Empirical treatment of lower urinary tract infections in the face of spreading multidrug resistance: in vitro study on the effectiveness of nitroxoline.

The spread of antimicrobial resistance challenges the empirical treatment of urinary tract infections (UTIs). Among others, nitrofurantoin is recommended for first-line treatment, but acceptance among clinicians is limited due to chronic nitrofurantoin-induced lung toxicity and insufficient coverage of Enterobacteriaceae other than Escherichia coli. Nitroxoline appears to be an alternative to nitrofurantoin owing to its favourable safety profile, however data on its current in vitro susceptibility are sparse. In this study, susceptibility to nitroxoline was tested against 3012 urinary clinical isolates (including multidrug-resistant bacteria and Candida spp.) by disk diffusion test and/or broth microdilution. At least 91% of all Gram-negatives (n = 2000), Gram-positives (n = 403) and yeasts (n = 132) had inhibition zone diameters for nitroxoline ≥18 mm. Except for Pseudomonas aeruginosa, nitroxoline MIC90 values were ≤16 mg/L and were 2- to >16-fold lower compared with nitrofurantoin. In extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus (MRSA), MIC90 values of nitroxoline were two-fold higher compared with non-ESBL-producing enterobacteria and methicillin-susceptible S. aureus (MSSA). The in vitro efficacies of nitroxoline and nitrofurantoin against ATCC strains of E. coli, Enterococcus faecalis and Proteus mirabilis were compared by time-kill curves in Mueller-Hinton broth and artificial urine. Nitroxoline was non-inferior against E. coli, P. mirabilis and E. faecalis in artificial urine. In conclusion, nitroxoline showed a broad antimicrobial spectrum, with inhibition zone diameters and MICs of nitroxoline well below the EUCAST breakpoint for E. coli for most organisms, and thus may also be a target for therapy of uncomplicated UTIs.

Study on the utility of a statewide counselling programme for improving mortality outcomes of patients with Staphylococcus aureus bacteraemia in Thuringia (SUPPORT): a study protocol of a cluster-randomised crossover trial.

INTRODUCTION: Staphylococcus aureus bacteraemia (SAB) is a frequent infection with high mortality rates. It requires specific diagnostic and therapeutic management such as prolonged intravenous administration of antibiotics and aggressive search for and control of infectious sources. Underestimation of disease severity frequently results in delayed or inappropriate management of patients with SAB leading to increased mortality rates. According to observational studies, patient counselling by infectious disease consultants (IDC) improves survival and reduces the length of hospital stay as well as complication rates. In many countries, IDC are available only in some tertiary hospitals. In this trial, we aim to demonstrate that the outcome of patients with SAB in small and medium size hospitals that do not employ IDC can be improved by unsolicited ID phone counselling. The SUPPORT trial will be the first cluster-randomised controlled multicentre trial addressing this question. METHODS AND ANALYSIS: SUPPORT is a single-blinded, multicentre interventional, cluster-randomised, controlled crossover trial with a minimum of 15 centres that will include 250 patients with SAB who will receive unsolicited IDC counselling and 250 who will receive standard of care. Reporting of SAB will be conducted by an electronic real-time blood culture registry established for the German Federal state of Thuringia (ALERTSNet) or directly by participating centres in order to minimise time delay before counselling. Mortality, disease course and complications will be monitored for 90 days with 30-day all-cause mortality rates as the primary outcome. Generalised linear mixed modelling will be used to detect the difference between the intervention sequences. We expect improved outcome of patients with SAB after IDC. ETHICS AND DISSEMINATION: We obtained ethics approval from the Ethics committee of the Jena University Hospital and from the Ethics committee of the State Chamber of Physicians of Thuringia. Results will be published in a peer-reviewed journal and additionally disseminated through public media. TRIAL REGISTRATION NUMBER: DRKS00010135.

Effect of pre-operative octenidine nasal ointment and showering on surgical site infections in patients undergoing cardiac surgery.

OBJECTIVE: To evaluate the effect of pre-operative octenidine (OCT) decolonization on surgical site infection (SSI) rates. DESIGN: Before-and-after cohort study. PATIENTS: Patients undergoing an elective isolated coronary artery bypass graft (CABG) procedure: control group (1st January to 31st December 2013), N=475; intervention group (1st January to 31st December 2014), N=428. INTERVENTIONS: The intervention consisted of nasal application of OCT ointment three times daily, beginning on the day before surgery, and showering the night before and on the day of surgery with OCT soap. RESULTS: A median sternotomy was performed in 805 (89.1%) patients and a minimally invasive direct coronary artery bypass procedure was performed in 98 (10.9%) patients. Overall, there was no difference in SSI rates between the control and intervention groups (15.4% vs 13.3%, P=0.39). The rate of harvest site SSIs was significantly lower in patients in the intervention group (2.5% vs 0.5%, P=0.01). Patients who had undergone a median sternotomy in the intervention group had a significantly lower rate of organ/space sternal SSIs (1.9% vs 0.3%, P=0.04). However, there was a trend towards an increased rate of deep incisional sternal SSIs (1.2% vs 2.9%, P=0.08). Multi-variate analysis did not identify a significant protective effect of the intervention (odds ratio 0.79, 95% confidence interval 0.53-1.15, P=0.27). CONCLUSIONS: Pre-operative decolonization with OCT did not reduce overall SSI rates in patients undergoing an elective isolated CABG procedure, but significantly decreased harvest site and organ/space sternal SSIs. Randomized controlled trials, including controlled patient adherence to the intervention, are required to confirm these observations and to determine the clinical utility of OCT in pre-operative decolonization.

Predictors for and coverage of influenza vaccination among HIV-positive patients: a cross-sectional survey.

OBJECTIVES: Influenza vaccination is recommended for HIV-infected patients, but limited data about vaccination rates are available. The aim of this study was to evaluate the coverage of and predictors for influenza vaccination among HIV-positive patients. METHODS: All HIV-positive patients who visited the HIV out-patient department of the University Hospital of Vienna, Austria, between June and August 2015 were asked to participate in this survey by completing a questionnaire. RESULTS: A total of 455 HIV-positive patients completed a questionnaire, with 359 male and 96 female participants with a mean age of 46 years. The influenza vaccination rate for the previous season (2014/2015) was 11.9% [n = 54/455; 95% confidence interval (CI) 9.2-15.2%]. Older age was significantly associated with a positive influenza vaccination status. Obtaining information through a medical consultation or receiving a direct recommendation for vaccination by a physician had a significant impact on vaccination behaviour. The probability of being vaccinated against influenza was about 13 times higher among patients who received a recommendation for vaccination by their family physician or by their HIV specialist (P < 0.001). Important reasons for declining vaccination were fear of side effects (39%), not considering influenza as a severe disease (36%) and reasons related to HIV: 17% were worried that the vaccine could worsen the course of HIV infection and 16% believed vaccination would fail because of their compromised immune system. CONCLUSIONS: A low influenza vaccination rate of 11.9% was detected in this HIV-positive cohort. The most effective impact for a positive vaccination status was direct recommendation of the influenza vaccine by the attending physician.

Febrile patients admitted to remote hospitals in Northeastern Kenya: seroprevalence, risk factors and a clinical prediction tool for Q-Fever.

BACKGROUND: Q fever in Kenya is poorly reported and its surveillance is highly neglected. Standard empiric treatment for febrile patients admitted to hospitals is antimalarials or penicillin-based antibiotics, which have no activity against Coxiella burnetii. This study aimed to assess the seroprevalence and the predisposing risk factors for Q fever infection in febrile patients from a pastoralist population, and derive a model for clinical prediction of febrile patients with acute Q fever. METHODS: Epidemiological and clinical data were obtained from 1067 patients from Northeastern Kenya and their sera tested for IgG antibodies against Coxiella burnetii antigens by enzyme-linked-immunosorbent assay (ELISA), indirect immunofluorescence assay (IFA) and quantitative real-time PCR (qPCR). Logit models were built for risk factor analysis, and diagnostic prediction score generated and validated in two separate cohorts of patients. RESULTS: Overall 204 (19.1 %, 95 % CI: 16.8-21.6) sera were positive for IgG antibodies against phase I and/or phase II antigens or Coxiella burnetii IS1111 by qPCR. Acute Q fever was established in 173 (16.2 %, 95 % CI: 14.1-18.7) patients. Q fever was not suspected by the treating clinicians in any of those patients, instead working diagnosis was fever of unknown origin or common tropical fevers. Exposure to cattle (adjusted odds ratio [aOR]: 2.09, 95 % CI: 1.73-5.98), goats (aOR: 3.74, 95 % CI: 2.52-9.40), and animal slaughter (aOR: 1.78, 95 % CI: 1.09-2.91) were significant risk factors. Consumption of unpasteurized cattle milk (aOR: 2.49, 95 % CI: 1.48-4.21) and locally fermented milk products (aOR: 1.66, 95 % CI: 1.19-4.37) were dietary factors associated with seropositivity. Based on regression coefficients, we calculated a diagnostic score with a sensitivity 93.1 % and specificity 76.1 % at cut off value of 2.90: fever >14 days (+3.6), abdominal pain (+0.8), respiratory tract infection (+1.0) and diarrhoea (-1.1). CONCLUSION: Q fever is common in febrile Kenyan patients but underappreciated as a cause of community-acquired febrile illness. The utility of Q fever score and screening patients for the risky social-economic and dietary practices can provide a valuable tool to clinicians in identifying patients to strongly consider for detailed Q fever investigation and follow up on admission, and making therapeutic decisions.

Should daptomycin-rifampin combinations for MSSA/MRSA isolates be avoided because of antagonism?

PURPOSE: There is increasing clinical evidence from observational studies, that combination therapy of daptomycin with rifampin is a valuable treatment option for biofilm-associated difficult to treat Staphylococcus aureus infections such as osteomyelitis, prosthetic joint infection and endocarditis. However, two studies analyzing a limited number of S. aureus isolates reported an antagonism of those two drugs questioning the benefit of this combination. METHODS: To estimate the frequency of this possible antagonism, we performed in vitro checkerboard assays on 58 consecutive clinical isolates of S. aureus (MSSA n = 9, MRSA n = 49). We determined the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI). All isolates were characterized by a microprobe array detecting 336 different genes/alleles to ensure their non-clonal origin. RESULTS: For all isolates, the FICI was between 1.00 and 1.25 indicating additive effects for the daptomycin/rifampin combination. Neither antagonism nor synergism as defined by the FICI was found for any of the isolates. CONCLUSION: Based on these data, there is no evidence to advise against the daptomycin/rifampin combination therapy.

[Vaccinations from the pulmonologist's point of view]. / Impfungen aus pneumologischer Sicht.

BACKGROUND: The best strategy for prevention of acute respiratory tract infections is primary prophylaxis against diseases preventable by vaccination. From the pulmonologist's point of view, vaccinations against pneumococci, influenza A and B viruses and Bordetella pertussis are of particular clinical relevance. OBJECTIVES: This review article discusses the disease burden of these pathogens and the recommendations for immunization in adults. CURRENT DATA: For immunization against pneumococci a less immunogenic but broad-spectrum 23-valent polysaccharide vaccine (PPV23) and a highly immunogenic 13-valent conjugate vaccine (PCV13) with a more narrow-spectrum are approved. A sequential vaccination with PCV13 followed by PPV23 is a new option in adults. In the US this vaccination strategy is recommended as routine vaccination for all adults over 65. In Germany sequential pneumococcal vaccination is proposed only in special indications such as patients with asplenia. Trivalent and quadrivalent split-virus vaccines are the standard vaccines against seasonal influenza in adults. The Standing Committee on Vaccinations (STIKO) recommends a yearly vaccination as standard over 60 and in indications for special risk groups (e.g. infants with underlying diseases, immunocompromised patients, chronically ill patients and pregnant women). For the primary prophylaxis of pertussis only an acellular vaccine is available. Neither vaccination nor a previous infection provide lifelong immunity; therefore, the STIKO recommends an additional booster vaccine for all adults. CONCLUSION: Vaccination against pneumococci, influenza A and B viruses as well as Bordetella pertussis are recommended as standard and in special indications for adults by the STIKO at the Robert Koch Institute. For selection of the various vaccines individual factors such as age, immune status, comorbidities and pregnancy have to be considered.

[Pneumococcal vaccination for prevention of pneumonia]. / Pneumonieprävention durch Pneumokokkenimpfung.

Aging of the immune system, so-called immunosenescence, is well documented as the cause of increased infection rates and severe, often complicated courses of infections in older adults. This is particularly true for pneumococcal pneumonia in older adults; therefore, the standing committee on vaccination of the Robert Koch Institute (STIKO) recommends a once only vaccination with 23-valent pneumococcal polysaccharide vaccine for all persons aged 60 years and over. Furthermore, the 13-valent pneumococcal conjugate vaccine is also available for administration in adults and is recommended by the STIKO for particular indications. The advantage of the pneumococcal conjugate vaccine is the additional induction of a T-cell dependent immune response that leads to good immunogenicity despite immunosenescence. Initial data from a recent randomized controlled trial, so far only presented at conferences, confirm that the conjugate vaccine also provides protection against non-bacteremic pneumococcal pneumonia, which is not provided by the polysaccharide vaccine. Thus, there are two vaccines for prevention of pneumococcal diseases: one with a broader range of serotype coverage but with an uncertain protection against non-bacteremic pneumococcal pneumonia and another one with less serotype coverage but more effective protection. Vaccination of children with the conjugate vaccine also leads to a rapid decrease of infections by the 13 vaccine serotypes even in adults because of herd protection effects. For prevention of pneumonia in older adults the additional benefit of a concurrent application of influenza vaccine and pneumococcal vaccine should be considered.

Ross River virus infection in a Thuringian traveller returning from south-east Australia.

Ross River virus (RRV) is an arbovirus transmitted by Aedes and Culex mosquitos. It is endemic in Australia, New Zealand and south-east Asia. Clinical manifestation rates in adults range about 20-40%. Symptoms involve arthralgia, myalgia, lymphadenopathy, fever and rash. Here we report a case of RRV in a Thuringian traveller who visited the urban South-East of Australia.

[Vaccinations in pneumology]. / Impfungen in der Pneumologie.

The best measure to prevent infections of the respiratory tract is the use of vaccines against important respiratory tract pathogens. The Standing Vaccination Committee at the Robert Koch Institute recommends not only children but also adult vaccination against pneumococci, influenza A/B and Bordetella pertussis, because of a high disease burden. In the present review the clinical significance and safety of those vaccinations as well as advantages and disadvantages of the currently available vaccines are discussed.

Predictors of clinical and microbiological treatment failure in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective cohort study in a region with low MRSA prevalence.

Invasive infections with methicillin-resistant Staphylococcus aureus (MRSA) have been associated with increased morbidity and mortality. The aim of the present study was to identify independent predictors of early mortality and treatment failure in patients with MRSA bacteraemia. A total of 132 adult patients who developed MRSA bacteraemia during hospitalization in the University Hospital of Vienna between 2000 and 2011 were screened and 124 were included in a retrospective cohort study. Patient demographics, source of bacteraemia, antimicrobial treatment and microbiological characteristics were evaluated. The 28-day crude mortality was 30.6%. Predictors of early mortality identified in multivariate Cox regression analysis included higher patient age (adjusted hazard ratio (aHR) 1.03, 95% CI 1.01-1.06, p 0.006), pneumonia (aHR 3.86, 95% CI 1.83-8.12, p <0.001) and failure to use MRSA active treatment (aHR 8.77, 95% CI 3.50-21.93, p <0.001). Ninety-one (73.4%) patients received glycopeptides as specific MRSA treatment. Of 63 patients treated with vancomycin, only 14 (22.6%) patients had aimed trough levels of 15-20 mg/L. Vancomycin MIC ≥2 mg/L was detected in 28.2% and was associated with glycopeptide pretreatment (p 0.001). All MRSA isolates were susceptible to linezolid and tigecycline. Persistent bacteraemia ≥7 days was documented in 25 (20.2%) patients. Independent determinants for microbiological eradication failure in patients with MRSA bacteraemia included endocarditis (p <0.001) and vancomycin trough levels (p 0.014), but not vancomycin MIC. Failure of clinical and microbiological eradication of MRSA among patients with MRSA bacteraemia was associated with clinical entity rather than with bacterial traits. Pharmacokinetic parameters seem to be decisive on microbiological and clinical success.

Effectiveness and immunogenicity of pneumococcal vaccination in splenectomized and functionally asplenic patients.

The aim of the present study was to evaluate the effectiveness and immunogenicity of pneumococcal vaccination in 145 splenectomized and 2 functionally asplenic patients receiving the 23-valent pneumococcal polysaccharide vaccine and/or the 7-valent pneumococcal conjugate vaccine (PCV7) during the period 1996-2009. Progression of underlying malignant disease was the main cause of death in 68% of the 53 deceased patients, followed by septic shock in 13.2%. Twelve of 94 living patients developed post-vaccine complications: pneumonia in 9 patients, otitis media in 2, pneumococcal sepsis in 4. Compared with a non-splenectomized non-vaccinated control group (n=34), splenectomized patients vaccinated in the previous five years (n=15) had significantly higher GMCs (P<0.05) against serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. Our data demonstrated strong serological responses in splenectomized patients within the first 5 years after pneumococcal vaccination by PCV7. Nevertheless, post-vaccine pneumococcal sepsis was still diagnosed in 3.3% of splenectomized survivors.

Activation of cerebral peroxisome proliferator-activated receptors γ (PPARγ) reduces neuronal damage in the substantia nigra after transient focal cerebral ischaemia in the rat.

AIM: The function of brain (neuronal) peroxisome proliferator-activated receptor(s) γ (PPARγ) in the delayed degeneration and loss of neurones in the substantia nigra (SN) was studied in rats after transient occlusion of the middle cerebral artery (MCAO). METHODS: The PPARγ agonist, pioglitazone, or vehicle was infused intracerebroventricularly over a 5-day period before, during and 5 days after MCAO (90 min). The neuronal degeneration in the SN pars reticularis (SNr) and pars compacta (SNc), the analysis of the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurones and the expression of the PPARγ in these neurones were studied by immunohistochemistry and immunofluorescence staining. The effects of PPARγ activation on excitotoxic and oxidative neuronal damage induced by glutamate and 6-hydroxydopamine were investigated in primary cortical neurones expressing PPARγ. RESULTS: Pioglitazone reduced the total and striatal infarct size, neuronal degeneration in both parts of the ipsilateral SN, the loss of TH-IR neurones in the SNc and increased the number of PPARγ-positive TH-IR neurones. Pioglitazone protected primary cortical neurones against oxidative and excitotoxic damage, prevented the loss of neurites and supported the formation of synaptic networks in neurones exposed to glutamate or 6-hydroxydopamine by a PPARγ-dependent mechanism. CONCLUSIONS: Activation of cerebral PPARγ confers neuroprotection after ischaemic stroke by preventing both, neuronal damage within the peri-infarct zone and delayed degeneration of neurones and neuronal death in areas remote from the site of ischaemic injury. Pioglitazone and other PPARγ agonists may be useful therapeutic agents to prevent progression of brain damage after cerebral ischaemia.

[Imaging techniques in the evaluation of primary large vessel vasculitides: Part 2: duplex ultrasound, positron emission tomography, computed tomography, and ophthalmological methods]. / Bildgebende Techniken zur Diagnostik primärer Grossgefässvaskulitiden : Teil 2: Duplexsonographie, Positronenemissionstomographie, Computertomographie und ophthalmologische Diagnostik.

This article focuses on the clinical application and technical aspects of imaging methods which are used alternatively or additionally to angiography or magnetic resonance imaging in patients with Takayasu's arteritis or giant cell arteritis. Providing a high spatial resolution, duplex ultrasound is particularly suitable for the evaluation of peripheral arteries. With the exception of cranial arteries, positron emission tomography as a whole body examination is the best imaging modality for the assessment of inflammatory activity. Computed tomography is used for angiographic examinations and enables evaluation of wall thickening in large arteries. It is the method of choice in the case of emergencies due to aortic aneurysm or dissection. In addition to angiographic and ultrasound techniques, ophthalmological methods comprise biomicroscopy, including funduscopy and optical coherence tomography.

New approach for the synthesis of [18F]fluoroethyltyrosine for cancer imaging: simple, fast, and high yielding automated synthesis.

O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) is one of the first (18)F-labeled amino acids for imaging amino acid metabolism in tumors. This tracer overcomes the disadvantages of [(18)F]fluorodeoxyglucose, [(18)F]FDG, and [(11)C]methionine, [(11)C]MET. Nevertheless, the various synthetic methods providing (18)F[FET] exhibit a big disadvantage concerning the necessity of two purification steps during the synthesis including HPLC purification, which causes difficulties in the automation, moderate yields, and long synthesis times >60 min. A new approach for the synthesis of [(18)F]FET is developed starting from 2-bromoethyl triflate as precursor. After optimization of the synthesis parameters including the distillation step of [(18)F]-FCH(2)CH(2)Br combined with the final purification of [(18)F]FET using a simple solid phase extraction instead of an HPLC run the synthesis [(18)F]FET could be significantly simplified, shortened, and improved. The radiochemical yield (RCY) was about 45% (not decay corrected and calculated relative to [(18)F]F(-) activity that was delivered from the cyclotron). Synthesis time was only 35 min from the end of bombardment (EOB) and the radiochemical purity was >99% at the end of synthesis (EOS). Thus, this simplified synthesis for [(18)F]FET offers a very good option for routine clinical use.

[Imaging techniques in the evaluation of primary large vessel vasculitides: part 1: angiography, interventional therapy, and magnetic resonance imaging]. / Bildgebende Techniken zur Diagnostik primärer Grossgefässvaskulitiden: Teil 1: Angiographie, interventionelle Therapie und Magnetresonanztomographie.

Imaging methods have become indispensable for the diagnosis and follow-up of giant cell arteritis and Takayasu's arterititis, in addition to physical examination and laboratory parameters. The choice of method is predominantly determined by clinical presentation and localization of the vascular territory to be examined. Furthermore, aspects of radiation protection, contrast media intolerance and other contraindications, as well as the varying costs of the different procedures need to be considered. This article reviews the clinical and morphological features of primary large vessel vasculitides which are fundamental to the identification of the disease and the assessment of inflammatory activity using imaging modalities. Angiography is the gold standard for the evaluation of stenotic lesions and can be combined with interventional treatment. Vessel wall thickening as a defining diagnostic criterion is outlined only by cross-sectional imaging. In addition to MR angiography, MRI techniques in particular enable vizualization of inflammatory processes in central as well as in peripheral arteries.

Simplified fast and high yielding automated synthesis of [18F]fluoroethylcholine for prostate cancer imaging.

(11)C- and (18)F-labeled choline analogues are successful tracers for prostate cancer imaging using positron emission tomography (PET). Due to the practical advantages of the longer-living radioisotope (18)F (t(1/2)=110 min) instead of (11)C (t(1/2)=20 min), [(18)F]fluoroethylcholine has been introduced to increase the opportunity of widespread clinical application. Nevertheless, the various known synthetic methods provide [(18)F]fluoroethylcholine for human use only in moderate overall yields of up to 30% so far. Here, a new simplified and high yield two-step-synthesis for [(18)F]fluoroethylcholine is described for potential clinical applications starting from 2-bromoethyl triflate (BETfO) using a modified, commercially available fully automated synthesis module. All synthesis parameters were subsequently optimized resulting in a total yield of 47+/-5% (not decay corrected) in only 40min. [(18)F]fluoroethylcholine could be obtained ready for human use as physiological solution after fixation on Sep-Pak Accell Light cartridges (waters((R))) and formulation with saline without the need of GC or HPLC purification. Radiochemical purity was >99.9% and no contamination of the sterile solution with chemicals used during the synthesis was detected.