Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intra-abdominal infections. The Intra-Abdominal Infection Study Group.

OBJECTIVE: In a randomized, double-blind, multicenter trial, ciprofloxacin/metronidazole was compared with imipenem/cilastatin for treatment of complicated intra-abdominal infections. A secondary objective was to demonstrate the ability to switch responding patients from intravenous (IV) to oral (PO) therapy. SUMMARY BACKGROUND DATA: Intra-abdominal infections result in substantial morbidity, mortality, and cost. Antimicrobial therapy often includes a 7- to 10-day intravenous course. The use of oral antimicrobials is a recent advance due to the availability of agents with good tissue pharmacokinetics and potent aerobic gram-negative activity. METHODS: Patients were randomized to either ciprofloxacin plus metronidazole intravenously (CIP/MTZ IV) or imipenem intravenously (IMI IV) throughout their treatment course, or ciprofloxacin plus metronidazole intravenously and treatment with oral ciprofloxacin plus metronidazole when oral feeding was resumed (CIP/MTZ IV/PO). RESULTS: Among 671 patients who constituted the intent-to-treat population, overall success rates were as follows: 82% for the group treated with CIP/MTZ IV; 84% for the CIP/MTZ IV/PO group; and 82% for the IMI IV group. For 330 valid patients, treatment success occurred in 84% of patients treated with CIP/MTZ IV, 86% of those treated with CIP/MTZ IV/PO, and 81% of the patients treated with IMI IV. Analysis of microbiology in the 30 patients undergoing intervention after treatment failure suggested that persistence of gram-negative organisms was more common in the IMI IV-treated patients who subsequently failed. Of 46 CIP/MTZ IV/PO patients (active oral arm), treatment success occurred in 96%, compared with 89% for those treated with CIP/MTZ IV and 89% for those receiving IMI IV. Patients who received intravenous/oral therapy were treated, overall, for an average of 8.6 +/- 3.6 days, with an average of 4.0 +/- 3.0 days of oral treatment. CONCLUSIONS: These results demonstrate statistical equivalence between CIP/MTZ IV and IMI IV in both the intent-to-treat and valid populations. Conversion to oral therapy with CIP/MTZ appears as effective as continued intravenous therapy in patients able to tolerate oral feedings.

Alterations of neutrophil responses to tumor necrosis factor alpha and interleukin-8 following human endotoxemia.

Interleukin-8 (IL-8), a neutrophil chemoattractant and activating cytokine, has been implicated as a proinflammatory mediator in gram-negative sepsis. In vitro data support the notion of IL-8 as an endothelial adherence inhibitor. To evaluate this issue, we infused six volunteers with reference endotoxin and measured plasma levels of IL-8, neutrophil tumor necrosis factor alpha (TNF-alpha) receptors, TNF-alpha-induced adherence to fibronectin, and neutrophil chemotaxis to IL-8 and other attractants. We found that, at 3 h postinfusion, IL-8 but not TNF-alpha plasma levels were elevated. Neutrophils had shed L-selectin (mean channel fluorescence decrease, 79 +/- 9 to 49 +/- 7; P = 0.0625) and TNF-alpha receptors (decrease in number of receptors per cell, 1,596 +/- 340 to 574 +/- 93; P = 0.004). Cells were chemotactically desensitized to IL-8. TNF-alpha-induced adherence to fibronectin was suppressed from 69% +/- 5% of the phorbol myristate acetate response to 38% +/- 7% (P = 0.0154). These findings support the notion that release of IL-8 into the vascular space may be an in vivo mechanism for suppression of neutrophil accumulation at extravascular sites. L-Selectin loss would reduce the ability of neutrophils to adhere to activated endothelial cells. The specific loss of migratory response to IL-8 would impair neutrophil delivery to areas where IL-8 was the predominant chemoattractant. Loss of TNF-alpha-induced adherence to fibronectin would blunt those responses, including production of oxidants, capacitated by adherence.

The pull-through procedure: technical factors in influencing outcome, with emphasis on pouchitis.

BACKGROUND: The purpose of the study was to review those features that we believed to be critical to the successful performance of the ileal pouch-anal anastomosis, or pull-through, procedure, and specifically the complication of pouchitis. METHODS: The charts of 205 patients who successfully underwent ileal pouch-anal anastomosis procedure were reviewed. No follow-up was available in five patients; therefore, the basis of this report and its analysis was based on 200 consecutive procedures in which at least two of the three surgeons participated. Particular emphasis was placed on continence, particularly nighttime continence. The incidence of pouchitis, either a single episode or intermittent episodes, was surveyed. Particular attention was paid to the level of rectal mucosectomy and anastomosis at the top of the columns of Morgagni, thus retaining the transitional zone. RESULTS: Only 5% of patients were incontinent in the absence of pouchitis. Twenty-five patients (13%) wore a pad at night, but only nine (5%) wore a pad during the day. Of those patients with pouchitis, 6% (12) have had a single episode and 12% (23) were intermittently on medication. Therapy of pouchitis was usually carried out with ciprofloxacin 500 mg by mouth everyday or twice a day. CONCLUSIONS: Ileal pouch-anal anastomosis is an excellent procedure, provided technical details are adhered to. Satisfactory outcome with respect to nighttime continence can be achieved with rectal mucosectomy with minimal manipulation and retaining the transitional epithelium, performing the pouch anastomosis at the top of the columns of Morgagni. The incidence of pouchitis is disappointing but need not be inhibiting of either patients or carrying out this life-saving procedure in patients with ulcerative colitis and familial polyposis.

Circulating factors contribute to elevation of intracellular cyclic-3',5'-adenosine monophosphate and depression of superoxide anion production in polymorphonuclear leukocytes following thermal injury.

We have previously demonstrated that bactericidal activity and superoxide anion (O2-) production are depressed concomitantly in polymorphonuclear leukocytes (PMNs) following thermal injury in a guinea pig model, and the bactericidal defect is related to elevation of intracellular cyclic-3',5'-adenosine monophosphate (cAMP). The purpose of the present investigation was to determine the relationship between elevation of intracellular cAMP and depression of O2- production in PMNs following thermal injury and determine the involvement of circulating factors in the development of these alterations. The kinetics of O2- production and dose responses to formylmethionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA) were depressed in peripheral PMNs following thermal injury in this experimental model. Sera obtained during the period of PMN dysfunction induced depression of O2- production in response to fMLP and elevation of intracellular cAMP in normal PMNs. Pretreatment of normal PMNs with nonsteroidal anti-inflammatory drugs (NSAID; indomethacin or piroxicam) inhibited the elevation of intracellular cAMP mediated by sera from the injured animals but had no effect on the depression of O2- production observed under similar conditions. Treatment of PMNs from injured animals with NSAID under conditions known to reduce the cAMP content of the cells and correct the bactericidal defect did not normalize O2- production. Studies utilizing sera from two thermally injured patients confirmed findings in the guinea pig model of serum-mediated elevation of intracellular cAMP and depression of O2- production in normal PMNs and effects observed with NSAID. These results suggest that circulating factors contribute to the elevation of intracellular cAMP and depression of O2- production in PMNs following thermal injury. Whereas the increase in intracellular cAMP may be involved in the depression of O2- production, our results suggest that there is not a direct link between these alterations.

Guidelines for clinical care: anti-infective agents for intra-abdominal infection. A Surgical Infection Society policy statement.

Several antibiotics have been marketed for therapeutic use in intra-abdominal infection. Often, these agents do not provide a sufficient spectrum activity against both facultative and obligate anaerobic gram-negative organisms, or have certain toxic effects that would not otherwise support their use. Guidelines have been developed for selection of antibiotic therapy for intra-abdominal infections and are presented as a statement of the Surgical Infection Society endorsed by the Executive Council. These guidelines are restricted to infections derived from the gastrointestinal tract and deal with those microorganisms commonly seen in such infections. The recommendations are based on in vitro activity against enteric bacteria, experience in animal models, and documented efficacy in clinical trials. Other concerns regarding pharmacokinetics, mechanisms of action, microbial resistance, and safety were also used in the formation of these guidelines. For community-acquired infections of mild to moderate severity, single-agent therapy with cefoxitin, cefotetan, or cefmetazole or ticarcillin-clavulanic acid is recommended. For more severe infections, single-agent therapy with carbapenems (imipenem/cilastatin) or combination therapy with either a third-generation cephalosporin, a monobactam (aztreonam), or an aminoglycoside plus clindamycin or metronidazole is recommended. Regimens with little or no activity against facultative gram-negative rods or anaerobic gram-negative rods are not considered acceptable.

Bactericidal defect of neutrophils in a guinea pig model of thermal injury is related to elevation of intracellular cyclic-3',5'-adenosine monophosphate.

PG of the E series inhibit major effector functions of polymorphonuclear leukocytes (PMN) by elevating intracellular cAMP. The present study investigated the involvement of this mechanism in the bactericidal defect of PMN induced by thermal injury in a guinea pig model. Peripheral and peritoneal exudate PMN harvested from thermally injured guinea pigs at 1 or 2 days postburn had decreased bactericidal activity against Pseudomonas aeruginosa and a marked increase in cAMP content. Production of PGE1 by these cells in the absence of exogenous PMN activators was also increased. Treatment of PMN in vitro or in vivo with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen, and piroxicam) restored bactericidal activity to normal and concomitantly reduced cAMP content and PGE1 production. A concomitant reduction in cAMP content and PGE1 production was also observed as bactericidal activity of PMN returned to normal under natural conditions during 4 to 7 days postburn. The enhancement of PMN bactericidal activity mediated by NSAID was fully counteracted by purified PGE1, theophylline, and by cAMP itself. These results suggest that the bactericidal defect of PMN induced by thermal injury is related to elevation of cAMP and that PGE1 plays a significant role in this phenomenon.

Hemodynamic and metabolic alterations during experimental sepsis in young and adult rats.

Cecal ligation and puncture (CLP) has been extensively used as a model of sepsis in adult rats. It is not known if the response to sepsis is similar in young and adult rats. This investigation was done to compare hemodynamic and metabolic alterations in young (four to six weeks of age, 60 to 90 grams) and adult (12 to 14 weeks of age, 270 to 340 grams) rats after CLP. In one series of experiments, survival rate was determined for 96 hours, and in other experiments, mean arterial blood pressure (MAP), heart rate (HR), white blood cell count, hematocrit, platelets, plasma glucose, lactate, amino acids, blood urea nitrogen (BUN), blood and peritoneal cultures and resting energy expenditure (REE) were determined eight and 16 hours after CLP. Levels of glycogen in liver and muscle were determined 16 hours after CLP. Mortality rate was similar in young and adult rats. MAP was stable throughout the course of sepsis, with no significant differences between the two groups of rats. HR was higher in young rats at all times studied. The adult rats became hyperglycemic after CLP while the young were hypoglycemic eight hours after CLP but normalized at 16 hours. Plasma lactate and BUN were similar in the two groups of rats, and no alterations were seen during sepsis. Both young and adult rats became hypoaminoacidemic after CLP. The phenylalanine to tyrosine ratio increased in a similar manner during sepsis in both experimental groups. REE was higher in young than in adult rats, but no significant changes were observed during the course of sepsis in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial infectibility of chronically implanted endothelial cell-seeded expanded polytetrafluoroethylene vascular grafts.

Vascular prosthetic grafts become more resistant to infection as the interval between implantation and bacteremic challenge increases. Endothelial cell (EC) seeding of such grafts has been shown to improve measurably their ability to resist a bacteremic challenge several weeks after implantation, presumably by reducing the amount of thrombus-free area (TFA) on their luminal surface. However, no investigators have reported the impact of EC seeding on the ability of chronically implanted vascular prostheses to resist a late bacteremic challenge. Bilateral common carotid interposition grafts were placed in 15 adult mongrel dogs with a 4 mm internal diameter, experimental, expanded polytetrafluoroethylene (ePTFE) prosthesis. One animal died shortly after operation and the grafts in two dogs thrombosed, thereby leaving 12 animals with at least one patent graft for subsequent study. At a mean interval of 45 weeks after implantation, five dogs (seven patent grafts) were challenged with an intravenous infusion of 3 X 10(8) radiolabeled Staphylococcus aureus; bacterial adherence and the TFA of the graft's luminal surface were determined for each of the patent grafts. There was no statistically significant difference in bacterial adherence or TFA between EC-seeded and control grafts. At a mean interval of 53 weeks after implantation, the remaining seven dogs (14 patent grafts) received a similar bacterial infusion and the animals were allowed to recover. Five days later, the grafts were harvested and cultured. Once again, there was no significant difference in the infectibility of EC-seeded vs. control grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Liver resection. A comparison using the Nd-YAG laser, an ultrasonic surgical aspirator, or blunt dissection.

Before gaining wide acceptance, possible surgical tools should be compared with the standard ones. This study, therefore, compared the Nd-YAG laser and the CUSA with the standard blunt dissection technique for liver resection in 24 dogs (8 in each group). Using a noncontact technique, the Nd-YAG laser was used for cutting as well as coagulation. The Nd-YAG laser or the CUSA reduced the resection time, with the laser being the faster of the two, and was accompanied by a probable but not significant decrease in perioperative blood loss. The CUSA delineated the blood vessels and bile ducts and gave superior control. It also caused significantly less tissue damage on light and electron microscopic examination than the other two methods. Cultures taken 1 week after operation showed that the risk of bacterial infection correlated well with the extent of tissue necrosis and was significantly greater after use of the Nd-YAG laser than after use of the CUSA. The numbers of animals are small and the conclusions should be tempered by caution, but it appears that the CUSA, but not the Nd-YAG laser, may improve the results of elective liver resection.

Bacterial adherence to endothelial-seeded polytetrafluoroethylene grafts.

Since infections of an arterial prosthesis pose a serious threat to life and limb, efforts to produce a graft that is resistant to hematogenous bacteremia continue. We studied the effect of endothelial seeding on bacterial adherence to polytetrafluoroethylene grafts in a canine model. Enzymatically derived venous endothelial cells were seeded in 10 cm long, 4 mm inner diameter polytetrafluoroethylene grafts, which were then implanted as carotid interpositions opposite contralateral unseeded controls. After 4 to 8 weeks, each dog received an intravenous infusion of 3 X 10(8) radiolabeled Staphylococcus aureus. Seeded grafts had significantly fewer adherent viable bacteria than had control grafts (mean, 432 versus 989; p less than 0.05) and significantly fewer radiolabeled bacteria (mean, 2 X 10(5) versus 8 X 10(5); p less than 0.05). Seeded grafts also had significantly more thrombus-free, luminal surface area than had control grafts (mean, 72% versus 40.6%; p less than 0.05). Scanning electron microscopy and autoradiography of seeded grafts confirmed that the sites of bacterial adherence largely corresponded to accumulations of surface thrombus. In this experiment, endothelial seeding appeared to protect against bacterial adherence after a hematogenous challenge 4 to 8 weeks after implantation by reducing luminal thrombi.

Theoretical interrelationships among immunologic and hematologic sequelae of thermal injury.

A hypothesis of possible interrelationships among immunologic and hematologic sequelae of thermal injury is presented. It is postulated that there are definable pathways involving series of abnormalities with multiple interconnections among these pathways. The initiating step of each pathway should be amenable to blockade. Such blockade would theoretically circumvent the occurrence of the abnormalities or lessen their severity and thereby preserve host resistance.

Staphylococcus in toxic shock syndrome and other surgical infections. Development of new bacteriophages.

Recent studies of Staphylococcus aureus isolates from patients with toxic shock syndrome (TSS) have shown the dominance of phage type 29/52 with the capacity to produce pyrogenic exotoxin C and enterotoxin F. They also showed that 29% of the isolates were nontypable and 90% of them had similar toxigenic properties. The existence of unknown and important phages in this disease was postulated. Five new phages were then developed and used for typing three groups of staphylococcal isolates: 236 from patients with TSS, 67 from patients without TSS, and 159 from patients with infected burns. Results showed a high correlation between the lytic action of the new phages and the 29/52 phages, and an additional typing capability in 35% of the previously nontypable TSS isolates, emphasizing further the potential of bacteriophage typing of S aureus in these infections.

Association between microorganism growth at the catheter insertion site and colonization of the catheter in patients receiving total parenteral nutrition.

Catheter-related sepsis is one of the major complications of total parenteral nutrition (TPN) therapy. The relationship between microbial colonization of the skin at the site of catheter insertion and colonization of the central venous catheter was investigated in 74 catheters used to administer TPN therapy in 53 patients. Semiquantitative culture specimens were obtained from the insertion site and intravascular and subcutaneous catheter segments at the time of catheter removal. Bacteria and/or fungi were recovered from 19 catheters and 19 insertion sites; of the 19 colonized catheters, 6 had sterile insertion sites. Organisms isolated from the remaining 13 catheters were isolated concurrently from the insertion site. Catheter-associated bacteremia or fungemia was observed in 10 of the 19 patients with colonized catheters. The association between colonization of catheters and the presence of more than 10(3) bacterial or fungal colony-forming units at the insertion site was significant (P less than 0.005). These results demonstrated that colonization of catheters by organisms present on the skin at the site of catheter insertion occurred twice as frequently as colonization by the hematogenous route. The results also suggested that colonization of catheters by organisms present at the insertion site occurred only after a threshold number of organisms was reached.

Serum-mediated inhibition of polymorphonuclear leukocyte function following burn injury.

Serial serum samples from 12 bacteremic burned patients were tested at a physiologic concentration for their ability to facilitate phagocytosis and intracellular killing of the homologous infecting Staphylococcus aureus strains by normal human polymorphonuclear leukocytes in comparison to pooled normal human serum. Serum-mediated inhibition of leukocyte bactericidal activity was demonstrated in three of the patients during 13 to 56 days after burn. Decreased bacterial activity was related to an inhibitory effect of the burn sera on the phagocytic process, which reduced the number of internalized bacteria available for intracellular killing. The serum-mediated inhibition of phagocytosis was not found to be dependent on bacterial surface properties unique to S. aureus. The inhibitory effect was shown to involve a direct interaction of the burn sera with the leukocytes, which was not associated with cell death and was not reversed by washing of the leukocytes.

Studies of the staphylococcal causation of toxic shock syndrome.

The data presented in this study indicate that the Staphylococcus aureus is related casually to the toxic shock syndrome and that the dominant phage type was 29. This type has occurred singly as well as in combination with phage type 52 and some other group I phage types. The 29, 52 complex was present in approximately two-thirds of a series of 159 isolates of Staphylococcus aureus obtained from patients with toxic shock syndrome, while another fourth was nontypable. In further support of this concept was the evidence that 94.1 per cent of the isolates of the 29, 52 phage complex tested were capable of producing pyrogenic exotoxin C. These results gave confirmatory evidence of the etiologic importance of this phage type complex of Staphylococcus aureus. The high percentage of 25.8 per cent nontypable isolated has remained unexplained, and this is suggestive of the possibility that another important phage type may be present but obscure, since 83 per cent were shown to be capable of producing pyrogenic C toxin. The data reported also indicated that the current activity of this phage type is another manifestation of the versatility of Staphylococcus aureus and its ability to produce different pathogenic strains capable of causing different or new infections in clinical practice.

Reduction in alternative complement pathway mediated C3 conversion following burn injury.

Studies were performed to further investigate an abnormality of the alternative complement pathway associated with burn injury. C3 conversion by inulin and cobra venom factor was measured in serial serum samples from 18 burned patients and in the sera from 25 normal controls. C3 conversion by both activating substances in the patients' sera was significantly decreased during 50 days postburn in comparison to C3 conversion in the normal sera. The most marked reduction in C3 conversion occurred in patients with large full-thickness injuries and infectious complications. However, the abnormality was not more severe in patients with pneumonia and bacteremia in comparison to patients with bacteremia only. It was also not predictive of fatal outcome resulting from infectious complications. Preliminary evidence was presented to suggest that the abnormality is caused by a serum inhibitor, which has an affinity for cellulose and/or is inactivated by it.

Complement, opsonins, and the immune response to bacterial infection in burned patients.

Studies were performed to evaluate complement, opsonins, and the immune response to bacterial infection in burned patients. Concentrations and functional acitivities of components of the classical and alternative complement pathways were measured in the sera of four septic, two bacteremic, and four nonseptic burned patients. In addition, heat-labile and heat-stable opsonic activity and agglutinin titers directed against the infecting bacterial strains were measured in the sera of the four septic patients and in an additional group of 11 septic burned patients with abnormal complement profiles. Functional activity of the alternative complement pathway and the concentration of properdin were shown to be persistently decreased during eight weeks postburn in the septic, bacteremic, and nonseptic burned patients; reduced classical pathway activity was demonstrated during the initial postburn period only in the septic patients. Two of the 15 septic patients had decreased heat-labile serum opsonic activity for their infecting bacterial strains, which occurred only during the initial postburn period. Heat-stable opsonins and agglutinin titers in the patients' sera directed against the infecting bacterial strains were equivalent to those in normal human sera, except for the agglutinin titers to Streptococcus faecalis which were increased in the patients' sera in comparison to the normal sera. These results indicate that the multiple complement abnormalities which occur in septic burned patients do not predispose these patients to bacterial infection by decreasing serum opsonic activity. Moreover, heat-stable immune IgG antibodies are not produced during septicemia which facilitate opsonization of the infecting bacterial strains in the absence of an intact complement system.

The septic burned patient: a model for studying the role of complement and immunoglobulins in opsonization of opportunist micro-organisms.

Studies were performed to determine the effects of septicemia on complement levels and activities and opsonic function in septic and nonseptic burned patients. None of the nonseptic burned patients had consumption of classical pathway activity during their clinical course. Patients who did not survive septicemia had consumption of all of the classical complement components (C1-C5) prior to and during their septic episodes. Patients who survived septicemia had multiple patterns of classical complement pathway consumption. In these patients, classical pathway activity was restored to normal following the last positive blood culture. Alternative complement pathway consumption was demonstrated in only one of the septic burned patients, as evidenced by decreased factor B and C3b INA levels and decreased C3 and C5 conversion in sera treated with 10 mM ethylene glycol tetraacetic acid and 10 mM MgCl(2) (MgEGTA) and in untreated sera. In all of the other septic patients and in the nonseptic patients, reduction in C3 and C5 conversion in MgEGTA sera and untreated sera was not associated with decrease in factor B or C3b INA. Reduction in complement levels and activities did not reduce the ability of the patients' sera to promote phagocytosis and intracellular killing of their infecting micro-organisms by normal human peripheral polymorphonuclear leukocytes. The results indicate that measurement of classical pathway activity in burned patients can be used as a diagnostic tool for predicting the severity of septic episodes and for monitoring recovery. In addition, the observation that complement consumption did not reduce the opsonic capacity of the patients' sera for their infecting micro-organisms suggests that current concepts regarding the role of immunoglobulins and complement in opsonization of opportunist micro-organisms require re-evaluation.