Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. [Duration of antibiotic therapy for ventilator-associated pneumonia: comparison of 7 and 10 days. A pilot study]. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.
Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting.
                In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667.
                Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21.2% [65/307] vs 20.4% [64/314]; absolute difference 0.8%, 90% CI -4.6 to 6.2) and day 60 (30.0% [92/307] vs 26.1% [82/314]; 3.8%, -2.1 to 9.7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14.3 days [SD 9.1] vs 11.6 days [SD 8.2]; absolute difference 2.7 days, 95% CI 1.4 to 4.1, p<0.0001).
                A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes.
                Assistance Publique-Hôpitaux de Paris, France, and Brahms, Germany.
                Copyright 2010 Elsevier Ltd. All rights reserved. To evaluate an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia (VAP).
                Prospective, randomized, controlled clinical trial.
                A medical ICU from a university-affiliated urban teaching hospital.
                Between April 2002 and July 2003, 290 patients completed the clinical trial.
                Patients were assigned to have the duration of antibiotic treatment for VAP determined by an antibiotic discontinuation policy (discontinuation group) or their treating physician teams (conventional group).
                Severity of illness using APACHE (acute physiology and chronic health evaluation) II score (22.8 +/- 9.0 vs 23.2 +/- 9.4, p = 0.683) [mean +/- SD] and the clinical pulmonary infection score (7.1 +/- 0.9 vs 7.2 +/- 0.9, p = 0.222) were similar for both patient groups. The duration of antibiotic treatment for VAP was statistically shorter among patients in the discontinuation group compared to patients in the conventional antibiotic management group (6.0 +/- 4.9 days vs 8.0 +/- 5.6 days, p = 0.001). The occurrence of a secondary episode of VAP was not statistically different between these two groups (17.3% vs 19.3%, p = 0.667). Hospital mortality (32.0% vs 37.1%, p = 0.357) and ICU length of stay (6.8 +/- 6.1 days vs 7.0 +/- 7.3 days, p = 0.798) were also statistically similar.
                The application of an antibiotic discontinuation policy for clinically suspected VAP was associated with a decrease in the overall duration of antibiotic treatment. These findings suggest that shorter courses of empiric antibiotic therapy for patients treated for clinically suspected VAP can be safely achieved. To compare the efficiency of a 7-day antibiotics regimen with a 10-day regimen for ventilator-associated pneumonia (VAP).
                Prospective randomized study.
                Adults patients ventilated for more than 48 hours in the intensive care unit (ICU) with a clinical diagnosis of VAP documented by positive quantitative cultures of tracheal aspiration were included in this study. All included patients were randomized in two groups. Ten-day group: 10 days antibiotic therapy, and 7-day group: 7 days antibiotic therapy. Primary judgment criteria were 14- and 28-day mortality, the number of days without antibiotics. Secondary judgments criteria were rate of recurrent pulmonary infection, the evolution of the clinical pulmonary infection scores (CPIS), the length of ICU stay and the length of mechanical ventilation.
                Thirty patients were included in this study (16 in the 10-day group and 14 in the 7-day group). The demographic and clinical characteristics of the groups assigned to receive antibiotic therapy for 7 or 10 days were generally similar. The 14-day and 28-day mortality rate following VAP onset were 31.2 and 37.5% in the 10-day group and 7.1 and 35.7% in the 7-day group. The difference was not significant. The number of day without antibiotics and without mechanical ventilation turned out: 1.75 and 2.06 days versus 4.14 and 3.43 days in the 10-day group and 7-day group respectively, the recurrent rate of pulmonary infection (12.5% versus 14.3%, p=0.6), the length of stay in the ICU (27.7 days versus 26.0 days, p=0.8) and the evolution of the CPIS were no different in the two groups.
                In patients with microbiologically confirmed VAP who received appropriate empirical antibiotic therapy, a 7-day antibiotic regimen was as efficient clinically and microbiologically as a 10-day antibiotic regimen with a reduction of antibiotic use. 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. Inappropriate antibiotic use for pulmonary infiltrates is common in the intensive care unit (ICU). We sought to devise an approach that would minimize unnecessary antibiotic use, recognizing that a gold standard for the diagnosis of nosocomial pneumonia does not exist. In a randomized trial, clinical pulmonary infection score (CPIS) (Pugin, J., R. Auckenthaler, N. Mili, J. P. Janssens, R. D. Lew, and P. M. Suter. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" bronchoalveolar lavage fluid. Am. Rev. Respir. Dis. 1991;143: 1121-1129) was used as operational criteria for decision-making regarding antibiotic therapy. Patients with CPIS </= 6 (implying low likelihood of pneumonia) were randomized to receive either standard therapy (choice and duration of antibiotics at the discretion of physicians) or ciprofloxacin monotherapy with reevaluation at 3 d; ciprofloxacin was discontinued if CPIS remained </= 6 at 3 d. Antibiotics were continued beyond 3 d in 90% (38 of 42) of the patients in the standard as therapy compared with 28% (11 of 39) in the experimental therapy group (p = 0.0001). In patients in whom CPIS remained </= 6 at the 3 d evaluation point, antibiotics were still continued in 96% (24 of 25) in the standard therapy group but in 0% (0 of 25) of the patients in the experimental therapy group (p = 0.0001). Mortality and length of ICU stay did not differ despite a shorter duration (p = 0.0001) and lower cost (p = 0.003) of antimicrobial therapy in the experimental as compared with the standard therapy arm. Antimicrobial resistance, or superinfections, or both, developed in 15% (5 of 37) of the patients in the experimental versus 35% (14 of 37) of the patients in the standard therapy group (p = 0.017). Thus, overtreatment with antibiotics is widely prevalent, but unnecessary in most patients with pulmonary infiltrates in the ICU. The operational criteria used, regardless of the precise definition of pneumonia, accurately identified patients with pulmonary infiltrates for whom monotherapy with a short course of antibiotics was appropriate. Such an approach led to significantly lower antimicrobial therapy costs, antimicrobial resistance, and superinfections without adversely affecting the length of stay or mortality. In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.
We conclude that for patients with VAP not due to NF-GNB, a short fixed-course (seven or eight days) antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days). Use of an individualised strategy (incorporating clinical features or serum procalcitonin) appears to safely reduce duration of antibiotic therapy for VAP.