Kaysie L. Banton

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.).

Attenuated Salmonella typhimurium with interleukin 2 gene prevents the establishment of pulmonary metastases in a model of osteosarcoma

PURPOSE The current management of osteosarcoma (OS) entails an aggressive preoperative and postoperative chemotherapeutic regimen with limb salvage surgery. Despite these efforts, relapse-free survival is less than 60% in patients with classic OS, whereas most patients relapse with pulmonary metastases. In these studies, we sought to prevent the establishment of pulmonary metastases from OS with a single oral dose of SalpIL2. METHODS Mice were administered attenuated Salmonella typhimurium with (SalpIL2) and without a gene for human interleukin 2 (Sal-NG) 7 days before challenge with 2 x 10(5) OS cells via tail vein. Three weeks after injection, mice were harvested for splenic lymphocytes and tumor enumeration. RESULTS Prophylaxis with attenuated SalpIL2 significantly reduces pulmonary metastases in number and volume (P < .0001 and P < .0001) with respect to saline controls. Furthermore, splenic natural killer cell populations were increased 396% with SalpIL2 (P < .0007) and 426% with Sal-NG (P < .0003) compared to nontreated groups. CONCLUSIONS Host natural killer response is greatly amplified and maybe partially responsible for the effective immune response against the formation of pulmonary metastases. A single oral dose of SalpIL2 may be a novel form of adjuvant therapy for patients after early detection of primary OS.

Pre-PCR DNA quantitation of soil and sediment samples: method development and instrument design

A simple and straightforward method for the quantitation of dsDNA in soil and sediment matrices has been developed to support rapid, in-the-field PCR analysis of environmental samples. This method uses PicoGreen nucleic acid stain, and a combination of UV/Vis and fluorescence spectroscopy, to quantitate dsDNA in the presence of interfering humic materials. The practical utility of this approach is that it compliments a seven-step DNA extraction procedure for environmental samples. The DNA quantitation method is utilized twice during the extraction procedure. Once, prior to a micro-spin column procedure to maximize the amount of DNA extracted, and a second time, just prior to PCR to optimize the PCR reaction conditions. A field-portable, assay-specific instrument has been developed based on this methodology. Software for this instrument steps the analyst through the experimental procedure, and has been designed such that a minimum of technical expertise is required to perform the assay. Initial data obtained from the prototype unit indicates that this instrument compares with commercial instrumentation in terms of detection limit and sensitivity.

Pre-Operative Antiseptic Shower and Bath Policy Decreases the Rate of S. aureus and Methicillin-Resistant S. aureus Surgical Site Infections in Patients Undergoing Joint Arthroplasty

BACKGROUND Surgical site infection (SSI) following joint arthroplasty increases length of stay, hospital cost, and leads to patient and healthcare provider dissatisfaction. Due to the presence of non-biologic implants (the prosthetic joint) in these procedures, infection is often devastating and treatment of the infection is more difficult. For this reason, prevention of SSI is of crucial importance in this population. Staphylococcus aureus colonizes the nares of approximately 30-40% of the population, is the most common pathogen causing SSI, and is associated with high morbidity and mortality rate. A pre-operative shower or bath with an antiseptic is an inexpensive and effective method of removal of these transient skin pathogens prior to the procedure and may be used to decrease SSI. HYPOTHESIS We hypothesize that a preoperative antiseptic shower or bath will decrease the rate of SSI. METHODS A retrospective review was performed at two affiliated hospitals within the same system, one with a hospital-wide policy enforcing pre-operative antiseptic shower or bath and the other with no policy, with cases included from January 2010 to June 2012. International Classification of Disease-Ninth Revision-Clinical Modification (ICD-9-CM) codes and chart review were used to identify patients undergoing joint arthroplasty and to identify those with SSI. RESULTS Two thousand three-hundred forty-nine arthroplasties were performed at the University of Minnesota Medical Center, a tertiary-care hospital with a pre-operative antiseptic shower or bath policy in place. An additional 1,693 procedures were performed at Fairview Ridges Hospital, a community hospital with no pre-operative policy. There was no difference in the rate of SSI between the two hospitals (1.96% vs. 1.95%; p=1.0). However, the rate of SSI caused by S. aureus was significantly decreased by pre-operative antiseptic shower/bath (17% vs. 61%; p=0.03), as was the rate of methicillin-resistant S. aureus (MRSA) infections (2% vs. 24% p=0.002). CONCLUSIONS A pre-operative antiseptic shower and bath policy was associated with a significant decrease in S. aureus and MRSA SSI, but did not decrease the total incidence of SSI. This intervention may decrease the morbidity of S. aureus SSI in this population.

Safety and immunogenicity of Salmonella typhimurium expressing C-terminal truncated human IL-2 in a murine model

Salmonella enterica serovar Typhimurium preferentially colonizes tumors in vivo and has proven to be an effective biologic vector. The attenuated S. enterica Typhimurium strain χ4550 was engineered to express truncated human interleukin-2 and renamed SalpIL2. Previously, we observed that a single oral administration of SalpIL2 reduced tumor number and volume, while significantly increasing local and systemic natural killer (NK) cell populations in an experimental metastasis model. Here we report that in nontumor-bearing mice, a single oral dose of SalpIL2 resulted in increased splenic cytotoxic T and NK cell populations that returned to control levels by 4 weeks post oral administration. Though SalpIL2 was detected in mouse tissues for up to 10 weeks, no prolonged alterations in peripheral blood serum chemistry or complete blood cell counts were observed. Similarly, comparative histopathological analysis of tissues revealed no significant increase in pyogranulomas in SalpIL2-treated animals with respect to saline controls. In Rag-1 knockout mice, which have severely impaired B and T cell function, SalpIL2 reduced growth of hepatic metastases. Furthermore, SalpIL2 altered expression of several proinflammatory cytokines and chemokines in the serum of mice with pulmonary osteosarcoma metastases. These data further suggest that SalpIL2 is avirulent and induces a cell-mediated antitumor response.

Antioxidant oils and Salmonella enterica Typhimurium reduce tumor in an experimental model of hepatic metastasis

Fruit seeds high in antioxidants have been shown to have anticancer properties and enhance host protection against microbial infection. Recently we showed that a single oral dose of Salmonella enterica serovar Typhimurium expressing a truncated human interleukin-2 gene (SalpIL2) is avirulent, immunogenic, and reduces hepatic metastases through increased natural killer cell populations in mice. To determine whether antioxidant compounds enhance the antitumor effect seen in SalpIL2-treated animals, we assayed black cumin (BC), black raspberry (BR), and milk thistle (MT) seed oils for the ability to reduce experimental hepatic metastases in mice. In animals without tumor, BC and BR oil diets altered the kinetics of the splenic lymphocyte response to SalpIL2. Consistent with previous reports, BR and BC seed oils demonstrated independent antitumor properties and moderate adjuvant potential with SalpIL2. MT oil, however, inhibited the efficacy of SalpIL2 in our model. Based on these data, we conclude that a diet high in antioxidant oils promoted a more robust immune response to SalpIL2, thus enhancing its antitumor efficacy.

Postoperative severe microangiopathic hemolytic anemia associated with a giant hepatic cavernous hemangioma

Complications related to liver hemangioma are rare. We herein describe the case of a patient with three giant cavernous hemangiomas of the liver, of which two were resected for symptoms. A significant microangiopathic hemolytic anemia occurred in the early postoperative period, leading to acute renal failure and necessitating blood transfusions. The systematic evaluation of hemolytic processes in the postoperative patient is described. Surgeons should be aware of the potential for hemolytic complications after major surgery when giant hepatic hemangiomas are present.

Percutaneously drained intra-abdominal infections do not require longer duration of antimicrobial therapy.

BACKGROUND The length of antimicrobial therapy in complicated intra-abdominal infections (CIAIs) is controversial. A recent prospective, multicenter, randomized controlled trial found that 4 days of antimicrobial therapy after source control of CIAI resulted in similar outcomes when compared with longer duration. We sought to examine whether outcomes remain similar in the subpopulation who received percutaneous drainage for source control of CIAI. METHODS With the use of the STOP-IT database, patients with a CIAI who received percutaneous drainage were analyzed. Patients were randomized to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy or to receive a fixed course of antibiotics for 4 ± 1 days. Outcomes included incidence of and time to recurrent intra-abdominal infection, Clostridium difficile infection, and extra-abdominal infections as well as hospital days and mortality. RESULTS Of 518 enrolled patients, 129 met inclusion criteria. Baseline characteristics, including demographics, comorbidities, and severity of illness, were similar. When comparing outcomes of the 4-day group (n = 72) with those of the longer group (n = 57), rates of recurrent intra-abdominal infection (9.7% vs. 10.5%, p = 1.00), C. difficile infection (0% vs. 1.8%, p = 0.442), and hospital days (4.0 [2.0–7.5] vs. 4.0 [3.0–8.0], p = 0.91) were similar. Time to recurrent infection was shorter in the 4-day group (12.7 [6.2] days vs. 21.3 [4.2] days, p = 0.015). There was no mortality. CONCLUSION In this post hoc analysis of a prospective, multicenter, randomized trial, there was no difference in outcome between a shorter and longer duration of antimicrobial therapy in those with percutaneously drained source control of CIAI. LEVEL OF EVIDENCE Therapeutic/care management study, level IV.

Short-Course Antimicrobial Therapy Does Not Increase Treatment Failure Rate in Patients with Intra-Abdominal Infection Involving Fungal Organisms

BACKGROUND Fungi frequently are isolated in intra-abdominal infections (IAI). The Study to Optimize Peritoneal Infection Therapy (STOP-IT) recently suggested short-course treatment for patients with IAI. It remains unclear whether the presence of fungi in IAI affects the optimal duration of Antimicrobial therapy. We hypothesized that a shorter treatment course in IAI with fungal organisms would be associated with a higher rate of treatment failure. METHODS Patients enrolled in the STOP-IT trial were stratified according to the presence or absence of a fungal isolate. They were analyzed as a subgroup based on original randomization to either the control group or an experimental group that received a four-day course of Antimicrobial therapy and by comparison with those without a fungal component to their infection. Descriptive comparisons were performed using a χ2, Fisher exact, or Kruskal-Wallis test as appropriate. The primary outcome was a composite of recurrent IAI, surgical site infection, and death. RESULTS A total of 411 patients in the study (79%) had available culture data, of which 58 (14%) had positive fungal cultures. The most common organisms were Candida albicans and C. glabrata. The treatment failure rate was equivalent in the experimental and control arms (29.6% vs. 22.6%; p = 0.54). Patients with fungal isolates were more likely to have malignant disease (25.9% vs. 9.6%; p = 0.0004) and coronary artery disease (22% vs. 12%; p = 0.04), but were otherwise similar to those without fungal isolates. Patients with fungal isolates had more hospital days (median 10 vs. 7; p < 0.0001) and more days to resumption of enteral intake (median 5 vs. 3; p = 0.0006), but there was no difference in the composite outcome. CONCLUSIONS Patients with IAI involving fungal organisms randomized to a shorter course of Antimicrobial therapy had no difference in the rate of treatment failure. These results suggest that the presence of fungi in IAI may not indicate independently the need for a longer course of Antimicrobial therapy.

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.