Thomas G. Gleason

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.

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.

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.

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.

Contribution of Escherichia coli Alpha-Hemolysin to Bacterial Virulence and to Intraperitoneal Alterations in Peritonitis

ABSTRACT Alpha-hemolysin (Hly) is a common exotoxin produced byEscherichia coli that enhances virulence in a number of clinical infections. The addition of hemolysin production to laboratory bacterial strains is known to increase the lethality of E. coli peritonitis. However, the mechanisms involved have not been determined and the contribution of hemolysin to the alterations in the host intraperitoneal environment and the leukocyte response is not known. Utilizing a rat peritonitis model, we show that wild-type hemolytic E. coli strains have a significant competitive advantage over nonhemolytic strains within the peritoneum. To examine the specific contribution of Hly to E. coli-induced virulence and alterations within the peritoneum, a mixed peritonitis model of E. coli, Bacteroides fragilis, and sterile fecal adjuvant was used. Three transformed E. colistrains were utilized: one strongly secretes active hemolysin (WAF 270), a second secretes active hemolysin but a reduced amount (WAF 260), and the third does not produce hemolysin (WAF 108). After an equal inoculum of each of the three strains, WAF 270 produced a markedly increased lethality and an increased recovery of both E. coli and B. fragilis from the host relative to the other strains. Changes in the intraperitoneal pH, degree of erythrocyte lysis, and recruitment and viability of leukocytes within the peritoneum following the induction of peritonitis differed significantly between the strongly hemolytic and nonhemolytic strains. Induction of peritonitis with WAF 270 caused a pronounced decrease in intraperitoneal pH, lysis of most of the intraperitoneal erythrocytes, and a marked decrease in recoverable viable leukocytes compared to WAF 108. Thus, hemolysin production by E. coli within the peritoneum may alter not only the hosts ability to control the hemolytic strain itself but also other organisms.

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.

Cohort study of fever and leukocytosis as diagnostic and prognostic indicators in infected surgical patients.

Abstract. The presence of fever and leukocytosis have traditionally been utilized as important diagnostic markers of infection despite some who question their reliability. To examine this point, the role of fever and leukocytosis as diagnostic and prognostic indicators for surgical infections was evaluated. A prospective observational study was performed on all patients with suspected infection in 1997 on the general surgical services at a university hospital. Fever was defined as maximum temperature (Tmax) ≥ 38.5°C, and leukocytosis was defined as a white blood cell (WBC) count ≥ 11,000/μl. Among all infections, patients presenting with a Tmax ≥ 38.5°C were younger (51.3 ± 1.1 vs. 53.8 ± 0.9 years, p= 0.005) and had a higher APACHE II score (15.1 ± 0.5 vs. 11.4 ± 0.4; p < 0.001). By logistic regression analysis chronic renal insufficiency was associated with a Tmax < 38.5°C [odds ratio (OR) 0.371, 95% confidence interval (CI) 0.195–0.704], and chronic steroid therapy was associated with a WBC count < 11,000/μl (OR 0.556, 95% CI 0.335–0.921). In addition, infected transplant patients were more likely to present with a Tmax < 38.5°C and a WBC count < 11,000/μl (OR 0.195, 95% CI 0.075–0.502). Mortality rates for infected patients with a Tmax < 38.5°C or > 38.5°C were 11.6% and 12.9%, respectively (p < 0.7), and the lengths of stay were 14 ± 1 and 18 ± 1 days, respectively (p < 0.03). Mortality rates for patients with a WBC count < 11,000/μl or > 11,000/μl were 4.7% and 18.6%, respectively (p < 0.001), and the lengths of stay were 14 ± 1 and 19 ± 1 days, respectively (p < 0.001). In the setting of infection, chronic renal insufficiency and chronic steroid therapy are associated with suppression of fever and leukocytosis, respectively. Transplantation is an independent predictor of infection in patients presenting without fever or leukocytosis. Leukocytosis, but not fever, may be predictive of hospital mortality in infected surgical patients.

Outcome Analysis Of Intraabdominal Infection with Resistant Gram-Positive Organisms

BACKGROUND Although the microbiology of intraabdominal infection has been well described, the role of resistant organisms remains unclear. To evaluate the hypothesis that intraabdominal infections from resistant gram-positive cocci (rGPC) have worse outcomes compared to those with susceptible organisms, patient characteristics and outcomes were compared between these groups. METHODS Analysis of peritoneal infections was performed on prospectively collected data of all consecutive surgical infections from December 1996 to June 1999 at a university hospital. Intraabdominal infection was defined either by a positive peritoneal cavity culture or on clinical grounds (e.g., abscess), which prompted antimicrobial or surgical therapy. Resistant Staphylococcus and Enterococcus spp. were defined as those strains resistant to oxacillin, gentamicin, or vancomycin. RESULTS Compared to episodes of intraabdominal infection from susceptible organisms (n = 365), infections due to rGPC (n = 52) were associated with an increased severity of illness (p < 0.0001), longer time from admission to treatment (p < 0.0001), longer duration of therapy (p = 0.008), greater proportion of nosocomial infection (p < 0.0001), increased length of stay (p < 0.0001), and an increased mortality rate (9% versus 23%; p = 0.003). However, comparison of intraabdominal infection with rGPC to a group controlled for severity of illness demonstrated a prolonged time from admission until treatment and longer duration of hospitalization but a similar mortality rate between groups (17% versus 23%; p = 0.46). CONCLUSION Intraabdominal infection with rGPC is an indicator of poor prognosis and severe illness. Although not an independent predictor of mortality, the significantly increased duration of therapy and prolonged duration of hospitalization may have considerable economic impact.

Implications of 2,457 consecutive surgical infections entering year 2000.

ObjectiveTo assess the demographics and characteristics of infections in surgical patients to define areas that deserve emphasis in surgical education. Summary Background DataAs a result of evolving technology and diseases, the complexity of diagnosing and treating infections has increased during the past three decades for all patients, including those treated primarily by surgeons. No comprehensive analysis of these conditions in a single surgical cohort has been recently published. MethodsThe authors conducted a prospective, observational study of all infections occurring on the general and trauma surgery services at a single university hospital during a 3.5-year period. ResultsThe authors identified 2,457 infections: 608 community-acquired, 1,053 occurring on the wards, and 796 occurring in the intensive care unit. Although dependent on patient location, the most common sites were abdomen, lung, and wound; the most common isolates were Staphylococcus epidermidis, Staphylococcus aureus, and Candida albicans; and the most commonly used antibiotics were ciprofloxacin, vancomycin, and metronidazole. The overall death rate was 13%, ranging from 5% after community-acquired infections to 25% after infections acquired in the intensive care unit. ConclusionsMost infections treated by surgeons are hospital-acquired. Infections with gram-positive cocci and fungi are common, with pulmonary infections becoming more common. Fluoroquinolones have become important therapeutic agents. Depending on the type of practice, these data should be helpful to direct educational efforts so that surgeons can remain knowledgeable and active in the nonsurgical care of their patients.

Effect of changes in surgical practice on the rate and detection of nosocomial infections: a prospective analysis.

The practice of surgery is being performed increasingly on an outpatient basis. How these changes have influenced the nosocomial infection rate and the ability of standard, Center for Disease Control (CDC)-designed surveillance techniques to detect these infections is unknown. The goal of this study was to determine whether recent changes in surgical care have led to an increased nosocomial infection rate based on number of discharges and whether current surveillance techniques are adequate to detect these complications. Data were collected prospectively on all nosocomial infections over a 1-year period on the general surgery, trauma, and transplant units at a university hospital, as independently observed by both the study team [surgical auditors (SA)] and CDC-trained infection control practitioners (ICP). The patient study group had a high acuity of illness (for 516 episodes of infection, mean APACHE II score of 15.4, 45% intensive care unit-bound, mortality of 16%). The overall infection rate per 100 discharges was 23.8 for SA and 12.2 for ICP (P < 0.001 by &khgr;2), higher than historical reports. SA detected significantly more surgical site infections, pneumonias, and non-Clostridium difficile-related gastrointestinal infections. These relative rates of detection, however, were similar to those described previously in prior studies using similar methodologies. The nosocomial infection rate in surgical patients, based on number of discharges, appears to be increasing, perhaps due to increased inpatient acuity of illness. Current epidemiological methods provide estimates of infection rates with effectiveness similar to that reported in previous epidemiological studies but fail to recognize many infections otherwise identified by surgeons dedicated to infection control.