The Dutch Working Party on Antibiotic Policy (SWAB) guideline for the approach to suspected antibiotic allergy.

OBJECTIVES: Prudent handling of reported antibiotic allergies is an important aspect of antibiotic stewardship. The Dutch Working Party on Antibiotic Policy (SWAB) constituted a multidisciplinary expert committee to provide evidence-based recommendations for bedside decision-making in antibiotic therapy in patients that report an antibiotic allergy. METHODS: The guideline committee generated 12 key questions, most of which were population, intervention, comparison, and outcome questions relevant to both children and adults with suspected antibiotic allergies. For each question, a systematic literature search was performed and reviewed for the best available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The quality of evidence was graded from very low to high, and recommendations were formulated in structured discussions as strong or weak. RESULTS: Sixty recommendations were provided for suspected allergy to ß-lactam antibiotics (BLAs) and non-ß-lactam antibiotics. Owing to the absence of randomized controlled trials in this field, the underlying evidence was predominantly graded as low or very low. Available data support that a detailed allergy history should always be performed and critically appraised. When cross-allergy between BLA groups is not to be expected due to the absence of molecular similarity of the side chains, the patient can be safely exposed to the alternative BLA. An exception to this rule is severe delayed-type reactions in which re-exposure to a BLA should only be considered after consultation with a multidisciplinary team. CONCLUSIONS: Accumulated scientific data now support a more liberal approach that better balances the benefits of treatment with first choice and usually smaller spectrum antibiotics with appropriate avoidance of antibiotics in case of a truly high risk of a (severe) allergic reaction. In The Netherlands, a formal guideline was developed that provides recommendations for the approach toward suspected allergy to BLA and frequently used non-ß-lactam antibiotics, thereby strongly supporting antimicrobial stewardship.

First Case of Human Brucella canis Infection in the Netherlands.

A patient was diagnosed with Brucella canis following exposure to infected dogs in her breeding facility. Transboundary spread of B. canis through (illegal) import of infected dogs to non-endemic countries in Europe suggest that B. canis infection should be considered in European patients with occupational exposure to dogs.

Costs of a clinical pathway with point-of-care testing during influenza epidemic in a Dutch hospital.

Our study aim was to determine how a new clinical pathway, including PCR-based influenza point-of-care test (POCT), influences the hospitalisation costs of patients suspected of influenza presenting at the emergency department of a Dutch hospital during two consecutive influenza epidemics (2016-2017 and 2017-2018). Compared to mean costs per patient of €3661 in 2016-2017, the implementation of this new clinical pathway with influenza POCT in 2017 was associated with mean costs per influenza-positive patient of €2495 in 2017-2018 (P = .3). Our study suggests favourable economic results regarding a new clinical pathway with influenza POCT, reflecting a more efficient care of patients suspected of influenza presenting at the emergency department.

[Influenza point-of-care test in the GP practice and Emergency Department; analytical accuracy and added value]. / Influenzasneltests voor de huisartsenpraktijk en SEH.

An influenza epidemic can greatly increase the workload in primary care and the emergency department (ED) and can even disrupt the healthcare system. It is difficult to diagnose influenza by history taking and physical examination. A fast diagnosis usinginfluenza point-of-care tests (POCTs) could reduce unnecessary antibiotic prescriptions, diagnostic tests, consultations and hospital admissions. Moreover, length of stay on EDs and length of admission could be shortened. The analytical accuracy of antigen detection tests for influenza is relatively low compared to the well performing RT-PCR assays (sensitivity and specificity approximately 95%). Only 1 randomized controlled trial has shown the effect of a (combined) RT-PCR assay for influenza detection on clinically relevant outcome measures. Observational research suggests that introduction of RT-PCR assays for influenza detection reduces length of stay on the ED and decreased time from sample reception to result. For practical reasons, we should embrace the introduction of RT-PCR assays for influenza detection on EDs. Before POCTs can be implemented in primary care (family medicine) the analytical accuracy and time to receive results should be improved and effects of its clinical impact should be proven.

Outbreak of NDM-1-Producing Klebsiella pneumoniae in a Dutch Hospital, with Interspecies Transfer of the Resistance Plasmid and Unexpected Occurrence in Unrelated Health Care Centers.

In the Netherlands, the number of cases of infection with New Delhi metallo-beta-lactamase (NDM)-positive Enterobacteriaceae is low. Here, we report an outbreak of NDM-1-producing Klebsiella pneumoniae infection in a Dutch hospital with interspecies transfer of the resistance plasmid and unexpected occurrence in other unrelated health care centers (HCCs). Next-generation sequencing was performed on 250 carbapenemase-producing Enterobacteriaceae isolates, including 42 NDM-positive isolates obtained from 29 persons at the outbreak site. Most outbreak isolates were K. pneumoniae (n = 26) and Escherichia coli (n = 11), but 5 isolates comprising three other Enterobacteriaceae species were also cultured. The 26 K. pneumoniae isolates had sequence type 873 (ST873), as did 7 unrelated K. pneumoniae isolates originating from five geographically dispersed HCCs. The 33 ST873 isolates that clustered closely together using whole-genome multilocus sequence typing (wgMLST) carried the same plasmids and had limited differences in the resistome. The 11 E. coli outbreak isolates showed great variety in STs, did not cluster using wgMLST, and showed considerable diversity in resistome and plasmid profiles. The blaNDM-1 gene-carrying plasmid present in the ST873 K. pneumoniae isolates was found in all the other Enterobacteriaceae species cultured at the outbreak location and in a single E. coli isolate from another HCC. We describe a hospital outbreak with an NDM-1-producing K. pneumoniae strain from an unknown source that was also found in patients from five other Dutch HCCs in the same time frame without an epidemiological link. Interspecies transfer of the resistance plasmid was observed in other Enterobacteriaceae species isolated at the outbreak location and in another HCC.

Listeria Endocarditis: A Diagnostic Challenge.

A 74-year-old hemodialysis patient with a history of an atrial septum defect closure, coronary bypass surgery, and a St. Jude aortic prosthetic valve was diagnosed with pneumonia and volume overload. Blood cultures were positive for Listeria monocytogenes, and amoxicillin was given for 2 weeks. Immediately after discontinuation of amoxicillin, fever relapsed. Transthoracic and transesophageal echocardiography showed no sign of endocarditis. Given the fever relapse and 3 positive minor Duke criteria, an 18F-FDG PET-CT scan (18F-fluorodeoxyglucose-positron emission tomography-computed tomography) scan was performed. This scan showed activity at the aortic root, proximal ascending aorta, and inferior wall of the heart, making Listeria monocytogenes endocarditis a likely explanation. Amoxicillin was given for 6 weeks with good clinical result. Diagnosing a life-threatening Listeria monocytogenes endocarditis can be challenging and an 18F-FDG PET-CT scan can be helpful.

Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice.

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response.

Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-ß-lactamase-producing bacteria.

We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-ß-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of ≥ 3, an age of ≥ 75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received ß-lactam-ß-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality.

Minocycline inhibits apoptotic cell death in a murine model of partial flap loss.

For breast reconstruction, the deep inferior epigastric perforator (DIEP) flap has become standard therapy. A feared complication is partial or even total flap loss. In a novel murine model of partial DIEP flap loss, the contribution of apoptotis to flap loss was investigated. The clinically available apoptosis-inhibiting compound minocycline was tested for its ability to reduce cell death. The effect of minocycline on cell proliferation was studied in cell cultures of breast carcinoma. In 12 mice, pedicled DIEP flaps were raised, which were subjected to 15 minutes of ischemia and 4 days of reperfusion. Six mice were treated with minocycline 2 hours before surgery and every 24 hours for 4 days. Apoptosis was revealed by injecting annexin A5 30 minutes before sacrifice. Annexin A5 binds to phosphatidylserines, which are expressed on the cell membrane during apoptotis. Prior to sacrifice, necrosis was measured using planimetry. Minocycline reduced cell death after 4 days from 35.9% (standard deviation = 10.6) to 13.9% (standard deviation = 8.0; P < 0.05). Apoptosis, as shown by annexin A5 binding in nontreated animals, was abundant. Minocycline did not influence tumor growth in cell cultures of human breast cancer. Minocycline treatment leads to increased DIEP flap viability in mice. This study widens the perspective in the improvement of free flap survival in patients.

Cathepsin K gene disruption does not affect murine aneurysm formation.

Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE-/- mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE-/- and catK-//-apoE-/- mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK-/-//apoE-/- versus apoE-/- mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE-/- mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK-/-//apoE-/- mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK-/-//apoE-/- compared to apoE-/- mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK-//-apoE-/- mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation.

To do or not to do: IVF and ICSI in chronic hepatitis B virus carriers.

Several assisted reproduction procedures, such as IVF and ICSI, are available for a variety of infertility problems. In fertility clinics, patients are screened for blood-borne viral infections, including hepatitis B virus (HBV). Reasons for screening are prevention of vertical transmission and laboratory safety. We present the case of a 26-year-old female patient with a chronic HBV infection, whose husband tested negative for hepatitis B. She and her husband were referred to our fertility clinic because of subfertility. Analysis of the husband's semen indicated the necessity of an ICSI procedure. The current Dutch guidelines advise against ICSI in chronic HBV carriers, since the risks and effects of chromosomal integration of HBV DNA in the fetus are not well-known. In this article, we review the scientific evidence for the risk of introducing HBV virus into the oocyte and subsequent integration of HBV DNA into the human genome, and debate the question of whether to do, or not to do, IVF and ICSI.

Cathepsin cysteine proteases in cardiovascular disease.

Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis. Furthermore, cathepsins are involved in lipid metabolism. Cathepsins have the capability to degrade low-density lipoprotein and reduce cholesterol efflux from macrophages, aggravating foam cell formation. Although expression studies also demonstrated differential expression of cathepsins in cardiovascular diseases like aneurysm formation, neointima formation, and neovascularization, in vivo studies to define the exact role of cathepsins in these processes are lacking. Evaluation of the feasibility of cathepsins as a diagnostic tool revealed that serum levels of cathepsins L and S seem to be promising as biomarkers in the diagnosis of atherosclerosis, whereas cathepsin B shows potential as an imaging tool. Furthermore, cathepsin K and S inhibitors showed effectiveness in (pre) clinical evaluation for the treatment of osteoporosis and osteoarthritis, suggesting that cathepsin inhibitors may also have therapeutic effects for the treatment of atherosclerosis.