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Background: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to non-beta-lactam antimicrobials poses a significant challenge in treating severe MRSA bloodstream infections. This study explores resistance development and mechanisms in MRSA isolates, especially after the first dalbavancin-resistant MRSA strain in our hospital in 2016. Methods: This study investigated 55 MRSA bloodstream isolates (02/2015–02/2021) from the University Hospital of the Medical University of Vienna, Austria. The MICs of dalbavancin, linezolid, and daptomycin were assessed. Two isolates (16–33 and 19–362) resistant to dalbavancin were analyzed via whole-genome sequencing, with morphology evaluated using transmission electron microscopy (TEM). Results: S.aureus BSI strain 19–362 had two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene. Isolate 16–33 had a 534 bp deletion in the DHH domain of GdpP and a SNV in pbp2 (p.G146R). Both strains had mutations in the rpoB gene, but at different positions. TEM revealed significantly thicker cell walls in 16–33 (p < 0.05) compared to 19–362 and dalbavancin-susceptible strains. None of the MRSA isolates showed resistance to linezolid or daptomycin. Conclusion: In light of increasing vancomycin resistance reports, continuous surveillance is essential to comprehend the molecular mechanisms of resistance in alternative MRSA treatment options. In this work, two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene were newly identified as possible causes of dalbavancin resistance. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) testing is generally available in most care centres, but it is rarely performed because clinicians' seldom suspect RSV to be the underlying pathogen in adults with respiratory disease. Here, we evaluate the impact of broad combined influenza/RSV testing on the clinical practice. Overall, 103 patients were tested positively for RSV. Our study indicates that positively tested patients were mostly of advanced age and suffered from chronic diseases. Mortality was significant in our cohort and higher in patients with advanced age. Further, we report a significant increase in detected RSV cases but also in detection rate. Together, these findings suggest that implementation of a combined influenza/RSV testing led to a significant increase in detection rate, supported clinicians establishing the correct diagnosis and allowed a safe and controlled handling of RSV patients. [ABSTRACT FROM AUTHOR]

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Background: Cystic echinococcosis (CE) is a globally occurring zoonosis, whereas alveolar echinococcosis (AE) is endemic only in certain parts of the Northern Hemisphere. The socioeconomic impact of human echinococcosis has been shown to be considerable in highly endemic regions. However, detailed data on direct healthcare-related costs associated with CE and AE are scarce for high income countries. The aim of this study was to evaluate direct costs of human disease caused by CE and AE in Austria. Methods: Clinical data from a registry maintained at a national reference center for echinococcosis at the Medical University of Vienna were obtained for the years 2012–2014. These data were used in conjunction with epidemiological data from Austria’s national disease reporting system and diagnostic reference laboratory for echinococcosis to assess nationwide costs attributable to CE and AE. Results: In Austria, total modelled direct costs were 486,598€ (95%CI 341,825€ – 631,372€) per year for CE, and 683,824€ (95%CI 469,161€ - 898,486€) for AE. Median costs per patient with AE from diagnosis until the end of a 10-year follow-up period were 30,832€ (25th– 75th percentile: 23,197€ - 31,220€) and 62,777€ (25th– 75th percentile: 60,806€ - 67,867€) for inoperable and operable patients, respectively. Median costs per patients with CE from diagnosis until end of follow-up after 10 years were 16,253€ (25th– 75th percentile: 8,555€ - 24,832€) and 1,786€ (25th– 75th percentile: 736€ - 2,146€) for patients with active and inactive cyst stages, respectively. The first year after inclusion was the most cost-intense year in the observed period, with hospitalizations and albendazole therapy the main contributors to direct costs. Conclusions: This study provides detailed information on direct healthcare-related costs associated with CE and AE in Austria, which may reflect trends for other high-income countries. Surgery and albendazole therapy, due to surprisingly high drug prices, were identified as important cost-drivers. These data will be important for cost-effectiveness analyses of possible prevention programs. [ABSTRACT FROM AUTHOR]

Background. Fosmidomycin-piperaquine is being developed as nonartemisinin-based combination therapy to meet the challenge of emerging artemisinin resistance. Methods. The study was a phase 2, single-arm, proof-of-concept study of the efficacy, tolerability, and safety of fosmidomycin- piperaquine for the treatment of uncomplicated Plasmodium falciparum monoinfection in Gabon. Adults and children of both sexes with initial parasite counts between 1000 and 150 000/µL received oral treatment with fosmidomycin (twice daily doses of 30 mg/ kg) and piperaquine (once daily dose of 16 mg/kg) for 3 days and followed-up for 63 days. The primary efficacy endpoint was the per-protocol polymerase chain reaction (PCR)-corrected day 28 adequate clinical and parasitological response (ACPR). Results. One hundred patients were enrolled. The PCR-corrected day 28 ACPR rate was 83/83, or 100% (95% confidence interval, 96-100). Fourteen patients had asexual parasitaemia between day 28 and day 63; all were typed by PCR as new infections. Fosmidomycin-piperaquine therapy led to rapid parasite clearance (median, 36 hours; interquartile range [IQR], 6-60) and fever clearance time (median, 12 hours; IQR, 6-48). The electrocardiogram assessments showed 2 patients with prolonged QT interval >500 msec following study drug administration. The majority of adverse events affected the gastrointestinal and respiratory tracts and were transient and mild to moderate in severity. Conclusions. This is the first report of the use of the combination fosmidomycin-piperaquine. The combination appeared to have high efficacy and be safe and well tolerated despite observed transient changes in electrocardiogram with prolongation of the QT interval. Clinical Trials Registration. NCT02198807. [ABSTRACT FROM AUTHOR]

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)-the first-line anthelminthic drug for medical treatment of CE-is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = −0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 μg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 μg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 μg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts ( β = −17.2 μg/L/cm; 95th CI, −35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis. [ABSTRACT FROM AUTHOR]

Background: Cerebral malaria remains a medical emergency with high mortality. Hypo-perfusion due to obstructed blood vessels in the brain is thought to play a key role in the pathophysiology of cerebral malaria leading to neurological impairment, long-term neuro-cognitive sequelae and, potentially, death. Due to the rapid reversibility of vascular obstruction caused by sequestered Plasmodium falciparum, it is hypothesized that mild medical hypothermia—a standard intervention for other medical emergencies—may improve clinical outcome. This preclinical in vitro study was performed to assess the impact of mild hypothermia on parasite growth and the intrinsic activity of anti-malarials drugs. Methods: Three laboratory-adapted clones and two clinical isolates were used for growth assays and standardized drug sensitivity assessments using the standard HRP2 assay. All assays were performed in parallel under normothermic (37 °C), mild hypothermic (32 °C), and hyperthermic (41 °C) conditions. Results: Parasite growth was higher under standard temperature condition than under hypo- or hyperthermia (growth ratio 0.85; IQR 0.25-1.06 and 0.09; IQR 0.05-0.32, respectively). Chloroquine and mefloquine had comparable in vitro activity under mild hypothermic conditions (ratios for IC50 at 37 °C/32 °C: 0.88; 95 % CI 0.25-1.50 and 0.86; 95 % CI 0.36-1.36, respectively) whereas dihydroartemisinin was more active under mild hypothermic conditions (ratio for IC50 at 37 °C/32 °C: 0.27; 95 % CI 0.19-0.27). Hyperthermia led by itself to almost complete growth inhibition and precluded further testing of the activity of anti-malarial drugs. Conclusion: This preclinical evaluation demonstrates that mild medical hypothermia inhibits in vitro growth of P. falciparum and enhances the pharmacodynamic activity of artemisinin derivatives. Based on these preclinical pharmacodynamic data, the further clinical development of mild medical hypothermia as adjunctive treatment to parenteral artesunate for cerebral malaria is warranted. [ABSTRACT FROM AUTHOR]

Rapid and reliable diagnosis is essential in the fight against malaria, which remains one of the most deadly infectious diseases in the world. In the present study we take advantage of a droplet microfluidics platform combined with a novel and user-friendly biosensor for revealing the main malaria-causing agent, the Plasmodium falciparum (P. falciparum) parasite. Detection of the parasite is achieved through detection of the activity of a parasite-produced DNA-modifying enzyme, topoisomerase I (pfTopoI), in the blood from malaria patients. The assay presented has three steps: (1) droplet microfluidics-enabled extraction of active pfTopoI from a patient blood sample; (2) pfTopoI-mediated modification of a specialized DNA biosensor; (3) readout. The setup is quantitative and specific for the detection of Plasmodium topoisomerase I. The procedure is a considerable improvement of the previously published Rolling Circle Enhanced Enzyme Activity Detection (REEAD) due to the advantages of involving no signal amplification steps combined with a user-friendly readout. In combination these alterations represent an important step towards exploiting enzyme activity detection in point-of-care diagnostics of malaria. [ABSTRACT FROM AUTHOR]

Objectives: Streptococcus agalactiae constitutes an important cause of neonatal infections in sub-Saharan Africa. Sulfadoxine/pyrimethamine-the current intermittent preventive treatment of malaria in pregnancy (IPTp)-has proven in vitro activity against group B Streptococcus (GBS). Because of specific drug resistance to sulfadoxine/pyrimethamine, mefloquine-an antimalarial without in vitro activity against GBS-was evaluated as a potential alternative. This study assessed the potential of sulfadoxine/pyrimethamine-IPTp to reduce the prevalence of GBS colonization in pregnant women in Gabon when compared with the inactive control mefloquine-IPTp. Methods: Pregnant women participating in a randomized controlled clinical trial evaluating mefloquine-IPTp versus sulfadoxine/pyrimethamine-IPTp were invited to participate and recto-vaginal swabs were collected at delivery for detection of GBS colonization. Prevalence of recto-vaginal GBS colonization was compared between IPTp regimens and risk factor and birth outcome analyses were computed. Results: Among 549 participants, 106 were positive for GBS colonization at delivery (19%; 95% CI=16%-23%). Prevalence of maternal GBS colonization showed no significant difference between the two IPTp regimens (mefloquine-IPTp: 67 of 366 women=18%; 95% CI=14%-22%; sulfadoxine/pyrimethamine-IPTp: 39 of 183 women=21%; 95% CI=15%-27%). Risk factor analysis for GBS colonization demonstrated a significant association with illiteracy (adjusted OR=2.03; 95% CI=1.25-3.30). GBS colonization had no impact on birth outcome, anaemia at delivery, gestational age and birth weight. Conclusions: Sulfadoxine/pyrimethamine did not reduce colonization rates when used as the IPTp drug during pregnancy. Illiteracy was associated with GBS colonization. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to evaluate adherence and causes for non-adherence to antihypertensive therapy in Austrian patients. A special focus was placed on social parameters and behavioural theories. Methods: Patients were invited via advertisements in community pharmacies in Austria to complete an online survey. Inclusion criteria were an age of 18 years or older, a diagnosis of arterial hypertension and a current prescription of antihypertensive medication. Adherence was measured by the four-item Morisky scale. Non-adherence was defined by at least one point in the Morisky scale. Several demographic, social and behavioural parameters were analysed as potential co-variables associated with adherence. Results: A total of 323 patients completed the online survey, of which 109 (33.7 %) met the criteria for non-adherence. In a multivariable model, self-efficacy and age were associated with adherence, whereas intention and barriers were linked to non-adherence; 56 patients (17.3 %) were classified as intentionally non-adherent. Conclusion: This study demonstrates that non-adherence affects an important proportion of patients in the treatment of arterial hypertension. Young age was a particularly important risk factor for non-adherence, and this patient population is, therefore, in need of special attention. Modifiable risk factors were identified that could help improving the treatment of arterial hypertension and potentially other chronic conditions. [ABSTRACT FROM AUTHOR]

Background Children below the age of six months suffer less often from malaria than older children in sub-Saharan Africa. This observation is commonly attributed to the persistence of foetal haemoglobin (HbF), which is considered not to permit growth of Plasmodium falciparum and therefore providing protection against malaria. Since this concept has recently been challenged, this study evaluated the effect of HbF erythrocytes and maternal plasma on in vitro parasite growth of P. falciparum in Central African Gabon. Methods Umbilical cord blood and peripheral maternal blood were collected at delivery at the Albert Schweitzer Hospital in Gabon. Respective erythrocyte suspension and plasma were used in parallel for in vitro culture. In vitro growth rates were compared between cultures supplemented with either maternal or cord erythrocytes. Plasma of maternal blood and cord blood was evaluated. Parasite growth rates were assessed by the standard HRP2-assay evaluating the increase of HRP2 concentration in Plasmodium culture. Results Culture of P. falciparum using foetal erythrocytes led to comparable growth rates (mean growth rate =4.2, 95% CI: 3.5 - 5.0) as cultures with maternal red blood cells (mean growth rate =4.2, 95% CI: 3.4 - 5.0) and those from non-malaria exposed individuals (mean growth rate =4.6, 95% CI: 3.8 - 5.5). Standard in vitro culture of P. falciparum supplemented with either maternal or foetal plasma showed both significantly lower growth rates than a positive control using non-malaria exposed donor plasma. Conclusions These data challenge the concept of HbF serving as intrinsic inhibitor of P. falciparum growth in the first months of life. Erythrocytes containing HbF are equally permissive to P. falciparum growth in vitro. However, addition of maternal and cord plasma led to reduced in vitro growth which may translate to protection against clinical disease or show synergistic effects with HbF in vivo. Further studies are needed to elucidate the pathophysiology of innate and acquired protection against neonatal malaria. [ABSTRACT FROM AUTHOR]

Background: Cancer patients are at high risk of developing venous thromboembolism (VTE). Red cell distribution width (RDW) has been reported to be associated with arterial and venous thrombosis and mortality in several diseases. Here, we analyzed the association between RDW and other red blood cell (RBC) parameters with risk of VTE and mortality in patients with cancer. Methods: RBC parameters were measured in 1840 patients with cancers of the brain, breast, lung, stomach, colon, pancreas, prostate, kidney; lymphoma, multiple myeloma and other tumor sites, that were included in the Vienna Cancer and Thrombosis Study (CATS), which is an ongoing prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Primary study outcome is occurrence of symptomatic VTE and secondary outcome is death during a maximum follow-up of 2 years. Results: During a median follow-up of 706 days, 131 (7.1%) patients developed VTE and 702 (38.2%) died. High RDW (>16%) was not associated with a higher risk of VTE in the total study cohort; in competing risk analysis accounting for death as competing variable the univariable subhazard ratio (SHR) was 1.34 (95% confidence interval [CI]: 0.80–2.23, p = 0.269). There was also no significant association between other RBC parameters and risk of VTE. High RDW was associated with an increased risk of mortality in the total study population (hazard ratio [HR, 95% CI]: 1.72 [1.39–2.12], p<0.001), and this association prevailed after adjustment for age, sex, hemoglobin, leukocyte and platelet count (HR [95% CI]: 1.34 [1.06–1.70], p = 0.016). Conclusions: RDW and other RBC parameters were not independently associated with risk of VTE in patients with cancer and might therefore not be of added value for estimating risk of VTE in patients with cancer. We could confirm that high RDW is an independent predictor of poor overall survival in cancer. [ABSTRACT FROM AUTHOR]

Background: Bacteraemia is a frequent and severe condition with a high mortality rate. Despite profound knowledge about the pre-test probability of bacteraemia, blood culture analysis often results in low rates of pathogen detection and therefore increasing diagnostic costs. To improve the cost-effectiveness of blood culture sampling, we computed a risk prediction model based on highly standardizable variables, with the ultimate goal to identify via an automated decision support tool patients with very low risk for bacteraemia. Methods: In this retrospective hospital-wide cohort study evaluating 15,985 patients with suspected bacteraemia, 51 variables were assessed for their diagnostic potency. A derivation cohort (n = 14.699) was used for feature and model selection as well as for cut-off specification. Models were established using the A2DE classifier, a supervised Bayesian classifier. Two internally validated models were further evaluated by a validation cohort (n = 1,286). Results: The proportion of neutrophile leukocytes in differential blood count was the best individual variable to predict bacteraemia (ROC-AUC: 0.694). Applying the A2DE classifier, two models, model 1 (20 variables) and model 2 (10 variables) were established with an area under the receiver operating characteristic curve (ROC-AUC) of 0.767 and 0.759, respectively. In the validation cohort, ROC-AUCs of 0.800 and 0.786 were achieved. Using predefined cut-off points, 16% and 12% of patients were allocated to the low risk group with a negative predictive value of more than 98.8%. Conclusion: Applying the proposed models, more than ten percent of patients with suspected blood stream infection were identified having minimal risk for bacteraemia. Based on these data the application of this model as an automated decision support tool for physicians is conceivable leading to a potential increase in the cost-effectiveness of blood culture sampling. External prospective validation of the model's generalizability is needed for further appreciation of the usefulness of this tool. [ABSTRACT FROM AUTHOR]

The article reports on a study which investigated the epidemiology of loiasis in a cohort of pregnant women participating in a drug trial for preventing malaria during pregnancy. Topics discussed include the prevalence of loaiais, the characteristics of Loa loa infection as well as the microfilarial invasion of the placenta. The limitations of the study are explored.