[Serious side effects of fluoroquinolones: low risk of connective tissue-related disorders such as aneurysms]. / Ernstige bijwerkingen van fluorochinolonen.

Fluoroquinolones are frequently prescribed antibiotics. Recently, the Dutch medicines evaluation board CBG warned about the risk of aortic aneurysms and dissections with the use of fluoroquinolones. We reviewed the three articles used in this warning. We consider that the evidence for a causal relationship is limited. The hazard ratio for the association with fluoroquinolones and aortic aneurysms was around 2. The absolute risk is low given the low prevalence in the general population. However, aortic aneurysms and dissections are life-threatening conditions and must be taken serious. We advise what to do in case of known aortic aneurysms or the presence of multiple risk factors.

[Diagnostic algorithm for COVID-19 at the ER]. / Diagnostisch algoritme voor COVID-19 op de SEH.

OBJECTIVE: Evaluation of a diagnostic algorithm for estimating the risk of COVID-19 in patients who are referred to an emergency department for being suspected of having the disease. DESIGN: Retrospective study. METHOD: Patients with fever with no apparent cause and patients with recently developed respiratory symptoms, whether or not in combination with fever, were routinely given a PCR test, blood tests (lymphocyte count and LDH levels) and a chest CT scan. The CT scan was assessed according to the CO-RADS classification. Based on the findings, the patients were divided into 3 cohorts (proven COVID-19, strong suspicion of COVID-19, and low suspicion of COVID-19) and the appropriate isolation measures were taken. RESULTS: In the period from 8 to 31 March 2020, the algorithm was applied to 312 patients. COVID-19 was proven for 69 (22%) patients. COVID-19 was strongly suspected for 151 (48%) patients and suspicion was low for the remaining 92 (29%) patients. The percentage of patients with positive PCR results and the percentage of patients with abnormal laboratory test results increased as the CO-RADS score increased. Among patients with a CO-RADS score of 4 or 5, this percentage increased further when they also had lymphopenia or elevated LDH levels. We have adjusted the flowchart based on our findings. CONCLUSION: In case of patients who have been referred to an emergency department for suspected COVID-19, a good COVID-19 risk assessment can be made on the basis of clinical signs, laboratory abnormalities and low-dose CT scans. Even before the results of the PCR test are known and even if the results are negative, patients can be classified as 'proven COVID-19 patients' using the algorithm.

Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals.

BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

Plasmodium falciparum malaria recrudescence occurring 2.5 years after leaving an endemic country.

Malaria tropica is almost exclusively diagnosed within two months after returning from an endemic country. We present here a male patient with severe P. falciparum malaria diagnosed 2.5 years after returning from Burkina-Faso. We speculate that our patient was chronically infected with PF malaria for more than 2 years, with an undetectable parasite index and without symptoms. Because of waning immunity clinically overt PF malaria was able to develop. This case illustrates the importance of malaria suspicion as a cause of illness in immigrants from malaria-endemic countries. Even when these immigrants did not travel for a long time, malaria should be considered in patients with typical symptoms.

[Drug-induced tubulointerstitial nephritis]. / Medicamenteuze tubulo-interstitiële nefritis.

Three patients were diagnosed with drug-induced tubulointerstitial nephritis: a 72-year-old woman who was using a proton pump inhibitor, an 83-year-old woman who had recently been treated with antibiotics and an 83-year-old man who was using omeprazole. Discontinuation of the medications in question and the initiation of glucocorticoids resulted in improved renal function. In two of these patients, the diagnosis was established by renal biopsy. Acute tubulointerstitial nephritis is an important cause of renal insufficiency. It is characterized by inflammatory changes in interstitial tissue. Frequently prescribed medications such as proton pump inhibitors, antibiotics and nonsteroidal anti-inflammatory drugs may cause acute tubulointerstitial nephritis. Other causes are infections and auto-immune diseases. Renal failure may be reversible when use of the offending drug is discontinued. Partial or total renal insufficiency may, however, persist. Early treatment with steroids seems to improve the recovery of renal function in patients with drug-induced tubulointerstitial nephritis, although the evidence is not conclusive.

Leptospirosis in a Dutch catfish farm.

A 51-year-old farm worker presented with jaundice and fever. There had been a rat infestation around the farm ponds and in the shed. He was admitted to our hospital with acute renal and liver failure, thrombocytopenia and rhabdomyolysis. Because of the clinical clues, leptospirosis was suspected and diagnosed in blood by polymerase chain reaction and serology. Also his son, a co-worker on the farm, showed a positive serology. Clinicians should be aware of these occupational outbreaks and should recognise the clinical picture.

[Melioidosis: the importance of a detailed medical history, including recent travels]. / Melioidosis: het belang van een goede reisanamnese.

A 70-year-old woman was admitted to hospital with fever and signs of bronchopneumonia following a recent visit to Southeast Asia. She was diagnosed with melioidosis and treated with ceftazidime i.v. for two weeks, followed by oral co-trimoxazol and folinic acid. She recovered and had no recurring disease in the first year following recovery. Melioidosis is caused by an infection with Burkholderia pseudomallei. Clinical presentation can vary, but pneumonia is present in most patients. The diagnosis should be considered in patients with reduced immunological resistance who have been in endemic areas such as Southeast Asia, especially during the rainy season. It is important to determine which countries have been visited by patients who have recently returned from tropical areas. In addition, the time of onset, the duration of symptoms and a detailed physical examination are essential in the assessment of patients presenting with exotic diseases.

Concentration-dependency of beta-lactam-induced filament formation in Gram-negative bacteria.

Ceftazidime and cefotaxime are beta-lactam antibiotics with dose-related affinities for penicillin-binding protein (PBP)-3 and PBP-1. At low concentrations, these antibiotics inhibit PBP-3, leading to filament formation. Filaments are long strands of non-dividing bacteria that contain enhanced quantities of endotoxin molecules. Higher concentrations of ceftazidime or cefotaxime cause inhibition of PBP-1, resulting in rapid bacterial lysis, which is associated with low endotoxin release. In the present study, 37 isolates of Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. were studied over a 4-h incubation period in the presence of eight concentrations of ceftazidime or cefotaxime. As resistance of Gram-negative bacteria is an emerging problem in clinical practice, 14 isolates of E. coli and Klebsiella pneumoniae that produced extended-spectrum beta-lactamases (ESBLs) were also investigated. Morphological changes after exposure to the beta-lactam antibiotics revealed recognisable patterns in various bacterial families, genera and isolates. In general, all isolates of Enterobacteriaceae produced filaments within a relatively small concentration range, with similar patterns for E. coli and K. pneumoniae. Pseudomonas and Acinetobacter spp. produced filaments in the presence of clinically-relevant concentrations of both antibiotics as high as 50 mg/L. In all genera, filament-producing capacity was clearly related to the MIC. Ceftazidime induced filament production in more isolates and over wider concentration ranges than did cefotaxime. Interestingly, ESBL-producing isolates were not protected against filament induction. The induction of filament production may lead to additional risks during empirical treatment of severe infections.

Pathophysiology of in-vitro induced filaments, spheroplasts and rod-shaped bacteria in neutropenic mice.

This study compared the in-vitro properties and in-vivo effects of Escherichia coli filaments, spheroplasts and normal cells in a murine thigh infection model. E. coli was exposed to ceftazidime, meropenem or saline to obtain filaments, spheroplasts or normal bacilli, which were then injected into neutropenic mice. After 24 h, morphology, CFUs, local and circulating endotoxin levels, cytokine levels and mortality were recorded, and correlations between bacterial and host parameters of infection were investigated. Filaments and spheroplasts contained more endotoxin/CFU than controls. Histological studies showed that morphologically altered bacteria changed into rod-shaped cells in the absence of antibiotics. Bacterial spread to the liver was significantly higher in mice challenged with rod-shaped cells, compared with antibiotic-exposed bacteria (p 0.007). Muscle endotoxin levels correlated significantly with circulating interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha, and both pro-inflammatory cytokines were correlated significantly (p 0.011). Despite a tendency toward higher local and systemic concentrations of endotoxin in the filament group, inflammatory responses and survival did not differ between groups. It was concluded that morphologically altered bacteria contain more endotoxin and can regain a rod shape after withdrawal of antibiotics, while non-antibiotic-exposed bacteria show greater spread to the liver. There was a clear intra-individual relationship between local endotoxin, systemic endotoxin, TNF-alpha and IL-6 production, but these parameters did not differ among groups.

Neurological complications following Plasmodium falciparum infection.

Several neurological complications are associated with severe falciparum malaria. Cerebral malaria is one of the most life-threatening complications. A few patients may experience a neurological syndrome after complete recovery from Plasmodium falciparum infection. In the literature especially the postmalaria neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM) and delayed cerebellar ataxia have been reported. We describe a case of a 53-year-old woman who was readmitted after an adequately treated P. falciparum infection with word-finding difficulties, confusion and tremor. Peripheral blood smears were repeatedly negative for malarial parasites. The clinical features best fitted a PMNS. Because of the severity of the syndrome she was treated with high-dose prednisone. She recovered completely. The possibility of ADEM is also discussed. Aetiology of these syndromes is still unknown, but it could be mediated by an immunological mechanism. PMNS or ADEM must be considered when neurological signs and symptoms occur after recovery from a P. falciparum infection.