A pragmatic randomized trial of a primary care antimicrobial stewardship intervention in Ontario, Canada

Abstract Background More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care. Methods Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences. Results There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37). Conclusions A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations. Trial registration clinicaltrials.gov ( NCT03517215 )

Homing Receptor Expression Is Deviated on CD56⁺ Blood Lymphocytes during Pregnancy in Type 1 Diabetic Women

<div><p>Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56^bright NK cells, into early decidua basalis and a 2^nd trimester shift towards Type 2 immunity. Decidual CD56^bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. <i>In vitro</i> studies show that T1DM reduces interactions between blood CD56⁺ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1⁺) and Type 2 (IL1RL1⁺) CD56^bright NK, CD56^dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56^bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2^nd trimester. At this time, these receptors were expressed at very low levels by CD56^bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56^bright NK cells. This implicates CD56^bright NK cells in diabetic pregnancy complications.</p></div

Detection of cytokines, chemokines and growth factors in control and T1DM patients across pregnancy and postpartum (PP).

<p>The representative scheme demonstrates 10 cytokines that were sporadically detected in the plasma from 13 patients: controls (C0) and T1DM (S0). Three cytokines were detected in a frequency higher than 40% (IL1RA, IL4 and PGFFB) while seven cytokines were detected in a frequency lower than 40% (IL9, IL12, IL17, FGF, IFNG, CCL3 and CCL11). The low frequency of cytokines/chemokines/growth factors detection is evident in T1DM patients. The symbol Ø identifies samples that were not available for the experiment.</p

Homing receptor expression by Type 2 CD56^bright NK cells.

<p>In (A) the percentage of Type 2 CD56^bright NK cells expressing ITGA4 in control patients was significantly increased in the 2^nd trimester versus 1^st and 3^rd trimesters (*P<0.05). No significant differences were detected in T1DM patients. In (B) Log of and (C-D) percentage of Type 2 CD56^bright NK cells expressing SELL (B), CXCR3 (C) and CXCR4 (D) are shown. A significant increase in Type 2 CD56^bright NK cells expressing SELL (B), CXCR3 (C) and CXCR4 (D) was detected in 2^nd compared to 1^st trimester (*P<0.05; **P<0.01). Type 2 CD56^bright NK cells expressing CXCR3 were also significantly higher in 2^nd trimester than postpartum (*P<0.05). Control patients had more Type 2 CD56^bright NK cells expressing SELL (B), CXCR3 (C) and CXCR4 (D) than T1DM patients in 2^nd trimester (#P<0.05).</p

Type 1/Type 2 ratio (IL18R1⁺/IL1RL1⁺) of specific lymphocyte subsets.

<p>Type 1/Type 2 ratio of CD56^bright NK cells (A), CD56^dim NK cells (B), NKT cells (C) and T cells (D). The data are expressed as percentage following lognormal transformation (A) and percentage (B-D) of cells expressing IL18R1 /IL1RL1. (A) Type 1/Type 2 ratio of CD56^bright NK cells was significantly lower in 2^nd trimester compared with 1^st and 3^rd trimesters in control pregnancies (*P<0.05), but not in T1DM patients. (B) CD56^dim NK cells had significantly higher Type 1/Type 2 ratios in 1^st trimester control than postpartum samples (*P<0.05). CD56^dim NK cells Type 1/Type 2 ratio from T1DM patients did not significantly differ across pregnancy and postpartum. (C) Type 1/Type 2 ratios of NKT cells did not differ significantly across pregnancy and postpartum in control and T1DM patients, or between control and T1DM patients. (D) Type 1/Type 2 ratio for T cells was higher in 1^st than 2^nd trimesters in control pregnancies (*P<0.05), but not in T1DM patients.</p

Quantification of blood lymphocytes by flow cytometry.

<p>(A) Total blood lymphocytes were gated by forward and side scatter (left histogram), and divided by CD3 and CD56 expression (right histogram): CD3^-CD56^bright (CD56^bright NK cells), CD3^-CD56^dim (CD56^dim NK cells), CD3⁺CD56⁺ (NKT cells) and CD3⁺CD56^- (T cells). (B) Pie-chart histograms represent the proportion of different lymphocyte subsets from total blood lymphocytes during pregnancy and postpartum in control (upper panel) and T1DM (bottom panel) patients. No significant changes were observed in the percentage of any lymphocyte subset over pregnancy and postpartum, or between groups (control <i>vs</i>. T1DM; P>0.05).</p

Homing receptor expression by Type 1 CD56^bright NK and NKT cells.

<p>(A) Representative contour plots of Type 1 CD56^bright NK cells expressing ITGA4 analysis from a control (upper panel) and a T1DM (bottom panel) patient are shown. (B) Representative pseudocolor dot plot of Type 1 NKT cells (CD3⁺CD56⁺) expressing ITGA4 from a control (upper panel) and T1DM (bottom panel) patient.</p