Vancomycin area under the curve to minimum inhibitory concentration ratio predicting clinical outcome: a systematic review and meta-analysis with pooled sensitivity and specificity.

BACKGROUND: Vancomycin is a first-line antibiotic for methicillin-resistant Staphylococcus aureus infections or other Gram-positive infections. The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter. How well clinical efficacy is predicted by this measure has not been established. OBJECTIVE: Determine the test performance characteristics (TPC) of AUC:MIC of vancomycin for prediction of positive outcome. DATA SOURCES: PubMed and Ovid Medline (1946 to 2018) and EMBASE (1974 to 2018). Study Eligibility Criteria and Participants: Studies of patients treated with vancomycin for any type of infection in peer reviewed publications. All patient populations were included. INTERVENTIONS: Vancomycin AUC:MIC or AUC was related to patient clinical outcome. METHODS: Searches of medical databases using relevant terms were performed. Screening, study reviewing, data extracting and assessing data quality was performed independently by two reviewers. Studies were stratified by type of primary outcome for calculation of pooled sensitivity, specificity and construction of hierarchical summary receiver operating characteristic (HSROC) curves. RESULTS: Nineteen studies including 1699 patients were meta-analysed. Pooled sensitivity and specificity were 0.77 (95% CI 0.67-0.84) and 0.62 (95% CI 0.53-0.71) respectively for the seven studies with primary outcome of mortality and 0.65 (95% CI 0.53-0.75), 0.58 (95% CI 0.48-0.67) for studies with composite or clinical cure outcome (n = 12). HSROC curves suggested considerable heterogeneity. An additional 11 studies were described but could not be included for meta-analysis because data were not available. The majority of these studies (9/11) failed to demonstrate a relationship between AUC:MIC and positive clinical outcome. CONCLUSIONS: Vancomycin AUC:MIC performance was modest and inconsistent. Analysis was limited by studies without sufficient data; therefore, meta-analytic results may overestimate TPC values. Given this, as well as the lack of standardization of methods, widespread adoption of AUC:MIC as the preferred vancomycin monitoring parameter may be premature.

Proton pump inhibitors increase significantly the risk of Clostridium difficile infection in a low-endemicity, non-outbreak hospital setting.

BACKGROUND: Proton pump inhibitors (PPI) have been linked to higher risk of Clostridium difficile infection (CDI). The relevance of this association in hospitals with low disease activity, where an outbreak strain is nondominant, has been assessed in relatively few studies. AIM: To assess the association of PPI and CDI in a setting of low disease activity. METHODS: A retrospective cohort study was conducted at two hospitals. Patients admitted for > or = 7 days receiving antibiotics were included. Demographics, exposure to PPI, antibiotics and other drugs in relation to diagnosis of CDI were assessed by univariate and multivariate analyses. RESULTS: Of 14 719 patients, 149 (1%) first episode CDI were documented; PPI co-exposure increased CDI [1.44 cases/100 patients vs. 0.74 cases/100 non-exposed (OR: 1.96, 95% CI: 1.42-2.72)]. By logistic regression, PPI days (adjusted OR: 1.01 per day, 95% CI: 1.00-1.02), histamine-2 blockers, antidepressants, antibiotic days, exposure to medications, age, admission service and length of admission were significant predictors. CONCLUSIONS: A statistically significant increase in CDI was observed in antibiotic recipients who received PPI, but the absolute risk increase is modest. In settings of with low rates of CDI, the benefit of PPI therapy outweighs the risk of developing CDI. These data support programmes to decrease inappropriate use of PPI in hospitalized patients.

Effects of ferulic acid, an allelopathic compound, on leaf expansion of cucumber seedlings grown in nutrient culture.

Cucumber seeds and seedlings at various ages (7-19 days old) were treated with a single treatment or multiple treatments (at 2-day intervals) of ferulic acid in nutrient culture. Ferulic acid treatments of cucumber seeds during stages of germination and radicle growth did not significantly reduce subsequent seedling growth. Ferulic acid treatments to seedlings reduced leaf area, leaf expansion, and dry weight of cucumber seedlings. Pretreatment of seeds and seedlings with 0.1 or 0.2 mM ferulic acid did not modify the effects of a single 1 mM ferulic acid treatment on leaf expansion when a single treatment was given at various times to seedlings ranging from 7 to 19 days of age. Treatments of 1mM or greater induced rapid wilting of leaves, but visible recovery occurred within 24-48 hr and subsequent treatments did not cause wilting. Once seedlings were removed from ferulic acid treatments, leaf expansion resumed. The magnitude of recovery depended on the concentration of ferulic acid, frequency of ferulic acid application and age of the seedling. Mean relative rates of leaf expansion recovered rapidly even in the presence of ferulic acid. Recovery of leaf expansion after ferulic acid treatments was faster for seedlings grown in an adequate nutrient environment than for seedlings grown in a limited nutrient environment. Ferulic acid disappeared from nutrient solutions with time, and two microbial metabolic products of ferulic acid (i.e., vanillic and protocatechuic acid) were identified in nutrient solutions.

Effects of various mixtures of ferulic acid and some of its microbial metabolic products on cucumber leaf expansion and dry matter in nutrient culture.

Cucumber seedlings (Cucumis sativus cv. 'Early Green Cluster') ranging from 6 to 16 days of age were treated with various concentrations (0- 1 mM) of caffeic, ferulic,p-coumaric,p-hydroxybenzoic, protocatechuic, sinapic, syringic, and vanillic acids and mixtures of ferulic acid and one or two of the other phenolic acids. Seedlings were grown in full-strength Hoagland's solution which was changed every other day. Phenolic acid treatments were given with each nutrient solution change starting at day 6 or given once when seedlings were 13 or 14 days old. Leaf area, mean relative rates of leaf expansion, transpiration rates, water utilization, and the concentrations of the phenolic acids in nutrient solution were determined at one- or two-day intervals. Seedling dry weight was determined at final harvest. Seedling leaf area and dry weight were linearly related. Since leaf areas can be easily obtained without destructive sampling and leaf area expansion responds rapidly to phenolic acid treatments, it was utilized as the primary indicator of plant response. The resulting data suggested that a number of ferulic acid microbial metabolic products, as well as two other phenolic acids observed in soils (p-coumaric and syringic acid), can reduce seedling dry weight, leaf expansion, and water utilization of cucumber seedlings in a similar manner. The magnitude of impact of each of the phenolic acids, however, varied with phenolic acid and concentration. It appears that the inhibitory activity of these phenolic acids involved water relations of cucumber seedlings, since the phenolic acid treatments resulted in closure of stomata which then remained closed for several days after treatment. The data also demonstrated that the effects of mixtures of phenolic acids on cucumber seedlings may be synergistic, additive, or antagonistic. The type of response observed appeared to be related to the factor measured, the compounds in the nmixture, and the magnitued of inhibition associated with each compounds. The data also indicated that the effects of the various phenolic acids were reversible, since seedling leaf area increased rapidly once phenolic acids were removed from the root environment. Mean relative rates of leaf expansion recovered even in the presence of the various phenolic acids.

Effects of ferulic andp-coumaric acids in nutrient culture of cucumber leaf expansion as influenced by pH.

Cucumber seedlings were grown in 5 mM MES [2-(N-morpholino)ethanesulfonic acid] -buffered nutrient solutions adjusted to a pH of 5.5, 6.25, or 7.0. Nutrient solutions were changed on alternate days. Seedlings were treated for a two-day period with various concentrations (0-1 mM) of ferulic acid,p-coumaric acid, or mixtures of these phenolic acids when 16 days old. Leaf growth, dry weight, and water utilization of the seedlings; pH of the solutions; and disappearance of the phenolic acids from nutrient solutions were monitored. Leaf area expansion of cucumber seedlings was inhibited by both ferulic andp-coumaric acid, and the magnitude of these inhibitions was influenced by concentration and pH. Inhibition of leaf area expansion was greater at pH 5.5 and nominal at pH 7.O. Ferulic acid was more inhibitory thanp-coumaric acid. The effect of pH on growth was best described by data for mean relative rates of leaf expansion. For example, the mean relative rates of leaf expansion by both acids at 0.5 mM for the 16- to 18-day growth period (treatment period) were reduced by 45, 31, and 8% for the pH 5.5, 6.25, and 7.0 treatments, respectively. The dry weight of seedlings at harvest (day 22) was significantly reduced for seedlings grown in the pH 5.5 and 6.25 treatments, but not for the pH 7.0 treatment. There was, however, one exception; the dry weight of seedlings treated withp-coumaric acid solutions adjusted to a pH of 5.5 was not significantly reduced. Water utilization by the seedlings was reduced by both ferulic andp-coumaric acid. Again, the impact of ferulic acid was greater thanp-coumaric acid. The effect of ferulic acid on water utlization decreased with increasing pH of the nutrient solution. The pH effects were not so consistent forp-coumaric acid. The effects of equimolar mixtures of the two phenolic acids were additive for all variables measured. There was a linear correlation between mean relative rates of leaf expansion and water utilization.

Effects of ferulic acid and some of its microbial metabolic products on radicle growth of cucumber.

An initial survey of the effects of aqueous solutions of ferulic acid and three of its microbial metabolic products at pH 4.5, 6.0, and 7.5 was determined on radicle growth of 11 crop species in Petri dishes. These bioassays indicated that cucumber, ladino clover, lettuce, mung bean, and wheat were inhibited by ferulic, caffeic, protocatechuic, and/or vanillic acids and that the magnitude of inhibition varied with concentration (0-2 mM), phenolic acid, and pH of the initial solution. The pH values of the initial solutions changed considerably when added to the Petri dishes containing filter paper and seeds. The final pH values after 48 hr were 6.6, 6.8, and 7.1, respectively, for the initial 4.5, 6.0, and 7.5 pH solutions. The amounts of the phenolic acids in the Petri dishes declined rapidly over the 48 hr of the bioassay, and the rate of phenolic acid decline was species specific. Cucumber was subsequently chosen as the bioassay species for further study. MES buffer was used to stabilize the pH of the phenolic acid solutions which ranged between 5.5 and 5.8 for all subsequent studies. Inhibition of radicle growth declined in a curvilinear manner over the 0-2 mM concentration range. At 0.125 and 0.25 mM concentrations of ferulic acid, radicle growth of cucumber was inhibited 7 and 14%, respectively. A variety of microbial metabolic products of ferulic acid was identified in the Petri dishes and tested for toxicity. Only vanillic acid was as inhibitory as ferulic acid. The remaining phenolic acids were less inhibitory to noninhibitory. When mixtures of phenolic acids were tested, individual components were antagonistic to each other in the inhibition of cucumber radicle growth. Depending on the initial total concentration of the mixture, effects ranged from 5 to 35% lower than the sum of the inhibition of each phenolic acid tested separately. Implications of these findings to germination bioassays are discussed.

Allelopathic substances in ecosystems : Effectiveness of sterile soil components in altering recovery of ferulic acid.

Recovery studies were conducted with ferulic acid, a common allelopathic agent, using various soils and soil components. Ferulic acid was placed into sterile soil components (gibbsite, geothite, Georgia kaolin, and Utah bentonite), and different sterile soil materials (from different horizons in the same profile) varying in mineralogy and in organic matter content. The initial concentration of ferulic acid added to the soil materials was 1000 µg/g (5.149 mmol/g). The pH of the soil materials was adjusted and maintained at approximately 4.5 or 7.5. Samples were extracted with 0.03 M EDTA at days, 1, 4, 7, 10, and 13 after addition of ferulic acid. Concentrations of ferulic acid in the extracts were determined with a high performance liquid chromatograph. No breakdown products were detected. Models were developed to describe the recovery of ferulic acid from each soil material and soil component over time. Organic matter was the most active soil component involved in the irreversible retention of ferulic acid. The inorganic soil components were much less active than organic matter but appeared to be similar to each other in activity. Irreversible retention of ferulic acid by soil and soil components was greatest as pH 7.5.