The effect of the acute phase of infection on absorption of and exposure to orally administered antibiotics in non-critically ill, hospitalized patients.

OBJECTIVES: During the acute phase of infection, IV antibiotics are preferred to ensure adequate systemic exposure. To assess whether adequate exposure may also be achieved with oral antibiotics, we investigated exposure to oral antibiotics and PTA during the acute phase of infection and after defervescence. METHODS: We enrolled hospitalized, non-critically ill febrile patients treated with IV antibiotics other than amoxicillin or ciprofloxacin. The study consisted of two visits: when patients had received <24 h IV treatment; and when patients had become afebrile. On both visits, patients received one additional dose of 750 mg amoxicillin, or 500 mg ciprofloxacin, depending on the presumed infection, after which serial blood samples were obtained. The primary endpoint was the ratio of the AUC during the febrile and the afebrile phase. The AUCs were considered to be equivalent when the ratio of the mean AUCs and its 90% CI was contained within the acceptance interval of 80%-125%. The secondary endpoint was PTA. RESULTS: Forty-four patients (15 amoxicillin, 29 ciprofloxacin) completed both study visits. The median time between the two study visits was 65.8 h (range 33.8-427.4). The ratio of the mean AUCs (study visit 1/study visit 2) was 97% (90% CI of 80%-117%) for amoxicillin and 112% (90% CI of 108%-116%) for ciprofloxacin. The PTA for amoxicillin and ciprofloxacin did not differ between the two phases and was adequate to treat common pathogens. CONCLUSIONS: The acute phase of infection in non-critically ill febrile patients does not influence the exposure to, or PTA of, orally administered amoxicillin and ciprofloxacin. This might justify earlier IV-to-oral switching.

Comparative effectiveness of ß-lactams for empirical treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective cohort study.

OBJECTIVES: Standard once-daily dosing of ceftriaxone may not lead to adequate antibiotic exposure in all cases of Staphylococcus aureus bacteraemia (SAB). Therefore, we compared clinical effectiveness of empirical antibiotic treatment with flucloxacillin, cefuroxime and ceftriaxone in adult patients with MSSA bacteraemia. METHODS: We analysed data from the Improved Diagnostic Strategies in Staphylococcus aureus bacteraemia (IDISA) study, a multicentre prospective cohort study of adult patients with MSSA bacteraemia. Duration of bacteraemia and 30 day SAB-related mortality were compared between the three groups using multivariable mixed-effects Cox regression analyses. RESULTS: In total, 268 patients with MSSA bacteraemia were included in the analyses. Median duration of empirical antibiotic therapy was 3 (IQR 2-3) days in the total study population. Median duration of bacteraemia was 1.0 (IQR 1.0-3.0) day in the flucloxacillin, cefuroxime and ceftriaxone groups. In multivariable analyses, neither ceftriaxone nor cefuroxime was associated with increased duration of bacteraemia compared with flucloxacillin (HR 1.08, 95% CI 0.73-1.60 and HR 1.22, 95% CI 0.88-1.71). In multivariable analysis, neither cefuroxime nor ceftriaxone was associated with higher 30 day SAB-related mortality compared with flucloxacillin [subdistribution HR (sHR) 1.37, 95% CI 0.42-4.52 and sHR 1.93, 95% CI 0.67-5.60]. CONCLUSIONS: In this study, we could not demonstrate a difference in duration of bacteraemia and 30 day SAB-related mortality between patients with SAB empirically treated with flucloxacillin, cefuroxime or ceftriaxone. Since sample size was limited, it is possible the study was underpowered to find a clinically relevant effect.

A clinical and biological review of keratoacanthoma.

Keratoacanthoma (KA) is a common skin tumour that remains controversial regarding classification, epidemiology, diagnosis, prognosis and management. Classically, a KA manifests as a rapidly growing, well-differentiated, squamoid lesion with a predilection for sun-exposed sites in elderly people and a tendency to spontaneously regress. Historically, KAs have been considered a variant of cutaneous squamous cell carcinoma (cSCC) and are often reported as KA-type cSCC. However, the penchant for regression has led many to categorize KAs as biologically benign tumours with distinct pathophysiological mechanisms from malignant cSCC. The clinical and histopathological similarities between KA and cSCC, particularly the well-differentiated variant of cSCC, have made definitive differentiation difficult or impossible in many cases. The ambiguity between entities has led to the general recommendation for surgical excision of KAs to ensure a potentially malignant cSCC is not left untreated. This current standard creates unnecessary surgical morbidity and financial strain for patients, especially the at-risk elderly population. There have been no reports of death from a definitive KA to date, while cSCC has an approximate mortality rate of 1·5%. Reliably distinguishing cSCC from KA would shift management strategies for KAs towards less-invasive treatment modalities, prevent unnecessary surgical morbidity, and likely reduce associated healthcare costs. Herein, we review the pathophysiology and clinical characteristics of KA, and conclude on the balance of current evidence that KA is a benign lesion and distinct from cSCC.

The distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus: Adipokinetic hormone, corazonin and adipokinetic hormone/corazonin-related peptide.

We have examined the distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus. These neuropeptides, adipokinetic hormone (RhoprAKH), corazonin (CRZ) and adipokinetic hormone/corazonin-related peptide (RhoprACP) are present in distinct, non-overlapping neuronal subsets in the central nervous system (CNS), as determined by immunohistochemistry. Corazonin-like immunoreactive cell bodies are present in the brain and ventral nerve cord, whereas ACP-like immunoreactive cell bodies are only present in the brain, and AKH-like immunoreactive cell bodies only present in the corpus cardiacum (CC). The immunoreactivity to ACP, CRZ and AKH in R. prolixus suggests that ACP and CRZ are released within the CNS, and that CRZ and AKH are released as neurohormones from the CC. Injection of RhoprAKH into adult males elevated haemolymph lipid levels, but injection of CRZ or RhoprACP failed to have any effect on haemolymph lipid levels. Corazonin stimulated an increase in heart-beat frequency in vitro, but RhoprAKH and RhoprACP failed to do so. Thus, although all three neuropeptides share sequence similarity, the AKH and CRZ receptors only respond to their own ligand.

Reprint of "The distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus: Adipokinetic hormone, corazonin and adipokinetic hormone/corazonin-related peptide".

We have examined the distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus. These neuropeptides, adipokinetic hormone (RhoprAKH), corazonin (CRZ) and adipokinetic hormone/corazonin-related peptide (RhoprACP) are present in distinct, non-overlapping neuronal subsets in the central nervous system (CNS), as determined by immunohistochemistry. Corazonin-like immunoreactive cell bodies are present in the brain and ventral nerve cord, whereas ACP-like immunoreactive cell bodies are only present in the brain, and AKH-like immunoreactive cell bodies only present in the corpus cardiacum (CC). The immunoreactivity to ACP, CRZ and AKH in R. prolixus suggests that ACP and CRZ are released within the CNS, and that CRZ and AKH are released as neurohormones from the CC. Injection of RhoprAKH into adult males elevated haemolymph lipid levels, but injection of CRZ or RhoprACP failed to have any effect on haemolymph lipid levels. Corazonin stimulated an increase in heart-beat frequency in vitro, but RhoprAKH and RhoprACP failed to do so. Thus, although all three neuropeptides share sequence similarity, the AKH and CRZ receptors only respond to their own ligand.

[A 34-year old man with fever, joint pain and red spots]. / Een man met koorts, gewrichtsklachten en rode vlekjes.

A 34 year old man visits the emergency room with variable complaints, including persistent fever, non-itchy rash on arms and legs and painful and swollen joints. He and his male partner have recently tested negative for HIV, Lues and Chlamydia. In our hospital, the blood culture became positive for Neisseria gonorrhoeae.Conflict of interest and financial support: none declared.

Neuropeptide and neurohormone precursors in the pea aphid, Acyrthosiphon pisum.

Aphids respond to environmental changes by developing alternative phenotypes with differing reproductive modes. Parthenogenetic reproduction occurs in spring and summer, whereas decreasing day lengths in autumn provoke the production of sexual forms. Changing environmental signals are relayed by brain neuroendocrine signals to the ovarioles. We combined bioinformatic analyses with brain peptidomics and cDNA analyses to establish a catalogue of pea aphid neuropeptides and neurohormones. 42 genes encoding neuropeptides and neurohormones were identified, of which several were supported by expressed sequence tags and/or peptide mass analyses. Interesting features of the pea aphid peptidome are the absence of genes coding for corazonin, vasopressin and sulfakinin and the presence of 10 different genes coding insulin related peptides, one of which appears to be very abundantly expressed.

[Lymphogranuloma venereum, an STI that is sometimes recognized late in secondary care]. / Lymphogranuloma venereum.

Lymphogranuloma venereum (LGV) is an invasive sexually transmitted infection caused by Chlamydia trachomatis genotypes L1, L2 and L3. Until recently, LGV was rarely seen in developed countries. However, an outbreak of LGV infections in Europe amongst men who have sex with men (MSM) has been reported in the past decades. Diagnosing LGV can be challenging since there is no pathognomic clinical presentation. Most patients are diagnosed with LGV by Community Healthcare Services and general practitioners. Recent data show that a significant diagnostic delay can occur when patients present in a hospital with symptoms due to LGV infection. This can result in unnecessary additional diagnostic procedures and a subsequent diagnostic delay. In order to create more awareness, we describe 3 cases in our hospital with an initially unrecognized LGV infection. We also discuss the epidemiology, clinical manifestations, diagnostic process and treatment of LGV infection.

Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.

OBJECTIVES: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. METHODS: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. RESULTS: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: -15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: -8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). CONCLUSIONS: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

Familial Mediterranean Fever (FMF): a single centre retrospective study in Amsterdam.

BACKGROUND: Familial Mediterranean Fever (FMF) is the earliest described and most prevalent hereditary auto-inflammatory disease. Its clinical presentation is diverse, leading to possible delay in diagnosis and treatment. Due to immigration, FMF became common in non-Mediterranean European regions. In the present single centre retrospective study, the clinical, demographic, and genetic characteristics of patients with FMF of different ancestry in Amsterdam are described. METHODS: Case records of patients with FMF, who met the Tel-Hashomer diagnostic criteria, were retrospectively analysed. The international disease severity score was used. RESULTS: Between 1990-2012, 53 patients were identified, 28 were female. Main country of origin was Turkey. The mean age at the time of analysis was 29.1 years; 13.8 years at onset of symptoms; and at time of diagnosis, 22.0 years. Most frequent symptoms were peritonitis (91%) and fever (81%). The mean C-reactive protein and erythrocyte sedimentation rate during acute attacks were 133 mg/l and 37 mm/first hour, respectively. One patient developed amyloidosis as a complication. Seventeen patients underwent abdominal surgery before diagnosis. Most patients (92%) received colchicine treatment and were responsive (81%). Most patients classified their disease as a mild disease (42%). MEFV gene mutation analysis was performed in 46 patients; most patients were compound heterozygotes (n = 17), and the most frequent mutation was M694V (n = 18). CONCLUSION: FMF in Amsterdam is diagnosed in relatively young patients and the delay to diagnosis is 8.2 years. Disease manifestations and genetic distribution of our FMF patients are comparable to those in Mediterranean regions, suggesting that ancestry is more important than environment.

[Diagnostic image (391). A man with fever and urticaria after a trip to Uganda]. / Diagnose in beeld (391). Een man met koorts en urticaria na een reis door Uganda.

A 35-year-old man presented with fever and severe urticaria after visiting Uganda. His symptoms were caused by acute invasive schistosomiasis, also known as Katayama fever.

Pitfalls in SIADH-diagnosed hyponatraemia: Report of two cases.

In the majority of hospitalised patients with hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the primary cause. Before considering SIADH, adrenal, thyroid and pituitary insufficiency should be ruled out. However, the evaluation of these contains potential pitfalls which could lead to incorrect diagnosing of SIADH. Here we present two cases in which a suspected SIADH turned out to be caused by hypopituitarism, emphasising the importance of correctly excluding adrenal, thyroid and pituitary insufficiency.

Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission.

Macrophage-tropic, non-syncytium-inducing, HIV-1 variants predominate in the asymptomatic phase of infection and may be responsible for establishing infection in an individual exposed to the mixture of HIV-1 variants. Here, genotypical and phenotypical characteristics of virus populations, present in sexual, parenteral, or vertical donor-recipient pairs, were studied. Sequence analysis of the V3 domain confirmed the presence of a homogeneous virus population in recently infected individuals. Biological HIV-1 clones were further characterized for syncytium inducing capacity on the MT2 cell line and for macrophage tropism as defined by the appearance of proviral DNA upon inoculation of monocyte-derived macrophages. Both sexual and parenteral transmission cases revealed a selective outgrowth in the recipient of the most macrophage-tropic variant(s) present in the donor. In three out of five vertical transmission cases, more than one highly macrophage-tropic virus variant was present in the child shortly after birth, suggestive of transmission of multiple variants. In three primary infection cases, homogeneous virus populations of macrophage-tropic, non-syncytium-inducing variants were present prior to seroconversion, thus excluding humoral immunity as the selective pressure in favour of macrophage-tropic variants. These observations may have important implications for vaccine development.

[Granulomatous mastitis: a rare cause of breast swelling]. / Een zeldzame oorzaak van een mammagezwel: granulomateuze mastitis.

Three women, aged 37, 39 and 29 years, presented with unilateral painful swelling of the breast. Ultrasound revealed inflammation with abscess formation. Histological biopsies contained granulomatous tissue without necrosis. Corynebacterium species were cultured in the first two patients. All 3 patients were diagnosed with granulomatous mastitis and were successfully treated with doxycycline. Granulomatous mastitis is a rare disorder that may mimic breast carcinoma. It occurs most frequently in fertile women. Diagnosis is based on histological biopsy which shows granulomas without necrosis, while other causes of granulomatous inflammation, especially tuberculosis, have been excluded. The aetiology is not fully understood. It is hypothesised that the granulomatous mastitis is caused by a type IV allergic reaction. Recently an association with Corynebacterium species was suggested. Best practice treatment methods are unclear. Most patients are treated with surgical intervention and steroids, but the rate of recurrence is high (50%). Treatment with doxycycline must be considered in patients with cultured Corynebacterium species.

[Splenic abscess]. / Het miltabces.

Splenic abscess is a rare and potentially lethal clinical condition. The most common symptoms of a splenic abscess - abdominal pain, nausea and fever - are non-specific. As a result, a splenic abscess is often not considered in the initial work-up. This might lead to a delay in diagnosis and treatment. In this case series we successively describe a 41-year-old female with a splenic abscess after Streptococcus milleri bacteraemia, a 78-year-old male with a splenic abscess caused by a colon carcinoma and a 52-year-old male with a splenic abscess resulting from a colosplenic fistula after bariatric surgery. By emphasizing the different aetiologies, the different clinical presentations and the different therapeutic options of a splenic abscess, we aim to create greater awareness of this rare clinical phenomenon.

[Thrombocytopenia]. / Trombocytopenie.

Thrombocytopenia can be caused by many different underlying disorders. The diagnostic approach to this haematological abnormality may, therefore, be challenging for physicians. Causes of thrombocytopenia may be classified according to decreased production, increased peripheral consumption or destruction, or abnormal distribution of platelets. Additionally, it is important to rule out pseudothrombocytopenia, a laboratory artefact caused in vitro by ethylenediaminetetraacetic acid (EDTA) anticoagulants. Here we discuss the clinical and laboratory evaluation of drug-induced thrombocytopenia based on the description of two patients, one with ceftriaxone-induced thrombocytopenia and the other with heparin-induced thrombocytopenia. Drug-induced thrombocytopenia is rare, but it is an important consideration in the differential diagnosis of thrombocytopenic patients. The aetiology is often not recognised or is ascribed to other complications such as disseminated intravascular coagulation (DIC) or immune thrombocytopenia (ITP). Misdiagnosis or late recognition may result in morbidity and mortality due to bleeding or thrombotic complications.

Molecular aspects of drug resistance in parasitic helminths.

Parasitic helminths (worms) cause serious infectious diseases in humans and animals. As control of these infections relies mostly on chemotherapeutics, the anthelmintics, resistance has developed against most of these drugs in several parasite species. These resistant parasites are being used to elucidate the molecular mechanisms of drug action.