Trial of short-course antimicrobial therapy for intraabdominal infection.

BACKGROUND: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Sex- and diagnosis-dependent differences in mortality and admission cytokine levels among patients admitted for intensive care.

OBJECTIVES: To investigate the role of sex on cytokine expression and mortality in critically ill patients. DESIGN: A cohort of patients admitted to were enrolled and followed over a 5-year period. SETTING: Two university-affiliated hospital surgical and trauma ICUs. PATIENTS: Patients 18 years old and older admitted for at least 48 hours to the surgical or trauma ICU. INTERVENTIONS: Observation only. MEASUREMENTS AND MAIN RESULTS: Major outcomes included admission cytokine levels, prevalence of ICU-acquired infection, and mortality during hospitalization conditioned on trauma status and sex. The final cohort included 2,291 patients (1,407 trauma and 884 nontrauma). The prevalence of ICU-acquired infection was similar for men (46.5%) and women (44.5%). All-cause in-hospital mortality was 12.7% for trauma male patient and 9.1% for trauma female patient (p = 0.065) and 22.9% for nontrauma male patients and 20.6% for nontrauma female patients (p = 0.40). Among trauma patients, logistic regression analysis identified female sex as protective for all-cause mortality (odds ratio, 0.57). Among trauma patients, men had significantly higher admission serum levels of interleukin-2, interleukin-12, interferon-γ, and tumor necrosis factor-α, and among nontrauma patients, men had higher admission levels of interleukin-8 and tumor necrosis factor-α. CONCLUSIONS: The relationship between sex and outcomes in critically ill patients is complex and depends on underlying illness. Women appear to be better adapted to survive traumatic events, while sex may be less important in other forms of critical illness. The mechanisms accounting for this gender dimorphism may, in part, involve differential cytokine responses to injury, with men expressing a more robust proinflammatory profile.

Fever Is Associated with Reduced Mortality in Trauma and Surgical Intensive Care Unit-Acquired Infections.

Background: Fever is a common response to both infectious and non-infectious physiologic insults in the critically ill, and in certain populations it appears to be protective. Fever is particularly common in trauma patients, and even more so in those with infections. The relationship between fever, trauma status, and mortality in patients with an infection is unclear. Patients and Methods: A review of a prospectively maintained institutional database over a 17-year period was performed. Surgical and trauma intensive care unit (ICU) patients with a nosocomial infection were extracted to compare in-hospital mortality among trauma and non-trauma patients with and without fever. Univariable analyses compared patient and infection characteristics between trauma and non-trauma patients. A multivariable logistic regression model was created to identify predictors of in-hospital mortality, with a focus on fever and trauma status. Results: Nine hundred forty-one trauma patients and 1,449 non-trauma patients with ICU-acquired infections were identified. Trauma patients were younger (48 vs. 59, p < 0.001), more likely to be male (73% vs. 56%, p < 0.001), more likely to require blood transfusion (74% vs. 47%, p < 0.001), had lower Acute Physiology and Chronic Health Evaluation (APACHE) II scores (18 vs. 19, p = 0.02), and had lower rates of comorbidities. Trauma patients were more likely to develop a fever (72% vs. 43%, p < 0.001) and had lower in-hospital mortality (9.6% vs. 22.6%, p < 0.001). In multivariable analysis, non-trauma patients with fever had a lower odds of mortality compared with non-trauma patients without fever (odds ratio [OR] 0.63, p = 0.004). Trauma patients with fever had the lowest odds ratio for mortality when compared to non-trauma patients without fever (OR 0.25, p < 0.001). Conclusions: In this large cohort of trauma and surgical ICU patients with ICU-acquired infections, fever was associated with a lower odds of mortality in both trauma and non-trauma patients. Further investigation is needed to determine the mechanisms behind the interplay between trauma status, fever, and mortality.

Identification of risk factors for the development of clostridium difficile-associated diarrhea following treatment of polymicrobial surgical infections.

OBJECTIVE: To identify risk factors for Clostridium difficile-associated diarrhea (CDAD) in surgical patients following treatment of polymicrobial infections. SUMMARY BACKGROUND DATA: Infections among surgical patients are frequently anaerobic or mixed aerobic-anaerobic infections and are therefore subject to polymicrobial antibiotic coverage, including metronidazole. While multiple antibiotics are known to contribute to the development of CDAD, the role of preventive antibiotics is unproven. METHODS: An 11-year dataset of consecutive infections treated in surgical patients at a single hospital was reviewed. All intra-abdominal, surgical site, or skin/skin structure infections were identified. Each infection was evaluated for antibiotic coverage and subsequent CDAD. Antibiotic usage was assessed using chi analysis. A multiple logistic regression was used to identify independent predictors of CDAD. RESULTS: A total of 4178 intra-abdominal, surgical site, or skin/skin structure infections were identified. Of these infections, 98 were followed by CDAD. Only carbapenem use affected the incidence of CDAD: 3.5% of infections treated with a carbapenem were followed by CDAD, whereas only 2.1% of infections treated without carbapenems were followed by CDAD (P = 0.04). Metronidazole had no association with future CDAD. Only age and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with CDAD by multiple logistic regression analysis. CONCLUSIONS: Older patients with a high severity of illness are at greatest risk for developing CDAD following treatment of polymicrobial infections. No specific antibiotic class, including fluoroquinolones, is associated with an increased incidence of CDAD in this population. Although use of metronidazole in the treatment of polymicrobial infections is appropriate for anaerobic coverage, it does not reduce the risk of future CDAD.

Choosing antibiotics for intra-abdominal infections: what do we mean by "high risk"?

BACKGROUND: The definition of "high risk" in intra-abdominal infections remains vague. The purpose of this study was to investigate patient characteristics associated with a high risk of isolation of resistant pathogens from an intra-abdominal source. METHODS: All complicated intra-abdominal and abdominal organ/space surgical site infections treated over a ten-year period in a single hospital were analyzed. Infections were categorized by pathogen(s). Organisms designated "resistant" were those that had a reasonable probability of being resistant to the broad-spectrum agents imipenem/cilastatin and piperacillin/tazobactam, and included non-fermenting gram-negative bacilli (e.g., Pseudomonas aeruginosa), resistant gram-positive pathogens, vancomycin-resistant enterococci, and fungi. Patient characteristics were analyzed to define associations with the risk of isolation of "resistant" pathogens. RESULTS: A total of 2,049 intra-abdominal infections were treated during the period of study, of which 1,182 had valid microbiological data. The two genera of pathogens isolated from more than 25% of health care-associated infections and more commonly than from community-acquired infections were Enterococcus spp. (29%) and Candida spp. (33%). Health care association, corticosteroid use, organ transplantation, liver disease, pulmonary disease, and a duodenal source all were associated with resistant pathogens. By multivariable analysis, several acute and chronic measures of disease were predictive of death, with a strong interaction between solid organ transplantation, resistant pathogens, and death. Other links between specific pathogens and patient characteristics were documented, for example, between fungal infection and a gastric, duodenal, or small bowel source, and between liver transplantation and vancomycin-resistant enterococci. CONCLUSIONS: On the basis of clinical characteristics, it may be possible to identify patients with intra-abdominal infections caused by pathogens that are potentially resistant to broad-spectrum antibacterial agents. Under these circumstances, and if warranted clinically, broadened coverage probably ought to include specific anti-enterococcal and anti-candidal therapy.

Estradiol is associated with mortality in critically ill trauma and surgical patients.

OBJECTIVE: Sexual dimorphism (variation in outcome related to sex) after trauma-hemorrhage and sepsis is well documented in animals, with the pro-estrus state being proinflammatory and associated with a survival advantage. Although some observational studies confirm this pattern in humans, others demonstrate no difference in mortality. Estrogens are important modulators of the inflammatory response and insulin resistance in humans and have been linked to increased mortality during sepsis. Our objective was to determine whether sex hormone levels were associated with outcomes in critically ill surgical patients. DESIGN: Prospective cohort. PATIENTS: A total of 301 adult critically ill or injured surgical patients remaining in the intensive care unit for > or = 48 hrs at two academic medical centers. INTERVENTIONS: None. MEASUREMENTS: Blood was collected 48 hrs after intensive care unit admission and assayed for sex hormones (estradiol, testosterone, prolactin, and progesterone) and cytokines (tumor necrosis factor-alpha and interleukin-1, -2, -4, -6, -8, and -10). Demographic and outcome data were also collected. MAIN RESULTS: Estradiol was significantly higher in nonsurvivors (p < .001). Analysis by quartiles of estradiol demonstrated greater than a three-fold increase in the mortality rate for the highest vs. the lowest estradiol quartiles (29% vs. 8%, p < .001). Estradiol was also higher in nonsurvivors. An estradiol level of 100 pg/mL was associated with an odds ratio for death of 4.60 (95% confidence interval, 1.56-13.0) compared with a reference estradiol level of 45 pg/mL. CONCLUSIONS: We conclude that serum estradiol correlates with mortality in critically ill and injured surgical patients and discuss potential mechanisms for this observation.

Is fever protective in surgical patients with bloodstream infection?

BACKGROUND: Sepsis from bloodstream infection (BSI) is an important cause of morbidity and mortality among surgical patients. Our hypothesis was that fever and leukocytosis during BSI would be associated with gram-negative pathogens and worse outcomes among hospitalized surgical patients. STUDY DESIGN: A prospectively collected dataset of all infections diagnosed on the adult general and trauma surgery services between December 1996 and December 2005 at the University of Virginia Hospital was reviewed. Fever was considered a temperature of > or = 38.5 degrees C, and leukocytosis was defined as a white blood cell count > or = 15,000/microL within 24 hours of treatment for infection. Logistic regression was used to identify predictors of fever and mortality. RESULTS: Over 9 years, 823 BSIs were analyzed. One hundred forty-eight BSIs resulted in death (18.0%), and 541 (65.7%) patients were febrile at diagnosis; mortality for these two groups were 12.9% and 27.7%, respectively (p < 0.0001). Febrile patients had a trend toward fewer gram-negative infections (27.0% versus 31.9%, p = 0.13), 403 had a leukocytosis at diagnosis and 420 did not; mortality for the two groups was 19.1% and 16.9%, respectively (p = NS). Higher maximum temperature was protective against mortality in the logistic regression analysis (odds ratio = 0.60 per C degrees, p < 0.0001). CONCLUSIONS: Among surgical patients with sepsis, fever during BSI was not associated with a gram-negative cause and correlated with survival, although increasing WBC had little effect. Mortality after BSI appears associated more with an initially blunted physiologic response than with a robust, proinflammatory response. In addition, a threshold for blood culture other than temperature > or = 38.5 degrees C should be considered.

Longer-Duration Antimicrobial Therapy Does Not Prevent Treatment Failure in High-Risk Patients with Complicated Intra-Abdominal Infections.

BACKGROUND: Recent studies have suggested the length of treatment of intra-abdominal infections (IAIs) can be shortened without detrimental effects on patient outcomes. However, data from high-risk patient populations are lacking. We hypothesized that patients at high risk for treatment failure will benefit from a longer course of antimicrobial therapy. METHODS: Patients enrolled in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated retrospectively to identify risk factors associated with treatment failure, which was defined as the composite outcome of recurrent IAI, surgical site infection, or death. Variables were considered risk factors if there was a positive statistical association with treatment failure. Patients were then stratified according to the presence and number of these risk factors. Univariable analyses were performed using the Kruskal-Wallis, χ2, and Fisher exact tests. Logistic regression controlling for risk factors and original randomization group, either a fixed four-day antimicrobial regimen (experimental) or a longer course based on clinical response (control), also was performed. RESULTS: We identified corticosteroid use, Acute Physiology and Chronic Health Evaluation II score ≥5, hospital-acquired infection, or a colonic source of IAI as risk factors associated with treatment failure. Of the 517 patients enrolled, 263 (50.9%) had one or two risk factors and 16 (3.1%) had three or four risk factors. The rate of treatment failure rose as the number of risk factors increased. When controlling for randomization group, the presence and number of risk factors were independently associated with treatment failure, but the duration of antimicrobial therapy was not. CONCLUSIONS: We were able to identify patients at high risk for treatment failure in the STOP-IT trial. Such patients did not benefit from a longer course of antibiotic administration. Further study is needed to determine the optimum duration of antimicrobial therapy in high-risk patients.

Patients with Risk Factors for Complications Do Not Require Longer Antimicrobial Therapy for Complicated Intra-Abdominal Infection.

A prospective, multicenter, randomized controlled trial found that four days of antibiotics for source-controlled complicated intra-abdominal infection resulted in similar outcomes when compared with a longer duration. We hypothesized that patients with specific risk factors for complications also had similar outcomes. Short-course patients with obesity, diabetes, or Acute Physiology and Chronic Health Evaluation II ≥15 from the STOP-IT trial were compared with longer duration patients. Outcomes included incidence of and days to infectious complications, mortality, and length of stay. Obese and diabetic patients had similar incidences of and days to surgical site infection, recurrent intra-abdominal infection, extra-abdominal infection, and Clostridium difficile infection. Short- and long-course patients had similar incidences of complications among patients with Acute Physiology and Chronic Health Evaluation II ≥15. However, there were fewer days to the diagnosis of surgical site infection (9.5 ± 3.4 vs 21.6 ± 6.2, P = 0.010) and extra-abdominal infection (12.4 ± 6.9 vs 21.8 ± 6.1, P = 0.029) in the short-course group. Mortality and length of stay was similar for all groups. A short course of antibiotics in complicated intra-abdominal infection with source control seems to have similar outcomes to a longer course in patients with diabetes, obesity, or increased severity of illness.

Association of excessive duration of antibiotic therapy for intra-abdominal infection with subsequent extra-abdominal infection and death: a study of 2,552 consecutive infections.

BACKGROUND: We hypothesized that a longer duration of antibiotic treatment for intra-abdominal infections (IAI) would be associated with an increased risk of extra-abdominal infections (EAI) and high mortality. METHODS: We reviewed all IAI occurring in a single institution between 1997 and 2010. The IAI were divided into two groups consisting of those with a subsequent EAI and those without; the data for each group were analyzed. Patients with EAI following IAI were matched in a 1:2 ratio with patients who did not develop EAI on the basis of their Acute Physiology and Chronic Health Evaluation (APACHE II) score±1 point. Statistical analyses were done with the Student t-test, χ(2) analysis, Wilcoxon rank sum test, and multi-variable analysis. RESULTS: We identified 2,552 IAI, of which 549 (21.5%) were followed by EAI. Those IAI that were followed by EAI were associated with a longer initial duration of antimicrobial therapy than were IAI without subsequent EAI (median 14 d [inter-quartile range (IQR) 10-22 d], vs. 10 d [IQR 6-15 d], respectively, p<0.01), a higher APACHE II score (16.6±0.3 vs. 11.2±0.2 points, p<0.01), and higher in-hospital mortality (17.1% vs. 5.4%, p<0.01). The rate of EAI following IAI in patients treated initially with antibiotics for 0-7 d was 13.3%, vs. 25.1% in patients treated initially for >7 d (p<0.01). A successful match was made of 469 patients with subsequent EAI to 938 patients without subsequent EAI, resulting in a mean APACHE II score of 15.2 for each group. After matching, IAI followed by EAI were associated with a longer duration of initial antimicrobial therapy than were IAI without subsequent EAI (median 14 d [9-22 d], vs. 11 d [7-16 d], respectively, p<0.01), and with a higher in-hospital mortality (14.9% vs. 9.0%, respectively, p<0.01). Logistic regression showed that days of antimicrobial therapy for IAI was an independent predictor of subsequent EAI (p<0.001). CONCLUSIONS: A longer duration of antibiotic therapy for IAI is associated with an increased risk of subsequent EAI and increased mortality.

Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study.

BACKGROUND: Antimicrobial treatment in critically ill patients can either be started as soon as infection is suspected or after objective data confirm an infection. We postulated that delaying antimicrobial treatment of patients with suspected infections in the surgical intensive care unit (SICU) until objective evidence of infection had been obtained would not worsen patient mortality. METHODS: We did a 2-year, quasi-experimental, before and after observational cohort study of patients aged 18 years or older who were admitted to the SICU of the University of Virginia (Charlottesville, VA, USA). From Sept 1, 2008, to Aug 31, 2009, aggressive treatment was used: patients suspected of having an infection on the basis of clinical grounds had blood cultures sent and antimicrobial treatment started. From Sept 1, 2009, to Aug 31, 2010, a conservative strategy was used, with antimicrobial treatment started only after objective findings confirmed an infection. Our primary outcome was in-hospital mortality. Analyses were by intention to treat. FINDINGS: Admissions to the SICU for the first and second years were 762 and 721, respectively, with 101 patients with SICU-acquired infections during the aggressive year and 100 patients during the conservative year. Compared with the aggressive approach, the conservative approach was associated with lower all-cause mortality (13/100 [13%] vs 27/101 [27%]; p=0·015), more initially appropriate therapy (158/214 [74%] vs 144/231 [62%]; p=0·0095), and a shorter mean duration of therapy (12·5 days [SD 10·7] vs 17·7 [28·1]; p=0·0080). After adjusting for age, sex, trauma involvement, acute physiology and chronic health evaluation (APACHE) II score, and site of infection, the odds ratio for the risk of mortality in the aggressive therapy group compared with the conservative therapy group was 2·5 (95% CI 1·5-4·0). INTERPRETATION: Waiting for objective data to diagnose infection before treatment with antimicrobial drugs for suspected SICU-acquired infections does not worsen mortality and might be associated with better outcomes and use of antimicrobial drugs. FUNDING: National Institutes of Health.

Diagnosis-dependent relationships between cytokine levels and survival in patients admitted for surgical critical care.

BACKGROUND: Death after trauma, infection, or other critical illness has been attributed to unbalanced inflammation, in which dysregulation of cytokines leads to multiple organ dysfunction and death. We hypothesized that admission cytokine profiles associated with death would differ based on admitting diagnosis. STUDY DESIGN: This 5-year study included patients admitted for trauma or surgical intensive care for more than 48 hours at 2 academic, tertiary care hospitals between October 2001 and May 2006. Cytokine analysis for interleukin (IL)-1, -2, -4, -6, -8, -10, -12, interferon-gamma, and tumor necrosis factor (TNF)-alpha was performed using ELISA on specimens drawn within 72 hours of admission. Mann-Whitney U test was used to compare median admission cytokine levels between alive and deceased patients. Relative risks and odds of death associated with admission cytokines were generated using univariate analysis and multivariate logistic regression models, respectively. RESULTS: There were 1,655 patients who had complete cytokine data: 290 infected, nontrauma; 343 noninfected, nontrauma; and 1,022 trauma. Among infected patients, nonsurvivors had higher median admission levels of IL-2, -8, -10, and granulocyte macrophage-colony stimulating factor; noninfected, nontrauma patients had higher IL-6, -8, and IL-10; and nonsurviving trauma patients had higher IL-4, -6, -8, and TNF-alpha. IL-4 was the most significant predictor of death and carried the highest relative risk of dying in trauma patients, and IL-8 in nontrauma, noninfected patients. In infected patients, no cytokine independently predicted death. CONCLUSIONS: Cytokine profiles of certain disease states may identify persons at risk of dying and allow for selective targeting of multiple cytokines to prevent organ dysfunction and death.