Drug monitoring during ciprofloxacin prophylaxis of allogeneic stem cell transplant patients: associations with bacterial infections through a monocentric observational prospective study.

BACKGROUND: Bacterial infection ranks amongst the most common causes of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT). Although ciprofloxacin (CIP) prophylaxis is recommended, information on serum levels and clinical course is lacking. AIM: To investigate relationships between CIP level and failure of prophylaxis, particularly in terms of whether different pharmacokinetic (PK) indices [area under the concentration-time curve (AUC0-24h) vs single time samples] correlate differently with the outcome. METHODS: This prospective observational monocentric study was conducted at a 1500-bed teaching hospital (March 2018-March 2019), including 63 adult patients with alloHSCT receiving CIP prophylaxis. Blood samples were drawn at three sampling times (1, 6 and 12 h post-administration), twice per week, and measured via high performance liquid chromatography. The onset of febrile episodes (FEBs) indicated suspected failure of CIP prophylaxis. Positive blood cultures [bloodstream infection (BSI)] indicated confirmed failure of prophylaxis. FINDINGS: Seven of 63 patients died without significant differences in their average CIP levels compared with survivors, with patients experiencing FEBs (54/63) displaying a 13% [95% confidence interval (CI) 4-22%] lower probability of survival. In total, 225 sets of three values (triplets) were obtained from 58 primary CIP episodes. Triplets preceding BSI with Gram-negative bacteria (GNB-BSI) showed lower AUC0-24h on average, but similar single time sample indices. An AUC0-24h of ≤21.61 mgh/L resulted in four-fold higher odds of GNB-BSI (adjusted odds ratio 3.96, 95% CI 1.21-13.00). These results were independent of the administration route, patient demographics or sampling protocol deviations, indicating reduced CIP exposure upon GNB-BSI events. CONCLUSION: Monitoring CIP levels, using multiple sampling times, may be useful to reduce alloHSCT-associated bacterial infections. Further analysis is needed to investigate causality.

[Spontaneous remission of HCV infection after autologous stem cell transplantation in a 58-year-old man]. / Spontane Remission einer HCV-Infektion nach autologer Stammzelltransplantation bei einem 58-jährigen Patienten.

We report about a 58-year-old man with a chronic and treatment-naive hepatitis C virus (HCV) infection of genotype 1b, who had undergone autologous stem cell transplantation twice due to multiple myeloma. Subsequently, a high-level viremic reactivation of an occult hepatitis B virus (HBV) infection and also a reverse seroconversion was observed. Furthermore, a sustained spontaneous remission of HCV infection was seen. Antiviral therapy of HBV infection was initiated with tenofovir. Seven months after therapy initiation, the patient acquired an "anti-HBc-only" status. Antiviral therapy with tenofovir is still continued. The patient is in a good clinical condition.

[Ocular complications in a patient with dengue fever]. / Okuläre Komplikation bei einer Patientin mit Dengue-Fieber.

This article presents the spontaneous development of ocular complications in a case of dengue fever in a young tourist returning from Thailand. Despite severe inital clinical symptoms, a clear remission occurred after several months without any therapy; however, a partial atrophy of the optic nerve remained.

[B symptoms, lymphadenopathy and signs of systemic disease in a 21-year-old female]. / B-Symptomatik, Lymphknotenschwellung und Zeichen einer Systemerkrankung bei einer 21-Jährigen.

Sarcoidosis is a multi-systemic disease. A 21-year-old female patient was admitted to our department with lymphadenopathy, B symptoms, erythema nodosum and joint pain. Sarcoidosis showed a very atypical course, lacking any pulmonary symptoms or typical laboratory values. The diagnosis was finally confirmed histologically and thus various differential diagnoses such as microbiological and malignant diseases could be excluded. Oral steroid medication led to remission.

Aquaporins AQP1 and AQP4 in the cerebrospinal fluid of bacterial meningitis patients.

Aquaporins facilitate water transport through cell membranes. Due to the localization of AQP1 and AQP4 in the brain, they might contribute to cerebral edema. Our study aimed to determine whether AQP1 and AQP4 can be measured in cerebrospinal fluid (CSF), and whether there is a difference in AQP1 and AQP4 concentration between patients with bacterial meningitis (BM) and healthy controls. AQP1 and AQP4 concentrations in CSF from 35 patients with BM and 27 controls were analyzed using a commercial ELISA. The mean concentration of AQP1 in CSF was significantly elevated in patients with BM (BM: 3.8±3.4ng/ml, controls: 0.8±0.5ng/ml; p<0.001). AQP4 had a tendency to be increased, however the difference was not significant (BM: 1.8±3.1ng/ml, controls: 0.1±0.2ng/ml; p=0.092). AQP1 and AQP4 in CSF of BM patients were inversely correlated (r=-0.47, p=0.004). We could not find any other correlation between concentration of AQP1 or AQP4 in CSF and CSF leukocytes, lactate, protein, albumin CSF/serum ratio, age, a prediction score, an outcome score or the Glasgow Coma Scale at admission in patients with BM. Control patients displayed a correlation between AQP1 and the albumin CSF/serum ratio (r=0.390, p=0.040). This is the first study that detected AQP1 and AQP4 in CSF. Whether the significant elevation of AQP1 is due to a higher expression and subsequent shedding into CSF or a BM-induced cell damage needs to be determined.

The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis--the experience from one year of a university hospital's Lyme neuroborreliosis outpatients clinic.

BACKGROUND AND PURPOSE: Studies addressing the diagnostic relevance of anti-Borrelia burgdorferi (BB) serum antibodies in patients with non-specific symptoms and suspected chronic Lyme neuroborreliosis (LNB) are scarce. METHODS: In this study, we enrolled within 1 year 122 patients with suspected chronic LNB. One hundred and fourteen patients had previously tested positive for BB. All patients had previously received antibiotic treatment. Each patient received a clinical examination and measurement of BB-specific antibodies. The diagnosis of neuroborreliosis was made according to the national guidelines of the German Society of Neurology. Nine patients had acute borreliosis. One of the nine met the criteria of acute LNB. Of the remaining 113 patients, 85 patients underwent a lumbar puncture. Ten seronegative subjects without lumbar puncture were also considered. In 61.8% of these 95 patients the quality of life, of sleep, mood, and anxiety were assessed. RESULTS: Of 95 patients, 25.3% had symptoms without a somatic cause or evidence of borreliosis, 38.9% had a well-defined illness unrelated to BB infection, and 29.5% suffered from symptoms without a detectable somatic cause, displaying antibodies against BB. Six patients were grouped as post-LNB syndrome. Most common symptoms in all categories were arthralgia, myalgia, dysaesthesia, depressive mood and chronic fatigue. CONCLUSION: Patients with persistent symptoms with elevated serum antibodies against BB but without signs of cerebrospinal fluid inflammation require further diagnostic examinations to exclude ongoing infection and to avoid co-infections and other treatable conditions (e.g. autoimmune diseases). One patient with acute LNB, who was treated with ceftriaxone for 3 weeks suffered from LNB with new headaches and persistent symptoms 6 months later. These data should encourage further studies with new experimental parameters.

[Successful management of malaria tropica with 50% parasitaemia]. / Erfolgreiche Therapie einer Malaria tropica mit 50%-iger Parasitämie.

HISTORY: A 52-year-old woman was hospitalized with fever after a 3-week stay in tropical Kenya. Prophylaxis against malaria had been carried out with chloroquine. DIAGNOSIS: Falciparum malaria with 28% parasitaemia at first examination, rising to 50% after 3 hours. TREATMENT AND COURSE: Treatment with quinine dihydrochloride i.v. was initiated immediately after diagnosis. In addition, in view of increasing parasitemia of up to 50%, a partial exchange blood transfusion was carried out. No clinical signs of organ damage caused by malaria were observed. Because of a drop in blood pressure the patient needed catecholamine treatment for a short time. After decrease of the parasitemia the patient rapidly recovered and complete cure was achieved. CONCLUSION: Despite extremely high parasitemia the clinical signs were unusually mild. Standard treatment for severe malaria is intravenous administration of quinine. However, this drug is no longer sold in Germany, so that difficulty in obtaining it must be expected. A stockpiling of quinine is recommended for hospitals treating patients with malaria. Transfusion may improve outcome and must be considered if parasite counts are high or if there are clinical signs of malaria complications.

Autoantibodies to human manganese superoxide dismutase (MnSOD) in children with facial palsy due to neuroborreliosis.

AIM: Acute peripheral facial palsy due to neuroborreliosis is associated with a distal neuritis. In patients with Lyme disease the activity of antioxidant enzymes is decreased. With respect to the pathogenesis of neuroborreliosis, sera of children with acute peripheral facial palsy were investigated for autoantibodies against human manganese superoxide dismutase (MnSOD), which were suspected of raising the oxidative injury of infected tissues. METHODS: Sera of 20 children with acute peripheral palsy with neuroborreliosis, sera of 20 children with facial palsy without reference to Lyme disease and sera of 14 blood donors were tested for antibodies against human MnSOD using an ELISA. RESULTS: The concentrations of IgM autoantibodies to MnSOD of the children with neuroborreliosis were significantly increased, compared with the two control groups. CONCLUSIONS: We propose that the antibodies detected block the protective effects of MnSOD resulting in an increased oxidative inflammation.

Acute peripheral facial palsy in Lyme disease -- a distal neuritis at the infection site.

AIM: Children with acute peripheral facial palsy have often suffered tick bites and/or erythema migrans in the head/neck region on the same side. With respect to the pathogenesis of neuroborreliosis this topographical association was investigated in an animal model. METHODS: A Borrelia garinii strain, isolated from the CSF of a child with acute facial palsy, was injected in 9 rats intracutaneously in the right subauricular region. Infected rats were examined for clinical symptoms of Lyme disease, the spread of the spirochetes was investigated by PCR of necropsies (facial nerves, trigeminus nerves, heart, brain, skin) up to 47 days after infection. The nerve tissues were investigated by histology, immunohistochemistry and electron microscopy. RESULTS: None of the rats developed a facial palsy or other symptoms of Lyme disease. Borrelia DNA was found in the heart after 5 days and in the brain after 7 days of infection up to the end of investigation (47 days), as well as in the ipsilateral peripheral nerves after 7 to 33 days. Borrelia was detected by electron microscopy near endoneural vessels of the facial nerve. Peri-, epi-, and endoneural infiltrations of macrophages, plasma cells and B cells characterized an inflammation of the facial and trigeminus nerves ipsilateral to the infection site. CONCLUSION: An infection with Borrelia garinii in the subauricular region induces an ipsilateral neuritis of peripheral nerves. The particular vulnerability of the human facial nerve may be a result of its long intraosseus course. Thus, an inflammatory edema may injure the nerve in the canalis facialis.

["Peculiar infection" with fever, splenomegaly and acute kidney failure in a 24-year-old forestry student]. / "Eigentümliche Infektion" mit Fieber, Splenomegalie und akutem Nierenversagen bei einem 24-jährigen Forstwirtschaftsstudenten.

When confronted by the combination of initial high fever associated with intense malaise, splenomegaly, elevated levels of transaminases, and acute renal failure, consideration must be given to the differential diagnosis of leptospirosis even in Germany. As a rule, the diagnosis is confirmed by serological testing based on the titer curve. Renal involvement is frequent, but usually has a good prognosis, especially if jaundice has not developed. Treatment with doxycycline or penicillin can shorten the disease course and exudation, possibly also the nephritis, or hinder it.

Analysis of the tumour suppressor genes, FHIT and WT-1, and the tumour rejection genes, BAGE, GAGE-1/2, HAGE, MAGE-1, and MAGE-3, in benign and malignant neoplasms of the salivary glands.

AIMS: Molecular genetic changes involved in tumorigenesis and malignant transformation of human tumours are novel targets of cancer diagnosis and treatment. This study aimed to analyse the expression of putative tumour suppressor genes, FHIT and WT-1, and tumour rejection genes, BAGE, GAGE-1/2, MAGE-1, MAGE-3, and HAGE (which are reported to be important in human cancers), in salivary gland neoplasms. METHODS: Gene expression was analysed by reverse transcription polymerase chain reaction (RT-PCR) in normal salivary gland tissue and 44 benign and malignant salivary gland tumours. RESULTS: Aberrant FHIT transcripts were found in one of 38 normal salivary glands, three of 28 adenomas, and two of 16 carcinomas. WT-1 mRNA was detectable in two adenomas and five carcinomas. Immunoblotting showed that WT-1 mRNA expression was associated with raised WT-1 protein concentrations. RT-PCR for detection of BAGE, GAGE, and MAGE gene expression was positive in two adenomas and nine carcinomas, but negative in normal salivary gland tissue. HAGE mRNA was found in two normal salivary glands, 11 benign, and eight malignant tumours. CONCLUSIONS: FHIT mRNA splicing does not appear to be involved in the genesis of salivary gland neoplasms. The upregulation of WT-1 mRNA in tumours of epithelial/myoepithelial phenotype may imply a potential role of WT-1 in the genesis and/or cellular differentiation of these salivary gland tumours. The tumour rejection genes were more frequently, but not exclusively, expressed in malignant salivary gland tumours than in benign neoplasms, although none was suitable as a diagnostic marker of malignancy in salivary gland neoplasms.

Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies.

The authors investigated the frequency and quantity of intrathecal antibody synthesis against Chlamydia pneumoniae and the presence of C pneumoniae antigen in 25 children with MS. C pneumoniae genome was present in two children. In seven children an intrathecal synthesis of C pneumoniae antibodies was detected, representing only a small part of the total intrathecal immunoglobulin G, suggesting that this intrathecal synthesis is part of a polyspecific, oligoclonal immune response.

Genetic analysis of the human oncoprotein MDM2 in benign and malignant tumors of the salivary gland.

INTRODUCTION: Genetic alterations of oncogene MDM2 promote malignant transformation of several human tumors. In tumors of the salivary gland, however, the genetic status of MDM2 has not been evaluated so far. METHODS AND RESULTS: Benign and malignant tumors of the salivary gland (6 pleomorphic adenomas, 3 Warthin's tumors, 1 adenocarcinoma, 1 basal cell adenocarcinoma, 1 mucoepidermoid carcinoma, 3 acinic cell carcinomas, 2 adenoid cystic carcinoma, 1 squamous cell carcinoma) were analyzed by fluorescence-based PCR techniques and immunochemistry for MDM2 gene amplification, MDM2 gene expression, MDM2 gene mutation, MDM2 RNA splicing and MDM2 accumulation. Data show that all samples contained nonamplified MDM2 genes with nonmutant zinc finger regions. However, in two benign and two malignant samples, novel MDM2 mRNA splicing variant types 1 and 2 were detected. Furthermore, three malignant tumors revealed significant nuclear MDM2 accumulation. Correlation between levels of MDM2 mRNA and MDM2 protein could not be detected in the specimens. CONCLUSION: The present study suggests that MDM2 gene mutation and gene amplification do not contribute to MDM2 accumulation detected in malignant tumors of the salivary gland. However, the role of novel MDM2 splicing variants in MDM2 expression and malignant transformation must be elucidated further.

Reduced release of DNA from streptococcus pneumoniae after treatment with rifampin in comparison to spontaneous growth and ceftriaxone treatment.

In order to study the release of DNA from Streptococcus pneumoniae in vitro during spontaneous growth and treatment with ceftriaxone or rifampin, a semiquantitative polymerase chain reaction was used. During spontaneous growth, high concentrations of bacterial DNA were released. Exposure to 10 microg/ml of ceftriaxone decreased the DNA release, in median, by 19 times (P=0.03 vs. spontaneous growth). Treatment with 10 microg/ml of rifampin led to a reduction of DNA release, in median, by a factor of 49 (P=0.03 vs. ceftriaxone; six experiments performed on different days).

(99m)Tc-E-selectin binding peptide for imaging acute osteomyelitis in a novel rat model.

INTRODUCTION: In the present study, (99m)Tc-radiolabelled E-selectin binding peptide ((99m)Tc-IMP-178) was investigated for its potential to image acute pyogenic osteomyelitis in a new animal model. Intraindividual comparisons were performed using an irrelevant peptide ((99m)Tc-IMP-100) to demonstrate specificity. METHODS: An acute pyogenic osteomyelitis was induced by injecting 0.05 ml of 5% sodium morrhuate and 5x10(8) CFU of Staphylococcus aureus into the medullary cavity of the right tibia in 16 rats. Sixteen additional rats served as untreated controls. Whole-body imaging of pyogenic (n=4) and untreated (n=4) animals was performed continuously during the first 8 h (12 MBq i.v. of (99m)Tc-IMP-178 and (99m)Tc-IMP-100 for control), and one further single image was acquired after 16 h p.i. Tissue biodistribution studies were performed in 12 rats with an acute pyogenic osteomyelitis and in 12 untreated rats 1, 4 and 24 h after injection. Data of the histological/radiological and haematological investigations were obtained in all animals. RESULTS: Histopathologically, 15 of 16 treated rats (93%) developed an acute pyogenic osteomyelitis showing a major infiltration of the bone marrow by polymorphonuclear leukocytes as well as the formation of sequestra. Haematologically, the number of leukocytes increased by 100%, the lymphocytes by 11% and the granulocytes decreased by 39%. After i.v. injection, (99m)Tc-IMP-178 rapidly cleared from the body resulting in good scintigraphic target-to-background (T/B) ratios. The highest uptake of the tracer in the pyogenic bone was observed at 60 min p.i. (0.43+/-0.02% ID.g-1 for (99m)Tc-IMP-178 and 0.30+/-0.02% ID.g-1 for (99m)Tc-IMP-100), resulting in a higher osteomyelitis-to-healthy collateral ratio with T/B of 2.40+/-0.65 ((99m)Tc-IMP-178) compared with 1.85+/-0.48 ((99m)Tc-IMP-100). No adverse reactions were seen after injection of (99m)Tc-IMP-178. CONCLUSIONS: (99m)Tc-IMP-178 allows imaging of an acute osteomyelitic lesions, presumably by interaction of (99m)Tc-IMP-178 with activated upregulated vascular endothelium.

Fragments of human oncoprotein MDM2 reveal variable distribution within and on cultivated human hepatoma cells.

Human oncoprotein MDM2 reveals a MHC class I binding motif HMDM441 characterizing MDM2 as a potential tumor antigen. To analyze the distribution of MDM2 proteins containing this motif in liver cancer cells we produced rabbit anti-HMDM441 serum. The novel antibodies bound to an MDM2 fragment of approximately 55 kDa which lacked the N-terminal region and was present in lysate and supernatant of a human hepatoma cell line overexpressing normal 90-kDa MDM2. The 55-kDa fragment was detected in the cytoplasm and nucleoli and at the nuclear envelope of hepatoma cells, whereas normal hepatocytes were negative. Double-fluorescence labeling indicated that the MDM2 fragments and MHC class I molecules were coexpressed on the surface of the hepatoma cells. Further studies must clarify whether MDM2 fragments containing motif HMDM441 are novel targets of immunotherapy and immunochemical tumor diagnosis.

D- and L-lactate in rabbit and human bacterial meningitis.

Increased total CSF lactate is an important indicator differentiating bacterial from aseptic meningitis. Bacteria can produce D- and L-lactate; mammalian cells produce only L-lactate. We measured D- and L-lactate production of Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis and Escherichia coli in vitro, of S. pneumoniae and E. coli in rabbit experimental meningitis and of various common pathogens in CSF from patients with bacterial meningitis. Despite marked in vitro production of D-lactate by S. aureus (maximum: 4.59 mmol/l; i.e. 34.9% of total lactate), N. meningitidis (4.62 mmol/l; i.e. 98.1%) and E. coli (3.14 mmol/l; i.e. 97.2%), minimal amounts were measured in human S. aureus (0.38 mmol/l; i.e. 1.3% of total lactate) or N. meningitidis (0.28 mmol/l; i.e. 3.9%) and experimental E. coli meningitis (0.75 mmol/l; i.e. 4.4%). In only 9 of 54 human CSF samples did D-lactate exceed 0.15 mmol/l. S. pneumoniae did not produce significant amounts of D-lactate in vitro (maximum: 0.55 mmol/l; i.e. 2.7% of total lactate), in experimental meningitis (0.18 mmol/l; i.e. 3%) or in human cases of meningitis (0.28 mmol/l; i.e. 1.9%). In conclusion, increased total CSF lactate in meningitis consists mainly of L-lactate and originates predominantly from host cells. CSF D-lactate is of limited diagnostic value.

Primarily chronic and cerebrovascular course of Lyme neuroborreliosis: case reports and literature review.

As part of an ongoing study aiming to define the clinical spectrum of neuroborreliosis in childhood, we have identified four patients with unusual clinical manifestations. Two patients suffered from a primarily chronic form of neuroborreliosis and displayed only non-specific symptoms. An 11 year old boy presented with long standing symptoms of severe weight loss and chronic headache, while the other patient had pre-existing mental and motor retardation and developed seizures and failure to thrive. Two further children who presented with acute hemiparesis as a result of cerebral ischaemic infarction had a cerebrovascular course of neuroborreliosis. One was a 15 year old girl; the other, a 5 year old boy, is to our knowledge the youngest patient described with this course of illness. Following adequate antibiotic treatment, all patients showed substantial improvement of their respective symptoms. Laboratory and magnetic resonance imaging findings as well as clinical course are discussed and the relevant literature is reviewed.

Lower lipoteichoic and teichoic acid CSF concentrations during treatment of pneumococcal meningitis with non-bacteriolytic antibiotics than with ceftriaxone.

In the rabbit model of Streptococcus pneumoniae meningitis, treatment with rifabutin, quinupristin-dalfopristin, moxifloxacin and trovafloxacin led to smaller increases of the CSF concentrations of the pro-inflammatory cell wall components lipoteichoic and teichoic acids (LTA and TA) than did treatment with ceftriaxone. Low doses of moxifloxacin were associated with higher LTA and TA concentrations in CSF than were high doses.