Jerome R. Lo-Ten-Foe

Use of whole-genome sequencing to trace, control and characterize the regional expansion of extended-spectrum β-lactamase producing ST15 Klebsiella pneumoniae

The study describes the transmission of a CTX-M-15-producing ST15 Klebsiella pneumoniae between patients treated in a single center and the subsequent inter-institutional spread by patient referral occurring between May 2012 and September 2013. A suspected epidemiological link between clinical K. pneumoniae isolates was supported by patient contact tracing and genomic phylogenetic analysis from May to November 2012. By May 2013, a patient treated in three institutions in two cities was involved in an expanding cluster caused by this high-risk clone (HiRiC) (local expansion, CTX-M-15 producing, and containing hypervirulence factors). A clone-specific multiplex PCR was developed for patient screening by which another patient was identified in September 2013. Genomic phylogenetic analysis including published ST15 genomes revealed a close homology with isolates previously found in the USA. Environmental contamination and lack of consistent patient screening were identified as being responsible for the clone dissemination. The investigation addresses the advantages of whole-genome sequencing in the early detection of HiRiC with a high propensity of nosocomial transmission and prolonged circulation in the regional patient population. Our study suggests the necessity for inter-institutional/regional collaboration for infection/outbreak management of K. pneumoniae HiRiCs.

The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis

The primary objective of this meta-analysis was to estimate the prevalence of adult community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae in Europe, adjusted for possible independent covariates. Two reviewers conducted a systematic literature search using PubMed on English-language articles that involved human subjects with CAP during the period from January 1990 to November 2011 across European countries. A mixed-effects meta-regression model was developed and populated with 24,410 patients obtained from 77 articles that met the inclusion criteria. The model showed that the observed prevalence of S. pneumoniae in CAP significantly varies between European regions, even after adjusting for explanatory covariates, including patient characteristics, diagnostic tests, antibiotic resistance, and health-care setting. The probability of detecting S. pneumoniae was substantially higher in studies that performed more frequently a diagnostic polymerase chain reaction assay compared to all the other diagnostic tests included. Furthermore, S. pneumoniae was more likely to be confirmed as the cause of a CAP in studies with intensive care unit patients as compared to those with hospital- or community-treated patients. This study provides estimates of the average observed prevalence of S. pneumoniae, which could be used for projecting the health and economic benefits of pneumococcal immunization.

Financial evaluations of antibiotic stewardship programs—a systematic review

Introduction: There is an increasing awareness to counteract problems due to incorrect antimicrobial use. Interventions that are implemented are often part of an Antimicrobial Stewardship Program (ASPs). Studies publishing results from these interventions are increasing, including reports on the economical effects of ASPs. This review will look at the economical sections of these studies and the methods that were used. Methods: A systematic review was performed of articles found in the PubMed and EMBASE databases published from 2000 until November 2014. Included studies found were scored for various aspects and the quality of the papers was assessed following an appropriate check list (CHEC criteria list). Results: 1233 studies were found, of which 149 were read completely. Ninety-nine were included in the final review. Of these studies, 57 only mentioned the costs associated with the antimicrobial medication. Others also included operational costs (n = 23), costs for hospital stay (n = 18), and/or other costs (n = 19). Nine studies were further assessed for their quality. These studies scored between 2 and 14 out of a potential total score of 19. Conclusions: This review gives an extensive overview of the current financial evaluation of ASPs and the quality of these economical studies. We show that there is still major potential to improve financial evaluations of ASPs. Studies do not use similar nor consistent methods or outcome measures, making it impossible draw sound conclusions and compare different studies. Finally, we make some recommendations for the future.

Mycoviruses : future therapeutic agents of invasive fungal infections in humans?

Invasive fungal infections are relatively common opportunistic infections in immunocompromised patients and are still associated with a high mortality rate. Furthermore, these infections are often complicated by resistance or refractoriness to current antimicrobial agents. Therefore, an urgent need exists for new therapeutic strategies based on the identification of new microbial targets and novel antimicrobial agents. One such hypothetical therapeutic strategy may involve the use of mycoviruses that are able to selectively infect fungi. Current knowledge of mycoviruses of human pathogenic fungi and the scope for using (recombinant) mycoviruses as future biological control agents are reviewed here.

Disseminated Rhodococcus equi infection in a kidney transplant patient without initial pulmonary involvement

Rhodococcus equi is increasingly recognized as an opportunistic pathogen in solid organ transplant recipients. Primary pulmonary involvement is the most common finding. We report a case of a 42-year-old female kidney transplant recipient who developed multiple disseminated abscesses caused by R. equi while on adequate antimicrobial therapy. The patient presented with subcutaneous abscesses in the hip region and mamma and had 2 intracerebral abscesses. There were no clinical and radiologic signs of pulmonary involvement in contrast to most clinical cases described in the literature. R. equi was cultured from all abscesses. The patient died of progressive neurologic complications. Post mortem examination confirmed infection with R. equi and showed microscopic evidence of necrotizing pneumonia. This report shows that R. equi should be considered as a cause of infection in solid organ transplant recipients even without initial clinical and radiologic signs of pulmonary involvement. Despite adequate therapy, the outcome can be fatal.

Double-Stranded RNA Mycovirus Infection of Aspergillus fumigatus Is Not Dependent on the Genetic Make-Up of the Host

Aspergillus fumigatus is a fungus that causes opportunistic infections in immunocompromised patients, with high morbidity and mortality. In its turn, A. fumigatus can become infected with mycoviruses. Most mycoviruses have a dsRNA genome and can cause fungal hypovirulence. For that reason, mycoviruses could theoretically be used as therapeutic tools to combat fungal infections. We determined if a certain genetic make-up of A. fumigatus was associated with the presence of mycoviruses in 86 clinical A. fumigatus isolates. Mycovirus screening was performed by isolating dsRNA from mycelial cultures using a Trizol/Chloroform method. The genetic relatedness of dsRNA infected A. fumigatus was determined by cell surface protein (CSP) typing and determination of the mating type. Sixteen (18.6%) of the 86 clinical A. fumigatus isolates contained dsRNA. The A. fumigatus collection could be divided into 11 different CSP types. DsRNA infected A. fumigatus isolates had similar CSP types as non-infected isolates. In both cases, the CSP types t01, t02, t03 and t04 were the most prevalent and the distribution comparable to the CSP types observed in other Dutch collections. Mating types MAT1-1 and MAT1-2 were evenly distributed among all A. fumigatus strains, regardless of CSP type. No difference was observed in mycovirus infections between MAT1-1 and MAT1-2 isolates. DsRNA mycovirus infections in A. fumigatus are not related to either CSP or mating type and therefore represent an interesting future therapeutic tool to combat fungal infections.

Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial

BackgroundIn The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands.Methods/designWe will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group.DiscussionWith this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy.Trial registrationClinicalTrials.gov, protocol record NL30340.042.09.

Evaluation of early implementations of antibiotic stewardship program initiatives in nine Dutch hospitals

BackgroundAntibiotic resistance is a global threat to patient safety and care. In response, hospitals start antibiotic stewardship programs to optimise antibiotic use. Expert-based guidelines recommend strategies to implement such programs, but local implementations may differ per hospital. Earlier published assessments determine maturity of antibiotic stewardship programs based on expert-based structure indicators, but they disregard that there may be valid deviations from these expert-based programs.AimTo analyse the progress and barriers of local implementations of antibiotic stewardship programs with stakeholders in nine Dutch hospitals and to develop a toolkit that guides implementing local antibiotic stewardship programs.MethodsAn online questionnaire based on published guidelines and recommendations, conducted with seven clinical microbiologists, seven infectious disease physicians and five clinical pharmacists at nine Dutch hospitals.ResultsResults show local differences in antibiotic stewardship programs and the uptake of interventions in hospitals. Antibiotic guidelines and antibiotic teams are the most extensively implemented interventions. Education, decision support and audit-feedback are deemed important interventions and they are either piloted in implementations at academic hospitals or in preparation for application in non-academic hospitals. Other interventions that are recommended in guidelines - benchmarking, restriction and antibiotic formulary - appear to have a lower priority. Automatic stop-order, pre-authorization, automatic substitution, antibiotic cycling are not deemed to be worthwhile according to respondents.ConclusionThere are extensive local differences in the implementation of antibiotic stewardship interventions. These differences suggest a need to further explore the rationale behind the choice of interventions in antibiotic stewardship programs. Rather than reporting this rationale, this study reports where rationale can play a key role in the implementation of antibiotic stewardship programs. A one-size-fits-all solution is unfeasible as there may be barriers or valid reasons for local experts to deviate from expert-based guidelines. Local experts can be supported with a toolkit containing advice based on possible barriers and considerations. These parameters can be used to customise an implementation of antibiotic stewardship programs to local needs (while retaining its expert-based foundation).

Cost-minimization model of a multidisciplinary antibiotic stewardship team based on a successful implementation on a urology ward of an academic hospital.

Background In order to stimulate appropriate antimicrobial use and thereby lower the chances of resistance development, an Antibiotic Stewardship Team (A-Team) has been implemented at the University Medical Center Groningen, the Netherlands. Focus of the A-Team was a pro-active day 2 case-audit, which was financially evaluated here to calculate the return on investment from a hospital perspective. Methods Effects were evaluated by comparing audited patients with a historic cohort with the same diagnosis-related groups. Based upon this evaluation a cost-minimization model was created that can be used to predict the financial effects of a day 2 case-audit. Sensitivity analyses were performed to deal with uncertainties. Finally, the model was used to financially evaluate the A-Team. Results One whole year including 114 patients was evaluated. Implementation costs were calculated to be €17,732, which represent total costs spent to implement this A-Team. For this specific patient group admitted to a urology ward and consulted on day 2 by the A-Team, the model estimated total savings of €60,306 after one year for this single department, leading to a return on investment of 5.9. Conclusions The implemented multi-disciplinary A-Team performing a day 2 case-audit in the hospital had a positive return on investment caused by a reduced length of stay due to a more appropriate antibiotic therapy. Based on the extensive data analysis, a model of this intervention could be constructed. This model could be used by other institutions, using their own data to estimate the effects of a day 2 case-audit in their hospital.

Cost-analysis of seven nosocomial outbreaks in an academic hospital

Objectives Nosocomial outbreaks, especially with (multi-)resistant microorganisms, are a major problem for health care institutions. They can cause morbidity and mortality for patients and controlling these costs substantial amounts of funds and resources. However, how much is unclear. This study sets out to provide a comparable overview of the costs of multiple outbreaks in a single academic hospital in the Netherlands. Methods Based on interviews with the involved staff, multiple databases and stored records from the Infection Prevention Division all actions undertaken, extra staff employment, use of resources, bed-occupancy rates, and other miscellaneous cost drivers during different outbreaks were scored and quantified into Euros. This led to total costs per outbreak and an estimated average cost per positive patient per outbreak day. Results Seven outbreaks that occurred between 2012 and 2014 in the hospital were evaluated. Total costs for the hospital ranged between €10,778 and €356,754. Costs per positive patient per outbreak day, ranged between €10 and €1,369 (95% CI: €49-€1,042), with a mean of €546 and a median of €519. Majority of the costs (50%) were made because of closed beds. Conclusions This analysis is the first to give a comparable overview of various outbreaks, caused by different microorganisms, in the same hospital and all analyzed with the same method. It shows a large variation within the average costs due to different factors (e.g. closure of wards, type of ward). All outbreaks however cost considerable amounts of efforts and money (up to €356,754), including missed revenue and control measures.