Traves D. Crabtree

Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit

Objective The development of antibiotic-resistant bacteria is associated with significant morbidity and mortality in critically ill patients. We postulated that quarterly rotation of empirical antibiotics could decrease infectious complications from resistant organisms in an intensive care unit (ICU). Design Prospective cohort study. Setting An ICU at a university medical center. Subjects All patients admitted to the general, transplant, or trauma surgery services who developed pneumonia, peritonitis, or sepsis of unknown origin. Interventions A 2-yr study consisting of 1 yr of nonprotocol-driven antibiotic use and 1 yr of rotating empirical antibiotic assignment. Measurements and Main Results Over 100 variables were recorded for each infectious episode, including patient characteristics (e.g., Acute Physiology and Chronic Health Evaluation [APACHE] II score, age, comorbidities), infection characteristics (e.g., site, organism), treatment characteristics (e.g., antibiotic, treatment duration) and outcome measures (e.g., mortality, length of stay, antibiotic cost). Of 1456 consecutive admissions to the ICU, 540 episodes of infection were treated. No differences were noted in age, APACHE II score, race, overall antibiotic utilization or duration of therapy between the 2 yrs of study. Outcome analysis revealed significant reductions in the incidence of antibiotic-resistant Gram-positive coccal infections (7.8 infections/100 admissions vs. 14.6 infections/100 admissions, p < .0001), antibiotic-resistant Gram-negative bacillary infections (2.5 infections/100 admissions vs. 7.7 infections/100 admissions, p < .0001), and mortality associated with infection (2.9 deaths/100 admissions vs. 9.6 deaths/100 admissions, p < .0001) during rotation. Logistic regression identified age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01–1.06), APACHE II score (OR, 1.06; 95% CI, 1.01–1.13), solid organ transplantation (OR, 9.50; 95% CI, 2.01–52.21), and malignancy (OR, 10.16; 95% CI, 4.11–26.96) as independent predictors of mortality. Antibiotic rotation was an independent predictor of survival (OR 6.27, 95% CI 2.78–14.16). Conclusion Rotation of empirical antibiotic therapy seems to be a promising method to reduce infectious mortality in an ICU.

Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients.

OBJECTIVEnTo investigate the hypothesis that occult hypoperfusion (OH) is associated with infectious episodes in major trauma patients.nnnMETHODSnData were collected prospectively on all adult trauma patients admitted to the Surgical/Trauma Intensive Care Unit from November of 1996 to December of 1998. Treatment was managed by a single physician according to a defined resuscitation protocol directed at correcting OH (lactic acid [LA] > 2.4 mmol/L).nnnRESULTSnOf a total of 381 consecutive patients, 118 never developed OH and 263 patients exhibited OH. Seventeen patients were excluded because their LA never corrected, and they all subsequently died. One hundred seventy-six infectious episodes occurred in 97 of the 364 patients remaining. The infection rate in patients with no elevation of LA was 13.6% (n = 118) compared with 12.7% (n = 110) in patients whose LA corrected by 12 hours, 40.5% (n = 79; p < 0.01 compared with all other groups) in patients whose LA corrected between 12 and 24 hours, and 65.9% (n = 57; p < 0.01 compared with all other groups) in patients who corrected after 24 hours. Among the patients with infections, there were 276 infection sites with 42% of infections involving the lung and 21% involving bacteremia. There was no difference in proportion of infections occurring at each site between groups. The mortality rate of patients who developed infections was 7.9% versus 1.9% in patients without infections (p < 0.05). Of the patients who developed infections, 69.8% versus 25.8% (p < 0.001) did not have their lactate levels normalized within 12 hours of emergency room admission. Logistic regression demonstrated that both the Injury Severity Score and OH > 12 hours were independently predictive of infection.nnnCONCLUSIONnA clear increase in infections occurred in patients with OH whose lactate levels did not correct by 12 hours, with an associated increase in length of stay, days in surgical/trauma intensive care unit, hospital charges, and mortality.

Impact of antibiotic-resistant Gram-negative bacilli infections on outcome in hospitalized patients.

ObjectiveThe impact of resistant (vs. nonresistant) Gram-negative infections on mortality remains unclear. We sought to define risk factors for and excess mortality from these infections. DesignProspective cohort study. SettingInpatient surgical wards at a university hospital. PatientsAll patients in the general, transplant, and trauma surgery services diagnosed with Gram-negative rod (GNR) infection. Measurements and Main ResultsAll culture-proven GNR infections (n = 924) from December 1996 to September 2000 were studied. Characteristics and outcomes were compared between GNR infections with and without antibiotic resistance. Univariate and logistic regression analysis identified factors associated with antibiotic-resistant GNR (rGNR) infection and mortality. rGNR infection (n = 203) was associated with increased Acute Physiology and Chronic Health Evaluation (APACHE) II scores (17.8 ± 0.5), multiple comorbidities, pneumonia and catheter infection, coexistent infection with antibiotic-resistant Gram-positive cocci and fungi, and high mortality (27.1%). Only seven isolates were resistant in vitro to all available antibiotics. Logistic regression demonstrated that rGNR infection was an independent predictor of mortality (odds ratio, 2.23; 95% confidence interval, 1.35–3.67;p = .002). Analysis of rGNR infection with controls matched by organism, age, APACHE II score, and site of infection, however, revealed that antibiotic resistance was not associated with increased mortality (23.6% vs. 29.2%, p = .35). Furthermore, analysis of all Pseudomonas aeruginosa infections demonstrated no significant difference in mortality between resistant and sensitive strains (18.9% vs. 20.0%, p = .85). ConclusionrGNRs are associated with prolonged hospital stay and increased mortality. Infection with rGNRs independently predicts mortality; however, this may be more closely related to selection of certain bacterial species with a high frequency of resistance rather than actual resistance to antibiotic therapy. Therefore, altering infection-control practices to limit the dissemination of certain bacterial species may be more effective than attempts to control only antibiotic-resistant isolates.

Diagnosis of intra-abdominal infection in the critically ill patient.

Intra-abdominal infection continues to pose a significant threat to critically ill patients in the year 2000. A review of the current literature reveals that despite remarkable developments in critical care medicine and extensive study of patients with tertiary peritonitis, the associated mortality rate remains nearly 30%. Progress has been limited by the difficulty of comparing heterogeneous patient populations, groups that manifest a host of comorbid, potentially confounding illnesses. Additionally, debate persists regarding the definitions of secondary and tertiary peritonitis, resulting in varied study inclusion criteria, and further complicating data analysis and interpretation. Scoring systems developed to identify those patients at risk for progression to tertiary peritonitis, the more chronic, lethal form of intra-abdominal infection associated with multisystem organ failure, reflect the current emphasis in the literature on the importance of early diagnosis and early intervention. This has led to a renewed interest in conservative, data-dependent surgical management employing radiographic and microbiologic evidence to guide therapy.

Preexposure of Murine Macrophages to CpG Oligonucleotide Results in a Biphasic Tumor Necrosis Factor Alpha Response to Subsequent Lipopolysaccharide Challenge

ABSTRACT Bacterial DNA and synthetic oligonucleotides containing CpG sequences (CpG-DNA and CpG-ODN) provoke a proinflammatory cytokine response (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], and IL-6) and increased mortality in lipopolysaccharide (LPS)-challenged mice via a TNF-α-mediated mechanism. It was hypothesized that preexposure of macrophages to CpG-ODN would result in an increased TNF-α response to subsequent LPS challenge in vitro. Using the murine macrophage cell line RAW 264.7, we demonstrated both a rapid proinflammatory cytokine response (TNF-α) and a delayed inhibitory cytokine response (IL-10) with CpG-ODN. Preexposure of macrophages to CpG-ODN for brief periods (1 to 3 h) augmented TNF-α secretion and mRNA accumulation following subsequent LPS challenge (1 μg/ml). However, prolonged preexposure to CpG-ODN (6 to 9 h) resulted in suppression of the TNF-α protein and mRNA response to LPS. The addition of anti-IL-10 antibody to CpG-ODN during preexposure resulted in an increase in the LPS-induced TNF-α response over that induced by CpG-ODN preexposure alone. Thus, while brief preexposure of macrophages to CpG-ODN augments the proinflammatory cytokine response to subsequent LPS challenge, prolonged preexposure elicits IL-10 production, which inhibits the TNF-α response. Although the initial proinflammatory effects of CpG-DNA are well established, the immune response to CpG-DNA may also include autocrine or paracrine feedback mechanisms, leading to a complex interaction of proinflammatory and inhibitory cytokines.

Bacteremia associated with central venous catheter infection is not an independent predictor of outcomes1

BACKGROUNDnInfection is the leading complication of central venous catheters. In the setting of suspected line infection, the CDC recognizes only catheter-related bloodstream infection but not catheter infection without bacteremia, which is designated colonization. To evaluate the hypothesis that catheter-related bloodstream infection has worse outcomes than catheter infection without bacteremia, we compared demographics, clinical data, and outcomes.nnnSTUDY DESIGNnAnalysis of catheter infections was performed on data collected prospectively for all episodes of infection occurring from December 1996 to September 1999 on the surgical services at a university hospital. Catheter tips were cultured only when infection was suspected. Catheter infection without bacteremia was defined as systemic evidence of infection, the presence of at least 15 colony-forming units on the catheter tip by a semiquantitative technique, and absence of bloodstream infection with the same organism as the catheter. Catheter-related bloodstream infection required the presence of bacteremia with the same organism as the catheter tip.nnnRESULTSnThe 59 patients with catheter-related bloodstream infection had more coexistent infections than the 91 patients with catheter infection without bacteremia (2.9+/-0.1 versus 1.7+/-0.1; p=0.0001), most commonly pneumonia (37.3% versus 16.5%, p = 0.004) and urinary tract infections (28.8% versus 8.8%, p = 0.001). Catheter-related bloodstream infection was associated with an increased proportion of gram-negative organisms compared with catheter infections without bacteremia (29.5% versus 16.9%, p = 0.04) and a trend toward fewer gram-positive organisms (61.5% versus 73.7%, p = 0.07). There were no differences in APACHE II score, WBC, length of hospital stay, time from admission to fever, time from fever to treatment, normalization of WBC, days of antibiotics, defervescence, gender, presence of comorbidities, occurrence of colonization while in an ICU, or mortality rate (18.6% with bacteremia, 24.2% without; p = 0.42).nnnCONCLUSIONSnThe presence of bloodstream infection in addition to catheter infection does not appear to alter outcomes. The definition of catheter infection perhaps should be extended to include catheter infections without bloodstream infection in the presence of systemic illness without another source.

Impact of bloodstream infection on outcomes among infected surgical inpatients

ObjectiveTo assess the importance of bloodstream infection (BSI) to outcomes among infected surgical patients. BackgroundBloodstream infection complicating infection is thought to connote a more serious condition compared with a primary infection alone. The authors recently reported, however, that BSI does not alter outcomes with central venous catheter colonization in the presence of sepsis. The significance of BSI with other infections has been incompletely evaluated. MethodsData on all episodes of infection among surgical patients were collected prospectively during a 38-month period at a single hospital, then analyzed retrospectively to determine the independent prognostic value of BSI for all infections by logistic regression analysis, and for abdominal infections and pneumonia using matched control groups. ResultsDuring the study period, 2,076 episodes of infection occurred, including 363 with BSI. Patients with BSI had a greater severity of illness and a greater death rate. After logistic regression, however, BSI did not independently predict death. After matching patients with abdominal infections and pneumonia with BSI to patients without BSI but with a similar site of infection, severity of illness, age, and causative organism, no difference in outcome was seen. ConclusionsBloodstream infection is associated with critical illness and death but appears to be a marker of severe primary disease rather than an independent predictor of outcome.

Tertiary peritonitis (recurrent diffuse or localized disease) is not an independent predictor of mortality in surgical patients with intraabdominal infection.

BACKGROUNDnIt is well documented that tertiary peritonitis is associated with different microbiological flora and worse outcomes than secondary peritonitis. It is unknown, however, if these differences can be explained simply by the nosocomial nature of tertiary peritonitis and underlying severity of illness.nnnMETHODSnWe reviewed all episodes of intraabdominal infection on the inpatient surgical services at a university hospital over a 46-month period. Univariate analysis and logistic regression were used to compare 91 episodes of secondary peritonitis that progressed to tertiary peritonitis (recurrent diffuse or localized intraabdominal infection) to all episodes of secondary peritonitis (n = 453) to identify predictors for developing tertiary peritonitis. Logistic regression was also used to identify predictors of mortality among patients with secondary (n = 473) or tertiary peritonitis (n = 129).nnnRESULTSnOf 602 episodes of intraabdominal infection identified, there were 473 episodes of secondary peritonitis, including 20 patients who died within seven days of diagnosis. A total of 129 episodes of tertiary peritonitis were identified, of which 91 were preceded by a single episode of secondary peritonitis, and 38 were preceded by an episode of secondary peritonitis and at least one prior episode of tertiary peritonitis. Tertiary peritonitis was associated with a high APACHE II score (14.9 +/- 0.7), pancreatic or small bowel source, drainage only at initial intervention, gram-positive and fungal pathogens, and a high mortality rate (19%). Increasing APACHE II score (OR 1.07, 95% CI 1.03-1.16, p = 0.0009) independently predicted progression from secondary to tertiary peritonitis while increasing age (OR 0.98, 95% CI 0.97-0.99, p = 0.01) and appendiceal source (OR 0.12, 95% CI 0.02-0.68, p = 0.02) predicted non-progression to tertiary peritonitis. Independent predictors of mortality in this population included increasing age (OR 1.06, 95% CI 1.03-1.1, p < 0.001), increasing APACHE II score (OR 1.18, 95% CI 1.11-1.3, p < 0.001), and four comorbidities: cerebrovascular disease (OR 4.3, 95% CI 1.4-13.1, p = 0.01), malignant disease (OR 2.9, 95% CI 1.3-6.5, p = 0.01), hemodialysis dependency (OR 3.8, 95% CI 1.3-11.2, p = 0.02), and liver disease (OR 4.2, 95% CI 1.6-15.1, p = 0.03). Tertiary peritonitis was not an independent predictor of mortality.nnnCONCLUSIONSnWe were unable to demonstrate, when compared to secondary peritonitis, that tertiary peritonitis is a significant independent predictor of mortality when other variables are taken into account. This suggests that the high mortality associated with tertiary peritonitis is more a function of the patient population in which it occurs than the severity of the pathologic process itself.

Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections

Immunosuppressed solid organ transplant patients may exhibit a blunted response to infection compared to non‐transplant patients. To test this hypothesis, we prospectively identified all episodes of bacterial and fungal infection on the in‐patient abdominal organ transplant service in our hospital, in 1997, and compared them to infected general surgery and trauma admissions treated simultaneously on the same wards. Eighty‐two infections occurred in transplant patients versus 463 in non‐transplant patients. Transplant patients demonstrated an overall greater physiologic response [Acute Physiology and Chronic Health Evaluation (APACHE II) and Acute Physiology Scores (APS) at the time of infection of 17.0±0.7 and 10.3±0.6, respectively, vs. 12.2±0.4 and 8.0±0.3 for non‐transplant patients, p≦0.003], with a similar maximum temperature (38.0±0.1 vs. 38.2±0.1°C, p=0.2) and white blood cell (WBC) count (12.1±1.0 vs. 13.9±0.4 k/mL, p=0.08). Upon further analysis of subgroups, patients receiving mycophenolate or azathioprine had significantly lower maximum temperatures (37.9±0.2°C) and WBC counts (11.0±0.9 k/mL) when compared to non‐transplant patients, while steroids appeared to have little effect on the systemic inflammatory response. Overall mortality was similar between groups. In general, solid organ transplant recipients exhibit a physiologic response to bacterial or fungal infection (as measured by the APS) at least as great as that seen in non‐transplant surgical patients, although mycophenolate and azathioprine appear to slightly depress the ability to respond with fever and leukocytosis. None of these differences appeared to affect overall mortality.

Characteristics of infectious complications associated with mortality after solid organ transplantation

Infection remains a common source of morbidity and mortality after solid organ transplantation. The purpose of this study was to characterize the continuously changing patterns of post‐transplantation infections, analyze early post‐transplantation infections, and evaluate characteristics associated with mortality. A secondary analysis was performed on prospectively collected data for all episodes of infection occurring between 10 December 1996 and 28 October 1998 on the surgery services at a university medical center. Post‐transplantation infections were compared with those in non‐transplantation patients randomly matched by severity of illness. Further analysis was performed on post‐transplantation infections occurring during the admission of transplantation compared with those in subsequent admissions. To evaluate factors associated with mortality, episodes occurring in survivors and non‐survivors were compared. The results demonstrated that infections in transplantation recipients (n=303) were associated with a younger age and had significantly lower white blood cell counts (WBC) compared with non‐transplantation patients. There was no difference in mortality (15.5 vs. 16.5%, p=0.74). Post‐transplantation infectious complications during the initial hospitalization (n=105) occurred at 38±6 compared with 695±66 d (p<0.0001) after transplantation and were associated with a longer length of stay (LOS) and increased mortality (30.5 vs. 7.6%, p<0.0001) compared with those occurring in subsequent admissions (n=198). Although multiple characteristics of post‐transplantation infections were associated with mortality, only the Acute Physiology and Chronic Health Evaluation (APACHE) II score was an independent predictor of mortality. Post‐transplantation infections remain a significant source of morbidity and mortality. The leukocyte response to infection was suppressed in the transplantation population. Post‐transplantation infections which occur during the admission for transplantation have a markedly increased mortality.