Procalcitonin and pyuria-based algorithm reduces antibiotic use in urinary tract infections: a randomized controlled trial.

BACKGROUND: Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure. METHODS: From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria-based algorithm (PCT-pyuria group). The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days. RESULTS: Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 [IQR, 5.0-14.0] vs. 10.0 [IQR, 7.0-16.0] days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different. CONCLUSIONS: A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes.

Effectiveness of Proadrenomedullin Enhanced CURB65 Score Algorithm in Patients with Community-Acquired Pneumonia in "Real Life", an Observational Quality Control Survey.

BACKGROUND: An intervention trial found a trend for shorter length of stay (LOS) in patients with community-acquired pneumonia (CAP) when the CURB65 score was combined with the prognostic biomarker proadrenomedullin (ProADM) (CURB65-A). However, the efficacy and safety of CURB65-A in real life situations remains unclear. METHODS: From September, 2011, until April, 2012, we performed a post-study prospective observational quality control survey at the cantonal Hospital of Aarau, Switzerland of consecutive adults with CAP. The primary endpoint was length of stay (LOS) during the index hospitalization and within 30 days. We compared the results with two well-defined historic cohorts of CAP patients hospitalized in the same hospital with the use of multivariate regression, namely 83 patients in the observation study without ProADM (OPTIMA I) and the 169 patients in the intervention study (OPTIMA II RCT). RESULTS: A total of 89 patients with confirmed CAP were included. As compared to patients with CURB65 only observed in the OPTIMA I study, adjusted regression analysis showed a significant shorter initial LOS (7.5 vs. 10.4 days; -2.32; 95% CI, -4.51 to -0.13; p = 0.04) when CURB65-A was used in clinical routine. No significant differences were found for LOS within 30 days. There were no significant differences in safety outcomes in regard to mortality and ICU admission between the cohorts. CONCLUSION: This post-study survey provides evidence that the use of ProADM in combination with CURB65 (CURB65-A) in "real life" situations reduces initial LOS compared to the CURB65 score alone without apparent negative effects on patient safety.

Procalcitonin, pyuria and proadrenomedullin in the management of urinary tract infections--'triple p in uti': study protocol for a randomized controlled trial.

BACKGROUND: Urinary tract infections (UTIs) are among the most common infectious diseases and drivers of antibiotic use and in-hospital days. A reduction of antibiotic use potentially lowers the risk of antibiotic resistance. An early and adequate risk assessment combining medical, biopsychosocial and functional risk scores has the potential to optimize site-of-care decisions and thus allocation of limited health-care resources. The aim of this factorial design study is twofold: first, for Intervention A, it investigates antibiotic exposure of patients treated with a protocol based on the type of UTI, procalcitonin (PCT) and pyuria. Second, for Intervention B, it investigates the usefulness of the prognostic biomarker proadrenomedullin (ProADM) integrated into an interdisciplinary assessment bundle for site-of-care decisions. METHODS AND DESIGN: This randomized controlled open-label trial has a factorial design (2 × 2). Randomization of patients will be based on a pre-specified computer-generated randomization list and independent for the two interventions. Adults with UTI presenting to the emergency department (ED) will be screened and enrolled after providing informed consent. For our first Intervention (A), we developed a protocol based on previous observational research to recommend initiation and duration of antibiotic use based on the clinical presentation of UTI, pyuria and PCT levels. For our second intervention (B), an algorithm was developed to support site-of care decisions based on the prognostic marker ProADM and distinct nursing factors on days 1 and 3. Both interventions will be compared with a control group conforming to the guidelines. The primary endpoints for the two interventions will be: (A) overall exposure to antibiotics and (B) length of physician-led hospitalization within a follow-up of 30 days. Endpoints are assessed at discharge from hospital, and 30 and 90 days after admission. We plan to screen 300 patients and enroll 250 for an anticipated estimated loss of follow-up of 20%. This will provide adequate power for the two interventions. DISCUSSION: This trial investigates two strategies for improved individualized medical care in patients with UTI. The minimally effective duration of antibiotic therapy is not known for UTIs, which is important for reducing the selection pressure for antibiotic resistance, costs and drug-related side effects. Triage decisions must be improved to reflect the true medical, biopsychosocial and functional risks in order to allocate patients to the most appropriate care setting and reduce hospital-acquired disability. TRIAL REGISTRATION NUMBER: ISRCTN13663741.

Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial.

Concerns about inadequate performance and complexity limit routine use of clinical risk scores in lower respiratory tract infections. Our aim was to study feasibility and effects of adding the biomarker proadrenomedullin (proADM) to the confusion, urea>7 mmol·L(-1), respiratory rate≥30 breaths·min(-1), blood pressure<90 mmHg (systolic) or ≤60 mmHg (diastolic), age≥65 years (CURB-65) score on triage decisions and length of stay. In a randomised controlled proof-of-concept intervention trial, triage and discharge decisions were made for adults with lower respiratory tract infection according to interprofessional assessment using medical and nursing risk scores either without (control group) or with (proADM group) knowledge of proADM values, measured on admission, and on days 3 and 6. An adjusted generalised linear model was calculated to investigate the effect of our intervention. On initial presentation the algorithms were overruled in 123 (39.3%) of the cases. Mean length of stay tended to be shorter in the proADM (n=154, 6.3 days) compared with the control group (n=159, 6.8 days; adjusted regression coefficient -0.19, 95% CI -0.41-0.04; p=0.1). This trend was robust in subgroup analyses and for overall length of stay within 90 days (7.2 versus 7.9 days; adjusted regression coefficient -0.18, 95% CI -0.40-0.05; p=0.13). There were no differences in adverse outcomes or readmission. Logistic obstacles and overruling are major challenges to implement biomarker-enhanced algorithms in clinical settings and need to be addressed to shorten length of stay.

Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial.

This study evaluated the effect of physiological l-thyroxine (L-T4) treatment on bone metabolism in patients with subclinical hypothyroidism. Sixty-six women with subclinical hypothyroidism (TSH 11.7 +/- 0.8 mIU/l) were randomly assigned to receive L-T4 or placebo for 48 weeks. Sixty-one of 66 patients completed the study. Individual L-T4 replacement (mean dosage 85.5 +/- 4.3 microg/day) was performed targeting euthyroid thyroid-stimulating hormone (TSH) levels. The primary outcome measure was 24- and 48-week change in markers of bone formation (total and bone alkaline phosphatase [ALP, bone ALP], osteocalcin [OC]) and resorption (pyridinoline [PYD] and deoxypyridinoline [DPD], C-terminal cross-linking telopeptide type I [CTX]). Secondary outcomes were 48-week changes in bone mineral density (BMD) of the lumbar spine and hip, measured by dual-energy X-ray absorptiometry. Compared with placebo, l-thyroxine ( n=31) resulted in significant activation of bone turnover. Overall, a significant treatment effect was observed for DPD (between-group difference 16.0%; 95%CI, 10.9 to 21.1), CTX (29.9%; 95%CI, 23.3 to 36.5), and bone ALP (13.2%; 95%CI, 6.6 to 19.7) after 24 weeks. At the end of the study, lumbar BMD in the both treatment groups differed by 1.3% (95%CI, -2.9 to 0.5) with lower levels in l-thyroxine treated women. Significant difference in BMD between groups was also observed at the trochanter. We conclude that physiological l-thyroxine treatment accelerates bone turnover reflecting early activation of bone remodeling units in the initial replacement of subclinical hypothyroidism. The observed bone loss could be interpreted as an adaptive mechanism on decreased bone turnover in preexistent hypothyroidism, and not as l-thyroxine-induced clinically important bone loss. However, long-term studies are needed to confirm this assumption.

Prolactin dysregulation in women with subclinical hypothyroidism: effect of levothyroxine replacement therapy.

This study investigated the effect of levothyroxine treatment on serum prolactin (PRL) levels in women with subclinical hypothyroidism. Sixty-six women (mean age, 58.5 +/- 1.3 years) with confirmed subclinical hypothyroidism (mean thyrotropin [TSH], 11.7 +/- 0.8 mIU/L) were randomly assigned to receive levothyroxine or placebo for 48 weeks. Based on blinded TSH monitoring, physiologic levothyroxine replacement (85.5 +/- 4.3 microg/d; TSH, 3.1 +/- 0.3 mIU/L) was ascertained throughout the study. PRL levels were measured before and after administration of thyrotropin-releasing hormone (TRH) at baseline, after 24 and 48 weeks. Sixty-three of the 66 women completed the study. At baseline, basal PRL levels were elevated in 19% of the patients. None of the patients reported menstrual disturbances, infertility, or galactorrhea. In the levothyroxine group (n = 31) basal and peak PRL levels were significantly reduced after 24 and 48 weeks (p = 0.03 and p = 0.001). Mean changes in PRL levels differed significantly between the two treatment groups after 24 weeks (p = 0.03 and p = 0.01). The treatment effect was more pronounced in patients with PRL and TSH levels above the median at baseline (i.e., PRL > 16 ng/mL; TSH > 11 mIU/L). Based on this double-blinded, placebo-controlled study we demonstrate that in subclinical hypothyroidism PRL regulation is altered with elevated basal and stimulated PRL levels, and that physiologic levothyroxine treatment restores PRL concentrations.

Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial.

Hypothyroidism is associated with premature atherosclerosis and cardiovascular disease. Recently, total homocysteine (tHcy) and C-reactive protein (CRP) emerged as additional cardiovascular risk factors. We first investigated CRP and tHcy in different severities of primary hypothyroidism and in a second study we evaluated the effect of L-thyroxine treatment in patients with subclinical hypothyroidism (SCH) in a double-blind, placebo-controlled trial. One hundred and twenty-four hypothyroid patients (63 with subclinical, 61 with overt hypothyroidism, OH) and 40 euthyroid controls were evaluated. CRP was measured using a latex-based high sensitivity immunoassay; tHcy was determined by a fluorescence polarization immunoassay. tHcy values were significantly elevated in OH (P=0.01). In SCH tHcy levels were not augmented as compared to controls. CRP values were significantly increased in OH (P=0.016) and SCH (P=0.022) as compared to controls. In a univariate analysis tHcy correlated significantly with fT4, vitamin B12, folic acid and creatinine levels. In multiple regression analysis only fT4 (beta=0.33) had a significant effect on tHcy. CRP did not correlate with thyroid hormones. In SCH, L-T4 replacement had no significant effect on either tHcy or CRP levels. This is the first paper to show that CRP values increase with progressive thyroid failure and may count as an additional risk factor for the development of coronary heart disease in hypothyroid patients. In contrast to overt disease, only CRP, but not tHcy values, are affected in SCH, yet without significant improvement after L-thyroxine therapy.

Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies.

Subclinical hypothyroidism is a frequent syndrome affecting about 10 million people in the United States. The management of such patients is open to debate. In a long-term prospective study we analyzed the spontaneous course and the value of predictive factors in the development of overt thyroid failure. We studied 82 female patients with subclinical hypothyroidism prospectively over a mean observation period of 9.2 yr. TSH, thyroid hormones, thyroid reserve after TRH administration, thyroid antibodies, and clinical parameters were assessed at yearly intervals. The cumulative incidence of overt hypothyroidism was calculated using life-table analysis and Kaplan-Meier curves. According to the initial serum TSH concentrations (TSH, 4-6/>6-12/>12 mU/liter), Kaplan-Meier estimates of the incidence of overt hypothyroidism were 0%, 42.8%, and 76.9%, respectively, after 10 yr (P < 0.0001). When only patients with TSH levels greater than 6 mU/liter were analyzed, the cumulative incidence was 55.3%. The incidence of overt hypothyroidism increased in patients with impaired thyroid reserve (52.6% vs. 38.1%; P = 0.05) and positive microsomal antibodies (58.5% vs. 23.2%; P = 0.03). This prospective long-term study demonstrates that only a part of the cohort of patients with subclinical hypothyroidism develops overt hypothyroidism over time and that a major group remains in the subclinical state after 10 yr. The measurement of TSH, microsomal (thyroperoxidase) antibodies, and thyroid reserve allows initial risk stratification for the development of overt thyroid failure (risk ratio ranging from 1.0-15.6). Our study helps to recognize the spontaneous course of subclinical hypothyroidism and in the identification of patients most likely to progress to overt hypothyroidism.