Purpose
Prognosis of solid organ transplant (SOT) recipients has improved, mainly because of better prevention of rejection by immunosuppressive therapies. However, SOT recipients are highly ...susceptible to conventional and opportunistic infections, which represent a major cause of morbidity, graft dysfunction and mortality.
Methods
Narrative review.
Results
We cover the current epidemiology and main aspects of infections in SOT recipients including risk factors such as postoperative risks and specific risks for different transplant recipients, key points on anti-infective prophylaxis as well as diagnostic and therapeutic approaches. We provide an up-to-date guide for management of the main syndromes that can be encountered in SOT recipients including acute respiratory failure, sepsis or septic shock, and central nervous system infections as well as bacterial infections with multidrug-resistant strains, invasive fungal diseases, viral infections and less common pathogens that may impact this patient population.
Conclusion
We provide state-of the art review of available knowledge of critically ill SOT patients with infections.
Background
Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a ...blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT‐guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta‐analysis first published in 2012 designed to look at the safety of PCT‐guided antibiotic stewardship.
Objectives
The aim of this systematic review based on individual participant 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.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017.
Selection criteria
We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT‐guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment.
Data collection and analysis
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 which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic‐related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed‐effect model. The different trials were added as random‐effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta‐analysis.
Main results
From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta‐analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic‐related side effects.
Primary endpoints: there were 286 deaths in 3336 procalcitonin‐guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin‐guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin‐guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4‐day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI ‐2.71 to ‐2.15, P < 0.001) and lower risk of antibiotic‐related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate‐data analysis based on all 32 eligible trials showed similar results.
Authors' conclusions
This updated meta‐analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic‐related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high‐quality research is needed to confirm the results in immunosuppressed patients and patients with non‐respiratory infections.
The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown.
To determine whether preemptive ...treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation.
A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018.
Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo.
The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis.
Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median IQR age, 61 50-70 years; 76 32% women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, -0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events.
In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting.
ClinicalTrials.gov identifier: NCT02152358.
To determine the effect of a 2-yr multifaceted program aimed at preventing ventilator-acquired pneumonia on compliance with eight targeted preventive measures.
Pre- and postintervention observational ...study.
A 20-bed medical intensive care unit in a teaching hospital.
A total of 1649 ventilator-days were observed.
The program involved all healthcare workers and included a multidisciplinary task force, an educational session, direct observations with performance feedback, technical improvements, and reminders. It focused on eight targeted measures based on well-recognized published guidelines, easily and precisely defined acts, and directly concerned healthcare workers' bedside behavior. Compliance assessment consisted of five 4-wk periods (before the intervention and 1 month, 6 months, 12 months, and 24 months thereafter).
Hand-hygiene and glove-and-gown use compliances were initially high (68% and 80%) and remained stable over time. Compliance with all other preventive measures was initially low and increased steadily over time (before 2-yr level, p < .0001): backrest elevation (5% to 58%) and tracheal cuff pressure maintenance (40% to 89%), which improved after simple technical equipment implementation; orogastric tube use (52% to 96%); gastric overdistension avoidance (20% to 68%); good oral hygiene (47% to 90%); and nonessential tracheal suction elimination (41% to 92%). To assess overall performance of the last six preventive measures, using ventilator-days as the unit of analysis, a composite score for preventive measures applied (range, 0-6) was developed. The median (interquartile range) composite scores for the five successive assessments were 2 (1-3), 4 (3-5), 4 (4-5), 5 (4-6), and 5 (4-6) points; they increased significantly over time (p < .0001). Ventilator-acquired pneumonia prevalence rate decreased by 51% after intervention (p < .0001).
Our active, long-lasting program for preventing ventilator-acquired pneumonia successfully increased compliance with preventive measures directly dependent on healthcare workers' bedside performance. The multidimensional framework was critical for this marked, progressive, and sustained change.
The optimal duration of antimicrobial treatment for ventilator-associated pneumonia (VAP) is unknown. Shortening the length of treatment may help to contain the emergence of multiresistant bacteria ...in the intensive care unit (ICU).
To determine whether 8 days is as effective as 15 days of antibiotic treatment of patients with microbiologically proven VAP.
Prospective, randomized, double-blind (until day 8) clinical trial conducted in 51 French ICUs. A total of 401 patients diagnosed as having developed VAP by quantitative culture results of bronchoscopic specimens and who had received initial appropriate empirical antimicrobial therapy were enrolled between May 1999 and June 2002.
A total of 197 patients were randomly assigned to receive 8 days and 204 to receive 15 days of therapy with an antibiotic regimen selected by the treating physician.
Primary outcome measures-death from any cause, microbiologically documented pulmonary infection recurrence, and antibiotic-free days-were assessed 28 days after VAP onset and analyzed on an intent-to-treat basis.
Compared with patients treated for 15 days, those treated for 8 days had neither excess mortality (18.8% vs 17.2%; difference, 1.6%; 90% confidence interval CI, -3.7% to 6.9%) nor more recurrent infections (28.9% vs 26.0%; difference, 2.9%; 90% CI, -3.2% to 9.1%), but they had more mean (SD) antibiotic-free days (13.1 7.4 vs 8.7 5.2 days, P<.001). The number of mechanical ventilation-free days, the number of organ failure-free days, the length of ICU stay, and mortality rates on day 60 for the 2 groups did not differ. Although patients with VAP caused by nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, did not have more unfavorable outcomes when antimicrobial therapy lasted only 8 days, they did have a higher pulmonary infection-recurrence rate compared with those receiving 15 days of treatment (40.6% vs 25.4%; difference, 15.2%, 90% CI, 3.9%-26.6%). Among patients who developed recurrent infections, multiresistant pathogens emerged less frequently in those who had received 8 days of antibiotics (42.1% vs 62.0% of pulmonary recurrences, P =.04).
Among patients who had received appropriate initial empirical therapy, with the possible exception of those developing nonfermenting gram-negative bacillus infections, comparable clinical effectiveness against VAP was obtained with the 8- and 15-day treatment regimens. The 8-day group had less antibiotic use.
Cerebral lesions are frequent complications of infective endocarditis (IE) and have a prognostic impact. Cerebral MRI identifies lesions in a high number of patients. However, their determinants have ...not been identified. The aim of the study was to define the determinants of cerebral lesions in patients with IE undergoing systematic cerebral MRI.
Determinants of ischemic lesions and of microbleeds were prospectively analyzed in 120 patients with left-sided IE, using systematic cerebral MRI.
Median age was 60 years (interquartile range 51-72); IE occurred on a prosthetic valve in 37 patients (30.8%) and was due to Streptococci in 47 patients and Staphylococci in 36; 15 (12.5%) had neurological symptoms. MRI detected ischemic lesions in 64 patients (53.3%; territorial lesions in 32 and small lesions in 57) and microbleeds in 72 (60.0%). In multivariate analysis, ischemic lesions were associated with vegetation length (odds ratio 1.10/mm; 95% confidence interval 1.03-1.16; P=0.003) and Staphylococcus aureus IE (odds ratio 2.65; 95% confidence interval 1.01-6.96; P=0.05). A vegetation length >4 mm identified ischemic lesions with a sensitivity of 74.6% and a specificity of 51.5%. Microbleeds were associated with prosthetic IE (odds ratio 8.01; 95% confidence interval 2.58-24.90; P=0.0003) and not with prior anticoagulant therapy (P=0.67).
Systematic cerebral MRI frequently detects ischemic lesions and microbleeds during acute IE. The high sensitivity of MRI shows that each millimeter increase in vegetation length is associated with a 10% increase in the rate of ischemic lesions. Conversely, microbleeds are associated only with prosthetic IE in this study.
http://www.clinicaltrials.gov. Unique identifier: NCT00144885.
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