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* From the Department of Pharmacy (Dr. Micek), Barnes-Jewish Hospital; and Pulmonary and Critical Care Medicine Division (Dr. Kollef), Division of Infectious Diseases (Dr. Fraser), and Department of Nursing (Ms. Ward), Washington University School of Medicine, St. Louis, MO.
Correspondence to: Marin H. Kollef, MD, FCCP, Pulmonary and Critical Care Medicine, Washington University School of Medicine, Campus Box 8052, 660 South Euclid, St. Louis, MO 63110; e-mail: kollefm{at}msnotes.wustl.edu
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Abstract |
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Design: Prospective, randomized, controlled clinical trial.
Setting: A medical ICU from a university-affiliated urban teaching hospital.
Patients: Between April 2002 and July 2003, 290 patients completed the clinical trial.
Interventions: 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).
Results: 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.
Conclusions: 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.
Key Words: clinical outcomes • critical care • hospital mortality • ICU • infection • risk factors • ventilator-associated pneumonia
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Introduction |
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We previously demonstrated that a clinical guideline for the treatment of VAP statistically increased the administration of adequate antimicrobial treatment and reduced the overall duration of antibiotic administration compared to local historical data.14 To further generalize these results, a clinical trial was performed with two main goals. First, we wanted to determine the impact of a formalized antibiotic discontinuation policy on the duration of antibiotic treatment for clinically diagnosed VAP. Second, we sought to determine the safety of this antimicrobial discontinuation policy.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Study Design and Data Collection
Patients were randomly assigned to have the duration of empiric antibiotic therapy for VAP determined using a formalized antibiotic discontinuation policy (discontinuation group) or according to the clinical judgment of the treating ICU physicians (conventional group). The main intervention or difference between the two study groups was that an investigator offered recommendations for patients in the discontinuation group during patient care rounds to discontinue antibiotics based on the policy described below.
One of the investigators made daily rounds in the medical ICUs to identify eligible patients with VAP and to record relevant data from medical records, bedside flow sheets, computerized bedside nursing stations (EMTEK Health Care Systems; Tempe, AZ), computerized radiographic reports, and reports of microbiologic studies (sputum Gram stains and sputum, blood, and pleural fluid cultures). Study patients were prospectively followed up from the initial diagnosis of VAP and start of empiric antibiotic treatment until they were discharged from the hospital or until death. All patients with a "high likelihood" of VAP were prospectively and independently reviewed by one of the investigators (M.H.K.), who confirmed the diagnosis based on predetermined criteria (see below). Patients could not be entered into the study more than once.
For all study patients, the following characteristics were prospectively recorded at the time of study entry: age, gender, race, primary reason for mechanical ventilation, ratio of PaO2 to fraction of inspired oxygen (FIO2), severity of illness based on APACHE (acute physiology and chronic health evaluation) II scores,15 the clinical pulmonary infection score,16 the premorbid lifestyle score,17 the presence of COPD requiring treatment with inhaled bronchodilators or systemic corticosteroids, congestive heart failure requiring treatment with afterload reducing agents or inotropic agents, underlying malignancy, immunosuppression, and HIV-antibody status. Specific processes of medical care examined during the period of intensive care included the administration of corticosteroids, vasopressors, histamine type-2 receptor antagonists, sucralfate, proton-pump inhibitors, prior antibiotic therapy during the same hospitalization, reintubation, and tracheostomy. The main outcome evaluated was the duration of antibiotic treatment for VAP. Secondary outcomes evaluated included hospital mortality, lengths of ICU and hospital stay, duration of mechanical ventilation, and occurrence of a second episode of VAP during the same ICU stay.
VAP Antibiotic Discontinuation Policy
The need for initial empiric antibiotic treatment for suspected VAP was based on the clinical judgment of the treating physicians for both treatment groups. The VAP antibiotic discontinuation policy was developed based on our prior clinical experience.61214 The main goals of the policy were to allow the initial administration of adequate antimicrobial treatment for patients with clinically suspected VAP and to discontinue treatment when clinical evidence of infection had resolved. This was accomplished by recommending initial IV combination antimicrobial treatment for patients in both study groups with vancomycin, 1 g q12h, or linezolid, 600 mg q12h (for Gram-positive bacterial infection), and the combination of cefepime, 1 g q12h, and either ciprofloxacin, 400 mg q12h, or gentamicin, 5 mg/kg qd (for Gram-negative bacterial infection). The combinations of cefepime and ciprofloxacin or cefepime and gentamicin were selected because they provided adequate treatment for > 90% of Gram-negative bacterial isolates from patients with VAP based on the medical ICU-specific antibiogram. Additionally, all antibiotic administration was adjusted for patients with renal insufficiency to minimize iatrogenic toxicity.
Recommendations to discontinue empiric antibiotic treatment for VAP were only provided to physicians managing patients in the discontinuation group based on the following policy. This policy was implemented by one of the investigators (S.T.M. or M.H.K.) during weekdays. The antibiotic discontinuation policy was only implemented on weekends and holidays if one of the investigators was available in the hospital. Antibiotic treatment was to be discontinued if any one of the following conditions were identified: (1) noninfectious etiology for the infiltrates was identified not requiring antibiotics (eg, atelectasis, pulmonary edema); (2) signs and symptoms suggesting active infection had resolved (eg, temperature 
38.3°C, circulating leukocyte count < 10,000/µL [10 x 109/L] or decreased by > 25% from the peak value, improvement or lack of progression on the chest radiograph, absence of purulent sputum, and a PaO2/FIO2 ratio > 250). All of these criteria had to be met for the antibiotic discontinuation recommendation to be made.
The antibiotic discontinuation policy was set up so that it could be overridden by any of the treating physicians. However, recommendations to stop antibiotic treatment were given if patients continued to meet criteria for antibiotic discontinuation. Routine VAP prevention measures were applied to all patients in the medical ICU. These included maintaining a semirecumbent body position, discontinuation of mechanical ventilation using an ICU-specific weaning protocol, avoidance of gastric distension by monitoring residual volumes following feedings, and routine inspection of ventilator circuits to remove condensate.18
Definitions
All definitions were selected prospectively as part of the original study design. APACHE II scores were calculated based on clinical data available from the first 24 h of ICU admission.15 Immunosuppression was defined as patients receiving corticosteroids, having a positive HIV antibody, having received chemotherapy within the past 45 days, having neutropenia (absolute neutrophil count < 1.0 x 109/L) resulting from the administration of chemotherapy, or recipients of an organ transplant (renal, liver, heart, or bone marrow) requiring immunosuppressive agents. The premorbid lifestyle score was used as previously defined17: 0 indicated that the patient was employed without restriction; 1 indicated that the patient was independent, fully ambulatory, not employed, or employed with restriction; 2 indicated that the patient had restricted activities, could live alone and get out of the house to do basic necessities, or had severely limited exercise ability; 3 indicated that the patient was housebound, could not get out of the house unassisted, could not live alone, or could not do heavy chores; and 4 indicated that the patient was bed-bound or chair-bound.
The diagnostic criteria for a high likelihood of VAP were modified from those established by the American College of Chest Physicians.19 This definition was applied to all patients enrolled in this study to identify those individuals who were begun on antibiotic therapy for clinically suspected VAP by their ICU physicians, but failed to meet more formal criteria for that diagnosis. VAP was prospectively defined as the occurrence of new and persistent radiographic infiltrates in conjunction with one of the following: positive pleural culture findings for the same organism as that recovered in the tracheal aspirate or sputum; radiographic cavitation; histopathologic evidence of pneumonia; or two of the following: fever, leukocytosis, and purulent tracheal aspirate or sputum. Persistence of an infiltrate was defined as having the infiltrate present radiographically for at least 72 h. Fever was defined as an increase in the core temperature of 1°C or higher and a core temperature > 38.3°C. Leukocytosis was defined as a 25% increase in the circulating leukocytes from the baseline admission value and a value > 10,000/µL (10 x 109/L). Tracheal aspirates were considered purulent if abundant neutrophils were present per high-power field using Gram stain (ie, > 25 neutrophils per high-power field). Additionally, when available, bronchoscopic BAL cultures with appropriate quantitative thresholds were employed to support the diagnosis of VAP. For all other patients, a tracheal aspirate culture specimen was obtained prior to the start of antibiotic treatment. A second episode of VAP was considered to have occurred if it was diagnosed at least 48 h after completion of the course of antibiotic treatment for the first episode of VAP, or if a different pathogen was identified in a lower airway culture obtained with BAL. Hospital mortality was defined as those patient deaths occurring during the initial hospital admission during which they were studied.
All patients were prospectively screened to exclude the following possible alternative causes for fever and radiographic chest densities. The presence of atelectasis was defined by the complete disappearance of radiographic densities within 48 h of evaluation. Congestive heart failure with pulmonary edema was defined by a suggestive hemodynamic profile on pulmonary artery catheterization or transesophageal Doppler ultrasound imaging (ie, increased pulmonary artery occlusion pressure or corrected flow time) and resolution of the pulmonary infiltrates following diuresis. Alveolar hemorrhage was defined by progressively bloodier return of BAL fluid and at least 20% hemosiderin-laden macrophages. Finally, pulmonary embolism was defined by the presence of at least two segmental or larger mismatched perfusion abnormalities on a ventilation-perfusion scan or suggestive radiographic findings on pulmonary angiography and spiral CT.
Adequate antimicrobial treatment was defined as the administration of an initial antimicrobial regimen with in vitro activity against the bacterial species associated with VAP.12 Patients without isolation of pathogenic microorganisms in their respiratory cultures were considered to be receiving adequate empiric antimicrobial treatment.
Statistical Analysis
Univariate analysis was used to compare variables for the two groups of interest. Comparisons were unpaired and all tests of significance were two tailed. Continuous variables were compared using Student t test for normally distributed variables and Wilcoxon rank-sum test for nonnormally distributed variables. The 
2 statistic or Fisher exact test was used to compare categorical variables. Correlation between variables was determined by using simple linear regression analysis. All values are presented as means and their SDs.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The initial administration of adequate antimicrobial treatment was statistically similar for both treatment groups (93.3% vs 93.6%, p = 0.935). Among those in the discontinuation group, 142 patients (94.7%) had at least one recommendation to discontinue antibiotics made to their treating physicians, and antibiotics were discontinued in 126 of these patients (88.7%) within 48 h of the recommendation. The overall duration of antibiotic treatment for VAP was statistically shorter in the discontinuation group compared to the conventional group (6.0 ± 4.9 days vs 8.0 ± 5.6 days, p = 0.001) [Fig 2 ]. Treatments with antibiotics directed against Gram-negative bacteria (5.8 ± 4.7 days vs 7.1 ± 5.1 days, p = 0.023) and antibiotics directed against Gram-positive bacteria (2.3 ± 3.2 vs 4.8 ± 4.4, p < 0.001) were statistically shorter for the discontinuation group. The duration of antibiotic therapy directed against anaerobic bacteria was similar for both treatment groups (1.2 ± 2.9 days vs 1.2 ± 2.5 days, p = 0.991). The duration of antibiotic treatment for VAP was statistically correlated with clinical pulmonary infection scores (r = 0.419; p < 0.001) [Fig 3 ].
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Outcomes
No statistically significant differences in hospital mortality, ICU or hospital lengths of stay, duration of mechanical ventilation, or the total number of subsequently occurring hospital-acquired infections were found between the two study groups (Table 4
).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Increasingly, clinicians practicing in the ICU environment are faced with competing concerns regarding their treatment decisions. The administration of adequate initial antibiotic therapy for VAP, and other potentially life-threatening infections, has been associated with statistically improved survival compared to antibiotic therapy that is found to be ineffective against the pathogen(s) associated with infection.612 Several studies2021 suggest that the administration of inadequate initial antibiotic therapy results in greater hospital mortality due to the temporal delays in achieving treatment with antibiotics to which the pathogens are susceptible. The increasing emergence of antibiotic-resistant bacteria in the ICU setting dictates that broad-spectrum antibiotics be administered initially in order to achieve adequate therapy.822 This is especially true for patients with risk factors for infection due to antibiotic-resistant bacteria (eg, prior antibiotic treatment during the same hospitalization, hospitalization for 
5 days, admission from a nursing home or extended care facility, home wound, or infusion therapy).823 Local knowledge concerning the most common bacteria associated with infection and their antibiotic susceptibility patterns will also greatly assist clinicians in determining the optimal initial empiric antibiotic treatment for VAP and other hospital-acquired infections.24
Competing with the need to administer adequate initial antibiotic therapy is the necessity to prevent further antibiotic resistance. Therefore, clinicians will have to learn how to extend the treatment lives of the currently available antibiotic agents. One of the most effective methods for preventing the emergence of antibiotic-resistant bacteria is the avoidance of unnecessary antibiotic use. Dennesen et al25 demonstrated that continuing adequate antibiotic therapy beyond 7 days for VAP increased airway colonization with potentially antibiotic-resistant bacteria. Other investigators have shown that efforts aimed at reducing the duration of empiric antibiotic therapy for VAP are associated with reductions in the subsequent emergence of antibiotic resistant bacteria. Singh et al16 found that limiting the duration of empiric antibiotic therapy to 3 days for patients with clinically suspected VAP and a clinical pulmonary infection score of 6 statistically reduced subsequent colonization or infection with antibiotic-resistant bacteria. Similarly, Ibrahim et al14 demonstrated that the application of a clinical guideline for the treatment of VAP increased the initial administration of adequate antimicrobial treatment and decreased the overall duration of antibiotics with fewer secondary infections due to antibiotic-resistant organisms.
Recently, the results of a large randomized trial26 comparing 8 days of adequate antibiotic therapy for VAP to 15 days of treatment were reported. Despite similar efficacy, the longer course of antibiotic therapy was associated with statistically greater emergence of multiple-resistant bacteria. Given the compelling findings supporting the link between the duration of antibiotic therapy and the emergence of antibiotic resistance, how should clinicians working in the ICU environment proceed? Our study suggests that the development and implementation of local antibiotic discontinuation policies can be an effective strategy for reducing unnecessary antibiotic therapy for clinically suspected VAP. Locally developed guidelines and protocols have the greatest likelihood of success, especially if cooperation and support is gathered from all parties affected by the new treatment practices.27 Having concise criteria for the discontinuation of antibiotic treatment, along with targeted individual responsibility for reviewing these criteria during ICU rounds when most treatment decisions are made, likely accounted for the success of this program. Additionally, the closed design of the ICU and patient management directed by intensivist-led multidisciplinary teams probably facilitated adherence to the antibiotic discontinuation recommendations.
Our investigation has several important limitations. First, it was performed within a single ICU and the results may not be generalizable to other treatment settings. However, other studies141626 have shown that empiric antibiotic treatment for VAP can be reduced in duration without adverse consequences. This supports the potential successful implementation of similar antibiotic discontinuation policies in other institutions. Additionally, the urgency of the problem of antimicrobial resistance should encourage hospitals to adapt antibiotic practices aimed at providing both effective treatment and less pressure for resistance.28 Second, we relied on clinical diagnosis of VAP as established by the treating physicians. This was purposefully done to study a patient cohort that more closely reflects how clinical decision making and antibiotic prescription for VAP occurs in many "real-world" settings. Similar diagnostic criteria have been employed by other investigators to develop and investigate new empiric antibiotic treatment strategies for VAP.16 Available data suggest that most clinical isolates of Gram-negative bacteria in the ICU are obtained from respiratory secretions, and that increasingly antibiotic treatment is directed at those pathogens whether they are simple colonizers or truly associated with infection.9 Therefore, new practices aimed at improving antibiotic utilization for VAP should incorporate currently employed diagnostic approaches in order to be successful.
A third limitation of this study is that some of the patients with a second episode of VAP may represent initial treatment failures due to premature discontinuation of antibiotics. This seems unlikely given the similar occurrence of secondary episodes of VAP in both treatment groups. Additionally, the results of other randomized trials examining the use of shorter empiric courses of antibiotic therapy for VAP have failed to identify differences in secondary episodes of VAP linked to the duration of initial antibiotic treatment.1626 Moreover, the study by Dennesen et al25 suggests that more prolonged administration of antibiotics will result in the development of secondary respiratory infections due to antibiotic-resistant bacteria. Another limitation is that we only consistently implemented this policy during the workweek and not on weekends. This may have biased the results by reducing the magnitude of the observed intervention on the duration of antibiotic therapy. Finally, one of the investigators also served as a treating physician during approximately 20% of the study period. It is possible that this may have also introduced a bias in favor of the study intervention during that time period. Despite these limitations, we were able to demonstrate a statistically significant reduction in the duration of antibiotic treatment for clinically diagnosed VAP. In summary, we showed that it is safe to discontinue antibiotics prescribed for clinically suspected VAP if someone is actively assessing the indication for antibiotic therapy and the patient response to treatment.
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Footnotes |
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This investigation was supported in part by the Barnes-Jewish Hospital Foundation and an unrestricted grant from Elan Pharmaceuticals.
Received for publication July 31, 2003. Accepted for publication September 28, 2003.
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