Infectious disease challenges in the 1990's.
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Communicable Disease Control↗
Biomedical subjects
S M Opal
Publications and source records attributed to S M Opal.
Antibiotics, cytokines, and endotoxin: a complex and evolving relationship in gram-negative sepsis.
Compelling experimental evidence now exists that antimicrobial agents induce the release of endotoxin from Gram-negative bacteria during the process of bacteriolysis. Different antimicrobial classes, particularly those which act upon the outer membrane of bacteria, vary in the amount of free endotoxin released from Gram-negative organisms. Despite this in vitro evidence, clinically important consequences of antibiotic-induced endotoxin release have yet to be consistently documented. Complexities in the host-pathogen interactions during actual infection with Gram-negative bacteria may account for the difficulties in demonstrating this phenomena in vivo. This brief review analyses these interactions and defines clinical settings where antibiotic-induced endotoxin release may prove to be clinically relevant.
Anti-Bacterial Agents↗
Antibiotic-induced D-lactic acidosis.
OBJECTIVE: To describe a case of oral antibiotic-induced D-lactic acidosis in a patient with enteric overgrowth of Lactobacillus acidophilus. DESIGN: Single case study. SETTING: University-affiliated community hospital. INTERVENTION: Oral carbohydrate challenge test with 4000 kcal/d. MAIN RESULTS: A patient had several episodes of D-lactic acidosis after receiving oral antibiotics. Stool cultures yielded Lactobacillus acidophilus resistant to the implicated agents. Provocative challenge with dietary carbohydrate alone, in the absence of antibiotics, failed to reproduce the syndrome. CONCLUSIONS: Oral antibiotics may induce D-lactic acidosis in patients with the short-bowel syndrome by promoting the overgrowth of resistant D-lactate-producing organisms. Interactions between carbohydrate intake and antibiotic use are likely determinants in the development of this syndrome. Periodic use of stool cultures with antimicrobial susceptibility testing may assist in the management of these patients by optimizing the selection of antimicrobial agents.
Acidosis, Lactic↗
Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids.
Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, > 10% in uninfected and > 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to > 10 micrograms/dl in uninfected and > 20 micrograms/dl in infected mice; and (c) decreases in thymic mass, > 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.
Animals↗
Fatal clostridial sepsis in a previously healthy woman.
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Aged↗
Clinical characteristics, management strategies, and cost implications of a statewide outbreak of enterovirus meningitis.
A statewide outbreak of enterovirus meningitis occurred in Rhode Island in the summer of 1991. A comprehensive chart review was conducted for determining the demographic and clinical characteristics of the epidemic and for assessing the interinstitutional variation in treatment strategies. Four hundred eight cases were reported, and enteroviruses were recovered in 61 (68%) of 90 cases in which viral isolation was attempted. Of six isolates that were serotyped, all were echovirus 30. Analysis of cerebrospinal fluid revealed that an increased total white blood cell count and an increased protein concentration were associated with increasing patient age; however, the percentage of polymorphonuclear leukocytes in the cerebrospinal fluid decreased with increasing patient age and longer durations of illness. Marked variations in treatment strategies between institutions were noted in the use of computed tomography of the head, the administration of empirical antimicrobial agents, and the duration of hospitalization. Considerable health resources could have been saved by rapid detection of the virus, dissemination of information about the outbreak, and a conservative approach to clinical management.
Adolescent↗
Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis.
A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P = 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/ permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.
Acute-Phase Proteins↗
Relative concentrations of endotoxin-binding proteins in body fluids during infection.
Endotoxin initiates the systemic inflammatory response, haemodynamic changes, and multi-organ failure that may occur as a consequence of systemic gram-negative bacterial infection. The serum protein lipopolysaccharide-binding protein (LBP) binds to the lipid A component of bacterial endotoxin and facilitates its delivery to the CD14 antigen on the macrophage, where inflammatory cytokines are released and a cascade of host mediators is initiated. The neutrophil granular protein bactericidal/permeability-increasing protein (BPI) competes with LBP for endotoxin binding and functions as a molecular antagonist of LBP-endotoxin interactions. We have measured concentrations of both proteins in body fluids from 49 consecutive patients. In 16 of 17 samples of fluid from closed-space infections, BPI was present in greater concentration than LBP (median BPI/LBP ratio 7.6 [95% CI 2.32-22.1]). The ratio of BPI and LBP was not significantly different from 1.0 in abdominal fluid from 10 patients with peritonitis (ratio 0.235 [0.18-0.47]), whereas the BPI/LBP ratio was low in 22 non-infected body fluids (0.01 [0.001-0.04]) and concentrations of both proteins approached those in normal human plasma. BPI concentrations were directly correlated with the quantity of neutrophils within clinical samples (rs = 0.81, p < 0.0001). Thus, within abscess cavities BPI is available in sufficient quantities for effective competition with LBP for endotoxin. BPI may attenuate the local inflammatory response and the systemic toxicity of endotoxin release during gram-negative infections.
Abscess↗
Superinfection with rifampin-isoniazid-streptomycin-ethambutol (RISE)-resistant tuberculosis in three patients with AIDS: confirmation by polymerase chain reaction fingerprinting.
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AIDS-Related Opportunistic Infections↗
Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.
OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.
Adult↗
Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis.
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Health Personnel↗
Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock.
Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine g1 antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-alpha monoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric g1 and g2a anti-murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p < or = 0.004), and prolonged survival to 45 h (p < or = 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p < or = 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the g1 isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p < or = 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine g1) being more efficacious than active isotypes (human g1 and murine g2a).
Animals↗
Affinity-purified Escherichia coli J5 lipopolysaccharide-specific IgG protects neutropenic rats against gram-negative bacterial sepsis.
Antibodies were raised in rabbits by immunization with the heat-killed J5 mutant of Escherichia coli O111 (Rc chemotype). Serum antibodies were separated into purified IgG and IgM by sequential affinity chromatography on protein G-Sepharose and anti-rabbit IgG-Sepharose columns. J5 lipopolysaccharide (LPS)-specific IgG was prepared by affinity chromatography of purified IgG on a J5 LPS-EAH Sepharose 4B affinity column. Purified IgM, IgG, and J5 LPS-specific IgG protected neutropenic rats against lethal challenge with Pseudomonas aeruginosa 12:4:4 (Fisher Devlin immunotype 6). Nine of 16 rats treated with the IgM fraction were protected (P < .001). Thirteen of 20 rats treated with the purified IgG and 6 of 8 treated with J5 LPS-specific IgG were protected compared with none of 25 treated with IgG made from the preimmune serum of the same rabbit (P < .001). These results demonstrate that purified J5 LPS-specific IgG protects against the lethal consequences of gram-negative bacteremia.
Animals↗
Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
OBJECTIVES: To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome. DESIGN: Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra. SETTING: Twelve academic medical center intensive care units in the United States. PATIENTS: Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo. INTERVENTIONS: Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. MEASUREMENTS AND MAIN RESULTS: A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated. CONCLUSIONS: This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.
Adult↗
Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a placebo-controlled study.
OBJECTIVES: To study the toxicology and pharmacology of the endotoxin-neutralizing agent, bactericidal/permeability-increasing protein. DESIGN: Prospective, randomized, placebo-controlled laboratory study. SETTING: Academic research laboratory. SUBJECTS: CD-1 mice (n = 259); Sprague Dawley rats (n = 26); New Zealand White rabbits (n = 19). INTERVENTIONS: Pharmacokinetics of intravenously injected bactericidal/permeability-increasing protein was assessed in mice. Toxicology was tested in mice and rats. Efficacy of intravenously administered bactericidal/permeability-increasing protein as an endotoxin-neutralizing agent was tested in mice, rats, and rabbits. MEASUREMENTS AND MAIN RESULTS: Administration of a single 10-mg/kg bolus injection of bactericidal/permeability-increasing protein resulted in no alterations in hematologic, renal, or hepatic function, activity level, or weight gain in animals observed over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mice from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) compared with a 100% (16/16) mortality rate in the saline-treated controls (p < .001). Bactericidal/permeability-increasing protein administered up to 1 hr after endotoxin provided significant protection against lethal endotoxin challenge. Furthermore, bactericidal/permeability-increasing protein reduced the induration and dermal necrosis observed in the localized dermal Shwartzman reaction. CONCLUSIONS: Bactericidal/permeability-increasing protein is a potent antiendotoxin that neutralizes endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia.
Animals↗
Outbreak of multidrug-resistant Enterococcus faecium with transferable vanB class vancomycin resistance.
Enterococcus faecium strains resistant to ampicillin, high levels of gentamicin, and vancomycin but susceptible to teicoplanin (vanB class vancomycin resistance) were recovered from 37 patients during an outbreak involving a 250-bed university-affiliated hospital. Three isolates with vancomycin MICs ranging from 8 to 256 micrograms/ml all hybridized with a vanB probe. Restriction endonuclease analysis of chromosomal and plasmid DNA suggested that all isolates tested were derived from a single clone. Vancomycin resistance was shown to be transferable. Risk factors for acquiring the epidemic strain included proximity to another case patient (P, 0.0005) and exposure to a nurse who cared for another case patient (P, 0.007). Contamination of the environment by the epidemic strain occurred significantly more often when case patients had diarrhea (P, 0.001). Placing patients in private rooms and requiring the use of gowns as well as gloves by personnel controlled the outbreak. These findings suggest that multidrug-resistant E. faecium strains with transferable vanB class vancomycin resistance will emerge as important nosocomial pathogens. Because extensive environmental contamination may occur when affected patients develop diarrhea, barrier precautions, including the use of both gowns and gloves, should be implemented as soon as these pathogens are encountered.
Adult↗
Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis.
Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.
Disseminated Intravascular Coagulation↗
The clinical evaluation of new drugs for sepsis. A prospective study design based on survival analysis.
OBJECTIVE: To develop a survival model and severity assessment method to estimate the 28-day mortality risk for patients with sepsis syndrome entering phase 2 and 3 drug evaluations. DESIGN: Retrospective analysis of intensive care unit admissions with sepsis syndrome by means of log-normal regression to identify risk factors for 28-day mortality. Prospective application of the model to patients with gram-negative infection meeting sepsis syndrome criteria from separate data collection (validation group). PATIENTS: A total of 58,737 intensive care unit admissions at 107 hospitals in the United States and Western Europe screened to yield 1195 patients meeting entry criteria for the sepsis syndrome study for the original model; 295 hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome for validation. MAIN OUTCOME MEASURES: Survival time and mortality at 28 days after fulfillment of the sepsis syndrome criteria. RESULTS: Acute physiologic abnormalities were the most important prognostic factors influencing outcome (82% of total chi 2). Specific disease resulting in intensive care unit admission and the time the patient was in the hospital and intensive care unit before qualification were also independent risks, as were age and a clinical history of cirrhosis. The model's overall classification accuracy was a Somers' Dyx of .52 (rank correlation between predicted risk and 28-day mortality) (receiver operating characteristic area, 0.76), with equal accuracy (Dyx = .59; receiver operating characteristic area, 0.80) in the independent group of patients. CONCLUSIONS: We created an accurate independent estimate for 28-day mortality risk for patients with sepsis syndrome (severe sepsis). This estimate could improve the evaluation of new drugs by investigating whether the drug's benefit varies by patient risk and then determining the amount of benefit for individual patients.
Adolescent↗