant contact risk factors were stay-out personnel with ill household member (AOR = 4.96; 95 % CI = 3.39-7.24), and stay-in personnel with ill bunkmate and household member (AOR = 3.55; 95 % CI = 2.57-4.91). Staying in camp with none ill in bunk and at home was a protective factor against FRI (AOR = 0.80; 95 % CI = 0.64-0.99). These contact risk factors were similarly observed for the five most common viruses detected, namely adenovirus, rhinoviruses, influenza A and B, and coxsackie/echovirus. CONCLUSION: Increasing age, smoker, recruit-camp, stay-out personnel with ill household members and stay-in personnel with ill bunkmates were independent risk factors of FRI in a semi-closed military environment. Early identification and isolation of ill personnel from their bunk may be effective to prevent and reduce transmission and disease burden.

Costs associated with febrile neutropenia in solid tumor and lymphoma patients - an observational study in Singapore.

BACKGROUND: The primary objective was to describe the total direct inpatient costs among solid tumor and lymphoma patients with chemotherapy-induced febrile neutropenia (FN) and the factors that were associated with higher direct cost. The secondary objective was to describe the out-of-pocket patient payments and the factors that were associated with higher out-of-pocket patient payments. METHODS: This was a single-center observational study conducted at the largest cancer center in Singapore. All of the adult cancer patients hospitalized due to FN from 2009 to 2012 were studied. The primary outcomes were the total hospital cost and the out-of-pocket patient payments (adjusted by government subsidy) per FN episode. Univariate analysis and multiple linear regression were conducted to identify the factors associated with higher FN costs. RESULTS: Three hundred and sixty seven adult cancer patients were documented with FN-related hospitalizations. The mean total hospital cost was US$4,193 (95% CI: US$3,779-4,607) and the mean out-of-pocket patient payment was US$2,230 (95% CI: US$1,976-2,484), per FN episode. The factors associated with a higher total hospital cost were longer length of stay, severe sepsis, and lymphoma as underlying cancer. The out-of-pocket patient payment was positively associated with longer length of stay, severe sepsis, lymphoma diagnosed as underlying cancer, the therapeutic use of granulocyte colony-stimulating factor (GCSF), the private ward class, and younger patients. CONCLUSIONS: The total hospital cost and out-of-pocket patient payments of FN management in lymphoma cases were substantial compared with other solid tumors. Factors associated with a higher FN management cost may be useful for developing appropriate strategies to reduce the cost of FN for cancer patients.

Clinical efficacy of adjunctive G-CSF on solid tumor and lymphoma patients with established febrile neutropenia.

BACKGROUND: The use of granulocyte colony-stimulating factor (G-CSF) as a prophylaxis against febrile neutropenia (FN) is well documented in the literature; however, the therapeutic use of G-CSF in the treatment of FN remains controversial. This study assessed the efficacy of adjunctive G-CSF in the treatment of FN by evaluating clinical outcomes. METHODS: This was a single-center, prospective cohort study conducted at the National Cancer Center in Singapore. Adult patients who had received chemotherapy and developed FN between January 2009 and January 2012 were included in the analysis. The clinical efficacy of adjunctive G-CSF was evaluated by investigating the duration of hospitalization, duration to absolute neutrophil count (ANC) recovery, duration of grade IV neutropenia, duration to fever resolution, duration of antibiotic therapy, and incidence of documented infections. A multivariate analysis was performed to identify patients who could potentially benefit from adjunctive G-CSF. RESULTS: Four hundred and thirty patients were analyzed. Majority manifested low-risk FN (81.2%) based on the Multinational Association of Supportive Care in Cancer (MASCC) scoring. Compared to patients who did not receive adjunctive G-CSF, patients receiving adjunctive G-CSF had a nonsignificant reduction in the duration of hospitalization (3.5 vs. 3.7 days, p = 0.41) and in ANC recovery time (3.4 vs. 3.5 days, p = 0.76). Neutropenia-related mortality was lower among those who have received adjunctive G-CSF (2.4 vs. 8.4%, p = 0.006). Patients of Indian ethnicity and those who underwent gemcitabine-containing chemotherapy were less likely to receive adjunctive G-CSF treatment. CONCLUSIONS: This observational study suggested that adjunctive G-CSF may confer clinical benefits among solid tumor and lymphoma patients with established febrile neutropenia. Further research should be conducted to validate the findings.

Direct costs associated with febrile neutropenia in inpatients with hematological diseases in Singapore.

PURPOSE: This prospective cohort study aims to investigate the direct hospitalization costs incurred during febrile neutropenia (FN) in inpatients with underlying hematological conditions and also to elucidate the factors associated with a high cost of managing febrile neutropenia. METHODS: Patients with underlying hematological conditions and documented FN were recruited between October 2008 and February 2011. FN-related costs included all costs incurred from the first day of FN until the last day of antibiotics prescribed. Relevant clinical factors were analyzed using generalized estimating equation models to elucidate the factors that were associated with higher costs of FN. RESULTS: A total of 175 patients were recruited with 303 documented episodes of FN. In non-transplant patients, 75.6 % of the FN episodes occurred. The median and mean cost incurred for each FN episode was USD9,060 (interquartile range = USD5,047-16,631) and USD15,298 (standard deviation ± USD17,459), respectively, accounting for approximately 38 % of the median total hospitalization cost and 37 % of the mean total hospitalization cost. The ward charges (44.1 %) constituted the largest component of the cost, followed by the laboratory charges (27.3 %) and medications (18.7 %), of which antimicrobials constituted 9.6 % of the cost of FN. The factors associated with higher costs of FN include cytomegalovirus reactivation (p < 0.001), longer duration of antibiotics (p < 0.001), lower absolute neutrophil count nadir (p < 0.001), allogeneic stem cell transplantation (p < 0.01), and diagnosis of invasive fungal infection (p < 0.05). CONCLUSION: The economic cost of management of FN in hematology inpatients is considerable and in addition to the overall risk of mortality for this condition. Strategies to reduce FN or ameliorate its costs are essential for this group of patients.

Antimicrobial stewardship auditing of patients reviewed by infectious diseases physicians in a tertiary university hospital.

BACKGROUND: The optimal way for antimicrobial stewardship programs (ASPs) to interact with existing infectious disease physician (IDP) services within the same institution is unknown. In our institution, IDPs and our prospective audit and feedback ASP operate independently, with occasionally differing recommendations offered for the same inpatient. We performed a retrospective audit on inpatients that had been reviewed by both IDPs and ASP within a 7-day period, focusing on cases where different therapy-modifying recommendations had been offered. We analyzed the outcomes in inpatients where the ASP recommendations were accepted and compared these with the inpatients where the IDP recommendations were accepted instead. Outcomes assessed were 30-day mortality post-ASP review, unplanned re-admission within 30 days post-discharge from hospital, and clinical deterioration at 7 days post-ASP review. FINDINGS: There were 143 (18.9%) patients where differing recommendations had been offered, with primary physicians accepting 69.9% of ASP recommendations. No significant differences in terms of demographics, clinical characteristics, 30-day mortality, and re-admission rates were observed, although clinical deterioration rates were lower in patients where the ASP recommendation was accepted (8.0% vs. 27.9%; p = 0.002). On multivariate analysis, hematology-oncology inpatients were associated with unplanned readmission. Increasing age and hematology-oncology inpatients were associated with clinical deterioration 7 days post-recommendation, whereas acceptance of ASP recommendations was protective. No characteristic was independently associated with 30-day mortality. CONCLUSION: In conclusion, independent reviews by both IDPs and ASPs can be compatible within large tertiary hospitals, providing primary physicians even in situations of conflicting recommendations viable alternative antimicrobial prescribing advice.

Specialist trainees on rotation cannot replace dedicated consultant clinicians for antimicrobial stewardship of specialty disciplines.

Our prospective-audit-and-feedback antimicrobial stewardship (AS) program for hematology and oncology inpatients was switched from one led by dedicated clinicians to a rotating team of infectious diseases trainees in order to provide learning opportunities and attempt a "de-escalation" of specialist input towards a more protocol-driven implementation. However, process indicators including the number of recommendations and recommendation acceptance rates fell significantly during the year, with accompanying increases in broad-spectrum antibiotic prescription. The trends were reversed only upon reverting to the original setup. Dedicated clinicians play a crucial role in AS programs involving immunocompromised patients. Structured training and adequate succession/contingency planning is critical for sustainability.

Prospective audit of post-chemotherapy febrile neutropenia in patients with solid cancer and lymphoma in two Singaporean cancer centres.

INTRODUCTION: Febrile neutropenia (FN) is a significant cause of mortality and morbidity in oncology and haematology units worldwide. The overall mortality in hospital surveys in Singapore surveys on post-chemotherapy FN has ranged between 3.0% and 8.8%. However, recent evidence indicates that outpatient management of patients with low-risk FN is safe and cost-effective. MATERIALS AND METHODS: We conducted a prospective audit on a cohort of adult patients with post-chemotherapy FN seen at 2 local public sector cancer centres over a 1-year period in order to define their epidemiological characteristics and outcomes, and also to assess the uptake of early discharge/outpatient management strategies for these patients. RESULTS: We reviewed 306 FN episodes from 248 patients. Patient characteristics and outcomes were similar between both institutions. Eleven (3.7%) FN episodes were managed as outpatient and none developed complications. Overall 30-day mortality was 6.6%, while the median length of stay (LOS) was 7 days (IQR: 4 to 11 days). The only independent risk factor for mortality was severe sepsis (OR:13.19; 95% CI: 1.98 to 87.7; P = 0.008). Factors independently associated with a longer LOS were vancomycin prescription (coefficient: 0.25; 95% CI: 0.08 to 0.41; P = 0.003), longer duration of intravenous antibiotics (coefficient: 0.08; 95% CI: 0.06 to 0.10; P <0.001), and prior review by an infectious diseases physician (coefficient: 0.16; 95% CI: 0.01 to 0.31; P = 0.034). CONCLUSION: This audit demonstrated that mortality from FN in our 2 cancer centres is low and comparable to international institutions. It also demonstrates that outpatient management of FN is safe in selected patients, and can be further expanded for right-siting of resources.

Spontaneous Pneumothorax in an Allogeneic Cell Transplant Recipient with Invasive Pulmonary Aspergillosis and Antecedent RSV Pneumonitis.

We report a case of invasive pulmonary aspergillosis (IPA) following respiratory syncytial virus infection in an allogeneic hematopoietic stem cell transplant (HSCT) recipient with chronic graft-versus-host disease. Delayed diagnosis of IPA resulted in the development of a pneumothorax, a rare consequence of fungal pneumonia. Respiratory virus infections are often harbingers of other infective organisms in HSCT recipients. More aggressive diagnostic investigations such as computed tomography scans of the thorax and bronchoscopy with bronchoalveolar lavage should be considered early in any HSCT patient presenting with respiratory virus pneumonia, particularly if atypical features are present or recovery is delayed.

Prevalence of invasive fungal disease in hematological patients at a tertiary university hospital in Singapore.

BACKGROUND: The use of newer azoles as prophylaxis in hematological patients undergoing stem cell transplantation or immunosuppressive chemotherapy has been shown to decrease the risk of developing invasive fungal disease (IFD). However, the cost-effectiveness of such a strategy is dependent on the local epidemiology of IFD. We conducted an audit of hematological patients with IFD in our institution in order to derive the prevalence and types of IFD that occur locally. FINDINGS: We conducted a retrospective chart review of all hematological patients who developed possible, probable or definite IFD according to EORTC/MSG criteria in the period from Oct 2007 to Apr 2010. The prevalence of IFD was determined via correlation with institutional database records of all hematological patients treated at our institution over the same time period.There were 39 cases of IFD diagnosed during the study period, with 8 (20.5%) possible, 19 (48.7%) probable and 12 (30.8%) definite cases of IFD. Aspergillus spp. accounted for 83.9% of all probable and definite infections. There was 1 case each of Rhinocladelia spp., Coprinopsis cinerea, Exserohilum spp. sinusitis and Rhizopus spp. sinusitis. IFD occurred in 12 of 124 (9.7%) AML and 4 of 103 (3.9%) ALL patients treated at our institution respectively. There were 10 (16.1%) infections among 62 allogeneic HSCT recipients, six of whom were having concurrent graft-versus-host disease (GVHD). Five other cases occurred after allogeneic HSCT failure, following salvage chemotherapy for disease relapse. The prevalence of IFD during induction chemotherapy was 8.9% (11 of 124 cases) for AML and 1.0% (1 of 103 cases) for ALL. Fluconazole prophylaxis had been provided for 28 out of the 39 (71.8%) cases, while 4 (10.3%) were on itraconazole prophylaxis. The in-hospital mortality was 28.2% (11 of 39 cases), of which 5 (12.8%) deaths were attributed to IFD. CONCLUSIONS: The burden of IFD is high in our institution, especially in allogeneic HSCT recipients and patients on induction chemotherapy for AML. A prophylactic strategy directed against invasive mould infections for local high-risk patients may be considered as the comparative costs of treatment, prolonged hospitalisation and subsequent delayed chemotherapy favours such an approach.

Recent advances in invasive pulmonary aspergillosis.

PURPOSE OF REVIEW: This review highlights the most important and salient recent developments with regards to invasive pulmonary aspergillosis (IPA), currently the most common opportunistic fungal pneumonia in patients with hematological malignancies. RECENT FINDINGS: Besides patients in hematology units, other immunosuppressed and critically ill patients are also at risk of IPA. Identification of patients who possess specific polymorphisms of Toll-like receptor 4 and dectin-1, both of which are involved in the immune sensing of Aspergillus spp., may facilitate risk-stratification. The use of the galactomannan assay in bronchoalveolar fluid to improve diagnosis of IPA is undergoing validation. Trending galactomannan and other biomarker results may prognosticate clinical outcomes. During intensive chemotherapy for leukemia, posaconazole and aerosolized liposomal amphotericin B (L-AMB) have demonstrated efficacy as prophylaxis against invasive fungal infection. However, fluconazole remains an effective prophylactic agent in the setting of hematopoietic stem cell transplantation despite availability of newer antifungal agents. Although voriconazole is still the drug of choice for IPA, both caspofungin and L-AMB are viable alternatives. SUMMARY: Despite increasing knowledge of IPA and availability of newer antifungal agents, clinical management remains a challenge in the setting of a compromised host defense system that is unable to mount an appropriate immune response against the pathogen.

Common and emerging fungal pulmonary infections.

Fungal pulmonary infections are becoming more prevalent as a consequence of the rising prevalence of immunocompromised patients. Besides ubiquitous opportunistic fungi such as Aspergillus spp and geographically delimited mycoses, fungi that were previously thought to be of uncertain pathogenicity, such as hyaline and dematiaceous molds, are increasingly being diagnosed as the causes of invasive disease in profoundly immunosuppressed hosts. Overall progress in the clinical management of fungal pulmonary infections has been slow compared with other areas of infectious diseases. However, recent encouraging advances in fungal diagnostics and therapeutics have resulted in improved clinical outcomes, particularly in vulnerable patient populations such as solid organ or allogeneic hematopoietic stem cell transplant recipients. This article provides an overview of endemic mycoses and other emerging fungal pulmonary infections. Recent developments in terms of the diagnosis and clinical management of these infections are also discussed.

Prospective audit of febrile neutropenia management at a tertiary university hospital in Singapore.

INTRODUCTION: Febrile neutropenia (FN) remains a major cause of morbidity and mortality in Oncology/Haematology units. We launched a new protocol for FN management that incorporates risk stratification at our institute from October 2008. An audit was performed concurrently to evaluate the protocol and to define the epidemiology of FN locally. MATERIALS AND METHODS: Case records of all inpatients with FN between October 2008 and June 2009 were reviewed prospectively. Clinical and microbiological characteristics were collated along with outcomes and programme adherence. Statistical testing was performed using Stata 10.1. RESULTS: There were 178 FN episodes (50 in patients with solid cancers) from 131 patients. Forty-two (23.6%) episodes were classified as high-risk according to MASCC criteria. Initial blood cultures were positive in 49 (27.5%) episodes, of which gram-negative bacilli (GNB) predominated. Overall compliance to the protocol was 56.7%, with the main issue being disinclination to use oral antibiotics as fi rst-line empirical therapy for low-risk episodes. Overall mortality was 7.3% and infection-related mortality was 4.5%. High-risk FN and the presence of central venous catheters were independently associated with bacteraemia on multivariate analysis, but there were no independent predictors of infection-related mortality. CONCLUSIONS: GNB accounted for the majority of bloodstream infections at our institute, unlike data from developed countries. Uptake of the new FN protocol was satisfactory, although the use of oral antibiotics as fi rst-line empirical therapy can be improved. A better method for predicting infections caused by antibiotic-resistant GNB is urgently required, and antibiotic resistance trends should be monitored to enable the implementation of more appropriate antibiotic regimens over time.