Impact of Statewide Program To Promote Appropriate Antimicrobial Drug Use

The Wisconsin Antibiotic Resistance Network (WARN) was launched in 1999 to educate physicians and the public about judicious antimicrobial drug use. Public education included radio and television advertisements, posters, pamphlets, and presentations at childcare centers. Physician education included mailings, susceptibility reports, practice guidelines, satellite conferences, and presentations. We analyzed antimicrobial prescribing data for primary care physicians in Wisconsin and Minnesota (control state). Antimicrobial prescribing declined 19.8% in Minnesota and 20.4% in Wisconsin from 1998 to 2003. Prescribing by internists declined significantly more in Wisconsin than Minnesota, but the opposite was true for pediatricians. We conclude that the secular trend of declining antimicrobial drug use continued through 2003, but a large-scale educational program did not generate greater reductions in Wisconsin despite improved knowledge. State and local organizations should consider a balanced approach that includes limited statewide educational activities with increasing emphasis on local, provider-level interventions and policy development to promote careful antimicrobial drug use

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

High-dose vitamin D-3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis:a double-blind randomised controlled trial

Background: Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. Methods: We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D3. This trial is registered with ClinicalTrials.gov number NCT00419068. Findings: 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (pinteraction=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36–48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (pinteraction=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001). Interpretation: Administration of four doses of 2·5 mg vitamin D3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism

Circulating immunological correlates of time to sputum culture conversion in PTB patients of African vs.

<p><b>Eurasian ancestry.</b> Higher ESR and serum MMP-1 concentration associated with slower sputum culture conversion in patients of African and Eurasian ancestry alike (A–B, p≤0.0080). Higher red blood cell count and lower serum vitamin D binding protein concentration associated with slower sputum culture conversion in patients of African ancestry but faster sputum culture conversion in those of Eurasian ancestry (C–D, p≤0.0075). Lower serum concentrations of CCL11 and IL-7 associated with slower sputum culture conversion in patients of African ancestry (p≤0.0028), but did not associate with treatment response in those of Eurasian ancestry (E–F). Higher plasma concentrations of cathelicidin LL-37 and lower serum concentration of CXCL10 associated with slower sputum culture conversion in patients of Eurasian ancestry (p≤4.98×10⁻⁰⁵), but did not associate with treatment response in those of African ancestry (G–H). Fast (solid lines) vs. slow (dashed lines) sputum clearance defined as time to sputum culture conversion <37.25 days vs. ≥37.25 days, respectively. Means ± SEM at 0, 2, 4, 6 and 8 weeks of treatment are presented. Data for all parameters except red blood cell count were normalised by log₁₀ transformation and the y-axis presented as 10∧(log value). P-values were generated using rank regression with covariates on the interaction term ‘week of sampling*speed of sputum culture conversion, with adjustment for the following covariates: age, sex, months of symptoms pre-diagnosis, duration of antimicrobial therapy pre-sampling, isoniazid sensitivity, allocation to vitamin D vs. placebo, week of sampling and subject ID. Parameters with a false discovery rate (q-value)>0.05, determined by the Benjamini Hochberg approach, were designated non-significant (ns).</p

Serum vitamin D binding protein (DBP) concentration in patients with newly-diagnosed PTB by <b><i>DBP</i></b><b> genotype and ethnic group.</b>

<p>DBP concentration varied with <i>DBP</i> genotype, with patients of Gc1F/1F genotype having the lowest concentrations, and those with Gc1S/1S genotype having the highest concentrations, irrespective of ethnic group (p<0.0001 for comparison by genotype with ethnic groups pooled; p>0.05 for ethnic comparison within each genotype). Kruskal-Wallis test with Dunn's multiple comparison test. AFR, African ancestry; EUA, Eurasian ancestry.</p

Differences in inflammatory profile in PTB patients of African vs. Eurasian ancestry.

<p>A: age, sex, duration of symptoms pre-diagnosis, duration of antimicrobial therapy pre-sampling, baseline serum 25-hydroxyvitamin D concentration; B: MTB genotype categorised as Indo-Oceanic, East Asian, East African-Indian, Euro-American and West African strain lineage. C: host <i>DBP</i> genotype categorised as Gc1F/1F, 1F/2, 2/2, 1F/1S, 2/1S and 1S/1S as per ref <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003468#ppat.1003468-Martineau2" target="_blank">[21]</a>. D: age, sex, duration of symptoms pre-diagnosis, duration of antimicrobial therapy pre-sampling, isolate sensitive vs. resistant to isoniazid, allocation to vitamin D vs. placebo. E. t-statistic (regression co-efficient/standard deviation ) represents magnitude of difference between ethnic groups; a negative t-statistic indicates a lower concentration of immunological parameter in participants of African vs. Eurasian ancestry, and vice versa. F, p values derived using the t-test for general linear models, with adjustment for covariates (A–D). Parameters with a false discovery rate (q-value)>0.05, determined by the Benjamini Hochberg approach, were designated non-significant (ns). For the purposes of applying this approach, each ‘family’ of hypotheses corresponded to a single column of presented p values for either circulating or antigen-stimulated samples. G, stimulated with recombinant culture filtrate protein, 10 kDa (rCFP-10).</p><p>MTB, <i>Mycobacterium tuberculosis</i>; CCL, CC chemokine ligand; CXCL, CXC chemokine ligand; DBP, vitamin D binding protein; IL, interleukin; RA, receptor antagonist; HGF, hepatocyte growth factor.</p

Baseline characteristics of tuberculosis patients of African vs. Eurasian ancestry.

<p>Data are number (%) or mean (standard deviation) except where stated. IQR, inter-quartile range; BMI, body mass index; AFB, acid-fast bacilli. DBP, vitamin D binding protein; A, Baseline sputum smear result unavailable for 2 Eurasian participants; B, <i>M. tuberculosis</i> genotype unavailable for one Eurasian participant.</p

Principal component analysis (PCA) plots generated using immunological parameters which contribute to variation in baseline inflammatory profile between PTB patients of African and Eurasian ancestry.

<p>Each point represents one patient, and its position in the plot is determined by the combined effects of all parameters measured for that patient sample that contribute significantly to ethnic variation in inflammatory profile. The distance between sample points represents Euclidean distance. The first 3 component vectors are displayed, along with a % figure signifying the proportion of the variability in the data that each component accounts for. Points representing patients with Eurasian ancestry have been coloured according to their ethnic subgroup (Central/South Asian (blue) and European/Middle Eastern (yellow) ancestry) to demonstrate that they cluster together and that they are separated from those representing patients of African ancestry (black). One patient of mixed South Asian and European ancestry is classified as a Eurasian (green) and clusters within samples from the Eurasian subgroups. A, PCA plot of circulating immunological parameters in patients of African (n = 45), Central/South Asian (n = 55), European/Middle Eastern (n = 27) and Eurasian (n = 1) ancestry at baseline. B, PCA plot of rCFP-10-stimulated immunological parameters in patients of African (n = 13), Central/South Asian (n = 22) and European/Middle Eastern (n = 7) ancestry at baseline.</p

Ethnic variation in inflammatory profile in PTB before and after intensive-phase antituberculous therapy.

<p>At diagnosis, patients of African ancestry had lower neutrophil counts (A), lower serum concentrations of CCL2 (B), CCL11 (C) and DBP (D), but higher serum concentrations of CCL5 (E) and higher antigen-stimulated IL-1RA and IL-12 (F,G) than those of Eurasian ancestry (p≤0.0030). These differences persisted after completion of intensive-phase antimicrobial therapy for all circulating parameters illustrated (A–E; p≤7.84×10⁻⁶). 8-week antigen-stimulated CCL11 concentrations were also lower in patients of African vs. Eurasian ancestry (H; p = 6.45×10⁻⁹). P-values were derived from the t-test for general linear models, separately applied to baseline and 8-week samples, with adjustment for the following covariates: age, sex, months of symptoms pre-diagnosis, duration of antimicrobial therapy pre-sampling and either baseline vitamin D status (baseline samples) or isoniazid sensitivity and allocation to vitamin D vs. placebo (8-week samples). P-values are only indicated for parameters with a false discovery rate (q-value)≤0.05, as determined by the Benjamini Hochberg approach. *** p<0.001, ** p = 0.001 to <0.01. Lines at median. LOD, limit of detection.</p

Three-dimensional principal component analysis plots depicting the correlation network of analytes significantly different between fast and slow culture converters of African and Eurasian ancestry during intensive phase anti-TB treatment.

<p>Plots for patients of African and Eurasian ancestry are shown in panels A and B, respectively. Individual points represent a single analyte. The distance between analytes is a measure of their Pearson correlation coefficients. Lines link analytes to their nearest neighbour, the analyte with the most similar pattern of change during the course of treatment. Each analyte is coloured according to its R-statistic value, calculated by rank regression interaction analysis. The concentration of analytes coloured blue is lower in patients with slow vs. fast sputum culture conversion, while the concentration of those coloured yellow is higher in patients with slow vs. fast sputum culture conversion. Component vectors are displayed, along with a % figure signifying the proportion of the variability in the data that each component accounts for.</p