Early oral antibiotic switch in Staphylococcus aureus bacteraemia: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Early Oral Switch Protocol.

BACKGROUND: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. PROTOCOL: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care). DISCUSSION: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.

[Current inpatient treatment options for COVID-19: an update]. / Medicamenteuze behandeling covid-19 in de tweede lijn.

In this article we provide an overview of the current treatment recommendations for COVID-19. These recommendations are made by the SWAB (StichtingWerkgroepAntibioticabeleid), in cooperation with the FMS (FederatieMedischSpecialisten (online: swab.nl/nl/covid-19.). Treatment options for patients in both ambulatory care and admitted to the hospital are listed. These treatment options include both antiinflammatory and antiviral therapy.

Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients.

OBJECTIVES: The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. METHODS: Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. RESULTS: Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. CONCLUSION: In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use.

External Validation of Three Prediction Tools for Patients at Risk of a Complicated Course of Clostridium difficile Infection: Disappointing in an Outbreak Setting.

OBJECTIVE Estimating the risk of a complicated course of Clostridium difficile infection (CDI) might help doctors guide treatment. We aimed to validate 3 published prediction models: Hensgens (2014), Na (2015), and Welfare (2011). METHODS The validation cohort comprised 148 patients diagnosed with CDI between May 2013 and March 2014. During this period, 70 endemic cases of CDI occurred as well as 78 cases of CDI related to an outbreak of C. difficile ribotype 027. Model calibration and discrimination were assessed for the 3 prediction rules. RESULTS A complicated course (ie, death, colectomy, or ICU admission due to CDI) was observed in 31 patients (21%), and 23 patients (16%) died within 30 days of CDI diagnosis. The performance of all 3 prediction models was poor when applied to the total validation cohort with an estimated area under the curve (AUC) of 0.68 for the Hensgens model, 0.54 for the Na model, and 0.61 for the Welfare model. For those patients diagnosed with CDI due to non-outbreak strains, the prediction model developed by Hensgens performed the best, with an AUC of 0.78. CONCLUSION All 3 prediction models performed poorly when using our total cohort, which included CDI cases from an outbreak as well as endemic cases. The prediction model of Hensgens performed relatively well for patients diagnosed with CDI due to non-outbreak strains, and this model may be useful in endemic settings. Infect Control Hosp Epidemiol 2017;38:897-905.

Antimicrobial susceptibility profiles of human and piglet Clostridium difficile PCR-ribotype 078.

In the last decade, outbreaks of nosocomial Clostridium difficile infections (CDI) occurred worldwide. A new emerging type, PCR-ribotype 027, was the associated pathogen. Antimicrobial susceptibility profiles of this type were extensively investigated and used to partly explain its spread. In Europe, the incidence of C. difficile PCR-ribotype 078 recently increased in humans and piglets. Using recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) we studied the antimicrobial susceptibility to eight antimicrobials, mechanisms of resistance and the relation with previously prescribed antimicrobials in human (n=49) and porcine (n=50) type 078 isolates. Human and porcine type 078 isolates showed similar antimicrobial susceptibility patterns for the antimicrobials tested. In total, 37% of the isolates were resistant to four or more antimicrobial agents. The majority of the human and porcine isolates were susceptible to amoxicillin (100%), tetracycline (100%) and clindamycin (96%) and resistant to ciprofloxacin (96%). More variation was found for resistance patterns to erythromycin (76% in human and 59% in porcine isolates), imipenem (29% in human and 50% in porcine isolates) and moxifloxacin (16% for both human and porcine isolates). MIC values of cefuroxim were high (MICs >256 mg/L) in 96% of the isolates. Resistance to moxifloxacin and clindamycin was associated with a gyr(A) mutation and the presence of the erm(B) gene, respectively. A large proportion (96%) of the erythromycin resistant isolates did not carry the erm(B) gene. The use of ciprofloxacin (humans) and enrofloxacin (pigs) was significantly associated with isolation of moxifloxacin resistant isolates. Increased fluoroquinolone use could have contributed to the spread of C. difficile type 078.

All-cause and disease-specific mortality in hospitalized patients with Clostridium difficile infection: a multicenter cohort study.

BACKGROUND: Mortality among patients with Clostridium difficile infection (CDI) is high. Because of high age and multiple underlying diseases, CDI-related mortality is difficult to estimate. We estimated CDI-related mortality in an endemic situation, not influenced by outbreaks and consequently certain patients and C. difficile strains. METHODS: Between 2006 and 2009, 13 Dutch hospitals included all hospitalized CDI patients. Nine hospitals individually matched each CDI patient to 2 control patients, based on ward and time of CDI hospitalization. Survival status was obtained via the Dutch Civil Registration System. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: We identified 1366 patients with CDI (1.33 per 1000 admissions). All-cause mortality risk was 13% after 30 days and 37% after 1 year. The highest mortality was seen among elderly patients and patients with polymerase chain reaction ribotype 027. Three hundred seventeen CDI patients were matched to 317 patients without diarrhea and 232 patients with diarrhea, with a 30-day mortality risk of 5.4% and 8.6%, respectively. CDI patients had a 2.5-fold increased 30-day mortality rate compared to controls without diarrhea (hazard ratio 2.5 [95% confidence interval, 1.4-4.3]) when adjusted for age, sex, and underlying diseases. CDI-related death occurred mainly within 30 days after diagnosis. CONCLUSIONS: Mortality among CDI patients is high, even in an endemic situation. Our results show that CDI is associated with to a 2.5-fold increase in 30-day mortality. This highlights the considerable disease burden and clinical impact of CDI, even in absence of an outbreak.

Analysis of a Clostridium difficile PCR ribotype 078 100 kilobase island reveals the presence of a novel transposon, Tn6164.

BACKGROUND: Clostridium difficile is the main cause of antibiotic associated diarrhea. In the past decade, the number of C. difficile patients has increased dramatically, coinciding with the emergence of two PCR ribotypes 027 and 078. PCR ribotype 078 is also frequently found during C. difficile outbreaks in pigfarms. Previously, the genome of the PCR ribotype 078 strain M120, a human isolate, was described to contain a unique insert of 100 kilobases. RESULTS: Analysis of this insert revealed over 90 open reading frames, encoding proteins originating from transposons, phages and plasmids. The insert was shown to be a transposon (Tn6164), as evidenced by the presence of an excised and circularised molecule, containing the ligated 5'and 3'ends of the insert. Transfer of the element could not be shown through filter-mating experiments. Whole genome sequencing of PCR ribotype 078 strain 31618, isolated from a diarrheic piglet, showed that Tn6164 was not present in this strain. To test the prevalence of Tn6164, a collection of 231 Clostridium difficile PCR ribotype 078 isolates from human (n = 173) and porcine (n = 58) origin was tested for the presence of this element by PCR. The transposon was present in 9 human, tetracycline resistant isolates, originating from various countries in Europe, and none of the pig strains. Nine other strains, also tetracycline resistant human isolates, contained half of the transposon, suggesting multiple insertion steps yielding the full Tn6164. Other PCR ribotypes (n = 66) were all negative for the presence of the transposon. Multi locus variable tandem repeat analysis revealed genetic relatedness among transposon containing isolates. Although the element contained several potential antibiotic resistance genes, it did not yield a readily distinguishable phenotype. CONCLUSIONS: Tn6164 is a newly described transposon, occurring sporadically in C. difficile PCR ribotype 078 strains. Although no transfer of the element could be shown, we hypothesize that the element could serve as a reservoir of antibiotic resistance genes for other bacteria. Further research is needed to investigate the transfer capabilities of the element and to substantiate the possible role of Tn6164 as a source of antibiotic resistance genes for other gut pathogens.

Renal failure and leukocytosis are predictors of a complicated course of Clostridium difficile infection if measured on day of diagnosis.

Nonsevere Clostridium difficile infection (CDI) and severe CDI, which carries a higher risk than nonsevere CDI for treatment failure and CDI recurrence, are difficult to distinguish at the time of diagnosis. To investigate the prognostic value of 3 markers of severe CDI suggested by recent guidelines (fever, leukocytosis, and renal failure), we used the database of 2 randomized controlled trials, which contained information for 1105 patients with CDI. Leukocytosis (risk ratio [RR], 2.29; 95% confidence interval [CI], 1.63-3.21) and renal failure (RR, 2.52; 95% CI, 1.82-3.50) were associated with treatment failure. Fever, although associated with treatment failure (RR, 2.45; 95% CI, 1.07-5.61), was rare. Renal failure was the only significant predictor of recurrence (RR, 1.45; 95% CI, 1.05-2.02). Different timing of measurements of leukocyte count and serum creatinine level around the CDI diagnosis led to a different severity classification in many cases. In conclusion, both leukocytosis and renal failure are useful predictors, although timing of measurement is important.

High prevalence of Clostridium difficile colonization among nursing home residents in Hesse, Germany.

Clostridium difficile is the most common cause of antibiotic-associated diarrhoea in hospitals and other healthcare facilities. The elderly are particularly susceptible and at increased risk for adverse outcome as a result of C. difficile infection. The aim of this study was to determine the prevalence of C. difficile colonization among residents of nursing homes in Hesse and to compare it with the prevalence in the general population living outside long-term care facilities (LTCF). We assessed possible risk factors for C. difficile colonization and determined the genotype of circulating strains. C. difficile was isolated from 11/240 (4.6%) nursing home residents and 2/249 (0.8%) individuals living outside LTCF (p = 0.02). Ten of 11 (90.9%) isolates from nursing homes and one of two isolates from the population outside LTCF were toxigenic. The prevalence of C. difficile colonization varied from 0% to 10% between different nursing homes. Facilities with known actual or recent CDI cases were more likely to have colonized residents than facilities without known CDI cases. C. difficile PCR-ribotypes 014 and 001 were the most prevalent genotypes and accounted for 30% and 20% of toxigenic isolates in nursing homes, respectively. Interestingly, no individuals carried the epidemic strain PCR-ribotype 027. Our results suggest that residents of nursing homes in Germany are at high risk for colonization by virulent C. difficile strains. The high prevalence of C. difficile colonization in nursing homes underscores the importance of good adherence to standard infection control precautions even in the absence of a diagnosed infection. They also emphasize the need for specific programs to increase the awareness of healthcare professionals in LTCF for CDI.

Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics.

BACKGROUND: Clostridium difficile infections (CDIs) are common in developed countries and affect >250,000 hospitalized patients annually in the USA. The most important risk factor for the disease is antibiotic therapy. METHODS: To determine the period at risk for CDI after cessation of antibiotics, we performed a multicentre case-control study in the Netherlands between March 2006 and May 2009. Three hundred and thirty-seven hospitalized patients with diarrhoea and a positive toxin test were compared with 337 patients without diarrhoea. Additionally, a control group of patients with diarrhoea due to a cause other than CDI (n=227) was included. RESULTS: In the month prior to the date of inclusion, CDI patients more frequently used an antibiotic compared with non-diarrhoeal patients (77% versus 49%). During antibiotic therapy and in the first month after cessation of the therapy, patients had a 7-10-fold increased risk for CDI (OR 6.7-10.4). This risk declined in the period between 1 and 3 months after the antibiotic was stopped (OR 2.7). Similar results were observed when the second control group was used. All antibiotic classes, except first-generation cephalosporins and macrolides, were associated with CDI. Second- and third-generation cephalosporins (OR 3.3 and 5.3, respectively) and carbapenems (OR 4.7) were the strongest risk factors for CDI. Patients with CDI used more antibiotic classes and more defined daily doses, compared with non-diarrhoeal patients. CONCLUSIONS: Antibiotic use increases the risk for CDI during therapy and in the period of 3 months after cessation of antibiotic therapy. The highest risk for CDI was found during and in the first month after antibiotic use. Our study will aid clinicians to identify high-risk patients.

Genetic markers for Clostridium difficile lineages linked to hypervirulence.

Rapid identification of hypervirulent Clostridium difficile strains is essential for preventing their spread. Recent completion of several full-length C. difficile genomes provided an excellent opportunity to identify potentially unique genes that characterize hypervirulent strains. Based on sequence comparisons between C. difficile strains we describe two gene insertions into the genome of hypervirulent PCR ribotypes 078 and 027. Analysis of these regions, of 1.7 and 4.2 kb, respectively, revealed that they contain several interesting ORFs. The 078 region is inserted intergenically and introduces an enzyme that is involved in the biosynthesis of several antibiotics. The 027 insert disrupts the thymidylate synthetase (thyX) gene and replaces it with an equivalent, catalytically more efficient, thyA gene. Both gene insertions were used to develop ribotype-specific PCRs, which were validated by screening a large strain collection consisting of 68 different PCR ribotypes supplemented with diverse 078 and 027 strains derived from different geographical locations and individual outbreaks. The genetic markers were stably present in the hypervirulent PCR ribotypes 078 and 027, but were also found in several other PCR ribotypes. Comparative analysis of amplified fragment length polymorphisms, PCR ribotype banding patterns and toxin profiles showed that all PCR ribotypes sharing the same insert from phylogenetically coherent clusters. The identified loci are unique to these clusters, to which the hypervirulent ribotypes 078 and 027 belong. This provides valuable information on strains belonging to two distinct lineages within C. difficile that are highly related to hypervirulent strains.

[Changing epidemiology of infections in the Netherlands in 2008/'09]. / Veranderingen in 2008/'09 van de epidemiologie van Clostridium difficile-infecties in Nederland.

OBJECTIVE: To describe the epidemiological characteristics of Clostridium difficile infection (CDI) in the Netherlands. DESIGN: Descriptive. METHOD: After the first outbreaks in 2005 of Clostridium difficile infection (CDI) due to the hypervirulent PCR ribotype 027, a national reference laboratory was started in the Leiden University Medical Centre for typing and characterisation of C. difficile. Data were obtained from this national reference laboratory and from a continuous surveillance in 14 Dutch hospitals. The study period was January 2008-June 2009. RESULTS: In 2008, the incidence of CDI was 18 per 10.000 admissions (range: 14-23) in the 14 participating hospitals in the national surveillance study. In the study period, a total of 1867 cases of CDI were reported from 63 centres. The number of CDI outbreaks caused by type 027 decreased in the period January 2008 to June 2009, compared to the preceding years: type 027 was the cause of outbreaks in 4 Dutch hospitals in 2008-2009, whereas all 14 hospitals experienced an outbreak due to this type in the period 2005-2007. Although no systemic surveillance has been carried out in nursing homes, 24 Dutch nursing homes reported outbreaks of C. difficile in the period 2005-2009, in 12 of which type 027 was isolated. There was an increase of CDI detected in patients with diarrhoea outside health care facilities which appeared to coincide with the emergence of other types. In particular, type 078 increased since the end of 2006 and became the third most frequent type in the Netherlands. This type has also been recognised since 2007 as an important cause of CDI infection in animals, especially pigs. Recently there have also been reports that at least a third of the patients with CDI outside health care institutions do not have known risk factors for CDI such as an underlying disease, recent hospitalization or antibiotic use. CONCLUSION: CDI can also develop in the community The general practitioner should consider C. difficile in the differential diagnosis of elderly patients with diarrhoea.

[Osteonecrosis as late complication in HIV-infected patients]. / Osteonecrose als late complicatie bij hiv-geïnfecteerde patiënten.

Osteonecrosis of the femoral head was diagnosed in a 22-year-old woman and a 46-year-old man, both with HIV infection . Both had groin pain and impaired mobility. Conservative treatment did not relieve the pain. Both patients underwent a surgical procedure, i.e. core decompression and total hip replacement. In HIV-infected patients, osteonecrosis, i.e. avascular necrosis is an increasingly common problem in view of current longer life expectancy. The incidence of osteonecrosis is higher in HIV-infected patients than in the general population. Osteonecrosis should be included in differential diagnosis of groin or hip pain in HIV-positive patients. This may enable more rapid diagnosis and reduce the need for surgery.