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Gram-negative septicemia remains one of the most serious forms of hospital-acquired infection. The most consistently virulent component of the gram-negative lipopolysaccharide (endotoxin) appears to be lipid A. Elucidation of the structure-function relationships of lipid A and the biochemical configurations required for endotoxicity makes possible the design of lipopolysaccharide antagonists and/or the production of poly- or monoclonal antibodies that may abrogate the biologic effects of endotoxin. The mechanisms of activity of lipopolysaccharide and the pathophysiologic events it triggers are now better understood than in the recent past. Lipid A triggers the release of mediators such as cachectin (tumor necrosis factor), thereby initiating a cascade of potentially lethal events. Although recent studies indicate no routine role for corticosteroids in gram-negative septic shock or acute respiratory distress syndrome, considerable progress has been made in the development of effective antibiotics. Recent studies of septicemia in neutropenic patients show survival rates significantly higher than those reported more than two decades ago.

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Mycobacterium tuberculosis bacteremia is being reported more frequently in patients with human immunodeficiency virus, type 1 (HIV-1) infection. We report 9 patients with bacteremia due to M. tuberculosis and HIV infection who were identified over a 36-month period. Of the 9 patients studied, 8 were male, 8 were black, 6 were born in Haiti, 3 were homeless, 2 were intravenous drug users, and 1 was homosexual. At the time of diagnosis, 3 patients had the acquired immunodeficiency syndrome (AIDS) and 5 patients had CD4 lymphocyte counts less than or equal to 170 cells/mm3, indicating marked immunodeficiency. All 9 patients presented with temperature greater than 38.3 degrees C, 5 (50%) had abnormal chest roentgenogram on admission, and each of the patients tested had elevations of at least 2 liver function tests. Eight patients (80%) had M. tuberculosis isolated from sputum or other body fluids and tissues. All blood isolates of M. tuberculosis were identified from Dupont Isolator tubes. Antibiotic-resistant isolates of M. tuberculosis were cultured from 3 of the 6 patients born in Haiti. One patient died before diagnosis and received no antimycobacterial therapy; 7 of the remaining 8 patients appeared to respond to treatment. Our data, and a review of the literature, suggest that bacteremia due to M. tuberculosis is becoming more frequent, and that blood cultures may be helpful in establishing or confirming a diagnosis of tuberculosis in patients with HIV-1 infection.

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Aztreonam was compared with aminoglycoside antibiotics (tobramycin and amikacin) in a randomized, prospective, clinical trial in serious infections caused by gram-negative bacilli (GNB). A total of 43 evaluable patients with 47 infected sites were treated with aztreonam, and 41 evaluable patients were treated with aminoglycosides for 43 infections. Of patients treated with aztreonam, 17 were bacteremic, as were 12 of those treated with aminoglycosides. Clinical and microbiologic response rates were similar, except that only 5 of 11 patients with pneumonia were considered to be clinically cured with aminoglycoside therapy, while 5 of 6 patients with pneumonia treated with aztreonam were cured. Renal impairment was observed in 9 of 54 patients who received aminoglycoside antibiotics, but in only 2 of 53 patients treated with aztreonam. Hearing impairment developed in one patient treated with tobramycin. Transient elevations of serum transaminase levels occurred in 9 of 53 patients treated with aztreonam and in only 2 of 54 aminoglycoside-treated patients. Diarrhea and superinfection occurred with equal frequency in both groups. Serum concentrations of bactericidal activity could not be correlated with the outcome of therapy. Aztreonam appears to have comparable clinical efficacy with aminoglycoside antibiotics for the treatment of serious infections caused by aerobic and facultative GNB. Its use as a single agent for the treatment of serious lower respiratory infections caused by GNB warrants further evaluation.

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Vaccines prepared from unheated and boiled, acetone-precipitated Salmonella minnesota R595 (Re chemotype mutant) were administered subcutaneously to 122 healthy volunteers. Titers of antibody to Re lipopolysaccharide, the basal core structure of endotoxin, as measured by indirect hemagglutination, rose in a dose-responsive fashion after immunization. Febrile reactions, usually mild, occurred after 7% of injections with the highest doses (2.0 and 3.0 x 10(10) organisms), and mild local soreness and tenderness were noted after approximately one-third of injections. Passive immunization of mice with sera from immunized subjects demonstrated that protective activity against challenge with both heterologous, viable gram-negative bacilli and endotoxin developed. Although measuring serum protective activity, developing a serological assay that correlates with protective activity, and potential vaccine toxicity remain problems, immunization of humans with the Re mutant results in serum protective activity against endotoxin and viable bacilli and has the potential for clinical usefulness.

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We evaluated the immunoglobulin class responsible for the protective activity in serum obtained from humans and rabbits after immunization with the R595 (Re chemotype) mutant of Salmonella minnesota. Whole serum obtained before immunization and the IgG and IgM fractions failed to protect mice against lethal challenge with viable Klebsiella pneumoniae or Morganella morganii or with Salmonella typhi lipopolysaccharide (LPS). The protective activity of postimmunization serum resided solely in IgM antibody, whereas IgG antibody exhibited no protective activity. IgM antibody to the Re mutant was protective against bacterial challenge with both test strains of bacteria and S. typhi LPS. IgM antibody, at approximately the same concentration present in postimmunization serum, increased the LD50 of K. pneumoniae from less than 8.0 x 10(2) to greater than 2.0 x 10(4). These findings indicate that commercially prepared human IgG with high titers of antibody to antigens of the core portion of LPS would have little clinical utility.

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Bacterial endotoxins or lipopolysaccharides (LPS) elicit a variety of biologic activities in intact animals and various in vitro systems. LPS from most gram-negative bacteria have appeared to have similar biologic activities regardless of the species of origin or method of preparation of the LPS. More recent studies have suggested differences in the effects of protein-rich as opposed to protein-free LPS in inducing mitogenesis of lymphocytes from endotoxin-resistant C3H/HeJ mice. These studies examine other activities of endotoxin-associated protein (EAP), purified to less than 0.007% contamination with LPS, and demonstrate that this material has activity mimicking some of the effects of interleukin-1 (IL-1). EAP proved to be as potent as LPS in eliciting rises in concentrations of serum amyloid A (SAA) and was active in both endotoxin-sensitive (CF1) and endotoxin-resistant (C3H/HeJ) mice. In contrast to LPS, which mediates its SAA-inducing activity by release of an inducer (IL-1) from LPS-stimulated macrophages, EAP appeared to act directly to induce SAA production, in that incubation with macrophages failed to increase its activity. EAP also exhibited IL-1-like activity in the lymphocyte-activating factor assay when both CF1 and C3H/HeJ thymocytes and macrophages were tested. The lymphocyte-activating factor activity of EAP was not blocked by addition of polymyxin B. In addition, EAP exerted stimulatory activity on resting human T lymphocytes, costimulated with Sepharose-bound anti-CD3 monoclonal antibody 64.1, comparable to that observed with purified human monocyte IL-1. These studies indicate that proteins from procaryotic cells may act as cytokines for some eucaryotic cells.

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Proteins coextracted with endotoxin, termed endotoxin-associated protein (EAP), have been shown to exert interleukin 1-like activities. The present studies demonstrate that EAP also exerts potent granulopoietic colony-stimulating activity (CSA) on human peripheral blood and bone marrow progenitor cells, comparable to that seen with various types of conditioned media. The CSA observed with EAP appeared to be heat (100 degrees C, 30 min) and trypsin resistant and partially pronase resistant. Similar resistance was observed with the porin proteins of the outer membrane of gram-negative bacteria, and similar CSA activity was observed with a purified porin preparation of Neisseria gonorrhoeae. The CSA of EAP could be demonstrated in human peripheral blood and bone marrow leukocytes rigorously depleted of monocytes, T lymphocytes, and B lymphocytes by treatment with specific monoclonal antibodies and complement.

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We prospectively studied 526 patients admitted to the medical intensive care unit (MICU) and 799 patients admitted to the surgical intensive care unit (SICU) at a municipal hospital over a 20-month period. Rates of nosocomial infection were higher in the SICU patients (31% vs 24%). The SICU patients had more urinary tract infections, bacteremias, and wound infections, and the MICU patients were older, had higher acute physiology scores on admission and were more often admitted with shock or coma. The SICU patients were more likely to have received prior antibiotic therapy and had significantly higher numbers of endotracheal tubes, arterial lines, central venous lines, and indwelling bladder catheters. Of the 23 variables univariately associated with nosocomial infection, only five remained significant after entry into step-wise regression models. The MICU patients had a higher fatality rate in the MICU than did the SICU patients (18% vs 10%), but the relative risk of a death following nosocomial infection was 3.5 for both groups. Thirty variables were significantly associated with hospital fatality; nine remained significant after analysis by stepwise logistic regression.

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Gram-negative nosocomial pneumonia may result from retrograde colonization of the pharynx from the stomach, and this may be more likely when the gastric pH is relatively high. We studied the rate of nosocomial pneumonia among 130 patients given mechanical ventilation in an intensive care unit who were receiving as prophylaxis for stress ulcer either sucralfate (n = 61), which does not raise gastric pH, or conventional treatment with antacids, histamine type 2 (H2) blockers, or both (n = 69). At the time of randomization to treatment, the two groups were similar in age, underlying diseases, and severity of acute illness. Patients in the sucralfate group had a higher proportion of gastric aspirates with a pH less than or equal to 4 (P less than 0.001) and significantly lower concentrations of gram-negative bacilli (P less than 0.05) in gastric aspirates, pharyngeal swabs, and tracheal aspirates than did patients in the antacid-H2-blocker group. The rate of pneumonia was twice as high in the antacid-H2 group as in the sucralfate group (95 percent confidence interval, 0.89 to 4.58; P = 0.11). Gram-negative bacilli were isolated more frequently from the tracheal aspirates of patients with pneumonia who were receiving antacids or H2 blockers. Mortality rates were 1.6 times higher in the antacid-H2 group than in the sucralfate group (95 percent confidence interval, 0.99 to 2.50; P = 0.07). Although our results fell just short of statistical significance when they were analyzed according to intention to treat, they suggest that agents that elevate gastric pH increase the risk of nosocomial pneumonia in patients receiving ventilation by favoring gastric colonization with gram-negative bacilli. We conclude that in patients receiving mechanical ventilation, the use of a prophylactic agent against stress-ulcer bleeding that preserves the natural gastric acid barrier against bacterial overgrowth may be preferable to antacids and H2 blockers.

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Sixty-four episodes of bacterial infection were identified over a 44-month period in 16 of 28 patients with the acquired immune deficiency syndrome (AIDS) and 14 of 31 patients with AIDS-related complex. Nineteen of the 30 infected patients were parenteral drug abusers, 10 were from Caribbean Islands and had no identified risk factor, and one was a homosexual male. Fourteen patients had 21 episodes of community-acquired pneumonia: Streptococcus pneumoniae (10), Haemophilus influenzae (three), other Haemophilus species (three), group B beta-hemolytic streptococci (one), Staphylococcus aureus (one), Branhamella catarrhalis (one), Legionella pneumophila (one), and Mycoplasma pneumoniae (one). Seven patients had eight episodes of nosocomial pneumonia caused by gram-negative bacilli. Twenty-five episodes of community-acquired bacteremia and nine episodes of nosocomial bacteremia were associated with specific sites of infection. Other infections included meningitis (two), urinary tract infection (one), and abscesses involving subcutaneous and deep tissues (12). Sixteen patients had recurrent infections; 11 of these had or eventually had AIDS. Community-acquired bacterial infections in patients with AIDS or AIDS-related complex are common and may be recurrent but have low fatality rates. In comparison, nosocomial bacterial infections occur primarily in patients with AIDS and have high fatality rates.

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We studied seven strains of group G streptococci isolated from clinically severe bacteremic infections in six intravenous drug abusers. These group G strains multiplied luxuriantly in fresh human blood. On electron microscopy, they exhibited surface fibrillae similar to those observed in M-protein-rich group A streptococci, but they were not serologically M typable with a battery of 39 M antisera. Rabbit antisera raised against two of the group G strains (1618 and 1750) opsonized the homologous but not the heterologous isolates and exhibited type-specific Ouchterlony immunoprecipitin reactions. Moreover, antisera raised against peptic extracts of strain 1750 also promoted phagocytic killing of that strain. Anti-1750 reacted in high titer in an enzyme-linked immunosorbent assay against peptic extracts of the homologous strain; these antibodies were removed by absorption with 1750 cells but not by absorption with heterologous strains. These studies represent, to our knowledge, the first analysis of virulence factors of group G streptococci isolated from invasive human disease. The seven epidemiologically related blood isolates of group G streptococci possess distinct type-specific, antiphagocytic surface virulence factors analogous to the M proteins of group A streptococci.

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Differences in molecular composition of lipopolysaccharides (LPS) between serum-sensitive (S) clinical isolates of Escherichia coli and serum-resistant (R) clones derived by serial passage in serum were demonstrated to determine sensitivity or resistance to killing by normal human serum (NHS). LPS from R clones had a greater proportion of higher-molecular-weight, more highly O-antigen-substituted subunits than LPS from their serum S parents. Utilization of a liposomal model with inserted LPS simulating bacterial cell walls established LPS as the site of serum bactericidal action. Liposomes containing S LPS were lysed, while liposomes containing R LPS were unaffected by NHS. R and S LPS were fractionated into higher (F1)- and lower (F2)-molecular-weight fractions. Liposomes containing R LPS or the F1 fraction of S and R LPS were not lysed by serum. Liposomes containing the F2 fraction of S or R LPS were lysed by serum analogous to that observed with liposomes containing intact S LPS. These findings establish LPS to be one site of serum bactericidal activity and demonstrate that the higher-molecular-weight, highly O-antigen-substituted LPS subunits mediate resistance to killing by NHS.

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We studied risk factors for nosocomial pneumonia and fatality in 233 intensive care unit patients requiring continuous mechanical ventilation. Ventilator-associated pneumonia was diagnosed in 49 (21%) of the 233 patients. Of the 8 risk factors univariately associated with the development of pneumonia, only the presence of an intracranial pressure monitor (p less than 0.002), treatment with cimetidine (p less than 0.01), hospitalization during fall-winter seasons (p less than 0.04), and mechanical ventilator circuit changes every 24 h rather than every 48 h (p less than 0.02) remained significant after stepwise logistic regression. The overall fatality rate for the 49 patients who developed ventilator-associated pneumonia was 55%. Ventilator-associated pneumonia was 1 of 18 variables univariately associated with overall patient fatality, but it was not among the 7 variables present after multivariate analysis. The data delineate risk factors associated with the development of nosocomial pneumonia and fatality in patients receiving continuous mechanical ventilation.

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Over a 15-month period, seven intravenous drug abusers had 10 admissions because of bacteremia due to methicillin-resistant Staphylococcus aureus. Seven episodes of probable bacterial endocarditis occurred in four patients; one patient had septic thrombophlebitis and two had soft tissue infections. All seven patients patronized a local "shooting gallery" where paraphernalia were provided and drugs were often administered by a "street doctor." All isolates were phage type 29/77/83A/84/85 and demonstrated resistance only to methicillin, oxacillin, and penicillin. This strain of methicillin-resistant S. aureus has a phage type and antibiogram that is distinct from nosocomial methicillin-resistant S. aureus and was probably acquired by intravenous drug abusers during visits to the "shooting gallery". The "shooting gallery" is an integral part of the drug culture and a likely source for the transmission of antibiotic-resistant organisms.

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We studied rates of peripheral intravenous (IV) catheter tip and insertion site colonization after randomly assigning patients to transparent polyurethane (TP) dressings (N = 316) or dry gauze (DG) dressings (N = 421). The study was conducted during both summer and fall seasons, in a facility which lacked air conditioning. All patients had a teflon plastic catheter inserted, maintained and cultured by a member of the IV therapy team; no antibiotic or antiseptic ointments were used. Colonization rates were higher in the summer than in the fall for both catheter tips (9.0% vs 3.5%, p = 0.005) and sites (21.6% vs 7.0%, p = 0.001). During the summer season, the rate of catheter tip colonization with TP dressings was nearly twice that of DG dressings (12.4% vs 6.8%, p = 0.04). Logistic regression analysis indicated that catheter tip colonization was associated with the summer season (odds ratio = 3.0, 95% CI 1.4-6.2) and TP dressings (odds ratio = 1.8, 95% CI 1.1-3.2), and that site colonization was associated with both summer (odds ratio = 4.0, 95% CI 2.2-7.1) and receipt of antibiotics (odds ratio = 1.9, 95% CI 1.1-3.2). Coagulase-negative staphylococci were isolated from 55.5% of the colonized catheter tips and insertion sites. The data suggest that bacterial colonization of peripheral IV catheters is increased in summer, and that use of TP dressings may increase both tip colonization and cost nearly twofold.

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Treatment of septic shock with naloxone was evaluated in a prospective, randomised, double-blind, placebo-controlled study in which ten episodes of shock were treated with naloxone (0.4 to 1.2 mg intravenously) and 13 with the vehicle for injection. Treatment groups were similar in terms of demographic characteristics, type of primary infection, prevalence of septicaemia, type of underlying disease, duration in shock, and vasopressor therapy. Mean systolic blood pressure rose by 13.3% in the naloxone group and 11.3% in the placebo group. Two-way analysis of variance for repeated measures of blood pressure, obtained over 30 min periods before and after treatment, revealed no significant difference (p greater than 0.10) between treatment groups. Survival rates in the two groups at 48 h and 7 days after the start of treatment were similar. Naloxone, 0.4 to 1.2 mg intravenously, was no better than placebo in ameliorating hypotension in septic shock.

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