[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.

Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients.

BACKGROUND: The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against COVID-19 has resulted in an ongoing discussion about the effectivity and toxicity of these drugs. Recent studies report no effect of (H)CQ on 28-day mortality. We investigated the effect of HCQ and CQ in hospitalized patients on the non-ICU COVID-ward. METHODS: A nationwide, observational cohort study was performed in The Netherlands. Hospitals were given the opportunity to decide independently on the use of three different COVID-19 treatment strategies: HCQ, CQ, or no treatment. We compared the outcomes between these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer to the intensive care unit (ICU). RESULTS: The analysis included 1064 patients from 14 hospitals: 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensity-matched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality on the COVID ward. However, HCQ was associated with a significantly decreased risk of transfer to the ICU (hazard ratio (HR) = 0.47, 95% CI = 0.27-0.82, p = 0.008) when compared with controls. This effect was not found in the CQ group (HR = 0.80, 95% CI = 0.55-1.15, p = 0.207), and remained significant after competing risk analysis. CONCLUSION: The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU mortality. However, we show that the use of HCQ - but not CQ - is associated with a 53% reduction in risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent prospective studies have reported on 28-day, all-cause mortality only; therefore, additional prospective data on the early effects of HCQ in preventing transfer to the ICU are still needed.

[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.

Colitis may be part of the antiepileptic drug hypersensitivity syndrome.

PURPOSE: To show that colitis may be part of the antiepileptic hypersensitivity syndrome. METHODS: Description of two case histories. RESULTS: The first patient was a 47-year-old man who developed fever, lymphadenopathy, influenza-like symptoms, facial edema, skin rash and diarrhea after 3 weeks of carbamazepine (CBZ) treatment. Laparotomy because of severe abdominal pain 2 weeks later showed severe colitis with perforations. The second patient was a 41-year-old woman who developed fever, diarrhea, and skin rash 4 weeks after start of CBZ treatment. A colon biopsy confirmed colitis. Stool examinations did not show pathogenic microorganisms, and there was no evidence of Crohn's disease or ulcerative colitis. Both patients had elevated liver enzymes, peripheral eosinophilia, and eosinophils in the infiltrate of the colon. CONCLUSIONS: In view of the close temporal relation between start of CBZ intake and development of colitis, the presence of fever, lymphadenopathy, and rash, and improvement after discontinuation of CBZ, we conclude that the two patients developed an AED hypersensitivity syndrome. Our case histories demonstrate that severe colitis may be part of this syndrome.

[Intracerebral tuberculomas in a pregnant Somalian woman]. / Intracerebrale tuberculomen bij een zwangere Somalische.

A pregnant Somalian woman aged 28 years, in the Netherlands for the last five years, suffered from a progressive hemiparesis, epilepsia, behavioural problems and low fever. Brain MRI showed multiple lesions with contrast enhancement. Extensive serologic and parasitologic tests on serum and cerebrospinal fluid did not disclose any cause. A brain biopsy revealed only necrosis, but bacterial culture and polymerase chain reaction (PCR) supplied the diagnosis of 'tuberculosis'. PCR on the cerebrospinal fluid remained negative. In the meantime the chest X-ray showed miliary tuberculosis and a spine MRI thoracic spondylodiscitis and a large paravertebral abscess. Subsequently the patient was treated successfully with tuberculostatic agents. Her healthy child which was born by caesarean section was treated with the tuberculostatic agents as well.

Schistosomiasis haematobium as a cause of vulvar hypertrophy.

Schistosomiasis is the most frequently imported helminthic infection in The Netherlands. Patients with Schistosoma haematobium infections usually present with fever, hematuria, dysuria, or urinary frequency. The ectopic localizations in female genital schistosomiasis are frequently misdiagnosed or confounded with sexually transmitted diseases or genital tract cancers. This paper describes a patient who presented with vulvar hypertrophy as a symptom of acute female genital schistosomiasis. The aim of this paper is to draw attention to a neglected parasitic disease that in the future will be encountered in increasing numbers in Western Europe.

Influence of low dose ciprofloxacin on microbial colonization of the digestive tract in healthy volunteers during normal and during impaired colonization resistance.

Ciprofloxacin in low doses is, in volunteers, effective for decontaminating the digestive tract [elimination of aerobic Gram-negative bacilli (GNB)] without disturbing colonization resistance. Before using this concept in neutropenic patients, we investigated if a low dose quinolone is still effective when the colonization resistance is disturbed by another antimicrobial agent. Ciprofloxacin 20 mg daily was effective in eliminating Gram-negative bacilli from the digestive tract in 4/5 volunteers, in 1 volunteer the GNB persisted in low concentration. No colonization with exogenous resistant GNB occurred. Following impairment of colonization resistance by addition of clindamycin 300 mg daily, 3/5 volunteers became colonized by spontaneously acquired exogenous GNB resistant to ciprofloxacin. We conclude that selective decontamination with a quinolone in low dosage cannot be recommended in neutropenic patients because there is, in the case of disturbed colonization resistance, a real risk of acquisition of quinolone-resistant strains.

[Systemic fat necrosis and septic arthritis in acute pancreatitis]. / Systemische vetnecrose en septische artritis bij acute pancreatitis.

Systemic fatty necrosis secondary to acute pancreatitis was diagnosed in a 47-year-old man with high fever and painful nodules on the arms and the upper legs. This was complicated by fatal septic shock, septic arthritis and extensive soft tissue infections with Enterobacter cloacae, which was unsuccessfully treated with several antibiotic regimens, and from which the patient died.

Concentration of pefloxacin in feces during infection prophylaxis in neutropenic patients.

Pefloxacin (400 mg twice daily) was administered orally for infection prophylaxis in neutropenic patients. Diffusible fecal pefloxacin concentration was determined by bioassay during 24 neutropenic periods. The median diffusible fecal pefloxacin concentration was 187 micrograms/g. This concentration was comparable with those found in volunteers following oral and intravenous administration of pefloxacin (400 mg twice daily) (median of 171 and 155 micrograms/g, respectively). From this study, it is concluded that pefloxacin administered orally results in a predictable high diffusible fecal concentration which leads to effective elimination of susceptible aerobic gram-negative bacilli from the colonic flora.