PU.1-mediated transcription is enhanced by HMG-I(Y)-dependent structural mechanisms.

The ets transcription factor PU.1 is an important regulator of the immunoglobulin heavy chain gene intronic enhancer, or mu enhancer. However, PU.1 is only one component of the large multiprotein complex required for B cell-specific enhancer activation. The transcriptional coactivator HMG-I(Y), a protein demonstrated to physically interact with PU.1, increases PU.1 affinity for the mu enhancer muB element, indicating that HMG-I(Y) may play a role in the transcriptionally active mu enhanceosome. Increased PU.1 affinity is not mediated by HMG-I(Y)-induced changes in DNA structure. Investigation of alternative mechanisms to explain the HMG-I(Y)-mediated increase in PU.1/mu enhancer binding demonstrated, by trypsin and chymotrypsin mapping, that interaction between PU.1 and HMG-I(Y) in solution induces a structural change in PU.1. In the presence of HMG-I(Y) and wild-type mu enhancer DNA, PU.1 becomes more chymotrypsin resistant, suggesting an additional change in PU.1 structure upon HMG-I(Y)-induced PU.1/DNA binding. From these results, we suggest that increased DNA affinity under limiting PU.1 concentrations is mediated by an HMG-I(Y)-induced structural change in PU.1. In functional assays, HMG-I(Y) further augments transcriptional synergy between PU.1 and another member of the ets family, Ets-1, indicating that HMG-I(Y) is a functional component of the active enhancer complex. These studies suggest a new mechanism for HMG-I(Y)-mediated coactivation; HMG-I(Y) forms protein-protein interactions with a transcription factor, which alters the three-dimensional structure of the factor, resulting in enhanced DNA binding and transcriptional activation. This mechanism may be important for transcriptional activation under conditions of limiting transcription factor concentration, such as at the low levels of PU.1 expressed in B cells.

Soft tissue infections.

Soft tissue infections vary widely in their nature and severity, and their nomenclature is confusing. A clear approach to management must allow rapid identification and treatment of the diffuse necrotizing infections because they are life-threatening. This review classifies soft tissue infections by their degree of localization and the presence of tissue necrosis. Most focal nonnecrotizing infections start in the skin or adnexae and are easily recognized and readily treated by local measures. Patients with cellulitis, the commonest diffuse nonnecrotizing infection, should be stratified from mild to severe and complicated and then treated with oral or systemic antibiotics. Focal necrotizing infections are relatively uncommon, but they are readily diagnosed on sight and effectively managed by local debridement and systemic antibiotics. In contrast, diffuse necrotizing infections may masquerade in many forms, delaying diagnosis and treatment. Edema out of proportion to erythema, subcutaneous gas, and skin vesicles are important markers. Aggressive sequential debridement and broad-spectrum intravenous antibiotics revised after 48 hours provide the best strategy for management.

Should antibiotic prophylaxis be used routinely in clean surgical procedures: a tentative yes.

BACKGROUND: The incidence of surgical site infection (SSI) after clean surgical procedure has traditionally been regarded as too low for routine antibiotic prophylaxis. But we now know that host factors may increase the risk of SSI to as high as 20%. We assessed the value of prophylactic cefotaxime in patients stratified for risk of SSI in a randomized double-blind trial. METHODS: Patients admitted for clean elective operations were enrolled, stratified for risk by National Nosocomial Infection Survey criteria, and randomized to receive intravenous cefotaxime 2 gm or placebo on call for operation. They were followed for 4 to 6 weeks for SSI diagnosed by Centers for Disease Control and Prevention criteria. RESULTS: Analysis of 775 patients showed that the 378 evaluable patients who received cefotaxime had 70% fewer SSI than those who did not--Mantel-Haenszel risk ratio (MH-RR) 0.31; 95% confidence intervals (CI) 0.11 to 0.83. Benefit was clear in the 616 low risk patients--0.97% versus 3.9% SSI (MH-RR 0.25, CI 0.07 to 0.87, p = 0.018), but only a trend was seen in 136 high risk patients--2.8% versus 6.1% SSI (MH-RR 0.48, CI 0.09 to 2.5). CONCLUSIONS: The results indicate clear benefit for routine antibiotic prophylaxis in clean surgical procedures. High risk patients need more study.

Comparison of single-dose cefotetan and multidose cefoxitin as intravenous prophylaxis in elective, open biliary tract surgery: a multicentre, double-blind, randomized study.

OBJECTIVE: To compare the safety, tolerance and prophylactic effectiveness of a single 2-g dose of cefotetan with a standard prophylactic regimen of cefoxitin in reducing the incidence of postoperative infections after elective, open biliary tract surgery. DESIGN: Multicentre, double-blind, randomized comparative study with a 4-week follow-up. SETTING: Five Canadian university centres. PARTICIPANTS: One hundred and eleven patients scheduled to undergo elective, open biliary tract surgery. INTERVENTIONS: The patients were randomly assigned to receive either cefotetan or cefoxitin in a ratio of 2:1; 76 patients received cefotetan and 35 received cefoxitin. MAIN OUTCOME MEASURES: Wound infection as defined by the Centers for Disease Control and Prevention and by clinical evaluation, adverse events and laboratory parameters. RESULTS: Two incisional wound infections were reported by patients in the cefotetan group, for an overall infection rate of 1.8% (2 of 111). No significant differences were found in the failure rate or in any other indicator of efficacy. The incidence of adverse events for cefotetan (12.6%) was not statistically different from that for cefoxitin (10.4%), and none of the 16 adverse events in the cefotetan group and 5 in the cefoxitin group was serious or severe. Only one event (rash) was possibly related to the study drugs. Several hematologic and biochemical parameters were found to be normal preoperatively and abnormal postoperatively, but no relation was found between these variations and the study drugs. These changes were mainly attributable to the operation. CONCLUSION: Cefotetan was found to be effective and comparable to cefoxitin, both in safety and in reducing the incidence of infection after elective, open biliary tract surgery.

Efficacy and distribution of single-dose preoperative antibiotic prophylaxis in high-risk gastroduodenal surgery.

Although a single preoperative dose of antibiotic is now the accepted means of preventing postoperative surgical infection, the method has not been investigated adequately. In patients at high risk of infection who underwent gastroduodenal operations, the authors compared single-dose prophylaxis by intravenous cefotaxime (26 patients) with short-course perioperative prophylaxis (27 patients). No wound infection occurred, but in one patient in each group a subphrenic abscess developed after leakage at the anastomosis. The half-life of cefotaxime (1.23 +/- 0.12 hours) and its apparent volume of distribution (16.7 +/- 2.6 L/1.73 m2 resulted in perioperative levels of the antibiotic in blood (34.76 +/- 4.21 micrograms/mL), gastric mucosa (32.04 +/- 5.22 micrograms/mL) and subcutaneous fat (24.98 +/- 5.89 micrograms/mL) more than twice the usual minimal inhibitory concentration of the drug for organisms grown from the stomach contents and wound fat. These clinical and pharmacologic findings validate the efficacy of a single preoperative intravenous dose of the antibiotic in preventing postoperative infection in high-risk patients who undergo gastroduodenal surgery.

Simple elective cholecystectomy: to drain or not.

We performed a large single-center prospective randomized controlled study to assess the role of peritoneal drainage in simple elective cholecystectomy. In 248 patients, drains were omitted; 122 patients had closed suction drains and 124 had Penrose drains. There were no deaths, and no patient required reoperation or drainage of a subhepatic collection. Wound infections occurred in eight patients with drains and in six patients without. Most infections were staphylococcal. Postoperative pulmonary complications and hospital stays were similar in patients with and without drains. Statistical analysis of the 10 available prospective controlled randomized studies (1,920 patients) by the method of odds ratios supported our findings. Simple elective cholecystectomy is safe without peritoneal drainage, but short-term drains do not increase morbidity.

Is neomycin necessary for bowel preparation in surgery of the colon? Oral neomycin plus erythromycin versus erythromycin-metronidazole.

In 132 patients who underwent elective surgery of the colon, the value of bowel preparation with a conventional oral antibiotic preparation of neomycin-erythromycin (N-E) was compared with erythromycin-metronidazole (E-M). Of 125 patients who were available for assessment, 61 received N-E and 64 E-M. The two groups were evenly matched. Two wound infections occurred in patients receiving E-M, neither due to anaerobic bacteria, but seven wound infections developed in patients given N-E (p = 0.057), five of them caused by anaerobic bacteria. Anaerobic bacteria of the colon are the dominant cause of postoperative wound infection in elective surgery of the colon. Adequate antibiotic preparation directed against these bacteria makes the use of neomycin unnecessary.

Natural history of vertical abdominal parietal closure: Prolene versus Dexon.

The long-term outcome of laparotomy incisions after mass closure (taking large tissue bites through all layers) with continuous polypropylene (Prolene) in 95 patients or interrupted polyglycolic acid (Dexon) sutures in 105 patients was compared by randomized prospective study. Of the 200 patients, 194 incisions were median and 2 were paramedian (4 patients were excluded). There was one wound dehiscence (0.51%) due to slippage of a polypropylene knot. At 5-year follow-up, 4 hernias were found in incisions repaired with polypropylene, compared with 11 in the polyglycolic acid group; 10 of the 11 occurred after the first year (p = 0.01). Wound infections were slightly more frequent in patients whose incision was closed with polypropylene. Only two hernias in each group occurred in patients who had had wound infections. Polypropylene and polyglycolic acid both allow rapid and secure closure of vertical laparotomy incisions, but late herniation is more common when polyglycolic acid sutures are used.

Cephalosporin therapy in intraabdominal infections. A multicenter randomized, comparative study of cefotetan, moxalactam, and cefoxitin.

Three broad-spectrum cephalosporins (cefotetan, moxalactam, and cefoxitin) proved effective in this randomized, prospective trial for treatment of 303 surgical patients with moderately severe regional peritonitis.

Biliary bacteria, antibiotic use, and wound infection in surgery of the gallbladder and common bile duct.

That clinical risk groups predict postoperative infection in biliary operations has recently been challenged. To reevaluate the risk of infection, we studied 215 patients stratified by clinical risk factors. Of 100 patients having simple "low-risk" cholecystectomy, 11 had positive bile cultures (90% pure), and one with sterile bile got a staphylococcal wound infection (WI). Among 92 "high-risk" patients with acute cholecystitis, obstructive jaundice, or choledochal stones, 42 had positive bile cultures (44% pure, 12% anaerobes). One of 52 patients who received preoperative cefazolin got a staphylococcal WI, but ten of 40 patients without antibiotic therapy developed WIs, nine caused by organisms that also grew from the bile. Of 23 patients with obstructive cholangitis, 22 had positive bile cultures (88% mixed, 23% anaerobes). Despite antibiotic therapy, four developed WIs caused by these organisms. The concept of clinical risk factors is validated.

The correlation between carotid plaque ulceration and cerebral infarction seen on CT scan.

The purpose of the study was to determine the association between cerebral infarction seen on CT scan and macroscopic ulceration of atheromatous carotid plaques in patients undergoing carotid endarterectomy. Following carotid endarterectomy in 65 patients, specimens were examined for the presence of ulceration without knowing the result of the preoperative CT brain scan. The 65 patients thus investigated underwent 68 carotid endarterectomies: 36 for a history of transient ischemic attacks (TIAs), 13 for amaurosis fugax, and six for prior strokes; 13 asymptomatic patients had prophylactic carotid endarterectomy prior to coronary bypass. A macroscopic ulcer was present in 42 specimens. Twenty-six (62%) of the patients with ulceration had one or more ipsilateral cerebral infarcts on CT scan. Only two (8%) of the 26 patients without an ulcer had cerebral infarcts. Of the 36 patients who presented with TIAs, 26 (72%) had carotid plaque ulcers and 23 (88%) of these had cerebral infarcts on CT scan also. In contrast, only three of 13 asymptomatic patients had plaque ulcers and only one of these had a cerebral infarct. There is a high incidence of cerebral infarction seen on CT scan in patients presenting with TIAs. These infarcts occur predominantly in patients with ulcerated atheromatous carotid lesions.

Knitted polypropylene (Marlex) mesh in the repair of incisional hernias.

In 50 consecutive patients, large incisional hernias or those difficult to manage were repaired by suture imbrication of the hernial sac and extrafascial onlay fixation of Marlex mesh. Seromas developed in three and wound infection in two. The use of closed suction drains for all patients and antibiotic prophylaxis before and after operation for patients with antecedent wound infections may prevent these complications. In the follow-up period (mean of 2.6 years), lateral recurrence of the hernias occurred in three patients, but there has been no recurrence in the last 2 years. The method of repair is simple and effective.

A single preoperative dose of cefazolin prevents postoperative sepsis in high-risk biliary surgery.

To test the ability of cefazolin, given in a single dose preoperatively, to prevent infection in high-risk patients after biliary tract surgery, the authors conducted a double-blind, prospective, randomized, controlled study. Of 92 patients operated on for acute cholecystitis or bile-duct disease, 46 were given 2 g of cefazolin intravenously before operation. Bile was contaminated with bacteria in 36% to 50% of patients with acute cholecystitis, obstructive jaundice, bile-duct disease without jaundice, or over 50 years old compared with only 5% of patients with chronic cholecystitis or under 50 years of age. Postoperative sepsis was eight times more frequent in patients with contaminated bile than in those without. Only 1 patient who received cefazolin had a wound infection, but 9 of the 46 patients in the control group did. The bacteria causing wound sepsis were similar to those in the contaminated bile. The authors conclude that a single dose of cefazolin given intravenously before operation provides effective prophylaxis against infection in high-risk biliary tract surgery.

Are first-generation cephalosporins effective for antibiotic prophylaxis in elective surgery of the colon?

First-generation cephalosporins have recently declined in popularity as antibiotics for prophylaxis in elective surgery of the colon, but their efficacy has not been defined precisely. In a prospective randomized study, 44 patients who underwent elective colonic operations received, preoperatively, cefazolin in a parenteral dose adequate to kill aerobic coliforms. Six had wound infections; Bacteroides fragilis was grown, along with other organisms, from all these wounds. In contrast, only 1 of 57 similar patients had a wound infection after receiving, preoperatively, erythromycin base and metronidazole orally--directed at anaerobic bacteria. Local contamination, predominantly by anaerobic bacteria, is the main cause of wound infection after elective surgery of the colon. Even in what seems to be adequate dosage, first-generation cephalosporins are not antibiotics of first choice for preventing wound infections after these operations.

Cefamandole in gastroduodenal surgery: a controlled, prospective, randomized, double-blind study.

Acceptance of the value of antibiotic prophylaxis in gastroduodenal surgery is growing, but only one controlled, double-blind study justifying this is available. In this second, controlled, randomized, double-blind study 60 patients underwent urgent and elective gastroduodenal operations. Among 32 patients receiving cefamandole perioperatively for prophylaxis, only 1 subsequently had a wound infection, but wound infections occurred in 8 of the 28 patients who received a placebo (P less than 0.01). Infection rates were higher in contaminated wounds and in urgent operations than in clean-contaminated wounds and elective surgery. The results confirm the value of antibiotic prophylaxis in this setting.

The conduct of cholecystectomy: incision, drainage, bacteriology and postoperative complications.

The benefits of some ancillary techniques of cholecystectomy are exaggerated by retrospective study of selected patients. Therefore, the authors performed a prospective, randomized study of 100 consecutive patients who underwent simple elective cholecystectomy for chronic cholecystitis and cholelithiasis. No patient was excluded because of incomplete hemostasis or fear of bile leakage. The frequency of pulmonary complications and wound infections was independent of the type of incision--vertical or subcostal. Peritoneal drainage was found to be unnecessary. Short-term drainage may increase the frequency of postoperative fever, but did not increase pulmonary complications or wound infections. In these patients, intra-abdominal sepsis is rare; wound infections were uncommon and the gallbladder bile was usually sterile and not the cause of postoperative infection.

Antibiotic prophylaxis in surgery.

This review examines the principles and practice of antibiotic prophylaxis in surgery. Such prophylaxis is required to decrease the frequency of postoperative infection in most patients with clean-contaminated and contaminated wounds, to prevent infrequent but devastating infection of prostheses in cardiovascular and orthopedic surgery and to prevent endocarditis in noncardiac surgery in patients who have valvular heart disease. Prophylaxis should begin before operation; it is usually unnecessary afterwards. The antibiotic may be given topically or parenterally. The latter is more certain, but oral prophylaxis in bowel surgery may offer additional protection by reducing colonic flora, and topical wound and peritoneal antibiotics may be augment protective antibiotic levels at those sites. Antibiotics, such as the cephalosporin cefazolin (but not cephalothin), which penetrate blood and tissues rapidly and for prolonged periods, afford excellent prophylaxis at most sites. But for prophylaxis in colonic surgery, antibiotics directed against Bacteroides fragilis may be superior, and to prevent endocarditis in noncardiac surgery, vancomycin or a combination of penicillin and an aminoglycoside is best.

Preventing anaerobic infection in surgery of the colon.

A randomized prospective study of antibiotic prophylaxis was carried out in patients who underwent elective surgery of the colon. The wound infection rate in 70 patients who received cephradine intravenously in the perioperative period (group 1) was 25%, compared with 8% in 60 patients who received metronidazole and erythromycin base orally before operation (group 2). Both Bacteroides fragilis and Escherichia coli were cultured from the majority of wound infections in group 1, but B. fragilis was not found in any group 2 patients. Wound contamination indicated by wound class or by culture of the subcutaneous tissue of the wound before closure was the best predictor of subsequent wound infections. These results suggest a dominant role for intestinal anaerobes in the genesis of wound infections after colonic surgery and show that antibiotics specifically directed against these organisms can substantially reduce the rate of wound infection.

Albumin: role and discriminative use in surgery.

Exogenous human serum albumin (HSA) is generally used empirically and its role in surgery is poorly defined. The function and kinetics of HSA in the body are reviewed to provide rational guidelines for its use in surgery. Starling's law of transcapillary exchange is important, especially when applied to the capillary beds of the skin and subcutaneous tissue, skeletal muscle, lungs and intestines; but it overestimates the importance of maintaining oncotic pressure in the two situations where HSA is clinically beneficial--hypovolemia and plasma volume sequestration. In hypovolemia, the harmful effects of protein dilution by massive crystalloid resuscitation are minimized initially by "edema safety factors", such as reduced oncotic pressure of interstitial fluid and increased flow of lymph, and subsequently by intravascular protein refill from extravascular sites. But in severe hypovolemia, albumin should be given early, with sufficient isotonic saline, to reduce the total volume of crystalloid required. In the first 24 hours of plasma volume sequestration, albumin infused intravenously may be lost from excessively permeable capillaries; but later, hyperoncotic HSA is useful to restore the plasma volume and to reduce interstitial edema.

Discriminate use of antibiotic prophylaxis in gastroduodenal surgery.

In a prospective study of 107 patients undergoing surgery for gastroduodenal disease, antibiotics were withheld from a group of 24 patients defined preoperatively to be at low risk of developing postoperative infections; no wound infection occurred in this group. Perioperative cephaloridine was randomized among the remaining patients (high risk). Wound infections developed in 11 of 42 patients who did not receive cephaloridine, but in none of the 41 patients who were given cephaloridine (p less than 0.02). Coliform bacteria were grown only from swabs of the stomach mucosa of patients in the high risk group and were the main cause of wound infections. Severe preoperative lymphocytopenia was frequently associated with the development of serious postoperative sepsis. The results validate a policy of restricting antibiotic prophylaxis in gastroduodenal operations to patients at high risk of postoperative infection and suggest a new risk factor--the preoperative blood lymphocyte count.