Acute respiratory infections (ARIs) comprise a large and heterogeneous group of infections including bacterial, viral and other aetiologies. In recent years, procalcitonin - the prohormone of ...calcitonin - has emerged as a promising marker for the diagnosis of bacterial infections and for improving decisions about antibiotic therapy. Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with acute respiratory infections and different settings ranging from primary care to emergency departments (EDs), hospital wards and intensive care units (ICUs).
The aim of this systematic review based on individual patient data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May 2011) and EMBASE (1974 to May 2011) to identify suitable trials.
We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm or usual care/guidelines. Trials were excluded if they exclusively focused on paediatric patients or if they used procalcitonin for another purpose than to guide initiation and duration of antibiotic treatment.
Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days. For the primary care setting, treatment failure was defined as death, hospitalisation, ARI-specific complications, recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection at follow-up. For the ED setting, treatment failure was defined as death, ICU admission, re-hospitalisation after index hospital discharge, ARI-associated complications, and recurrent or worsening infection within 30 days of follow-up. For the ICU setting, treatment failure was defined as death within 30 days of follow-up. Secondary endpoints were antibiotic use (initiation of antibiotics, duration of antibiotics and total exposure to antibiotics (total amount of antibiotic days divided by total number of patients)), length of hospital stay for hospitalised patients, length of ICU stay for critically ill patients, and number of days with restricted activities within 14 days after randomisation for primary care patients.For the two co-primary endpoints of all-cause mortality and treatment failure, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression. The hierarchical regression model was adjusted for age and clinical diagnosis as fixed-effect. The different trials were added as random-effects into the model. We fitted corresponding linear regression models for antibiotic use. We conducted sensitivity analyses stratified by clinical setting and ARI diagnosis to assess the consistency of our results.
We included 14 trials with 4221 participants. There were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared to 134 deaths in 2126 control patients (6.3%) (adjusted OR 0.94, 95% CI 0.71 to 1.23). Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting, or ARI diagnosis. These results proved robust in various sensitivity analyses. Total antibiotic exposure was significantly reduced overall (median (interquartile range) from 8 (5 to 12) to 4 (0 to 8) days; adjusted difference in days, -3.47, 95% CI -3.78 to -3.17, and across all the different clinical settings and diagnoses.
Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARI was not associated with higher mortality rates or treatment failure. Antibiotic consumption was significantly reduced across different clinical settings and ARI diagnoses. Further high-quality research is needed to confirm the safety of this approach for non-European countries and patients in intensive care. Moreover, future studies should also establish cost-effectiveness by considering country-specific costs of procalcitonin measurement and potential savings in consumption of antibiotics and other healthcare resources, as well as secondary cost savings due to lower risk of side effects and reduced antimicrobial resistance.
The clinical utility of serum procalcitonin levels in guiding antibiotic treatment decisions in patients with sepsis remains unclear. This patient-level meta-analysis based on 11 randomized trials ...investigates the impact of procalcitonin-guided antibiotic therapy on mortality in intensive care unit (ICU) patients with infection, both overall and stratified according to sepsis definition, severity, and type of infection.
For this meta-analysis focusing on procalcitonin-guided antibiotic management in critically ill patients with sepsis of any type, in February 2018 we updated the database of a previous individual patient data meta-analysis which was limited to patients with respiratory infections only. We used individual patient data from 11 trials that randomly assigned patients to receive antibiotics based on procalcitonin levels (the "procalcitonin-guided" group) or the current standard of care (the "controls"). The primary endpoint was mortality within 30 days. Secondary endpoints were duration of antibiotic treatment and length of stay.
Mortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs 23.7%; adjusted odds ratio 0.89, 95% confidence interval (CI) 0.8 to 0.99; p = 0.03). These effects on mortality persisted in a subgroup of patients meeting the sepsis 3 definition and based on the severity of sepsis (assessed on the basis of the Sequential Organ Failure Assessment (SOFA) score, occurrence of septic shock or renal failure, and need for vasopressor or ventilatory support) and on the type of infection (respiratory, urinary tract, abdominal, skin, or central nervous system), with interaction for each analysis being > 0.05. Procalcitonin guidance also facilitated earlier discontinuation of antibiotics, with a reduction in treatment duration (9.3 vs 10.4 days; adjusted coefficient -1.19 days, 95% CI -1.73 to -0.66; p < 0.001).
Procalcitonin-guided antibiotic treatment in ICU patients with infection and sepsis patients results in improved survival and lower antibiotic treatment duration.
Autonomic dysregulation is one of the recognized pathophysiological mechanisms in sepsis, generating the hypothesis that heart rate variability (HRV) can be used to predict mortality in sepsis.
This ...was a systematic review of studies evaluating HRV as a predictor of death in patients with sepsis. The search was performed by independent researchers in PubMed, LILACS and Cochrane, including papers in English, Portuguese or Spanish, indexed until August 20th, 2017 with at least 10 patients. Study quality was assessed by Newcastle-Ottawa Scale. To analyze the results, we divided the articles between those who measured HRV for short-term recordings (≤ 1 hour), and those who did long-term recordings (≥ 24 hours).
Nine studies were included with a total of 536 patients. All of them were observational studies. Studies quality varied from 4 to 7 stars in Newcastle-Ottawa Scale. The mortality rate in the studies ranged from 8 to 61%. Seven studies performed HRV analysis in short-term recordings. With the exception of one study that did not explain which group had the lowest results, all other studies showed reduction of several HRV parameters in the non-survivors in relation to the surviving septic patients. SDNN (Standard deviation of the Normal to Normal interval), TP (Total Power), VLF (Very Low Frequency Power), LF (Low Frequency Power), LF/HF (Low Frequency Power / High Frequency Power), nLF (Normalized Low Frequency Power), α1/α2 (short-term and long-term fractal scaling coefficients from DFA) and r-MSSD (Square root of the squared mean of the difference of successive NN-intervals) of the non-survivor group were reduced in relation to the survivors in at least one study. Two studies found that SDNN is associated with mortality in sepsis, even after adjusting for possible confounding factors. Three studies performed HRV analysis using long-term recordings. Only one of these studies found difference between surviving and non-surviving groups, and even so, in only one HRV parameter: LogHF.
Several HRV parameters are reduced in nonsurviving septic patients in short-term recording. Two studies have found that SDNN is associated with mortality in sepsis, even after adjusting for possible confounding factors.
Background. Procalcitonin algorithms may reduce antibiotic use for acute respiratory tract infections (ARIs). We undertook an individual patient data meta-analysis to assess safety of this approach ...in different ARI diagnoses and different clinical settings. Methods. We identified clinical trials in which patients with ARI were assigned to receive antibiotics based on a procalcitonin algorithm or usual care by searching the Cochrane Register, MEDLINE, and EMBASE. Individual patient data from 4221 adults with ARIs in 14 trials were verified and reanalyzed to assess risk of mortality and treatment failure—overall and within different clinical settings and types of ARIs. Results. Overall, there were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared with 134 deaths in 2126 control patients (6.3%; adjusted odds ratio, 0.94; 95% confidence interval CI, .71–1.23). Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%; adjusted odds ratio, 0.82; 95% CI, .71–.97). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting or ARI diagnosis. Total antibiotic exposure per patient was significantly reduced overall (median interquartile range, from 8 5–12 to 4 0–8 days; adjusted difference in days, −3.47 95% CI, −3.78 to −3.17) and across all clinical settings and ARI diagnoses. Conclusions. Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARIs was effective in reducing antibiotic exposure across settings without an increase in the risk of mortality or treatment failure. Further high-quality trials are needed in critical-care patients.
Inadequate antibiotic therapy, generally defined as microbiologically ineffective anti-infective therapy against the causative pathogen, can influence patient outcome. However, the detrimental ...effects of inadequate antibiotic therapy seem to become weaker in the most severely ill patients with short life expectancies. In addition to severity of illness, other methodological issues should be carefully examined in studies assessing the excess mortality due to inadequate therapy. To adjust for confounding as much as possible in order to obtain an unbiased estimate of the magnitude of the effect of inadequate therapy is a key methodological challenge for future research. With regard to the choice of antibiotic agents, β-lactam and aminoglycoside combination therapy does not seem to improve clinical outcome in most cases of sepsis caused by gram-negative bacteria, including Pseudomonas aeruginosa bacteremia. A potential benefit of combination therapy in the treatment of severe pneumococcal sepsis has been suggested in several observational studies, but recently published data have disputed this hypothesis. Finally, better risk scores and laboratory tools are urgently needed to improve the adequacy of empirical antibiotic therapy and patient outcomes.
Sepsis is a serious medical condition with increasing prevalence and high mortality. The role of the autonomic nervous system in pathophysiology of sepsis has been increasingly researched. The ...objective of this study is to evaluate the Heart rate variability (HRV) as a predictor of mortality in septic patients.
This was a prospective cohort of patients diagnosed with sepsis. Patient recruitment was carried out at ICU in tertiary university hospital between March 2012 and February 2014. Clinical data and laboratory exams were collected at admission. Each patient underwent a 20-minute Holter and a 24-hour Holter on the first day of enrollment. The primary outcome was the 28-day all-cause mortality.
A total of 63 patients were included. Patients were categorized into nonsurvivor group (n = 16) or survivor group (n = 47) depending on this endpoint. Survivors were younger (48.6 years vs. 63.0 years), had better renal function and lower values in severity scores (APACHE II and SOFA) compared to nonsurvivors. In the 20-minute Holter, SDNN, Total Power, VLF Power, LF Power and LF/HF of nonsurvivors were significantly lower than those of survivors (p = <0.001, p = 0.003, p = 0.002, p = 0.006, p = 0.009 respectively). ROC curve of SDNN was built, showing area under the curve of 0.772 (0.638-0.906) for mortality. The value of 17ms was chosen as best SDNN cutoff to discriminate survivors and nonsurvivors. In the Cox proportional regression, adjusted for SOFA score and for APACHE II, a SDNN ≤ 17ms was associated with a greater risk of death, with hazard ratios of 6.3 (1.4-28.0; p = 0.015) and 5.5 (1,2-24,8; p = 0.027), respectively. The addition of the dichotomized SDNN to the SOFA model reduced AIC and increased the concordance statistic and the R2, indicating that predictive power of the SDNN + SOFA model is better than predictive power of SOFA only.
Several HRV parameters are reduced in nonsurviving septic patients. SDNN ≤17 is a risk factor for death in septic patients, even after adjusting for severity scores.
The rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. We therefore sought to evaluate the effectiveness of a C-reactive protein-based ...protocol in reducing antibiotic treatment time in critically ill patients.
A randomized, open-label, controlled clinical trial conducted in two intensive care units of a university hospital in Brazil. Critically ill infected adult patients were randomly allocated to (i) intervention to receive antibiotics guided by daily monitoring of CRP levels and (ii) control to receive antibiotics according to the best practices for rational use of antibiotics.
One hundred thirty patients were included in the CRP (n = 64) and control (n = 66) groups. In the intention-to-treat analysis, the median duration of antibiotic therapy for the index infectious episode was 7.0 (5.0-8.8) days in the CRP and 7.0 (7.0-11.3) days in the control (p = 0.011) groups. A significant difference in the treatment time between the two groups was identified in the curve of cumulative suspension of antibiotics, with less exposure in the CRP group only for the index infection episode (p = 0.007). In the per protocol analysis, involving 59 patients in each group, the median duration of antibiotic treatment was 6.0 (5.0-8.0) days for the CRP and 7.0 (7.0-10.0) days for the control (p = 0.011) groups. There was no between-group difference regarding the total days of antibiotic exposure and antibiotic-free days.
Daily monitoring of CRP levels may allow early interruption of antibiotic therapy in a higher proportion of patients, without an effect on total antibiotic consumption. The clinical and microbiological relevance of this finding remains to be demonstrated.
ClinicalTrials.gov Identifier: NCT02987790. Registered 09 December 2016.
OBJECTIVESepsis survivors present a wide range of sequelae; few studies have evaluated psychiatric disorders after sepsis. The objective of this study was to define the prevalence of and risk factors ...for anxiety, depression and post-traumatic stress disorder (PTSD) symptoms in sepsis survivors. METHODAnxiety, depression and post-traumatic stress symptoms in severe sepsis and septic shock survivors 24 h and 1 year after intensive care unit (ICU) discharge were assessed using the Beck Anxiety/Depression Inventories and the PTSD Checklist-Civilian Version. Differences in psychiatric symptoms over time and the influence of variables on these symptoms were calculated with marginal models. RESULTSA total of 33 patients were enrolled in the study. The frequencies of anxiety, depression and PTSD 24 h after ICU discharge were 67%, 49%, and 46%, respectively and, among patients re-evaluated 1 year after ICU discharge, the frequencies were 38%, 50%, and 31%, respectively. Factors associated with PTSD included serum S100B level, age, and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score. Factors associated with depression included patient age and cumulative dose of dobutamine. IQCODE score and cumulative dose of haloperidol in the ICU were associated with anxiety after ICU discharge. CONCLUSIONPatients who survive sepsis have high levels of psychiatric symptoms. Sepsis and associated treatment-related exposures may have a role in increasing the risk of subsequent depression, anxiety, and PTSD.
Evaluate risk factors and clinical outcomes of infections caused by Enterobacteriaceae resistant to third-generation cephalosporins present in samples collected upon hospital admission.
Risk factors ...were evaluated using a 1:2 ratio case–control study. Influence of resistance on the appropriateness of antibiotic therapy, length of stay, and hospital mortality were prospectively evaluated. Characteristics independently associated with the presence of resistant enterobacteria were assessed by logistic regression.
Enterobacteria resistant to third-generation cephalosporins were quite common (26.0%). Male gender (OR: 2.66; 95% CI, 1.17–5.06; p=0.019), invasive prosthesis (OR: 3.79; 95% CI, 1.29–11.08; p=0.015), previous use of cephalosporins (OR: 2.77; 95% CI, 1.10–6.97; p=0.029) and hospitalization in the last 6 months (OR: 5.33; 95% CI, 2.29–12.44; p<0.001) were independently associated with the presence of these microorganisms. These bacteria were associated with higher frequency of inappropriate antimicrobial therapy, worse clinical response, and longer length of stay. Finally, older age, admission to the ICU, and site of infection other than urinary tract were independently associated to higher hospital mortality.
Risk factors identified in this study may help in the choice of empirical antibiotic therapy for infected patients suspected of harboring these bacteria and in the early implementation of measures to avoid the spread of these bacteria in the hospital environment.
C-reactive protein (CRP) is an inflammatory protein used in clinical practice to identify and monitor inflammatory and infectious processes. Recent data suggest CRP might be useful in guiding ...antibiotic therapy discontinuation among critical care patients. This meta-analysis analyzed the benefits and risks of CRP-guided protocols to guide antibiotic therapy in hospitalized patients in comparison with standard treatment.
Studies were searched in four databases: CENTRAL, Medline, Embase and LILACS. The search was performed until Jan 25th, 2023. The reference lists of the articles retrieved and related review studies were hand-screened to find eligible trials that might have been missed. Primary endpoints included the duration of antibiotic therapy for the index episode of infection. The secondary endpoint was the all-cause hospital mortality and infection relapses. The risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Random effects were used to pool the mean differences and odds ratio of individual studies. The protocol was registered in PROSPERO (CRD42021259977).
The search strategy retrieved 5209 titles, out of which three studies met the eligibility criteria and were included in this meta-analysis. 727 adult patients were analyzed, of whom 278 were included in the intervention group and 449 were included in the control group. 55,7% of all patients were women. Meta-analysis indicated that experimental groups (CRP-guided) had a lower duration of antibiotic therapy (days) MMD = -1.82, 95%IC -3.23; -0.40; with no difference in mortality OR = 1.19 95%IC 0.67-2.12 or in the occurrence of infection relapse OR = 3.21 95%IC 0.85-12.05.
The use of CRP-guided protocol reduces the total amount of time required for antibiotic therapy when compared to standard protocols of treatment in hospitalized patients with acute bacterial infection. We did not observe statistical differences regarding mortality and infection relapse rates.
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