Nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A secondary economic analysis of resource use from a Spanish perspective.

OBJECTIVES: Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. DESIGN: An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. SCOPE: Nosocomial pneumonia due to MRSA in hospitalized adults. PARTICIPANTS: The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. INTERVENTIONS: Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. PRIMARY ENDPOINTS: Analysis of HCRU outcomes and costs. RESULTS: Total costs were similar between the linezolid- (€17,782±€9,615) and vancomycin-treated patients (€17,423±€9,460) (P=.69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; P<.001). The total costs tended to be higher in patients who developed renal failure (€19,626±€10,840 vs. €17,388±€9,369; P=.14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2±10.7 vs. 7.6±3.6 days; P=.21; ICU stay: 14.4±10.5 vs. 9.9±6.6 days; P=.30; hospital stay: 19.5±9.5 vs. 16.1±11.0 days; P=.26) and cost (€17,219±€8,792 vs. €20,263±€11,350; P=.51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P=.98). CONCLUSIONS: From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events.

Assessing the impact of age, race, ethnicity and inhibitor status on functional limitations of patients with severe and moderately severe haemophilia A.

Few data exist on the impact of age and inhibitor status on activity levels among patients with severe and moderately severe haemophilia A. The aim of this analysis was to assess the impact of age, race/ethnicity and inhibitor status on functional limitations through retrospective analysis of data from the Hemophilia and Thrombosis Research Society (HTRS) Registry. Functional status data from patients with haemophilia A with or without inhibitors who were enrolled in the HTRS Registry between October 1999 and July 2008 were analysed by age, race and ethnicity. Of the 2497 registrants, 1340 had congenital haemophilia A (333 with inhibitors). Functional status was available for 274 subjects with haemophilia A with current inhibitors and 247 subjects without inhibitors who had moderately severe (FVIII levels ≤ 2%). Functional impairment increased with age across five levels of functional status (P < 0.01). Inhibitors were associated with greater functional impairment in two age groups (13-21 years and older than 21 years) [unrestricted activity in 57.8% vs. 63.6% (P = 0.06) and 18.3% vs. 28.6% (P = 0.04), respectively]. Blacks had worse functional status than caucasians across all ages regardless of inhibitor status. Functional status decreases with age, and impairment is greater among patients with inhibitors beginning in adolescence. These results reaffirm the need for early eradication of inhibitors and early treatment of bleeds in inhibitor and non-inhibitor patients. This analysis highlights the benefit of ongoing study of these patients through data collected for the HTRS Registry.

CT enterography and fistulizing Crohn's disease: clinical benefit and radiographic findings.

BACKGROUND: To estimate the clinical benefit of CT enterography (CTE) in patients with fistulizing Crohn's disease and describe the appearance of fistulas at CTE. METHODS: Crohn's patients who had undergone CTE, which diagnosed an abscess or fistula, were identified. A gastroenterologist reviewed clinical notes prior to and following CTE to assess the pre-CTE clinical suspicion for fistula/abscess, and post-CTE alteration in patient management. A radiologist reassessed all fistula-positive cases, which were confirmed by a non-CT reference standard, to describe their radiologic appearance. RESULTS: Fifty-six patients had CT exams identifying 19 abscesses and 56 fistulas. There was no or remote suspicion of fistula or abscess at pre-imaging clinical assessment in 50% of patients. Thirty-four patients (61%) required a change in or initiation of medical therapy and another 10 (18%) underwent an interventional procedure based on CT enterography findings. Among 37 fistulas with reference standard confirmation, 30 (81%) were extraenteric tracts, and 32 (86%) were hyperenhancing compared to adjacent bowel loops. Most fistulas (68%) contained no internal air or fluid. CONCLUSION: CTE detects clinically occult fistulas and abscesses, resulting in changes in medical management and radiologic or surgical intervention. Most fistulas appear as hyperenhancing, extraenteric tracts, usually without internal air or fluid.

Pathophysiology and burden of infection in patients with diabetes mellitus and peripheral vascular disease: focus on skin and soft-tissue infections.

Diabetes mellitus affects 284 million adults worldwide and is increasing in prevalence. Accelerated atherosclerosis in patients with diabetes mellitus contributes an increased risk of developing cardiovascular diseases including peripheral vascular disease (PVD). Immune dysfunction, diabetic neuropathy and poor circulation in patients with diabetes mellitus, especially those with PVD, place these patients at high risk for many types of typical and atypical infections. Complicated skin and soft-tissue infections (cSSTIs) are of particular concern because skin breakdown in patients with advanced diabetes mellitus and PVD provides a portal of entry for bacteria. Patients with diabetes mellitus are more likely to be hospitalized with cSSTIs and to experience related complications than patients without diabetes mellitus. Patients with PVD requiring lower extremity bypass are also at high risk of surgical site and graft infections. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent causative pathogen in cSSTIs, and may be a significant contributor to surgical site infections, especially in patients who are colonized with MRSA on hospital admission. Patients with cSSTIs and diabetes mellitus or PVD experience lower clinical success rates than patients without these comorbidities, and may also have a longer length of hospital stay and higher risk of adverse drug events. Clinicians should be vigilant in recognizing the potential for infection with multi-drug-resistant organisms, especially MRSA, in these populations and initiating therapy with appropriate antibiotics.

Implementing criteria-based early switch/early discharge programmes: a European perspective.

Early switch (ES) from intravenous (IV) to oral antibiotic therapy programmes is increasingly included as a component of hospital antimicrobial stewardship initiatives that aim to optimize antimicrobial therapy while limiting toxicity and resistance. In terms of prioritizing the most cost-effective stewardship interventions, ES has been seen as a 'low-hanging fruit', which refers to selecting the most obtainable targets rather than confronting more complicated issues. Administration of highly bioavailable oral antibiotics should be considered for nearly all non-critically ill patients and has been recommended as an effective and safe strategy for over two decades. However, to accrue the most benefit from ES, it should be combined with an early discharge (ED) plan, protocol, or care pathway. Benefits of this combined approach include improved patient comfort and mobility, reduced incidence of IV-line-related adverse effects, reduced IV antimicrobial preparation time, decreased hospital stays, reduced antimicrobial purchasing and administration costs, decreased patient deconditioning, and shortened recovery times. Results from published studies document decreases in healthcare resource use and costs following implementation of ES programmes, which in most studies facilitate the opportunity for ED and ED programmes. Barriers to the implementation of these programmes include clinician misconceptions, practical considerations, organizational factors, and a striking lack of awareness of IV to oral switch guidance. These and other barriers will need to be addressed to maximize the effectiveness of ES and ED programmes. As national antimicrobial stewardship programmes dictate the inclusion of ES and ED programmes within healthcare facilities, programmes must be developed and success must be documented.

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus.

Suboptimal antibiotic penetration into soft tissues can occur in patients with poor circulation due to peripheral vascular disease (PVD) or diabetes. We conducted a real-world analysis of antibiotic treatment, hospital resource use and clinical outcomes in patients with PVD and/or diabetes receiving linezolid or vancomycin for the treatment of methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections (MRSA cSSTIs) across Europe. This subgroup analysis evaluated data obtained from a retrospective, observational medical chart review study that captured patient data from 12 European countries. Data were obtained from the medical records of patients ≥ 18 years of age, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Hospital length of stay and length of treatment were compared between the treatment groups using inverse probability of treatment weights to adjust for clinical and demographic differences. A total of 485 patients had PVD or diabetes and received treatment with either vancomycin (n = 258) or linezolid (n = 227). After adjustment, patients treated with linezolid compared with vancomycin respectively had significantly shorter hospital stays (17.9 ± 13.6 vs. 22.6 ± 13.6 days; p < 0.001) and treatment durations (12.9 ± 7.9 vs. 16.4 ± 8.3 days; p < 0.001). The proportions of patients prescribed oral, MRSA-active antibiotics at discharge were 43.2% and 12.4% of patients in the linezolid and vancomycin groups, respectively (p < 0.001). The reduction in resource use may result in lower hospital costs for patients with PVD and/or diabetes and MRSA cSSTIs if treated with linezolid compared with vancomycin.

Weight-based antibiotic dosing in a real-world European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus.

We aimed to characterize real-world dosing of weight-based intravenous (IV) antibiotic therapy in patients hospitalized for methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTIs). This was a subgroup analysis of a retrospective chart review that captured data from 12 European countries. The study included patients ≥18 years old, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Patients treated with IV vancomycin, teicoplanin or daptomycin at any stage during hospitalization were included in this analysis. Analyses were conducted at the regimen level (dosing in mg/kg or in mg, frequency, and total daily dose (TDD)), with potentially multiple regimens per patient, and the patient level, categorizing patients into low, standard (labelled) and high dosing groups according to their initial MRSA-targeted regimen. Among the 1502 patients in the parent study, 998 patients contributed a total of 1050 daptomycin, teicoplanin or vancomycin regimens. Across all regimens, the mean initial TDDs were 6.3 ± 1.9 mg/kg for daptomycin, 10.5 ± 4.9 mg/kg for teicoplanin and 28.5 ± 11.5 mg/kg for vancomycin. A total of 789 patients received first-line therapy with one of the above antibiotics. The majority of patients receiving first-line teicoplanin and daptomycin (96% and 80%, respectively) received higher than labelled cSSTI doses, whereas vancomycin doses were lower than labelled doses in >40% of patients. These real-world data reveal significant deviation from labelled antibiotic dosing in 12 European countries and the potential for suboptimal outcomes in patients with MRSA cSSTIs.

Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.

The objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient.

The impact of parenteral nutrition preparation on bloodstream infection risk and costs.

BACKGROUND: Catheter-related bloodstream infections (BSIs) are a serious problem leading to increased morbidity, longer hospital stay, and hence, additional costs. This study evaluated the risk of BSI and the cost of parenteral nutrition (PN) in Germany. SUBJECTS/METHODS: A retrospective observational chart review of patients hospitalized from October 2009 to April 2011 and receiving PN via ready-to-use three-chamber bag (MCB), single bottle (SB) or hospital compounded admixture (CPN) was conducted across Germany. Propensity score-adjusted models were used to evaluate the association between the type of PN, BSI (Cox Proportional Hazards) and hospitalization cost (generalized linear models) within a subgroup receiving all three macronutrients (lipids, amino acids, glucose). RESULTS: Of the 1995 patient records reviewed (MCB=816; CPN=584; SB=595), 1457 patients received all three macronutrients. After adjustment, SB was associated with an increased hazard of BSI, vs MCB without additions (hazard ratio (HR) (95% confidence interval (CI))=2.53 (1.66-3.86)) in the total cohort. Adding supplements to MCB on the ward also increased the BSI risk in both total and subgroup analyses. In patients receiving all three macronutrients, adjusted total costs were MCB (no additions): \[euro]6,572 (95% CI: \[euro]6,896-6263); CPN: \[euro]6,869 (\[euro]7,283-6479); SB: \[euro]6,872 (\[euro]7,242-6521); MCB (ward additions): \[euro]7,402 (\[euro]7,878-6955); P<0.001; P<0.001. CONCLUSION: Use of MCB does not appear to increase treatment costs, possibly by reducing the risk of infection. This study identified several PN preparation methods associated with a significantly increased hazard for BSI; definitive CPN findings are limited by our inability to distinguish automated from manual pharmacy compounding.

Prioritizing comparative-effectiveness research topics via stakeholder involvement: an application in COPD.

A major priority for funding agencies and researchers involved in comparative-effectiveness research (CER) is to ensure that research questions will produce findings that are relevant and feasible to implement. In this article, we describe a process for involving experts and stakeholders in identifying and prioritizing CER studies, as illustrated by our experience in chronic obstructive pulmonary disease (COPD).

Control analysis of the role of triosephosphate isomerase in glucose metabolism in Lactococcus lactis.

Triosephosphate isomerase (TPI), which catalyses the conversion of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P), was studied for its control on glycolysis and mixed acid production in L. lactis subspecies lactis IL1403 and L. lactis subspecies cremoris MG1363. Strains in which the TPI activity was modulated from 3%-225% (IL1403) or 13%-103% (MG1363) of the wild-type level were constructed by changing the expression of the tpiA gene. The enzyme was found to be present in high excess in the wild-type cells and 10% TPI activity still supported more than 70% of the wild-type glycolytic flux in both strains. Homolactic product formation was preserved throughout the range of TPI activities studied, although a slight increase in the amount of acetate and formate production was observed in the strains with strongly reduced TPI activity for both IL1403 and MG1363. The upstream metabolites glucose-6-phosphate, fructose-1,6-bisphosphate and DHAP in the IL1403 derivatives were essentially unchanged for TPI activities from 26% to 225%. At a TPI activity of 3%, the level of DHAP increased four times. The finding that an increased level of DHAP coincides with an increase in formate production is surprising and indicates that pyruvate formate lyase is not inhibited by DHAP under these conditions.

Control analysis of the importance of phosphoglycerate enolase for metabolic fluxes in Lactococcus lactis subsp. lactis IL1403.

The glycolytic enzyme phosphoglycerate enolase (PGE) catalyses the step from 2-phosphoglycerate to phosphoenolpyruvate in glycolysis. A control analysis of PGE on growth, glycolytic flux and product formation in Lactococcus lactis subsp. lactis IL1403 is presented. A library of strains with a modulated expression of PGE from 36 to 232% relative to wildtype level was constructed. Selected strains were studied with respect to growth, glycolytic flux and product formation in a chemically defined medium. On the basis of these data, flux control coefficients of PGE on the respective fluxes were calculated. At wildtype level, PGE was found to have no significant flux control on growth, glycolytic flux or product formation, but at 36% of PGE activity relative to wildtype, the flux control on the growth rate was estimated to be C(PGE)J(micro) approximately equal to 0.7, on the glycolytic flux C(PGE)J(g) approximately equal to 0.8, on lactate formation C(PGE)J(lactate) approximately equal to 1.3, on formate formation C(PGE)J(formate) approximately equal to 0.5 and on acetate formation C(PGE) J(acetate) approximately equal to 0.25. These flux control coefficients show that the metabolism of L. lactis subsp. lactis IL1403 becomes slightly more mixed acid at reduced PGE activities. Estimation of the relative turnover of PGE indicates that excess capacity of PGE in L. lactis IL1403 may be as low as twofold.

Quantitative measurement and visual assessment of ileal Crohn's disease activity by computed tomography enterography: correlation with endoscopic severity and C reactive protein.

BACKGROUND: Few studies have correlated computed tomography (CT) enterography findings with endoscopic severity and C reactive protein (CRP) concentrations. AIM: To examine whether small bowel inflammation at CT enterography correlates with endoscopic severity and CRP in patients with Crohn's disease (CD). METHODS: CT enterography datasets from 143 CD patients undergoing ileoscopy were examined for three different CT parameters: CT bowel enhancement, as defined by the ratio of terminal ileal versus control ileal loop attenuation; vascular enlargement of the vasa recta ("the comb sign"); and mesenteric fat density. Correlations between CT scan parameters, endoscopy, and histology severity scores, and CRP were assessed using Spearman's rank correlation and logistic regression. RESULTS: Endoscopic score was significantly correlated with CT bowel enhancement, comb sign, and fat density (Spearman correlation coefficients 0.33-0.39; p<0.001). Correlations with histological inflammation were strongest for bowel enhancement (r = 0.34-0.38; p<0.001). CRP was elevated in patients with increased fat density versus those with increased bowel enhancement only (median 0.96 v 0.23, p = 0.002). CRP did not differ significantly between patients without evidence of active Crohn's and those with bowel enhancement and endoscopic inflammation not involving the perienteric tissues by CT (median 0.24 v 0.36; p = 0.38). CONCLUSION: Quantitative measures of bowel enhancement at CT enterography correlate with endoscopic and histological severity. CRP correlates with radiological findings of perienteric inflammation (increased fat density), but not of inflammation limited to the small bowel wall, underscoring the potential role of perienteric inflammation in CRP response in CD.

Twofold reduction of phosphofructokinase activity in Lactococcus lactis results in strong decreases in growth rate and in glycolytic flux.

Two mutant strains of Lactococcus lactis in which the promoter of the las operon, harboring pfk, pyk, and ldh, were replaced by synthetic promoters were constructed. These las mutants had an approximately twofold decrease in the activity of phosphofructokinase, whereas the activities of pyruvate kinase and lactate dehydrogenase remained closer to the wild-type level. In defined medium supplemented with glucose, the growth rate of the mutants was reduced to 57 to 70% of wild-type levels and the glycolytic flux was reduced to 62 to 76% of wild-type levels. In complex medium growth was even further reduced. Surprisingly, the mutants still showed homolactic fermentation, which indicated that the limitation was different from standard glucose-limited conditions. One explanation could be that the reduced activity of phosphofructokinase resulted in the accumulation of sugar-phosphates. Indeed, when one of the mutants was starved for glucose in glucose-limited chemostat, the growth rate could gradually be increased to 195% of the growth rate observed in glucose-saturated batch culture, suggesting that phosphofructokinase does affect the concentration of upstream metabolites. The pools of glucose-6-phosphate and fructose-6-phosphate were subsequently found to be increased two- to fourfold in the las mutants, which indicates that phosphofructokinase exerts strong control over the concentration of these metabolites.