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(Chest. 1999;115:462-474.)
© 1999 American College of Chest Physicians

Inadequate Antimicrobial Treatment of Infections*

A Risk Factor for Hospital Mortality Among Critically Ill Patients

Marin H. Kollef, MD, FCCP; Glenda Sherman, RN; Suzanne Ward, RN and Victoria J. Fraser, MD

* From the Department of Internal Medicine, Pulmonary and Critical Care Division (Drs. Kollef and Ward), Division of Infectious Diseases (Dr. Fraser), Washington University School of Medicine, St. Louis, MO; and the Center for Quality Management (Dr. Sherman), Barnes-Jewish-Christian Health System, St. Louis, MO.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objective: To evaluate the relationship between inadequate antimicrobial treatment of infections (both community-acquired and nosocomial infections) and hospital mortality for patients requiring ICU admission.

Design: Prospective cohort study.

Setting: Barnes-Jewish Hospital, a university-affiliated urban teaching hospital.

Patients: Two thousand consecutive patients requiring admission to the medical or surgical ICU.

Interventions: Prospective patient surveillance and data collection.

Measurements and results: One hundred sixty-nine (8.5%) infected patients received inadequate antimicrobial treatment of their infections. This represented 25.8% of the 655 patients assessed to have either community-acquired or nosocomial infections. The occurrence of inadequate antimicrobial treatment of infection was most common among patients with nosocomial infections, which developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001). Multiple logistic regression analysis, using only the cohort of infected patients (n = 655), demonstrated that the prior administration of antibiotics (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing acute physiology and chronic health evaluation (APACHE) II scores (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antimicrobial treatment. The hospital mortality rate of infected patients receiving inadequate antimicrobial treatment (52.1%) was statistically greater than the hospital mortality rate of the remaining patients in the cohort (n = 1,831) without this risk factor (12.2%) (relative risk [RR], 4.26; 95% CI, 3.52 to 5.15; p < 0.001). Similarly, the infection-related mortality rate for infected patients receiving inadequate antimicrobial treatment (42.0%) was significantly greater than the infection-related mortality rate of infected patients receiving adequate antimicrobial treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001). Using a logistic regression model, inadequate antimicrobial treatment of infection was found to be the most important independent determinant of hospital mortality for the entire patient cohort (adjusted OR, 4.27; 95% CI, 3.35 to 5.44; p < 0.001). The other identified independent determinants of hospital mortality included the number of acquired organ system derangements, use of vasopressor agents, the presence of an underlying malignancy, increasing APACHE II scores, increasing age, and having a nonsurgical diagnosis at the time of ICU admission.

Conclusions: Inadequate treatment of infections among patients requiring ICU admission appears to be an important determinant of hospital mortality. These data suggest that clinical efforts aimed at reducing the occurrence of inadequate antimicrobial treatment could improve the outcomes of critically ill patients. Additionally, prior antimicrobial therapy should be recognized as an important risk factor for the administration of inadequate antimicrobial treatment among ICU patients with clinically suspected infections.

Key Words: antibiotics • bacteremia • community-acquired infection • critical care • infection • nosocomial infection • outcomes • pneumonia


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The presence of infection is recognized as an important determinant of outcome for patients requiring ICU admission. This is especially true in the current era of increasing antimicrobial resistance among common bacterial pathogens.1 ,2 Both community-acquired infections necessitating ICU admission and nosocomial infections acquired in the ICU appear to influence the likelihood of mortality as well as the duration of hospitalizations.3 ,4 ,5 ,6 Antimicrobial therapy is recognized as the cornerstone of treatment for acquired infections along with drainage of infected fluid collections and the debridement or removal of infected tissues or prostheses.7 Once antimicrobial therapy is initiated, it should ideally be directed at the likely pathogens responsible for the clinically suspected infection. Additionally, the selection of antimicrobial agents should take into account the local antibiotic susceptibility patterns of those pathogens. The importance of providing early antimicrobial therapy, which is effective against the microorganisms responsible for infection in hospitalized patients (ie, adequate antimicrobial therapy), has been highlighted by several recent clinical investigations. These studies have demonstrated that the absence of adequate antimicrobial therapy in patients with pneumonia, peritonitis, bacteremia, or meningitis is associated with adverse patient outcomes, including increased rates of hospital mortality.8 ,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 Failure to treat infections with antimicrobial agents, delays in the administration of adequate antimicrobial treatment, or the initial use of antimicrobial agents to which the identified pathogens are resistant (ie, inadequate antimicrobial treatment) all appear to increase the risk for hospital mortality.8 ,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16

The overall incidence and clinical importance of inadequate antimicrobial treatment of microbiologically documented infections, as a risk factor for hospital mortality and other adverse clinical outcomes, has not been systematically evaluated in the ICU setting. Therefore, we performed a prospective cohort study with two main goals. First, we wanted to determine the magnitude of the problem of inadequate antimicrobial treatment among critically ill adult patients. Second, we sought to identify the reasons for the administration of inadequate antimicrobial treatment. We selected a cohort of critically ill patients for examination since they are the most likely to be adversely affected by the presence of infection.3 ,5 We also purposefully evaluated both community-acquired infections necessitating ICU admission and nosocomial infections that were acquired in the ICU. This was done to assess the relative importance of these infections on patient outcomes and to determine the occurrence of inadequate antimicrobial treatment for each of these classes of infection. It was our hope that such data would provide useful information for the improvement of existing algorithms outlining strategies for the empiric treatment of suspected infection among critically ill patients.17 ,18 ,19


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Study Location and Patients
The study was conducted at a university-affiliated urban teaching hospital: Barnes-Jewish Hospital (1,400 beds) in St. Louis. During an 8-month period (July 1997 to March 1998), all patients admitted to the medical ICU (19 beds) and surgical ICU (18 beds) were potentially eligible for this investigation. Patients were excluded if they were transferred to the medical or surgical ICU temporarily due to a lack of available beds in one of the other hospital ICUs. The study was approved by the Washington University School of Medicine Human Studies Committee.

Study Design and Data Collection
A prospective cohort study design was employed segregating infected patients according to the presence or absence of inadequate antimicrobial treatment of infection. Hospital mortality was the main outcome variable compared between the two study groups. Additionally, the entire study cohort was segregated according to the presence or absence of hospital mortality. This was done to identify risk factors for hospital mortality for this patient cohort. We also assessed secondary outcomes, including the durations of hospitalization, intensive care, and mechanical ventilation, and the occurrence of acquired organ system derangements. For purposes of this investigation, inadequate antimicrobial treatment of infection was defined as the microbiologic documentation of an infection (ie, a positive culture result) which was not being effectively treated at the time of its identification. Inadequate antimicrobial treatment included the absence of antimicrobial agents directed at a specific class of microorganisms (eg, absence of therapy for fungemia due to Candida albicans) and the administration of an antimicrobial agent to which the microorganism responsible for the infection was resistant (eg, empiric treatment with oxacillin for pneumonia subsequently attributed to oxacillin-resistant Staphylococcus aureus [ORSA] based on lower airway culture results).

For all study patients, the following characteristics were prospectively recorded: age; gender; race; serum albumin (g/dL); the ratio of arterial blood oxygen tension to the concentration of inspired oxygen (PaO2/FIO2) at the time of ICU admission; severity of illness based on acute physiology and chronic health evaluation (APACHE) II scores20 ; the presence of congestive heart failure requiring medical therapy with diuretics, inotropes, and/or vasodilators; COPD requiring medical therapy with inhaled bronchodilators or corticosteroids; underlying malignancy; positive serology for the HIV; and the need for surgical intervention. Specific processes of medical care examined included the administration of corticosteroids, antacids, sucralfate, vasopressors, or histamine type-2 receptor antagonists; dialysis; reintubation; presence of a tracheostomy; urinary tract catheterization and its duration; central vein catheterization and its duration; and the need for mechanical ventilation and its duration.

One of the investigators made daily rounds on all study patients recording relevant data from the medical records, bedside flow sheets, and the hospital's main frame computer for reports of microbiologic studies (Gram's stains and cultures of sputum, blood, pleural fluid, urine, wound, tissue, and lower respiratory tract specimens). All chest radiographs were prospectively reviewed by one of the investigators (MHK), and the computerized radiographic reports were also reviewed 24 to 48 h later. In addition to recording the presence of community-acquired infections necessitating ICU admission, all identified nosocomial infections were also recorded prospectively. Patients were evaluated for the development of nosocomial infections only during their stay in the ICU. Antibiotic treatment administered in the ICU setting, both perioperative prophylactic antibiotics and antibiotic treatment of suspected infections, were evaluated using patients' medical records and the ICU computerized bedside workstations (EMTEK Health Care Systems Inc; Tempe, AZ).

Definitions
All definitions were selected prospectively as part of the original study design. Community-acquired infection (urinary tract, bloodstream, pneumonia, biliary tract, meningitis, and soft tissue infections) were defined according to the patient's admission diagnosis and the treating physician's orders in the medical record documenting the need for antibiotic treatment of a specific community-acquired infection. Additionally, all community-acquired infections were required to be established within 48 h of hospital admission. Similar temporal cutoffs for separating community-acquired infections from hospital-acquired infections have been proposed by other investigators.21 Patients residing at a nursing home, skilled care facility, or rehabilitation center who developed an infection requiring hospital admission were classified as having community-acquired infections. Nosocomial infections (urinary tract, bloodstream, wound infection) were defined according to criteria established by the Centers for Disease Control and Prevention.22

The diagnostic criteria for ventilator-associated pneumonia (VAP) were modified from those established by the American College of Chest Physicians.21 Ventilator-associated pneumonia was considered to be present when a new or progressive radiographic infiltrate developed in conjunction with one of the following: radiographic evidence of pulmonary abscess formation (ie, cavitation within pre-existing pulmonary infiltrates); histologic evidence of pneumonia in lung tissue; a positive blood or pleural fluid culture; or two of the following: fever (temperature > 38.3°C), leukocytosis (leukocyte count > 10 x 103/mm3), and purulent tracheal aspirate. Blood and pleural fluid cultures could not be related to another source and both had to be obtained within 48 h before or after the clinical suspicion of VAP. Microorganisms recovered from blood or pleural fluid cultures also had to be identical to the microorganisms recovered from cultures of respiratory secretions. VAP-complicating community-acquired pneumonia was considered to be present if new or progressive infiltrates developed at least 48 h after the start of mechanical ventilation and empiric antibiotic treatment. The previous infiltrates, attributed to the community-acquired pneumonia, were also required to be stable or improving in their radiographic appearance for at least 48 h prior to the development of these new or progressive infiltrates. Last, the criteria for VAP noted above also had to be met.

We calculated APACHE II scores on the basis of clinical data available from the first 24-h period of intensive care.20 Acquired organ system derangements were defined using the modified criteria of Rubin and coworkers.23 The definitions used for the systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock, were those proposed by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.24 Mortality related to infection was predetermined to be present when a patient died during treatment for a community-acquired or nosocomial infection and the death could not be directly attributed to any other cause.

Prophylactic antimicrobial treatment was defined as any antimicrobial agent administered parenterally in the perioperative period for the prevention of infection resulting from the surgical procedure. All other antimicrobial administration in the ICU setting was classified as either empiric treatment or infection-directed treatment. Empiric treatment was considered to be present when antimicrobials were prescribed for fever or other systemic signs of infection (eg, hypothermia, leukocytosis) without identifying a specific localized source of infection. Infection-directed treatment was defined as the administration of antimicrobials for a specific clinically localized source of infection (eg, pneumonia, urinary tract, wound, bloodstream). The identified source of infection was required to be documented in the patient's medical record. Clinically localized sources of infection, excluding bloodstream infections, did not require microbiologic confirmation by Gram's stain or positive cultures in order to classify the associated antimicrobial therapy as infection-directed treatment. However, the classification of inadequate antimicrobial treatment required a microbiologically documented infection (ie, infection supported by positive culture results from an appropriate clinical specimen) to be present for the purpose of supporting this categorization. Last, antibiotic-resistant bacteria were defined as Gram-negative bacteria resistant to aminoglycosides; third-generation cephalosporins; extended-spectrum penicillins, quinolones, or imipenem; and Gram-positive bacteria resistant to oxacillin or vancomycin.

Statistical Analysis
All comparisons were unpaired and all tests of significance were two-tailed. Continuous variables were compared using the Student's t test for normally distributed variables and the Wilcoxon rank-sum test for non-normally distributed variables. The {chi}2 or Fisher's exact test were used to compare categorical variables. The primary data analysis compared infected patients who received inadequate antimicrobial treatment to infected patients receiving adequate antimicrobial treatment. A second data analysis compared hospital nonsurvivors to hospital survivors. To determine the relationship between hospital mortality (dependent variable) and inadequate antimicrobial treatment of infection (independent variable), a multiple logistic regression model was used to control for the effects of confounding variables.25 ,26 Multiple logistic regression analysis was also used to identify independent risk factors for the administration of inadequate antimicrobial treatment of infection.

A stepwise approach was used to enter new terms into the logistic regression models where 0.05 was set as the limit for the acceptance or removal of new terms. Model overfitting was examined by evaluating the ratio of outcome events to the total number of independent variables in the final models and specific testing for interactions between the independent variables was included in our analyses.27 Results of the logistic regression analyses are reported as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Relative risks (RRs) and their 95% CIs were calculated using standard methods.28 Values are expressed as the mean ± SD (continuous variables) or as a percentage of the group from which they were derived (categorical variables). All p values were two-tailed and p values of <= 0.05 were considered to indicate statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
A total of 2,000 consecutive eligible patients were prospectively evaluated (Table 1 ). The mean age of the patients was 57.7 ± 18.1 years (range, 13 to 105 years), and the mean APACHE II score was 15.2 ± 7.8 (range, 0 to 53). Nine-hundred forty-four (47.2%) patients were women and 1,056 (52.8%) were men. One thousand two-hundred seven (60.3%) patients were admitted to the ICU for a medical diagnosis, whereas 793 (39.7%) patients were admitted to the ICU following a surgical procedure.


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  		Table 1. Baseline Characteristics of the Study Cohort*

 
Inadequate Antimicrobial Treatment of Infection
One-hundred sixty-nine (8.5%) patients initially received inadequate treatment of an infection during their stay in the ICU (Tables 1 and 2 ). This represented 25.8% of the 655 patients assessed to have a clinically recognized infection present while in the ICU. Inadequate antimicrobial treatment of infection was most common among patients with nosocomial infections that developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001). Infected patients who initially received inadequate antimicrobial treatment had statistically greater APACHE II scores, younger ages, were more likely to have undergone surgery prior to ICU admission, and had lower values for serum albumin than infected patients who initially received adequate antimicrobial treatment (Table 1 ). Differences in the processes of medical care between infected patients receiving inadequate antimicrobial treatment and infected patients receiving adequate antimicrobial treatment are shown in Table 2 . Infected patients receiving inadequate antimicrobial treatment were statistically more likely to also receive antacids, histamine type-2 receptor antagonists, sucralfate, and vasopressors; to undergo tracheostomy, dialysis, central vein catheterization, and mechanical ventilation; and to have longer durations of urinary tract catheterization, central vein catheterization, and mechanical ventilation. Infected patients receiving inadequate antimicrobial treatment were also statistically more likely to develop sepsis, severe sepsis, septic shock, and bloodstream infections than infected patients receiving adequate antimicrobial treatment (Table 3 ).


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  		Table 2. Process of Care Variables*

 

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  		Table 3. Clinical Infections*

 
Multiple logistic regression analysis, using only the cohort of infected patients (n = 655), demonstrated that the prior administration of antibiotics (adjusted OR, 3.39; 95% CI, 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing APACHE II scores (1-point increments) (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (1-year increments) (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antimicrobial treatment of infections. Similar results were obtained when the multiple logistic regression analysis was repeated for the entire patient cohort (n = 2,000) except that the presence of pneumonia was also identified as a variable independently associated with the administration of inadequate antimicrobial treatment. The distribution of the APACHE II scores for infected patients receiving adequate and inadequate antimicrobial treatment are shown in Figure 1 .



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  		Figure 1. Box plots of APACHE II Scores for infected patients receiving either initially inadequate or adequate antimicrobial treatment. Boxes represent 25th to 75th percentiles with 50th percentile (solid line) and median (broken line) values shown with the boxes. The 10th and 90th percentiles are shown as capped bars, and symbols (solid circles) mark the 5th and 95th percentiles.

 
Infection Classification
Among the 655 infected patients admitted to the ICU, 442 (67.5%) had a community-acquired infection, 286 (43.7%) developed a nosocomial infection, and 73 (11.1%) patients had both community-acquired and nosocomial infections. Overall, 527 (80.5%) of the clinically identified infections were supported by positive cultures. Among the infected patients, 162 (24.7%) were classified as having an antibiotic-resistant Gram-negative bacterial infection and 88 (13.4%) were classified as having an antibiotic-resistant Gram-positive bacterial infection. The likelihood of acquiring an antibiotic-resistant Gram-negative bacterial infection was greatest for patients with nosocomial infections, which occurred following treatment of a community-acquired infection (41.1%), and patients with nosocomial infections alone (43.2%) and least for patients with community-acquired infections alone (10.8%) (p < 0.001). Similar results were found for patients acquiring an antibiotic-resistant Gram-positive infection (30.1%, 15.0%, 9.2%; p < 0.001). Multiple logistic regression analysis demonstrated that the duration of mechanical ventilation (1-day increments) (adjusted OR, 1.13; 95% CI, 1.10 to 1.16; p < 0.001), the duration of central vein catheterization (adjusted OR, 1.10; 95% CI, 1.05 to 1.11; p = 0.007), presence of a tracheostomy (adjusted OR, 2.10; 95% CI, 1.54 to 2.85; p = 0.016), and the use of histamine type-2 receptor antagonists (adjusted OR, 1.52; 95% CI, 1.25 to 1.85; p = 0.035) were independently associated with the occurrence of a nosocomial infection.

The distribution of the pathogens associated with clinically recognized community-acquired and nosocomial infections are shown in Table 4 . Pseudomonas aeruginosa was the most common Gram-negative bacterial pathogen isolated from infected patients receiving inadequate antimicrobial treatment (n = 53), whereas ORSA was the most common Gram-positive bacterial pathogen isolated from such individuals (n = 45). Interestingly, vancomycin-resistant enterococci (VRE) was responsible for inadequate antimicrobial treatment in 13 individuals of which six (45.2%) were classified as community-acquired infections. Escherichia coli was the most common Gram-negative bacterial pathogen isolated from infected patients receiving adequate antimicrobial treatment (n = 76), whereas oxacillin-sensitive S aureus was the most common Gram-positive bacterial pathogen isolated from these patients (n = 88).


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  		Table 4. Microorganisms Associated With Infections*

 
Reasons for the Administration of Inadequate Antimicrobial Treatment
The identified reasons for the initial administration of inadequate antimicrobial treatment of infections are shown in Table 5 . The main reason for the administration of inadequate antimicrobial therapy was the presence of either antibiotic-resistant Gram-negative bacteria or antibiotic-resistant Gram-positive bacteria not appropriately treated by the prescribed antibiotic regimen. Among patients with community-acquired infections, the absence of adequate treatment for ORSA, Gram-negative bacteria resistant to third-generation cephalosporins (eg, ceftriaxone and ceftazidime) or other antibiotics, Candida spp, and VRE accounted for the majority of the inadequate antimicrobial treatments. For patients with nosocomial infections, the absence of adequate treatment for Gram-negative bacteria, resistant to the administered third-generation cephalosporins or some other class of antibiotics, accounted for most instances of inadequate antimicrobial treatment. Inadequate antimicrobial treatment for ORSA, Candida spp, and VRE were also relatively common among patients classified as having nosocomial infections.


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  		Table 5. Classification of Inadequate Antimicrobial Treatment*

 
Hospital Mortality
Three hundred twelve (15.6%) patients died during their hospitalization. The hospital mortality rate of infected patients receiving inadequate antimicrobial treatment (52.1%) was statistically greater than the mortality rate of patients without this risk factor (12.2%) (RR, 4.26; 95% CI, 3.52 to 5.15; p < 0.001). Among the 655 patients with a clinically recognized infection, the hospital mortality rate from all causes was statistically greater for infected patients receiving inadequate antimicrobial treatment (52.1%) than the same rate for infected patients receiving adequate antimicrobial treatment (23.5%) (RR, 2.22; 95% CI, 1.79 to 2.76; p < 0.001) (Fig 2 ). Similarly, the infection-related mortality rate was statistically greater among infected patients receiving inadequate antimicrobial treatment (42.0%) than infected patients receiving adequate antimicrobial treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001).



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  		Figure 2. Hospital mortality and infection related mortality rates for infected patients from all causes (n = 655) receiving either initially inadequate or adequate antimicrobial treatment.

 
The hospital mortality rates for patients infected with antibiotic-resistant Gram-negative bacteria (n = 148; mortality, 41.2%), antibiotic-resistant Gram-positive bacteria (n = 74; mortality, 43.2%), and both antibiotic-resistant Gram-negative and antibiotic-resistant Gram-positive bacteria (n = 14; mortality, 35.7%) were statistically greater than the mortality rates for the remaining patients in the cohort (n = 1764; mortality, 12.1%; p < 0.001) and for the infected patients whose pathogens were not antibiotic-resistant bacteria (n = 419; mortality, 24.8%; p < 0.001). The mortality rate of infected patients who did not receive initial antibiotic therapy (n = 11; mortality, 45.5%) was not statistically different from the mortality rate of infected patients receiving initial antibiotic therapy (n = 644; mortality, 30.6%; p = 0.328).

Hospital nonsurvivors had statistically greater APACHE II scores, greater ages, lower PaO2/FIO2 ratios, lower serum albumin values, were more likely to have a diagnosis of congestive heart failure or underlying malignancy, and were less likely to have undergone surgery than patients who survived their hospitalization (Table 1 ). Differences in the processes of medical care for hospital nonsurvivors and survivors are shown in Table 2 . Hospital nonsurvivors were statistically more likely to receive vasopressors, sucralfate, and corticosteroids; to undergo dialysis, tracheostomy, urinary tract catheterization, central vein catheterization, and mechanical ventilation than hospital survivors. Nonsurvivors also had statistically longer durations of urinary tract catheterization, central line catheterization, and mechanical ventilation; were less likely to receive antibiotic prophylaxis in the ICU; and were more likely to receive both empiric and infection-directed antibiotics during their stay in intensive care. Additionally, hospital nonsurvivors were statistically more likely to meet clinical criteria for systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, and more likely to have developed community-acquired infections, nosocomial infections, or both types of infections than hospital survivors (Table 3 ).

Acquired Organ System Derangements and Lengths of Stay
Infected patients receiving inadequate antimicrobial treatment acquired a statistically greater number of organ system derangements than infected patients receiving adequate antimicrobial treatment (Table 6 ). Similarly, acquired derangements of lung, heart, bone marrow, and liver function occurred more commonly among infected patients receiving inadequate antimicrobial treatment. Hospital nonsurvivors also acquired a greater number of organ system derangements and derangements of each individual organ system examined than hospital survivors. The average ICU lengths of stay and the average durations of mechanical ventilation were statistically greater among patients receiving inadequate antimicrobial treatment and hospital nonsurvivors, respectively (Table 6 ).


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  		Table 6. Clinical Outcomes*

 
Risk Factors for Hospital Mortality
Multivariate analysis demonstrated that inadequate antimicrobial treatment of infection was the most important risk factor for hospital mortality (Table 7 ). An increasing number of acquired organ system derangements, the administration of vasopressors, the presence of an underlying malignancy, increasing APACHE II scores, and increasing patient age were also identified as independent predictors of hospital mortality. Additionally, admission to the ICU following a surgical procedure was found to be an independent risk factor favoring hospital survival.


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  		Table 7. Independent Risk Factors for Hospital Mortality*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
We demonstrated a statistically significant association between the initial administration of inadequate antimicrobial treatment of infections and hospital mortality for adult patients requiring ICU admission. Multiple logistic regression analysis, controlling for potential confounding variables, demonstrated that the risk of hospital mortality was more than four times as great among infected patients receiving inadequate antimicrobial treatment compared with patients who did not possess this risk factor (adjusted OR, 4.26; Table 7 ). Similarly, when only infected patients were examined, the risk of infection-related mortality was greater among individuals receiving inadequate antimicrobial treatment than patients receiving adequate antimicrobial treatment for their infections (Fig 2 ). We also identified potential risk factors for the administration of inadequate antimicrobial treatment of infections including the prior administration of antibiotics, presence of a bloodstream infection, severity of illness, and patient age. The significance of these findings are that they may help to explain, at least in part, the differences in hospital mortality observed between various groups of ICU patients. More importantly, these data could help to improve existing strategies for the treatment of suspected infection among critically ill patients. Last, our study results also support the observation that acquired infections, especially infections initially treated with inadequate antimicrobial treatment, are associated with an excess mortality above that attributable to patients' severity of illness at the time of ICU admission.4

Despite the widespread use of antimicrobial therapy in ICUs, few clinical studies have examined the influence of the adequacy of antimicrobial treatment on patient outcomes. The role of antimicrobial treatment as a determinant of outcome for critically ill patients is probably best documented for VAP and nosocomial bacteremia. Several epidemiologic studies have suggested that the administration of inadequate antibiotic treatment of VAP is an important determinant of hospital mortality.29 ,30 Indeed, the initial administration of inadequate antibiotic therapy may partially explain the excess patient mortality associated with VAP, especially when it is attributed to antibiotic-resistant bacteria.31 ,32 ,33 This hypothesis is further supported by other clinical investigations demonstrating a strong association between the initial administration of inadequate antimicrobial therapy and hospital mortality for patients with VAP.8 ,9 ,10 ,11 These four investigations independently demonstrated that patients receiving inadequate empiric antimicrobial treatment, initiated before obtaining the results of cultures from respiratory secretions, blood, and pleural fluid, had greater hospital mortality rates than patients receiving empiric antimicrobial regimens that provided full coverage of all identified pathogens. More importantly, the study by Luna et al9 found that subsequent changes in antimicrobial therapy based on the available culture results, for patients who initially received inadequate treatment, did not reduce their excess risk of hospital mortality. Therefore, it appears that the timing of the administration of adequate antimicrobial therapy is also an important determinant of outcome for patients with VAP.

Our study offers several potential explanations for the initial administration of inadequate antimicrobial treatment to infected patients. Prior antibiotic administration was found to be the most important risk factor associated with the occurrence of this undesirable medical practice. The prior administration of antibiotics to hospitalized patients, particularly to patients in ICUs, appears to predispose to colonization with bacteria that are often resistant to the previously prescribed classes of antibiotics.33 More importantly, colonization with antibiotic-resistant pathogens predisposes to subsequent infection with these same highly virulent microorganisms.18 ,33 Several groups of investigators have demonstrated an association between the prior administration of antibiotics and the occurrence of VAP due to antibiotic-resistant bacteria.31 ,32 ,33 Most recently, Trovillet and coworkers34 examined patients with VAP caused by potentially drug-resistant bacteria in hopes of identifying risk factors for this outcome. They identified a duration of mechanical ventilation of >= 7 days (OR, 6.0), prior antibiotic use (OR, 13.5), and the prior use of broad-spectrum antibiotics (OR, 4.1) as being independently associated with infection due to antibiotic-resistant bacteria. Additionally, these investigators demonstrated that patients with both prolonged durations of mechanical ventilation and prior antibiotic usage were more likely to acquire infection with antibiotic-resistant bacteria than patients having only one of these risk factors. Other investigators have also found an association between the duration of mechanical ventilation and the occurrence of VAP due to antibiotic-resistant bacteria.35 ,36 An analogous situation has also been described for patients developing urinary tract infections and bloodstream infections. The longer urinary tract catheterization and central vein catheterization are employed, the more likely it is for patients to develop urinary tract and bloodstream infections with antibiotic-resistant pathogens.37

In addition to prior antibiotic administration, we found that increasing APACHE II scores, lower age, and bloodstream infections were independently associated with the administration of inadequate antimicrobial therapy. Greater severity of illness has previously been associated with longer lengths of stay in the hospital and ICU, the need for antibiotic administration, and increased susceptibility to nosocomial infections.3 ,4 ,5 Therefore, it is not surprising that patients with a greater severity of illness are more likely to be at risk for receiving inadequate antimicrobial therapy. Similarly, patients with bloodstream infections, especially nosocomial bloodstream infections, often have received prior antibiotic therapy and have prolonged lengths of stay in the hospital, both factors predisposing to colonization and subsequent infection with antibiotic-resistant bacteria.5 Additionally, several studies13 ,14 suggest that nosocomial bacteremia due to antibiotic-resistant pathogens usually occur following previous antimicrobial treatment and are associated with worse patient outcomes. S aureus, antibiotic-resistant Gram-negative bacteria, and Candida spp are among the pathogens responsible for bloodstream infections, which are usually associated with the poorest outcomes.38 ,39 ,40 ,41 Interestingly, these are the same pathogens most commonly associated with the initial administration of inadequate antimicrobial treatment in our study. Two of these earlier studies39 ,41 also identified inadequate antimicrobial treatment of bloodstream infection as a risk factor for mortality. An explanation for the association of younger patient age with the administration of inadequate antimicrobial treatment of infections is less apparent from our study results. However, younger patients may be less likely to be suspected of having an infection, especially infection due to antibiotic-resistant bacteria, than older patients.

Recommendations for the Avoidance of Inadequate Antimicrobial Administration
Based on our experience from this investigation, and a review of the available medical literature, we have developed several initial recommendations aimed at the avoidance of inadequate antimicrobial treatment for infected ICU patients. First, it appears that antimicrobial therapy should be administered early in the course of infection to be most effective, especially prior to the development of severe sepsis and septic shock.5 ,9 This will require a high index of suspicion on the part of practitioners caring for critically ill patients in order to consider the diagnosis of infection in a timely manner. To facilitate this procedure, recommendations for the systematic evaluation of fever among critically ill patients have been developed.42 Additionally, guidelines for the administration of empiric antimicrobial therapy are available that can be used as a starting point for the selection of antimicrobial agents used for the treatment of suspected infections.17 ,18 Due to the greater mortality associated with delays in treatment,9 starting empiric antimicrobial treatment at the first suspicion of infection in critically ill patients seems prudent in most instances. However, in order to avoid increasing problems with drug-resistant infections, the antimicrobial regimen should subsequently be narrowed or discontinued altogether based on the patient's clinical course and culture results. This can usually be accomplished within 48 h of administrating the initial empiric antimicrobial regimen when culture results and bacterial antimicrobial sensitivity profiles become available. The recent application of computerized antimicrobial guidelines further supports such a practice by suggesting that more hospitalized patients can be successfully exposed to antimicrobial treatment without necessarily increasing the occurrence of antimicrobial-resistant infections.43 Additionally, such guidelines can also help to curtail the unnecessary use of antimicrobials and may improve patient outcomes.44

For patients with suspected infection who have received prior antimicrobial therapy directed at Gram-negative bacteria, subsequent empiric antimicrobial treatment should include coverage of pathogens that may be potentially resistant to the earlier administered antibiotics. Methods of achieving this would include selecting a new class of antimicrobial agents for the empiric treatment of Gram-negative infections (eg, a quinolone or carbapenem antibiotic in a patient having received prior treatment with a third-generation cephalosporin), including a new class of antimicrobial agents for empiric treatment in combination with the previously administered agent in order to minimize the likelihood of inadequate treatment due to bacterial resistance (eg, treatment with an aminoglycoside or a quinolone antibiotic along with a previously administered broad spectrum cephalosporin), or the routine administration of combination antimicrobial therapy with agents to which the patient has not had previous exposure and to which antimicrobial resistance is thought to be unlikely (eg, combinations of broad spectrum antibiotics directed against Gram-negative bacteria). Although the routine use of combination antimicrobial therapy with dual agents directed against Gram-negative bacteria is controversial,41 ,45 the administration of such therapy seems reasonable when attempting to avoid the occurrence of inadequate antimicrobial therapy due to antibiotic-resistant Gram-negative bacteria. Similar recommendations for the empiric treatment of Gram-positive bacteria cannot be made since the number of available antimicrobial agents for antibiotic-resistant Gram-positive cocci (eg, ORSA and VRE) is limited. Nevertheless, our study suggests that initial empiric treatment with vancomycin or quinupristin/dalfopristin for ORSA seems reasonable in patients at risk for infection with this specific pathogen.6 ,37

More sensitive and specific methods for the microbiologic diagnosis of certain infections may also be necessary in order to reduce the occurrence of inadequate antimicrobial treatment. However, this will require the development of new diagnostic probes and more rapid makers for the identification of specific classes of microorganisms in body fluids and tissues.46 ,47 ,48 Our study suggests that such probes should be directed at specific antibiotic-resistant bacteria (VRE, ORSA, P aeruginosa) and nonbacterial pathogens (Candida spp). Additionally, improvements in our diagnostic capabilities for these pathogens, in order to exclude infection by them, may also result in decreasing the administration of unnecessary antimicrobial therapy. This offers the advantage of potentially reducing the occurrence of antimicrobial-resistant infections.44 Finally, the more rapid diagnosis of infection due to these specific high-risk pathogens may allow for the earlier administration of adequate antimicrobial treatment and further improvement in clinical outcomes.9 An alternative to such an approach would be to more routinely include empiric coverage for Candida spp and antibiotic-resistant Gram-positive bacteria in the initially prescribed empiric antibiotic regimens, especially for patients with suspected nosocomial infections. However, this may result in increased antimicrobial costs and potentially further increases in the occurrence of antimicrobial resistance among these pathogens. Future clinical investigation are needed to determine the best strategy for empiric antimicrobial administration in the ICU setting.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
In summary, we demonstrated that the occurrence of inadequate antimicrobial treatment of infections among patients requiring intensive care is an independent determinant of hospital mortality. Clinicians caring for critically ill patients should be aware of these findings since they suggest that specific clinical practices should be adopted in order to avoid treating patients with inadequate antimicrobial regimens. Our study also suggests that clinicians must be aware of the prevailing pathogens accounting for community-acquired and nosocomial infections in their ICU as well as within the hospitals at which they practice. Additionally, the antibiotic-susceptibility profiles of these pathogens should be routinely available to physicians in order to guide their selection of antimicrobial agents. This implies that these antibiograms are updated on a regular basis in order to report and detect changes in the antimicrobial resistance patterns of these pathogens. The importance of prior antimicrobial administration, as a risk factor for subsequent administration of inadequate antimicrobial treatment, should also be recognized by clinicians prescribing antimicrobial treatment to critically ill patients. Last, consideration should be given to the empiric treatment of ICU patients with clinically suspected infection using an initially broad antimicrobial regimen, to include agents that were not previously administered especially for Gram-negative bacteria, in order to minimize the occurrence of inadequate antimicrobial treatment. Such broad treatment can usually be narrowed after a relatively short period of time (ie, 24 to 72 h) when the initial culture results become available usually without compromising patient outcomes.44 Future studies of antibiotic guidelines and protocols aimed at the reduction of inadequate antimicrobial treatment are needed to assess their influence on patient outcomes. Until such data are available, clinicians should at least consider the possibility of inadequate antimicrobial treatment whenever prescribing antimicrobial agents in the ICU.


   Footnotes
 
Supported in part by grants from the Centers for Disease Control and Prevention (UR8/CCU715087) and Bayer Corporation.

Correspondence to: Marin H. Kollef, MD, FCCP, Pulmonary and Critical Care Division, 660 S. Euclid Avenue, Campus Box 8052, St. Louis, MO 63110; e-mail: mkollef@pulmonary.wustl.edu

Abbreviations: APACHE = acute physiology and chronic health evaluation; CI = confidence interval; OR = odds ratio; ORSA = oxacillin-resistant Staphylococcus aureus; RR = relative risk; VAP = ventilator-associated pneumonia; VRE = vancomycin-resistant enterococci

Received for publication July 2, 1998. Accepted for publication August 19, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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