Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

[Analyses of the relationship between the concentrations of essential trace elements in total mixed ration and faeces samples from Holstein Friesian dairy cows and the estimation of faeces reference values]. / Untersuchungen zum Zusammenhang der Konzentrationen an essenziellen Spurenelementen in totalen Misch­rationen- und Kotproben bei Holstein Friesian Milchkühen und Ableitung von Kotreferenzwerten.

INTRODUCTION: Undersupply and oversupply of dairy cows with essential trace elements should be avoided from the point of view of animal health and environmental pollution. The aim of the study was to proof the results faecal analyzes on the nutritional supply situation with essential trace elements in comparison to measurements from total mixed ration (TMR) analyses. Concentrations of iron (Fe), copper (Cu), zinc (Zn), Mangan (Mn), selenium (Se), cobalt (Co), molybdenum (Mo) were measured as representative multicentric random sample in 574 TMR, 600 pooled faecal and blood samples from dairy cows. Trace elements, Fe in 0 %, Se 18 %, Zn 43 %, Cu 52 %, Co 53 % and Mn 59 %, were within the target range. Undersupply was found in 0 to 8 % and an oversupply in 39 to 100 % of the TMR samples. The tolerance limit for Fe was exceeded in 11 % and for Mo in 13 %. The results indicate the need for optimized ration design. The trace element concentrations in the faecal samples varied over a wide range. Results of pooled faecal samples (n=10 per pool) corresponded closely with the mean values calculated from the individual samples (r2 > 0,9). Correlation between element concentrations in the TMR and faecal samples for Fe (r=0,687), Cu (r=0,675), Zn (r=0,635), Mn (r=0,656), Se (r=0,573), Co (r=0,795), and Mo (r=0,708) were highly significant. No correlations were detected between the element concentrations in the TMR and in the blood samples. The regression analyzes showed a highly significant linear adjustment of the measured value distribution around the regression lines over the entire value range including the zero point. Reference values were calculated for the faecal concentrations of Cu, Zn, Mn, Se and Co. Tolerance reference limits in the TMR were calculated for the faecal concentrations of Fe and Mo. The trace element concentrations in the TMR samples reflect the nutritional supply situation. Knowledge of the nutritional supply situation of the herd is of great importance for the stock management of dairy cow. Fecal sample analyzes can be used as an alternative to TMR examinations to assess the nutritional supply situation.

INTRODUCTION: Les sous-approvisionnements et les surapprovisionnements des vaches laitières en oligo-éléments essentiels doivent être évités du point de vue de la santé animale et de la pollution de l'environnement. L'objectif de cette étude était de vérifier la pertinence des analyses de fèces pour évaluer l'apport nutritionnel en oligo-éléments essentiels en les comparant aux valeurs mesurées dans les analyses de RTM (ration totale mélangée). Dans un échantillon aléatoire multicentrique représentatif, les concentrations de fer (Fe), de cuivre (Cu), de zinc (Zn), de manganèse (Mn), de sélénium (Se), de cobalt (Co) et de molybdène (Mo) ont été mesurées dans 574 échantillons de RTM et 600 échantillons de fèces regroupés de vaches laitières et des échantillons de sang ont été analysés. La plage cible pour la teneur en oligo-éléments dans la RTM a été respectée pour Fe à 0 %, Se à 18 %, Zn à 43 %, Cu à 52 %, Co à 53 % et Mn à 59 %. La plage de sous-alimentation a été constatée dans 0 à 8 % des échantillons de RTM, la plage de suralimentation dans 39 à 100 %. La limite de tolérance pour le Fe a été dépassée dans 11 %, pour le Mo dans 13 %. Ces résultats indiquent la nécessité d'optimiser les rations. Dans les échantillons de fèces, les concentrations en oligo-éléments variaient sur une large plage. Les résultats d'analyse des échantillons de fèces regroupés (n=10 par pool) correspondaient étroitement, avec une valeur r2 supérieure à 0,9, aux valeurs moyennes calculées à partir des échantillons individuels. Il y avait des corrélations très significatives entre les concentrations d'éléments dans les échantillons de RTM et de fèces pour Fe (r=0,687), Cu (r=0,675), Zn (r=0,635), Mn (r=0,656), Se (r=0,573), Co (r=0,795), et Mo (r=0,708). Aucune corrélation n'a pu être établie entre les concentrations d'éléments dans le RTM et dans les échantillons de sang. Les analyses de régression ont montré un ajustement linéaire hautement significatif de la distribution des valeurs mesurées autour de la droite de régression sur l'ensemble de la plage de valeurs, y compris le point zéro. Des valeurs de référence ont été calculées pour les concentrations de Cu, Zn, Mn, Se et Co dans les fèces. Pour les concentrations de Fe et Mo dans les fèces, des limites de référence ont été calculées pour les limites de tolérance dans la RTM. Les concentrations en oligo-éléments dans les échantillons de RTM reflètent la situation nutritionnelle. Pour le suivi des troupeaux de vaches laitières, il est très important de connaître l'état nutritionnel du troupeau. Les analyses d'échantillons de fèces peuvent être utilisées comme alternative aux analyses de RTM pour évaluer la situation nutritionnelle.

An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review.

Introduction: Protein binding can diminish the pharmacological effect of beta-lactam antibiotics. Only the free fraction has an antibacterial effect. The aim of this systematic literature review was to give an overview of the current knowledge of protein binding of cephalosporins in human body fluids as well as to describe patient characteristics influencing the level of protein binding. Method: A systematic literature search was performed in Embase, Medline ALL, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials with the following search terms: "protein binding," "beta-lactam antibiotic," and "body fluid." Only studies were included where protein binding was measured in humans in vivo. Results: The majority of studies reporting protein binding were performed in serum or plasma. Other fluids included pericardial fluid, blister fluid, bronchial secretion, pleural exudate, wound exudate, cerebrospinal fluid, dialysate, and peritoneal fluid. Protein binding differs between diverse cephalosporins and between different patient categories. For cefazolin, ceftriaxone, cefpiramide, and cefonicid a non-linear pattern in protein binding in serum or plasma was described. Several patient characteristics were associated with low serum albumin concentrations and were found to have lower protein binding compared to healthy volunteers. This was for critically ill patients, dialysis patients, and patients undergoing cardiopulmonary bypass during surgery. While mean/median percentages of protein binding are lower in these patient groups, individual values may vary considerably. Age is not likely to influence protein binding by itself, however limited data suggest that lower protein binding in newborns. Obesity was not correlated with altered protein binding. Discussion/Conclusion: Conclusions on protein binding in other body fluids than blood cannot be drawn due to the scarcity of data. In serum and plasma, there is a large variability in protein binding per cephalosporin and between different categories of patients. Several characteristics were identified which lead to a lower protein binding. The finding that some of the cephalosporins display a non-linear pattern of protein binding makes it even more difficult to predict the unbound concentrations in individual patients. Taken all these factors, it is recommended to measure unbound concentrations to optimize antibiotic exposure in individual patients. Systematic Review Registration: PROSPERO, identifier (CRD42021252776).

Prescription opioids among older adults: ten years of data across five countries.

BACKGROUND: Opioid use has increased globally in the recent decade. Although pain remains a significant problem among older adults, susceptibility to opioid-related harms highlights the importance of careful opioid therapy monitoring on individual and societal levels. We aimed to describe the trends of prescription opioid utilisation among residents aged ≥65 in all Nordic countries during 2009-2018. METHODS: We conducted cross-sectional measurements of opioid utilisation in 2009-2018 from nationwide registers of dispensed drugs in Denmark, Finland, Iceland, Norway, and Sweden. The measures included annual opioid prevalence, defined daily doses (DDDs) per 1000 inhabitants per day (DIDs), and morphine milligram equivalents (MMEs) per user per day. RESULTS: From 2009 to 2018, an average of 808,584 of adults aged ≥65 used opioids yearly in all five countries; an average annual prevalence of 17.0%. During this time period, the prevalence decreased in Denmark, Norway, and Sweden due to declining codeine and/or tramadol use. Iceland had the highest opioid prevalence in 2009 (30.2%), increasing to 31.7% in 2018. In the same period, DIDs decreased in all five countries, and ranged from 28.3 in Finland to 58.5 in Denmark in 2009, and from 23.0 in Finland to 54.6 in Iceland in 2018. MMEs/user/day ranged from 4.4 in Iceland to 19.6 in Denmark in 2009, and from 4.6 in Iceland to 18.8 in Denmark in 2018. In Finland, Norway, and Sweden, MMEs/user/day increased from 2009 to 2018, mainly due to increasing oxycodone utilisation. CONCLUSIONS: The stable or decreasing opioid utilisation prevalence among a majority of older adults across the Nordic countries coincides with an increase in treatment intensity in 2009-2018. We found large cross-national differences despite similarities across the countries' cultures and healthcare systems. For the aged population, national efforts should be placed on improving pain management and monitoring future trends of especially oxycodone utilisation.

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial.

BACKGROUND: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. METHODS: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. DISCUSSION: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? TRIAL REGISTRATION: EudraCT number: 2017-004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.

Oral amoxicillin and amoxicillin-clavulanic acid: properties, indications and usage.

BACKGROUND: Amoxicillin has been in use since the 1970s; it is the most widely used penicillin both alone and in combination with the ß-lactamase clavulanic acid. OBJECTIVES: In this narrative review, we re-examine the properties of oral amoxicillin and clavulanic acid and provide guidance on their use, with emphasis on the preferred use of amoxicillin alone. SOURCES: Published medical literature (MEDLINE database via Pubmed). CONTENT: While amoxicillin and clavulanic acid have similar half-lives, clavulanic acid is more protein bound and even less heat stable than amoxicillin, with primarily hepatic metabolism. It is also more strongly associated with gastrointestinal side effects, including Clostridium difficile infection, and, thus, in oral combination formulations, limits the maximum daily dose of amoxicillin that can be given. The first ratio for an amoxicillin-clavulanic acid combination was set at 4:1 due to clavulanic acid's high affinity for ß-lactamases; ratios of 2:1, 7:1, 14:1 and 16:1 are currently available in various regions. Comparative effectiveness data for the different ratios are scarce. Amoxicillin-clavulanic acid is often used as empiric therapy for many of the World Health Organization's Priority Infectious Syndromes in adults and children, leading to extensive consumption, when some of these syndromes could be handled with a delayed antibiotic prescription approach or amoxicillin alone. IMPLICATIONS: Using available epidemiological and pharmacokinetic data, we provide guidance on indications for amoxicillin versus amoxicillin-clavulanic acid and on optimal oral administration, including choice of combination ratio. More data are needed, particularly on heat stability, pharmacodynamic effects and emergence of resistance in 'real-world' clinical settings.

Pharmacokinetics and Target Attainment of Ceftobiprole in Asian and Non-Asian Subjects.

Ceftobiprole is a broad-spectrum cephalosporin. The objective of this study was to test the hypothesis that the pharmacokinetics (PK) and exposure of ceftobiprole in Asian subjects are similar to those in non-Asian subjects. Three approaches were followed. The first compared the individual PK estimates between the 2 subgroups derived from a population PK model previously built. Next, it was determined whether "Asian subject" was a significant covariate. Finally, a pharmacodynamic analysis was performed by comparing measures of exposure and target attainment. No significant differences were found between PK parameter estimates for Asian and non-Asian subjects, with median values (range) for clearance of 4.82 L/h (2.12-10.47) and 4.97 L/h (0.493-20.6), respectively (P = .736). "Asian subject" was not a significant covariate in the population PK model. There were no significant differences between the measures of exposure. The geometric mean ratio for the fAUC was 1.022 (90%CI, 0.91-1.15), indicating bioequivalence. Taking a target of 60% coverage of the dose interval, more than 90% of the population in both subgroups was adequately exposed. This analysis demonstrated that there are no PK or pharmacodynamic differences between Asian and non-Asian subjects for a ceftobiprole dose of 500 mg every 8 hours as a 2-hour infusion.

Dynamics of colistin and tobramycin resistance among Enterobacter cloacae during prolonged use of selective decontamination of the digestive tract.

Background: A high prevalence of colistin resistance among E. cloacae isolates in two intensive care units (ICU) (of 16 and 6 beds) using selective digestive decontamination (SDD) since 1990 instigated a retrospective and prospective investigation to quantify the role of clonal transmission. SDD is topical application of colistin and tobramycin and systemic use of cefotaxime during the first days of ICU-admission. Methods: Multi-resistant E. cloacae (MREb) was defined as ESBL production and/or tobramycin non-susceptibility and/or colistin non-susceptibility. Incidence of acquisition and prevalence of carriage with MREb was determined from microbiological culture results. Results: Colistin-resistant E. cloacae was first detected in November 2009 and carriage was demonstrated in 141 patients until October 2014. Mean incidence of MREb acquisition was 4.61 and 1.86 per 1000 days at risk in ICUs 1 and 2, respectively, and the mean monthly prevalence of MREb in both ICUs was 7.0 and 3.1%, respectively, without a discernible trend in time. Conversion rates from carriage of colistin-susceptible to resistant E. cloacae were 0.20 and 0.13 per 1000 patient days, respectively. Whole genome sequencing of 149 isolates revealed eight clusters, with the number of SNPs of the largest two clusters ranging between 0 and 116 for cluster 1 (n = 49 isolates), and 0 and 27 for cluster 2 (n = 36 isolates), among isolates derived between 2009 and 2014. Conclusions: This study demonstrates a stable low-level endemicity of MREb in two Dutch ICUs with prolonged use of SDD, which was characterized by the persistent presence of two clusters, suggesting incidental clonal transmission.

Extended-spectrum ß-lactamase (ESBL) polymerase chain reaction assay on rectal swabs and enrichment broth for detection of ESBL carriage.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL) screening and contact precautions on patients at high risk for ESBL carriage are considered important infection control measures. Since contact precautions are costly and may negatively impact patient care, rapid exclusion of ESBL carriage and therefore earlier discontinuation of contact precautions are desired. AIM: In the present study, the performance of an ESBL polymerase chain reaction (PCR) targeting blaCTX-M genes was evaluated as a screening assay for ESBL carriage. METHODS: Two methods were assessed: PCR performed directly on rectal swabs and PCR on enrichment broth after incubation overnight. The reference standard was culture of ESBL-producing Enterobacteriaceae on selective agar after overnight enrichment and confirmation by the combination disc diffusion method. Microarray was used for discrepancy analysis. A secondary analysis was performed to evaluate the added value of including a blaSHV target in the PCR. FINDINGS: A total of 551 rectal swabs from 385 patients were included, of which 28 (5%) were ESBL positive in culture. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 86%, 98%, 67%, and 99%, respectively, for PCR directly on swabs, and 96%, 98%, 75%, and 100%, respectively, for PCR on enrichment broth. Adding a blaSHV target to the assay resulted in a lower PPV without increasing the sensitivity and NPV. CONCLUSION: Screening for ESBL by PCR directly on rectal swabs has a high negative predictive value, is up to 48h faster than traditional culture and therefore facilitates earlier discontinuation of contact precautions, thereby improving patient care and saving valuable resources in the hospital.

Nitrofurantoin's efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials.

OBJECTIVES: Nitrofurantoin has been used for the prevention of urinary tract infection (UTI) for over 60 years. We conducted a systematic review and meta-analysis to assess its efficacy and safety in the prophylaxis of UTI. METHODS: We performed a systematic review of all controlled trials in humans assessing nitrofurantoin for UTI prophylaxis published from 1946 to 2015. We further reviewed population-level cohort studies evaluating nitrofurantoin's toxicity. Meta-analyses assessing efficacy and adverse events were conducted on controlled trials. RESULTS: Twenty-six controlled trials including 3052 patients fulfilled entry criteria for the systematic review and meta-analysis on efficacy and toxicity, and 16 population-level cohort studies were identified for review of toxicity. Overall quality was poor, with all studies at increased risk for various biases. When compared with no prophylaxis, nitrofurantoin is effective in the prevention of UTI (risk ratio 0.38 in favour of nitrofurantoin, 95% CI 0.30-0.48). Its prophylactic efficacy is superior to that of methenamine hippurate and comparable to that of other antibacterials. Compared with patients receiving other antibacterials, those receiving nitrofurantoin had an increased risk of 2.24 (95% CI 1.77-2.83) for a non-severe adverse effect. In all controlled trials, only one patient experienced a severe adverse effect (interstitial pneumonia). Cohort studies reported severe adverse effect frequencies of 0.02-1.5 per 1000 nitrofurantoin users. CONCLUSIONS: Nitrofurantoin is effective in the prevention of UTI. Its use may be associated with increased non-severe adverse effects; severe adverse effects occur infrequently. The risk of severe toxicity seems to increase with the duration of nitrofurantoin prophylaxis.

[Evaluation of sulfur status in dairy cows in Germany]. / Untersuchungen zur Schwefelversorgung von Milchkühen in Deutschland.

OBJECTIVE: Sulfur deficiency and toxicity in livestock is associated with decreased performance and diseases. However, little is known about the diagnostics of sulfur status in dairy herds. The objectives of this study were to describe sulfur concentrations in feed rations in German dairy herds, to assess associations between feed sulfur concentrations and health and milk yield, to determine suitable laboratory diagnostic methods of sulfur status, and to propose reference values for the assessment of sulfur status in different sample media. MATERIALS AND METHODS: Between 2006 and 2014, a total of 569 dairy herds were visited. Blood, urine, and hair samples were obtained from 10 animals per group in the groups -3 to 0, 0 to 1, 3 to 5, and 15 to 18 weeks post partum (p. p.) (farms > 200 animals) or -3 to 0, 0 to 5, and 6 to 20 weeks p. p. (farms ≤ 200 animals). Pooled whole blood, serum, plasma, urine, and hair samples (n = 5663) were analyzed by ICP-OES. The sulfur content of the total mixed ration (TMR) of the group -3 to 0 weeks p. p. was determined in a certified feed laboratory (n = 625). Data analyses were performed using ANOVA, Chi-squared test and Spearman-correlation. Reference values were determined using the 2.5% and 97.5% percentiles. RESULTS: Median sulfur concentration in the feed rations was 2.3 g/kg dry matter (DM). Deficiency (< 1.6 g/kg DM; 31% of farms) and oversupply (> 4.0 g/kg DM; 11% of farms) of sulfur in feed rations were regularly diagnosed. Sulfur deficiency was associated with reduced milk yield (p  <   0.001), retained placenta (OR  =   1.74; p  =  0.037), milk fever (OR  =  2.68; p  <  0.001) and silent heat (OR  = 2.56; p   =  0.014). Positive correlations were found between sulfur concentration in feed rations and sulfur content in urine (r  =  0.50), serum (r  =  0.17), plasma (r  =  0.18) and whole blood (r = 0.16). Reference values for sulfur diagnostics in dairy herds were proposed. CONCLUSION AND CLINICAL RELEVANCE: Diagnostics of sulfur status in dairy herds is relevant for veterinary practitioners and can be performed using TMR analysis and clinical laboratory parameters. Urine can be considered a short-term parameter, serum, plasma, and whole blood as intermediate parameters, and hair as a long-term parameter for the evaluation of the sulfur status.

Use of old antibiotics now and in the future from a pharmacokinetic/pharmacodynamic perspective.

Because of the increase in bacterial resistance to commonly used antibacterial drugs, old antibiotics are being 'revived' and, once again, are attracting interest. Many of these old antibiotics were approved long ago, in an era when there was no clear process for development, and requirements for efficacy to be demonstrated in rigorous clinical trials did not exist. At the time of these approvals, pharmacokinetic and pharmacodynamic principles were largely unknown, and did not inform the dose-finding process or recommendations for optimal usage. Indeed, the task of generating basic vital information for these old antibiotics remains to be performed. In this review, we provide a brief overview of the most essential data needed for dose justification and optimization. An overview of the shortage of data for selected old antibiotics illustrates the scope of the problem. In order to prevent harming patients with clinical decisions based on inadequate evidence, a redevelopment procedure for old antibiotics is urgently needed, including a regulatory framework.

Exposure to ceftobiprole is associated with microbiological eradication and clinical cure in patients with nosocomial pneumonia.

The percentage of the dosing interval that the non-protein-bound plasma concentration is above the MIC (%fT>MIC) for cephalosporins has been shown to correlate with microbiological outcomes in preclinical studies. However, clinical data are scarce. Using data from a randomized double-blind phase 3 clinical trial, we explored the relationship of ceftobiprole exposure with microbiological and clinical outcomes in patients with nosocomial pneumonia. The individual ceftobiprole exposure was determined for different pharmacokinetic (PK)/pharmacodynamic (PD) indices using individual pharmacokinetic data and a previously published population model. The MICs used in the analysis were the highest MICs for any bacterium cultured at baseline or the end of treatment (EOT). Outcomes were microbiological cure at EOT and clinical cure at test of cure (TOC). Multiple logistic regression (MLR) and classification and regression tree (CART) analyses were applied to determine the relationships among exposure, patient characteristics, and outcomes. MLR indicated that the %fT>MIC of ceftobiprole was the best predictor for both microbiological eradication and clinical cure. CART analysis showed a breakpoint value of 51.1% (n = 159; P = 0.0024) for clinical cure, whereas it was 62.2% (n = 251; P < 0.0001) for microbiological eradication. Other factors also contributed, particularly to clinical outcome. These included the difference between VAP and non-VAP patients, systemic inflammatory response syndrome (SIRS), creatinine clearance, the use of anti-Pseudomonas combination therapy, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. There is a strong correlation between microbiological eradication and clinical cure with exposure to ceftobiprole. The %fT>MIC required to result in a favorable clinical outcome is >51% of the dosing interval, which is in line with the values found for microbiological eradication, the comparator ceftazidime, and preclinical models.

In vitro evaluation of the performance of Granada selective enrichment broth for the detection of group B streptococcal colonization.

A broth for the screening of group B streptococcal (GBS) carriage during pregnancy is about to be introduced. Simulating conditions in everyday practice, we have compared the sensitivity of this Granada tube broth (GT) with that of classical Amies transport medium (AT) in vitro. A total of 1,485 GT and 1,485 AT were tested with 33 well-characterized GBS strains in three different concentrations, five different incubation times, and three different temperatures. After initial incubation at room temperature (RT) or 4°C, GT were placed at 37°C. GT were scored for the presence of orange pigment. GT and AT were subcultured on blood agar (BA). Pigment was observed in 98% of GT incubated at 37°C. GBS could be cultured in 91%, 73%, and 55% of GT incubated at 37°C, RT, or 4°C, respectively. For AT, these percentages were only 20% at 37°C, 52% at RT, and 59% at 4°C. When GT initially incubated at RT or 4°C were subsequently incubated at 37°C, the sensitivity improved significantly. We conclude that GT is a more sensitive GBS transport and culture medium than the conventional method, especially for low inocula and prolonged transport/incubation times. GT does not exclude the presence of GBS, and should always be incubated at 37°C and subcultured on solid agar for optimal sensitivity.

Outbreak of severe sepsis due to contaminated propofol: lessons to learn.

Nosocomial infections are a frequent concern in healthcare. Despite the available knowledge on nosocomial infections and preventive measures, outbreaks of infections continue to occur. An outbreak of severe sepsis in patients who underwent minor procedures in an operating theatre during two consecutive days is described and analysed in this study. We performed a retrospective cohort study using epidemiological data in order to investigate the source of infection together with microbiological and on-site investigations and interviews. Seven patients met the case definition of postoperative systemic inflammatory response syndrome (SIRS). All other patients operated on over the same period served as controls. Of the risk factors investigated, general anaesthesia and propofol were statistically significant (P=0.003). Klebsiella pneumoniae and Serratia marcescens were cultured from opened vials of propofol, propofol-related devices and from blood cultures from two of the patients. These strains were genotypically indistinguishable. Lapses in aseptic preparation, handling and storage of the propofol were observed, and were the most probable cause of the extrinsic contamination. The daily procedure of handling propofol was not performed according to the manufacturer's recommendations, the main departure being the use of a single-use vial for multiple patients. This study documents the risk of infection due to contaminated propofol and the importance of having written guidelines for its handling.

Endogenous pro-inflammatory cytokines in children and adolescents during chemotherapy-induced neutropenia.

Monocyte-derived pro-inflammatory cytokines such as GM-CSF, IL-12, and IP-10 might protect patients with chemotherapy-induced neutropenia against infections. In settings with abundant neutrophils, G-CSF has been described as a suppressor of IL-12, but also as an inducer of GM-CSF. In 25 pediatric patients with chemotherapy-induced neutropenia the authors measured plasma levels of these four cytokines. GM-CSF was detectable in only a minority of patients (6/25). It was, however, positively correlated with high plasma levels of IL-12 and IP-10. G-CSF levels, however, were in no way correlated with the levels of any of these three cytokines.

Origin and evolution of primate social organisation: a reconstruction.

The evolution and origin of primate social organisation has attracted the attention of many researchers, and a solitary pattern, believed to be present in most nocturnal prosimians, has been generally considered as the most primitive system. Nocturnal prosimians are in fact mostly seen alone during their nightly activities and therefore termed 'solitary foragers', but that does not mean that they are not social. Moreover, designating their social organisation as 'solitary', implies that their way of life is uniform in all species. It has, however, emerged over the last decades that all of them exhibit not only some kind of social network but also that those networks differ among species. There is a need to classify these social networks in the same manner as with group-living (gregarious) animals if we wish to link up the different forms of primate social organisation with ecological, morphological or phylogenetic variables. In this review, we establish a basic classification based on spatial relations and sociality in order to describe and cope properly with the social organisation patterns of the different species of nocturnal prosimians and other mammals that do not forage in cohesive groups. In attempting to trace the ancestral pattern of primate social organisation, the Malagasy mouse and dwarf lemurs and the Afro-Asian bushbabies and lorises are of special interest because they are thought to approach the ancestral conditions most closely. These species have generally been believed to exhibit a dispersed harem system as their pattern of social organisation ('dispersed' means that individuals forage solitarily but exhibit a social network). Therefore, the ancestral pattern of primate social organisation was inferred to be a dispersed harem. In fact, new field data on cheirogaleids combined with a review of patterns of social organisation in strepsirhines (lemurs, bushbabies and lorises) revealed that they exhibit either dispersed multi-male systems or dispersed monogamy rather than a dispersed harem system. Therefore, the concept of a dispersed harem system as the ancestral condition of primate social organisation can no longer be supported. In combination with data on social organisation patterns in 'primitive' placentals and marsupials, and in monotremes, it is in fact most probable that promiscuity is the ancestral pattern for mammalian social organisation. Subsequently, a dispersed multi-male system derived from promiscuity should be regarded as the ancestral condition for primates. We further suggest that the gregarious patterns of social organisation in Aotus and Avahi, and the dispersed form in Tarsius evolved from the gregarious patterns of diurnal primates rather than from the dispersed nocturnal type. It is consequently proposed that, in addition to Aotus and Tarsius, Avahi is also secondarily nocturnal.

Aspects of social life in the fat-tailed dwarf lemur (Cheirogaleus medius): inferences from body weights and trapping data.

Body weight is an important attribute of any animal and influences its biology in many ways. In the case of the fat-tailed dwarf lemur (Cheirogaleus medius), this is of special interest because animals of this species store fat to survive extended torpor phases during the austral winter and, as a result, show extreme seasonal variation in body weight. In this paper, I present field data from a 20-month study at the Forestry Station of Ampijoroa in northwestern Madagascar on body weights of repeatedly trapped individuals combined with trapping results to investigate the general biology and notably the social life of C. medius. The most remarkable physical characteristic of wild C. medius is a dramatic weight-loss in males in September following emergence from torpor. Trapping results showed that adult males emerge from torpor earlier than females and offspring, even though food is still scarce. Early emergence from torpor puts males at an energetic disadvantage and confers no advantage in terms of access to females. Observation data from nightly follows indicate that males patrol their home range, probably to guarantee its integrity for the coming active season and to secure the food supply for their families. The high energetic costs of this strategy is argued to represent a form of paternal investment. Body weight data of repeatedly captured individuals showed that they may reach adult size and sexual maturity at 2 years of age but are not socially mature before the age of 3 years. The data presented may serve as a guide for keeping C. medius at a suitable weight in captivity.

Palindromic sequences and A+T-rich DNA elements promote illegitimate recombination in Nicotiana tabacum.

Illegitimate recombination is the prevailing molecular mechanism for the integration of recombinant DNA into the genome of most eukaryotic systems and the generation of deletions by intrachromosomal recombination. We developed a ?selectable marker system to screen for intrachromosomal illegitimate recombination events in order to assess the sequence and structure-specific requirements for illegitimate recombination in tobacco. In 12 illegitimate recombination products analysed, we found that all deletion termini localise to sites of palindromic structures or to A+T-rich DNA elements. All deletion termini showed microhomologies of two to six nucleotides. In three plants, the recombination products contained filler-DNA or an inversion of an endogenous segment. Our data strongly suggest that illegitimate recombination in plants is mediated by a DNA synthesis-dependent process, and that this mechanism is promoted by DNA regions that can form palindromic structures or facilitate DNA unwinding.