Biomedical subjects

W G Cheadle

Publications and source records attributed to W G Cheadle.

At least 55 records · Page 3Linked to original sources

PubMed1994

The natural history of bacterial biofilm graft infection.

A mouse model was developed to study the natural history of vascular prosthetic graft infection due to Staphylococcus epidermidis. Graft infections were established in the back subcutaneous tissue of 46 mice by implantation of Dacron prostheses colonized in vitro with slime-producing S. epidermidis to form an adherent bacterial biofilm [1.7 x 10(7) colony forming units (CFU)/cm2 graft]. Control animals (n = 16) had implantation of sterile Dacron prostheses. None of the control animals developed a graft infection or graft-cutaneous sinus tract. All study animals developed a biofilm graft infection with typical anatomic (perigraft abscess), microbiologic (low bacterial concentration in surface biofilm), and immunologic (normal white blood count) characteristics. A graft-cutaneous sinus tract developed in a significantly higher number of mice with infected grafts by 8-10 weeks (9 of 21) compared to infected grafts explanted at 2 and 4-6 weeks (1 of 25, P < 0.01) and controls (0 of 16, P < 0.03). By 8-10 weeks, 2 animals had no signs of graft infection and the S. epidermidis study strain was not recoverable from 7 grafts. The natural history of bacterial biofilm vascular prostheses infection in the mouse model was similar to that in man, provoking a chronic inflammatory process curiously presenting as a perigraft abscess or graft-cutaneous sinus tract.

Animals↗

PubMed1994

Tissue tumor necrosis factor mRNA expression following cecal ligation and puncture or intraperitoneal injection of endotoxin.

Tumor necrosis factor (TNF) has been implicated as a key mediator of the septic response. Although very high serum levels of TNF are detected in animal models of endotoxemia or gram-negative bacteremia, human patients with sepsis rarely have greatly elevated TNF serum levels. It has therefore been postulated that TNF may act in a paracrine fashion to cause local injury. In order to examine the role of locally produced TNF in sepsis, we compared serum TNF levels and TNF messenger RNA (mRNA) expression in various tissues following cecal ligation and puncture (CLP) or intraperitoneal injection of a sublethal dose of endotoxin. TNF mRNA expression was determined by the reverse transcription differential polymerase chain reaction using beta-actin as an internal standard. Serum levels of TNF were threefold higher after endotoxin administration compared to CLP. TNF mRNA in peritoneal macrophages rose fourfold after both endotoxin injection and CLP, with rapid return to normal in endotoxin-treated animals. There was a significant increase in TNF mRNA in the liver and lung, but not the spleen, during the first 24 hr after CLP. An increase in TNF mRNA was seen in all three tissues after injection of endotoxin. These results support the concept of locally produced TNF as a contributing factor in tissue damage and multiple organ failure during sepsis.

Animals↗

PubMed1994

The contribution of open extremity fractures to infection in multiply injured patients.

We sought to determine whether a contaminated open fracture was a reliable component for calculating the Outcome Predictive Score in patients with multiple injuries. We studied 41 patients whose primary source of contamination was open extremity fractures. Only one of the 41 patients developed osteomyelitis. The rate of infection from an open fracture is minimal in the multiply injured patient. Inclusion of patients with open fractures in studies that assess the likelihood of infection and the value of anti-infective agents incorrectly identified patients for clinical trials and results in an overestimation of survival based on the Outcome Predictive Score. These findings suggest that open fractures should be excluded as an entry criterion in future clinical trials.

Bacterial Infections↗

PubMed1994

Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture.

Macrophage tumour necrosis factor-alpha (TNF-alpha) production is thought to represent an important pathogenic mechanism by which Gram-negative sepsis is mediated. We compared the effects of caecal ligation and puncture (CLP) on endotoxin-sensitive (C3H/HeSnJ) and endotoxin-resistant (C3H/HeJ) mice. Mortality after CLP for C3H/HeSnJ mice compared with C3H/HeJ mice was not significantly different (32% and 55%, respectively). When survivors were injected with lipopolysaccharide intraperitoneally on the 7th day after CLP, the mortality rate was 82% for C3H/HeSnJ mice versus 0% for C3H/HeJ mice (P < 0.0001). Serum endotoxin levels at 24 h after CLP were only slightly elevated. Serum TNF levels and peritoneal macrophage TNF production were undetectable in C3H/HeJ mice and were only slightly elevated in C3H/HeSnJ mice by 24 h after CLP. Peritoneal macrophage mRNA levels for TNF-alpha, IL-1 beta, and I-A alpha displayed a similar pattern in the two strains of mice, with a 2- to 3-fold increase in TNF-alpha and IL-1 beta mRNA levels by 24 h and a sharp decrease in I-A alpha mRNA by 24 h. The cause of mortality in mice that undergo CLP cannot be attributed to overwhelming endotoxemia and/or TNF production.

Animals↗

PubMed1994

Antibiotic overkill of trauma victims?

Antibiotic usage was assessed in a prospective, randomized trial of recombinant interferon-gamma (rIFN-gamma) versus placebo for 212 severely injured trauma patients in four university hospitals. All patients were observed until death or discharge from the hospital. We found the number of antibiotics used and their associated costs staggering and difficult to justify, although serious antibiotic-related complications were infrequent. Regular antibiotic administration following severe trauma should be re-evaluated since clinical evidence supports the use of shorter courses for these patients, with presumed similar outcomes and much-reduced expenses.

Adolescent↗

PubMed1994

Pneumonia in the surgical intensive care unit. Immunologic keys to the silent epidemic.

OBJECTIVE: The authors undertook a prospective study of trauma victims in the intensive care unit (ICU) to investigate the clinical course of pneumonia and the local and systemic immune responses to the pneumonia. SUMMARY BACKGROUND DATA: The silent epidemic of pneumonia has been an "unappreciated killer" in terms of being overlooked in surgical ICUs for the past 5 years, and specifically, the most common major infection after severe trauma. Little is known about the immune response to an acute pulmonary infection. METHODS: The authors studied 50 consecutive, critically ill trauma patients, with a mean injury severity score of 28 +/- 2, who developed pneumonia while ventilated mechanically. Patients were observed clinically, and specific immunologic parameters, including major histocompatibility antigen HLA-DR, complement receptor (CR3), and Fc receptor (FcRIII), were measured in circulating and local alveolar leukocytes for up to 30 days. Eleven patients provided unique clinical data via bronchoscopy for unilateral pneumonia, with collection of bronchoalveolar lavage (BAL) fluid from both the infected and uninfected sides. RESULTS: Patients developed clinical pneumonia 5.3 +/- 0.4 days after admission to the ICU. At diagnosis, mean temperature was 101.4 F, white blood cell count was 16,000/mm3, arterial oxygen tension was 104 +/- 14, fraction of inspired oxygen was 0.47, and positive end-expiratory pressure was 5. Thirty patients (Group A) recovered relatively promptly; 20 patients had prolonged illnesses (Group B), 15 of whom ultimately survived, and five of whom died. Patients with poor outcomes had greater leukocytosis (p < 0.05) and temperature elevation (p < 0.05) after 5 days of pneumonia. Immunologically, peripheral leukocyte expression of HLA-DR, FcRIII, and CR3 was equivalent in both groups. However, the expression of all three antigens on local alveolar leukocytes was decreased to a greater extent in the poor outcome group compared to the good outcome group, evident before any clinical differentiation between the two outcome groups. CONCLUSIONS: Pneumonia prolonged duration of mechanical ventilation, ICU and hospital stay, and overall infectious morbidity. Although immune suppression has been recognized as a result of initial injury, the development of pneumonia coincided with the nadir of immune function. Poor outcome patients were clinically identifiable 5 days after pneumonia and immunologically identifiable within 2 days. Moreover, there was localized suppression of pulmonary leukocytes at the site of the infiltrate compared to the uninfected lobes. This same alteration was noted in experimental Klebsiella pneumoniae pneumonia. This evidence suggests that there is active immune participation within the respiratory system. It also suggests that there are predispositions to pulmonary infections, and it may allow immune modulation targeted to pulmonary leukocytes to hasten clinical recovery and minimize pulmonary dysfunction.

Adult↗

PubMed1994

Alteration of mononuclear cell immune-associated antigen expression, interleukin-1 expression, and antigen presentation during intra-abdominal infection.

Intact peritoneal macrophage (M phi) function is critical to successful localization of intra-abdominal infection. Peritoneal macrophage antigen presentation capacity (APC), interleukin-1 (IL-1) expression, and immune-associated (Ia) antigen expression and abscess formation were determined following cecal ligation and puncture. APC and IL-1 expression were measured by coculture with a T-helper cell clone and by measuring subsequent proliferation. Ia expression was determined in blood, peritoneal M phi, and splenocytes using anti-Ia monoclonal antibody stain and flow cytometric analysis. Significant reductions in both Ia expression and APC were found 1 and 4 days after CLP with no change in IL-1 expression. Muramyl dipeptide, which enhances M phi phagocytosis, partially abrogated the depression in antigen presentation but did not affect Ia expression. Peritoneal M phi Ia expression and APC, but not IL-1 expression, were depressed after experimental peritonitis. The recovery of M phi function by day 14 coincides with clinical recovery and abscess formation, and restoration of early M phi depression may improve outcome.

Abdominal Abscess↗

PubMed1994

Passive immunization against tumor necrosis factor and interleukin-1 fails to reduce lung neutrophil sequestration in chronic sepsis.

The proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) are produced within the lung during sepsis, and may induce neutrophil sequestration resulting in neutrophil-mediated lung injury. We hypothesized that, if there is a cause and effect between TNF alpha or IL-1 production and lung neutrophil sequestration during chronic sepsis, TNF alpha mRNA and IL-1 mRNA levels in the lung after cecal ligation and puncture should correlate with the number of sequestered neutrophils as measured by the myeloperoxidase (MPO) content of the lung. To test this hypothesis, Swiss Webster mice were subjected to varying degrees of infectious challenge by single and double-puncture cecal ligation and puncture, or simultaneous antibiotic treatment, and their lungs and blood were harvested at 24 h. Lung TNF alpha and IL-1 beta mRNAs were measured by the reverse-transcription differential polymerase chain reaction, and MPO was measured by colorimetric assay. TNF alpha serum levels showed no correlation with the MPO content of the lung, whereas IL-1 levels were undetectable. Lung TNF alpha mRNA correlated weakly, and IL-1 beta mRNA exhibited a strong correlation with lung MPO (r = .9, p < .01), but administration of anti-TNF alpha- or anti-IL-1-neutralizing antibodies did not prevent a rise in lung MPO. IL-1 beta mRNA in bronchoalveolar macrophages correlated well with whole lung tissue IL-1 beta mRNA levels (r = .91, p < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Enhanced survival from cecal ligation and puncture with pentoxifylline is associated with altered neutrophil trafficking and reduced interleukin-1 beta expression but not inhibition of tumor necrosis factor synthesis.

BACKGROUND: Our preliminary results showed that pentoxifylline improves survival after cecal ligation and puncture (CLP), even though in this model inhibition of tumor necrosis factor (TNF) activity decreases survival. In this study we tested the hypothesis that pentoxifylline improves survival after CLP, not by inhibiting TNF synthesis but by exerting its effect on leukocyte adhesiveness, neutrophil sequestration, recruitment of cells into the focus of sepsis, and interleukin-1 (IL-1) expression. METHODS: Pentoxifylline, 10 or 100 mg/kg/day, was administered to mice after CLP by infusion for 3 days. The following was measured at 24 hours for the group with improved survival: (1) serum TNF by enzyme-linked immunosorbent assay, (2) TNF and IL-1 beta mRNAs in lung and peritoneal macrophages by the differential polymerase chain reaction, (3) lung myeloperoxidase by a colorimetric assay, (4) leukocyte CD11b/CD18 by flow cytometry, and (5) peritoneal exudate cells by manual counting. RESULTS: Only the low-dose pentoxifylline increased survival. Pentoxifylline reduced IL-1 beta mRNA expression in lung and peritoneal macrophages but not TNF mRNA or immunoreactive TNF in the serum. The myeloperoxidase content of lung was reduced by pentoxifylline, but leukocyte CD11b/CD18 expression did not change. Pentoxifylline increased the number of cells in the peritoneum after CLP. CONCLUSIONS: Pentoxifylline improves survival after CLP without inhibiting TNF synthesis or expression of CD11b/CD18 on leukocytes. Pentoxifylline treatment reduced lung neutrophil sequestration and IL-1 beta mRNA levels and increased cell recruitment in the peritoneum.

Animals↗

PubMed1993

Regulation of macrophage TNF alpha, IL-1 beta, and Ia (I-A alpha) mRNA expression during peritonitis is site dependent.

Failure of the immune system to successfully prevent organ failure after injury or infection may be associated with a shift in macrophage function from antigen recognition and presentation to overexpression of inflammatory cytokines. Regulation may be due to changes in macrophage gene expression. Levels of mRNA for tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and the Ia subunit, I-A alpha, in peritoneal macrophages, liver, spleen, kidney, and lung were measured following cecal ligation and puncture (CLP) in Swiss Webster mice. Northern blot analysis was performed using 32P-labeled mouse cDNA probes. Peritoneal macrophage TNF alpha and IL-1 beta mRNA expression increased 2.5- and 2-fold, respectively, by 6 hr after CLP and remained elevated at 24 hr. Peritoneal macrophage I-A alpha mRNA levels decreased 8-fold by 24 hr after CLP. I-A alpha mRNA expression in liver, spleen, kidney, and lung decreased following CLP, with a return toward normal levels by 8 days in all tissues except spleen. IL-1 beta and TNF alpha mRNA were barely detectable in liver and kidney. IL-1 beta mRNA tended to increase over time in lung and spleen, whereas TNF alpha mRNA in these tissues did not vary greatly after CLP. Muramyl dipeptide or monophosphoryl lipid A pretreatment of animals prior to CLP was ineffective in altering the expression of TNF alpha and I-A alpha mRNA. We conclude that peritonitis is associated with an early increase in peritoneal macrophage TNF alpha and IL-1 beta mRNA levels and a sharp decline in macrophage I-A alpha mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1993

The human leukocyte antigens and their relationship to infection.

Human leukocyte antigen DR (HLA-DR) expression on peripheral blood monocytes has been found to correlate highly with infection in many clinical scenarios. This is particularly true for the trauma patient, where changes in HLA-DR expression predate and therefore often predict development of infection. Expression of this antigen is limited to immunocompetent cells, such as B lymphocytes, macrophages, and activated T cells. The HLA-DR heterodimer is required for major histocompatibility complex restricted antigen presentation, a key step in the development of a specific immune response. The degree of monocyte HLA-DR expression may reflect the ability eventually to present antigen, since close correlation has been found between the two. There was remarkable reproducibility of monocyte HLA-DR expression among > 100 asymptomatic volunteers without regard to age, gender, race, and sampling time. Immunosuppressive medication had no effect. Incubation of monocytes from severely infected patients with endotoxin distinguished survivors from those who died by enhanced HLA-DR expression in the survivors. Of several agents that enhance HLA-DR expression, interferon-gamma has received the most attention in experimental models as well as humans. Although promising in selected patients, further clinical trials will be needed to define its specific role. Identification of the patient at high risk for infection, particularly following trauma, will be crucial for the efficient evaluation of future therapeutic interventions. Monocyte HLA-DR expression is the first simple assessment of the host immune response to play an important role in this endeavor.

Bacterial Infections↗

PubMed1993

Lymphocyte subset responses to trauma and sepsis.

One hundred five trauma patients admitted to three trauma centers with injury Severity Scores of 20 or greater had lymphocyte phenotypic subsets characterized throughout their hospital course. Total lymphocytes, pan-T (CD2), helper T (CD4), suppressor T (CD8), pan B (CD20), and DR expressing lymphocytes were quantitated by monoclonal antibodies and flow cytometric analysis. Results were analyzed between three patient groups: uninfected, uneventful recovery (n = 64); major infection (n = 26); and dead (n = 15; 7 with sepsis). A significant lymphopenia, maximal at 3 days, occurred in the first postinjury week compared with controls (p < 0.05), which recovered over the study period. A hierarchical distribution was found between the three outcome groups with the lowest numbers of several lymphocyte phenotypes in those who died. T helper and suppressor cells were similarly affected, but lowest in patients destined to develop infection or die. The helper-suppressor ratio, however, was similar in all three outcome groups. Therefore, modulation early after injury aimed at restoring these subsets may reduce the risk of subsequent infection.

Adolescent↗

PubMed1993

Prospective randomized study of piperacillin/tazobactam therapy of surgically treated intra-abdominal infection. The Piperacillin/Tazobactam Intra-Abdominal Infection Study Group.

A randomized prospective trial was undertaken in adult patients with serious intra-abdominal infections to determine whether a new combination of antibiotic therapy could prove as efficacious as the combination that has been widely used in practice in the recent decade (clindamycin and gentamicin). Three hundred thirty-one patients were randomized in a 2:1 ratio, with the larger number of patients being treated parenterally with piperacillin and tazobactam. The results showed that both the clinical and microbiologic performance of the piperacillin/tazobactam combination was better than that of clindamycin and gentamicin. This clinical equivalence permits overall cost savings without compromising the existing quality of antimicrobial therapy for intra-abdominal infection.

Abdomen↗

PubMed1992

A randomized prospective clinical trial to determine the efficacy of interferon-gamma in severely injured patients.

Many aspects of the normal immune response are depressed after severe injury. Reduced monocyte human leukocyte antigen-DR (HLA-DR) levels have closely correlated with the development of major infection. After a pilot study with recombinant interferon-gamma (rIFN-gamma) showed restoration of depressed HLA-DR levels after major injury, a multicenter, prospective, randomized, double-blind trial was conducted. Two hundred thirteen trauma patients who were at high risk of infection received either placebo or rIFN-gamma (100 micrograms) subcutaneously each day for 10 days after admission. One hundred ninety-three patients were evaluable with respect to primary end points. Patients treated with rIFN-gamma were older (p = 0.10) and had more severe modes of injury (p = 0.02). By the third day, both monocyte HLA-DR antigen expression and outcome predictive score were significantly better in the rIFN-gamma-treated group than in the placebo group (p = 0.0001 and p = 0.0006, respectively). Nine deaths occurred in patients treated with rIFN-gamma compared with 12 deaths in the placebo group (p = 0.46). Major infections requiring surgical drainage or debridement occurred in 17 patients treated with rIFN-gamma compared with 22 treated with placebo. No difference between treatment arms was noted in overall major or minor infection rates, but there were fewer severe infections that required reoperation or computer tomographic-guided drainage in patients receiving IFN-gamma. While these results suggest that rIFN-gamma may be useful in some aspects of infection in the patient with severe trauma, a larger trial with longer treatment will be needed to prove the comprehensive value of rIFN-gamma.

Adult↗

PubMed1992

Effect of protein malnutrition and immunomodulation on immune cell populations.

Malnutrition has deleterious effects on immune functions, which predispose to an increased risk of infection. To study the effect of protein malnutrition on such immune functions and resistance to infection, we divided C57BL/6 mice into three groups: (1) control-standard diet, (2) protein-malnourished for 14 days, and (3) protein-malnourished for 14 days followed by standard diet for 3 days. The animals were further divided into subgroups: (1) an untreated group, (2) a muramyl dipeptide (MDP)-treated group, and (3) an interferon-gamma (IFN-gamma)-treated group before cecal ligation and puncture (CLP). Malnourished mice had significantly (P less than 0.05) lower body weight, serum albumin, spleen/body weight, percentage of splenic macrophages with Ia expression (%MOIa), increased splenic T suppressor cells, and greater mortality after CLP. Refeeding plus IFN-gamma or MDP significantly increased %MOIa (P less than 0.05) and also abrogated the increase in splenic lymphocytes seen in the malnourished animals. The increase in splenic suppressor T cells was not affected by refeeding or immunomodulation. Mortality after CLP was increased from 15% in the controls to 85% in the malnourished group and was significantly decreased by refeeding, MDP, and the combination of refeeding plus immunomodulators (P less than 0.05). These data show that 14-day malnutrition adversely affected the immune response to infection and increased mortality from CLP. Refeeding and immunomodulation restored macrophage Ia expression without CLP but not after the procedure, despite the significant reduction in mortality. The use of immunomodulation in protein malnourished conditions may serve as an adjuvant role to nutritional support.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1992

Prophylactic antibiotics prevent bacterial biofilm graft infection.

Bacterial biofilm graft infection is due to prostheses colonization by Staphylococcus epidermidis, a pathogen frequently recovered from perigraft tissues of man during vascular procedures despite the use of asepsis and prophylactic antibiotics. The effect of preoperative intraperitoneal cefazolin, administered at a standard (15 or 30 mg/kg) and high (120 mg/kg) dose, on the prevention of bacterial biofilm infection was studied in a rat model. Seventy-four Dacron grafts, colonized in vitro with S. epidermidis to produce an adherent biofilm (3.19 +/- 0.71 x 10(7) colony-forming units/cm2 graft), were implanted in the dorsal subcutaneous tissue at 0.5, 2, and 4 hr after antibiotic administration. The study strain was a slime-producing clinical isolate with minimum inhibitory concentration (MIC) of 15-30 micrograms/ml to cefazolin. Subcutaneous tissue antibiotic levels were determined at each time interval. One week after implantation, the concentration of bacteria in the surface biofilm by quantitative agar culture was significantly decreased (P less than 0.05) only for grafts implanted when antibiotic tissue levels were greater than or equal to the MIC of the study strain. The result of no growth by biofilm broth culture was significantly achieved (P less than 0.01) only for grafts implanted 0.5 hr after high dose cefazolin, in which the tissue antibiotic level was above the MIC of the study strain. Antibiotics can markedly reduce the bacteria concentration of a prosthetic surface biofilm. The effectiveness of prophylactic antibiotics on the prevention of graft infection is dependent upon maintaining an adequate antibiotic level in the perigraft tissues for the duration of the procedure.

Animals↗

PubMed1992

Current perspectives on antibiotic use in the treatment of surgical infections.

Infections that involve the attention of the surgeon include those that require operations for cure as well as those that complicate emergency and elective surgical procedures. Mechanical correction is of paramount importance in the eradication of such infections with antibiotics serving an adjuvant role, primarily to clear lymphatics and prevent bacteremia and seeding of distant sites. Review of the current hospital antibiotic susceptibility profile is important to determine likely sensitivity to expected pathogens. Infection of the urinary tract remains the most common nosocomial infection, but in surgical patients the severe infections are pneumonia, fasciitis, and peritonitis. Often caused by the gram-negative Enterobacteriaceae, empiric broad spectrum antibiotic therapy is initiated after cultures are obtained. Bacterial infection of the respiratory tract is often difficult to diagnose in severely ill patients because the underlying fever, leukocytosis, and chest X-ray changes are often nonspecific. Reliance on sputum gram stain and culture is important to guide antibiotic therapy. Empiric treatment of peritonitis requires knowledge of the normal enteric flora and the likely pathogenic organisms. The most lethal agent against obligate anaerobic organisms is atmospheric oxygen, yet antibiotic coverage against these organisms appears wise, particularly when debridement or resection will be delayed or not performed. Staphylococcus aureus is still the most commonly cultured organism from our Surgical Intensive Care Unit and Burn Unit and S. aureus is often responsible for central line and burn wound infection. For patients in septic shock, we favor administration of a broad-spectrum penicillin or cephalosporin combined with an aminoglycoside, with subsequent narrowing of the antibiotic spectrum based on culture results. Antibiotic efficacy, toxicity, efficiency, and cost all must be weighed in the decision-making process.

Anti-Bacterial Agents↗

PubMed1992

The role of the complement system in trauma and infection.

The complement system is an important immediate host defense mechanism after trauma, extensive burn injury and after invasion by microbial pathogens. Massive complement activation, however, seems to be detrimental and may contribute further to the disease process and eventually to multiple organ failure or the septic state. In clinical situations in which complement is damaging, the logical therapy should be, if at all possible, the removal of the activated complement components from the circulation. However, much of the protein is attached to the membrane and effective locally, so prevention of the enzymatic cascade may be more appropriate. There has been little progress in manipulating the complement system to effectively alter such disease processes caused by the clinical situations and there is an important need for further research in the field.

Bacterial Infections↗