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Background Borrelia miyamotoi is a relapsing fever spirochete that relatively recently has been reported to infect humans. It causes an acute undifferentiated febrile illness that can include meningoencephalitis and relapsing fever. Like Borrelia burgdorferi, it is transmitted by Ixodes scapularis ticks in the northeastern United States and by Ixodes pacificus ticks in the western United States. Despite reports of clinical cases from North America, Europe, and Asia, the prevalence, geographic range, and pattern of expansion of human B. miyamotoi infection are uncertain. To better understand these characteristics of B. miyamotoi in relation to other tickborne infections, we carried out a cross-sectional seroprevalence study across New England that surveyed B. miyamotoi, B. burgdorferi, and Babesia microti infections. Methods We measured specific antibodies against B. miyamotoi, B. burgdorferi, and B. microti among individuals living in 5 New England states in 2018. Results Analysis of 1153 serum samples collected at 11 catchment sites showed that the average seroprevalence for B. miyamotoi was 2.8% (range, 0.6%–5.2%), which was less than that of B. burgdorferi (11.0%; range, 6.8%–15.6%) and B. microti (10.0%; range, 6.5%–13.6%). Antibody screening within county residence in New England showed varying levels of seroprevalence for these pathogens but did not reveal a vectoral geographical pattern of distribution. Conclusions Human infections caused by B. miyamotoi, B. burgdorferi, and B. microti are widespread with varying prevalence throughout New England.

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Background Up to 20% of SA isolates in the United States are penicillin-susceptible (PSSA); however, treatment with penicillin has been discouraged because of concern that routine testing may miss strains that have the capacity to produce clinically significant ß-lactamase in vivo. We performed a retrospective analysis to determine whether PCN therapy for the treatment of PSSA bacteremia was of comparable efficacy and safety to standard therapies. Methods We identified all episodes of SA bacteremia (March 18, 2010–July 23, 2018). SA penicillin susceptibility testing in our lab was performed by broth microdilution followed by nitrocefin ß-lactamase testing per CLSI guidelines on these isolates. A retrospective chart review was performed and our primary outcome was a composite endpoint of clinical success (no change in PSSA therapy due to persistent or worsening signs and symptoms, no PSSA bacteremia recurrence or persistence, and no infection‐related mortality). Microbiologic failure was defined as either failure to clear bacteremia/infection or recurrence after completion of therapy. Patients were followed until last contact with our medical system, the only tertiary center in the region. We compared our rates of success, mortality, and adverse drug reaction to historical SA bacteremia controls from the literature. Results PSSA accounted for 13% (130/971) of SA bloodstream episodes. Nineteen patients with PSSA (15%) were treated with PCN and 79% (15/19) achieved the primary endpoint of clinical success. Of the 4 patients who did not achieve the endpoint, 2 developed rash and were switched to a different antibiotic and 2 died from complications of sepsis. One of the patients died after clearing blood cultures but had DIC and a catastrophic intracranial hemorrhage, the other died of overwhelming sepsis after 4 days (2 days nafcillin, 2 days PCN) with continued bacteremia. Thus, our only microbiologic failure was due to early death from sepsis. Rates of success, mortality and drug reaction were similar to prior reports of alternative standard therapies (Table 1). Conclusion PCN is a viable treatment option for PSSA bacteremia as identified by routine laboratory testing. Further study will include characterizing the presence of ß-lactamase in these patient’s isolates. Disclosures All authors: No reported disclosures.

Noninvasive vaginal infections by Staphylococcus aureus strains producing the superantigen TSST-1 can cause menstrual toxic shock syndrome (mTSS). With the objective of exploring the basis for differential susceptibility to mTSS, the relative responsiveness to TSST-1 of healthy women has been investigated. Peripheral blood mononuclear cells from healthy donors were incubated with purified TSST-1 or with the T-cell mitogen phytohemmaglutinin (PHA), and proliferation was measured. The concentrations of TSST-1 and PHA required to elicit a response equivalent to 15% of the maximal achievable response (EC15) were determined. Although with PHA, EC15 values were comparable between donors, subjects could be classified as being of high, medium, or low sensitivity based on responsiveness to TSST-1. Sensitivity to TSST-1-induced proliferation was associated with increased production of the cytokines interleukin-2 and interferon-γ. When the entire T lymphocyte population was considered, there were no differences between sensitivity groups with respect to the frequency of cells known to be responsive to TSST-1 (those bearing CD3(+) Vβ2(+)). However, there was an association between sensitivity to TSST-1 and certain HLA-class II haplotypes. Thus, the frequencies of DR7DQ2, DR14DQ5, DR4DQ8, and DR8DQ4 haplotypes were greater among those with high sensitivity, a finding confirmed by analysis of responses to immortalized homozygous B cell lines. Collectively, the results reveal that factors other than neutralizing antibody and the frequency of Vβ2(+) T lymphocytes determine immunological responsiveness to TSST-1. Differential responsiveness of lymphocytes to TSST-1 may form the basis of interindividual variations in susceptibility to mTSS.

Many cases of neonatal toxic shock syndrome (TSS)-like exanthematous disease but few cases of menstrual TSS (mTSS) have been reported in Japan. We determined the prevalence of mucosal colonization with Staphylococcus aureus and of positive antibodies to TSS toxin 1 (TSST-1) among 209 healthy Japanese women in Tokyo. S. aureus isolates from mucosal sites were characterized with respect to TSST-1 production and resistance genotype. Antibody titers were determined for test subjects and for 133 Japanese and 137 Caucasian control women living in the United States. S. aureus was isolated from at least one site in 108 of 209 women (52%) in Tokyo. Of the 159 S. aureus isolates recovered, 14 (9%) were TSST-1 positive (12 unique strains). Twelve of 209 women (6%) were colonized with a TSST-1-producing strain; two (S. aureus were comparable in Japan and the United States, despite low seropositivity to TSST-1 in Japan. Environmental factors appear to be important in promoting the development of anti-TSST-1 antibodies, as there was a significant difference in titers between Japanese women living in Tokyo and those living in the United States. Most colonizing TSST-1-producing S. aureus strains in Japan were genotypically similar to mTSS strains found in the United States.

Menstrual toxic shock syndrome (mTSS) is thought to be associated with colonization with toxic shock syndrome toxin 1 (TSST-1)-producing Staphylococcus aureus in women with insufficient antibody titers. mTSS has been associated with menstruation and tampon use, and although it is rare, the effects can be life threatening. It remains of interest because of the widespread use of tampons, reported to be about 70% of women in the United States, Canada, and much of Western Europe. This comprehensive study was designed to determine S. aureus colonization and TSST-1 serum antibody titers in 3,012 menstruating women in North America between the ages of 13 and 40, particularly among age and racial groups that could not be assessed reliably in previous small studies. One out of every four subjects was found to be colonized with S. aureus in at least one of three body sites (nose, vagina, or anus), with approximately 9% colonized vaginally. Eighty-five percent of subjects had antibody titers (≥1:32) to TSST-1, and the vast majority (81%) of teenaged subjects (13 to 18 years) had already developed antibody titers. Among carriers of toxigenic S. aureus , a significantly lower percentage of black women than of white or Hispanic women were found to have antibody titers (≥1:32) to TSST-1 (89% versus 98% and 100%). These findings demonstrate that the majority of teenagers have antibody titers (≥1:32) to TSST-1 and are presumed to be protected from mTSS. These findings also suggest that black women may be more susceptible to mTSS than previously thought.

Background Treatment of severe sepsis is expensive, often encompassing a number of discretionary modalities. The objective of the present study was to assess intercenter variation in resource and therapeutic modality use in patients with severe sepsis. Methods We conducted a prospective cohort study of 1028 adult admissions with severe sepsis from a stratified random sample of patients admitted to eight academic tertiary care centers. The main outcome measures were length of stay (LOS; total LOS and LOS after onset of severe sepsis) and total hospital charges. Results The adjusted mean total hospital charges varied from $69 429 to US$237 898 across centers, whereas the adjusted LOS after onset varied from 15.9 days to 24.2 days per admission. Treatments used frequently after the first onset of sepsis among patients with severe sepsis were pulmonary artery catheters (19.4%), ventilator support (21.8%), pressor support (45.8%) and albumin infusion (14.4%). Pulmonary artery catheter use, ventilator support and albumin infusion had moderate variation profiles, varying 3.2-fold to 4.9-fold, whereas the rate of pressor support varied only 1.92-fold across centers. Even after adjusting for age, sex, Charlson comorbidity score, discharge diagnosis-relative group weight, organ dysfunction and service at onset, the odds for using these therapeutic modalities still varied significantly across centers. Failure to start antibiotics within 24 hours was strongly correlated with a higher probability of 28-day mortality (r2 = 0.72). Conclusion These data demonstrate moderate but significant variation in resource use and use of technologies in treatment of severe sepsis among academic centers. Delay in antibiotic therapy was associated with worse outcome at the center level.

We report 3 cases of recurrent nonmenstrual toxic shock syndrome (TSS) and review the clinical manifestations, diagnosis, and treatment. The primary sites of infection were the genital tract (in a patient who underwent cesarean delivery), the upper respiratory tract, and a breast abscess. In all 3 patients, the initial illness was not recognized to be TSS; only after development of recurrent illness with desquamation was this diagnosis entertained. Strains of Staphylococcus aureus that were isolated from 2 patients produced TSS toxin-1, whereas the third strain produced staphylococcal enterotoxin B. All 3 patients lacked antibody to the implicated toxins at the time of presentation with recurrent illness. Nonmenstrual TSS can occur in a variety of clinical settings and may be recurrent. The presence of desquamation during a febrile, multisystem illness could suggest this diagnosis and should prompt the clinician to obtain appropriate cultures for S. aureus.

We report a skin and soft-tissue infection outbreak among football team members due to a USA300 methicillin-susceptible Staphylococcus aureus (MRSA) strain with genes coding for Panton-Valentine leukocidin and the arginine catabolic mobile element. We postulate that the strain is a community-associated USA300 MRSA strain that lost methicillin resistance but retained important virulence factors.

Presentation of Case A 42-year-old asplenic man was admitted to the hospital because of gram-negative sepsis. The patient had been well until one week earlier, when his left upper teeth began to ache. Four days before admission, he had abdominal cramps and two loose stools. The next morning, he awakened with diffuse aches, especially in the arms, legs, and lower back. After a small breakfast, he vomited several times and then had shaking chills with increasing fever. He was admitted to another hospital. His temperature was 40°C. The results of a physical examination were otherwise normal. The urine was normal. . . .

Clinical predictions alone are insufficiently accurate to identify patients with specific types of bloodstream infection; laboratory assays might improve such predictions. Therefore, we performed a prospective cohort study of 356 episodes of sepsis syndrome and did Limulus amebocyte lysate (LAL) assays for endotoxin. The main outcome measures were bacteremia and infection due to gram-negative organisms; other types of infection were secondary outcomes. Assays were defined as positive if the result was > or = 0.4 enzyme-linked immunosorbent assay units per milliliter. There were positive assays in 119 (33%) of 356 episodes. Assay positivity correlated with the presence of fungal bloodstream infection (P < .003) but correlated negatively with the presence of gram-negative organisms in the bloodstream (P = .04). A trend toward higher rates of mortality in the LAL assay-positive episodes was no longer present after adjusting for severity. Thus, results of LAL assay did not correlate with the presence of bacteremia due to gram-negative organisms or with mortality after adjusting for severity but did correlate with the presence of fungal bloodstream infection.

We conducted a prospective study of a chromogenic LAL assay in 346 patients with sepsis syndrome, as defined by a modification of the Bone criteria, and 131 healthy volunteers at eight member centers of the Academic Medical College Consortium (AMCC). We identified patients with endotoxemia (> 0.40 EU/ml) by measuring LAL-reactive material in whole blood, extracted by the Tamura nitric acid method, with the chromogenic LAL (Pyrochrome®) assay. The mean result in sepsis patients with detectable endotoxemia (n = 241) was 1.07 ± 1.57 EU/ml, and the mean result in 131 volunteers was 0.151 ± 0.113 EU/ml, with 73% of the volunteers' results falling below the detectable limit. The average incidence of endotoxemia in sepsis patients was 33%, but varied 2.7-fold among the clinical centers (range 16-44%). Assay results were repeatable when samples tested frozen at the clinical sites were compared to results on frozen samples tested at Associates of Cape Cod, Inc. (ACC). Multiple samples were obtained from 40 patients at 18-24 h interval(s). Fourteen multidraw patients (35%) were endotoxemic at one or more draw(s) and eight of these patients had two or more draws with endotoxin levels > 1.0 EU/ml. The presence of sulfa drugs gave false positive results in two patient samples. A positive LAL test did not correlate with culture-proven bacterial infection and did not significantly correlate with mortality. There was a correlation ( P = 0.014) between a patient having a positive LAL test and the presence of a fungal infection when mixed fungal and bacterial infections were included. There was no correlation with a positive LAL test when only a fungal infection was present (P = 0.425) or when only a fungal and a Gram-positive infection was present ( P = 0.087).

We present 2 patients with cutaneous Leishmania (Viannia) braziliensis infection who had recurrence of disease after completing standard courses of sodium stibogluconate but were cured upon subsequent treatment with liposomal amphotericin B. Amphotericin B may be an excellent agent for the treatment of clinically resistant or relapsed cutaneous leishmaniasis; the optimal dose and duration of therapy remain uncertain and will require further study.

To determine whether tampons composed of cotton or rayon differ in their effects on production of TSST-1 in vitro, two methods of bacterial cultivation, with and without agitation, were used to study the effects of 16 commercially available and experimental tampons on production of TSST-1. Experiments were done in blinded fashion. TSST-1 was produced in medium alone in the absence of a tampon by both methods. Neither cotton nor rayon tampons consistently increased toxin production, nor were there significant differences between them in their effects on TSST-1. In contrast, a tampon composed of carboxymethylcellulose and polyester foam increased production of TSST-1 to a large degree in both culture systems. Thus, neither cotton nor rayon amplifies production of TSST-1 in vitro, and cotton tampons cannot be claimed to be inherently safer on the basis of such data.

Objective : To determine the efficacy of a murine anti-tumor necrosis factor (TNF) monoclonal antibody in the treatment of Escherichia coli peritonitis and sepsis in the rabbit. Design : Prospective, paired, randomized, blinded, controlled animal trial. Setting : Animal research laboratory. Subjects : Male New Zealand white rabbits. Interventions : Anesthetized rabbits were cannulated with indwelling femoral arterial and venous catheters. Peritonitis and sepsis were induced by intraperitoneal challenge using live E. coli O18ac bacteria. All animals were treated with gentamicin and ceftriaxone 1 hr after challenge. One group (prophylaxis experiment) consisting often rabbit pairs (the prophylaxis group), was treated with either murine anti-TNF monoclonal antibody or an equivalent volume of 5% albumin 3 hrs before E. coli challenge. A second group (therapeutic experiment) of 17 rabbit pairs, the treatment group, was also treated with murine anti-TNF monoclonal antibody or albumin control 1 hr after E. coli challenge. Measurements and Main Results : All animals were bacteremic 1 hr after challenge. Physiologic measures of sepsis (heart rate, mean arterial pressure, serum bicarbonate, and arterial pH) did not differ between control, prophylaxis, and treatment groups. Peak serum TNF concentration was significantly (p

A recombinant endotoxin neutralizing protein was evaluated for its ability to ameliorate the effects of Escherichia coli sepsis in rats.Prospective, controlled animal trial.Hospital animal research laboratory.Wistar rats, treated with gentamicin 1 hr after challenge with intraperitoneal E. coli O18ac.The animals received a recombinant endotoxin neutralizing protein, in doses of 5, 25, or 50 mg/kg, either 30 or 60 mins after challenge; controls received saline.Geometric mean serum endotoxin concentrations in endotoxin neutralizing protein-treated animals did not differ from control animals. Tumor necrosis factor concentrations in animals treated with endotoxin neutralizing protein 30 mins after challenge were significantly lower than controls. Animals treated with 25 or 50 mg/kg of endotoxin neutralizing protein 30 mins after E. coli challenge had significant improvements in survival compared with controls. Animals treated with 50 mg/kg of endotoxin neutralizing protein 60 mins after E. coli challenge had significant improvements in survival compared with controls.Endotoxin neutralizing protein significantly reduces mortality from Gram-negative sepsis in an antibiotic-treatment model of E. coli peritonitis and bacteremia in rats, mediated by a neutralization of the biological effects of endotoxin.

Background Menstrual Toxic Shock Syndrome (mTSS) is thought to be associated with the vaginal colonization with specific strains of Staphylococcus aureus TSST-1 in women who lack sufficient antibody titers to this toxin. There are no published studies that examine the seroconversion in women with various colonization patterns of this organism. Thus, the aim of this study was to evaluate the persistence of Staphylococcus aureus colonization at three body sites (vagina, nares, and anus) and serum antibody to toxic shock syndrome toxin-producing Staphylococcus aureus among a small group of healthy, menstruating women evaluated previously in a larger study. Methods One year after the completion of that study, 311 subjects were recalled into 5 groups. Four samples were obtained from each participant at several visits over an additional 6-11 month period: 1) an anterior nares swab; 2) an anal swab; 3) a vagina swab; and 4) a blood sample. Gram stain, a catalase test, and a rapid S. aureus-specific latex agglutination test were performed to phenotypically identify S. aureus from sample swabs. A competitive ELISA was used to quantify TSST-1 production. Human TSST-1 IgG antibodies were determined from the blood samples using a sandwich ELISA method. Results We found only 41% of toxigenic S. aureus and 35.5% of non-toxigenic nasal carriage could be classified as persistent. None of the toxigenic S. aureus vaginal or anal carriage could be classified as persistent. Despite the low persistence of S. aureus colonization, subjects colonized with a toxigenic strain were found to display distributions of antibody titers skewed toward higher titers than other subjects. Seven percent (5/75) of subjects became seropositive during recall, but none experienced toxic shock syndrome-like symptoms. Conclusions Nasal carriage of S. aureus appears to be persistent and the best predicator of subsequent colonization, whereas vaginal and anal carriage appear to be more transient. From these findings, it appears that antibody titers in women found to be colonized with toxigenic S. aureus remained skewed toward higher titers whether or not the colonies were found to be persistent or transient in nature. This suggests that colonization at some point in time is sufficient to elevate antibody titer levels and those levels appear to be persistent. Results also indicate that women can become seropositive without experiencing signs or symptoms of toxic shock syndrome.

In April 2008, the Infectious Diseases Society of America (IDSA) entered into an agreement with Connecticut Attorney General Richard Blumenthal to voluntarily undertake a special review of its 2006 Lyme disease guidelines. This agreement ended the Attorney General's investigation into the process by which the guidelines were developed. The IDSA agreed to convene an independent panel to conduct a one-time review of the guidelines. The Review Panel members, vetted by an ombudsman for potential conflicts of interest, reviewed the entirety of the 2006 guidelines, with particular attention to the recommendations devoted to post-Lyme disease syndromes. After multiple meetings, a public hearing, and extensive review of research and other information, the Review Panel concluded that the recommendations contained in the 2006 guidelines were medically and scientifically justified on the basis of all of the available evidence and that no changes to the guidelines were necessary.

Limulus antilipopolysaccharide factor (LALF), an 11.8-kDa peptide isolated from amebocytes of Limulus polyphemus, neutralizes meningococcal lipooligosaccharide (LOS)-induced gelation of limulus amebocyte lysate. Rabbits challenged with an LD90 of LOS (10 micrograms/kg) premixed with LALF in vitro (n = 10) had significantly higher mean arterial pressure, arterial pH, serum bicarbonate concentrations, and survival (90% vs. 8%, P = .005) than did rabbits challenged with LOS alone. Relative to untreated controls, rabbits pretreated with LALF intravenously (iv) at 1.2 mg/kg (n = 21) also had significant improvements in physiologic measurements and higher survival (52% vs. 8%, P = .003). Even when LALF (1.2 mg/kg iv) was given 1/2 h after LOS challenge, animals showed significant improvements in physiologic measurements and survival (33% vs. 8% in untreated controls P = .028). LALF-treated animals also had significantly lower circulating endotoxin activity and tumor necrosis factor concentrations. Thus, LALF attenuates the toxic effects of meningococcal LOS in rabbits even when administered after LOS challenge and deserves further evaluation as a potential therapeutic agent for treating gram-negative septic shock.

A 57-year-old woman with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease developed peritoneal dialysis–related Mucor peritonitis after her pet cockatoo bit through her transfer set. The infection persisted despite more than 8 weeks of treatment with liposomal amphotericin B. On a compassionate basis, she then received oral posaconazole, 800 mg/d, in divided doses for 6 months. She experienced complete remission and has remained disease free since then, for more than 2 years. We review the medical literature about mucormycosis peritonitis which, albeit rare, carries very high mortality. The treatment of choice is liposomal amphotericin B, which failed in our patient. Our case report suggests that posaconazole is an attractive treatment option in patients with peritoneal dialysis–related Mucor peritonitis.

Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed.We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy.Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004).Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

Menstrual toxic shock syndrome (mTSS) is an acute febrile disease accompanied by hypotension and multiple organ involvement. Infection with Staphylococcus aureus producing the superantigen toxic shock syndrome toxin-1 (TSST-1) vaginally is necessary; however, only a small fraction of those infected with TSST-1 producing bacteria actually develop mTSS, suggesting that host factors modulate disease susceptibility. Serum antibodies to the toxin protect against development of the syndrome, but not all antibodies can neutralize the toxin. We set out to determine whether risk of developing the syndrome is related to the absence of neutralizing antibody and if antibody isotypes influence the neutralization capacity. In healthy subjects, TSST-1-binding serum antibodies were exclusively of the IgG and IgM classes; however, toxin-neutralizing capacity was correlated to the TSST-1-specific IgG1 and IgG4 antibodies (r 2=0.88, p

To examine the relationship of pulmonary artery catheter (PAC) use to patient outcomes, including mortality rate and resource utilization, in patients with severe sepsis in eight academic medical centers.Case-control, nested within a prospective cohort study.Eight academic tertiary care centers.Stratified random sample of 1,010 adult admissions with severe sepsis.None.The main outcome measures were in-hospital mortality, total hospital charge, and length of stay (LOS) for patients with and without PAC use. The case-matched subset of patients included 141 pairs managed with and without the use of a PAC. The mortality rate was slightly but not statistically significantly lower among the PAC use group compared with those not using a PAC (41.1% vs. 46.8%, p =.34). Even this trend disappeared after we adjusted for the Charlson comorbidity score and sepsis-specific Acute Physiology and Chronic Health Evaluation (APACHE) III (adjusted odds ratio, 1.02; 95% confidence interval, 0.61-1.72). In linear regression models adjusted for the Charlson comorbidity score, sepsis-specific APACHE III, surgical status, receipt of a steroid before sepsis onset, presence of a Hickman catheter, and preonset LOS, no significant differences were found for total hospital charges (139,207 US dollars vs. 148,190, adjusted mean comparing PAC and non-PAC group, p =.57), postonset LOS (23.4 vs. 26.9 days, adjusted mean, p =.32), or total LOS in intensive care unit (18.2 vs. 18.8 days, adjusted mean, p =.82).Among patients with severe sepsis, PAC placement was not associated with a change in mortality rate or resource utilization, although small nonsignificant trends toward lower resource utilization were present in the PAC group.

Nonmenstrual toxic shock syndrome (TSS) in adults has been associated with various staphylococcal respiratory tract infections, including pharyngitis, tonsillitis, pneumonia, and postinfluenza respiratory tract infections. In children, nonmenstrual TSS has also been described as a complication of bacterial tracheitis. We describe the case of a 40-year-old woman who presented with laryngotracheitis as well as clinical and laboratory evidence of TSS. Culture of her sputum samples yielded pure growth of Staphylococcus aureus, which was shown to produce TSS toxin 1 (TSST-1). The patient responded promptly to therapy with iv clindamycin. We discuss the association of TSS with staphylococcal laryngotracheitis and the role of clindamycin in the treatment of TSS. To our knowledge, there are no previous reports of TSS complicating laryngotracheitis in adults.

OBJECTIVES Limulus anti-lipopolysaccharide factor, an 11.8-kilodalton peptide isolated from amebocytes of Limulus polyphemus inhibits the biologic activities of endotoxin in vitro, including gelation of Limulus amebocyte lysate. A recombinant version of Limulus anti-lipopolysaccharide factor, termed endotoxin neutralizing protein, has now been expressed in yeast. Endotoxin-neutralizing protein was evaluated for its potential prophylactic and therapeutic effects in rabbits challenged with Escherichia coli endotoxin. DESIGN Controlled animal trial. SETTING Animal research laboratory. SUBJECTS A total of 112 New Zealand white rabbits were studied. INTERVENTIONS Rabbits were challenged with an LD80 dose of E. coli endotoxin (100 micrograms/kg); control animals (n = 52) were treated with saline solution at the time of endotoxin challenge; experimental animals received endotoxin-neutralizing protein 2.5 mg/kg prechallenge (n = 20), 5.0 mg/kg prechallenge (n = 20), or 5.0 mg/kg 30 mins postchallenge (n = 20).

BACKGROUND AND METHODS Endotoxin shock is mediated by various cytokines, including tumor necrosis factor. Treatment of patients with i.v. immunoglobulin has been shown to reduce the concentration of circulating cytokines. The purpose of this study was to determine the protective effects of immunoglobulin for i.v. use on meningococcal endotoxin-induced shock in a rabbit model. Experimental animals were challenged with i.v. meningococcal endotoxin (lipo-oligosaccharide) 10 micrograms/kg, and treated with either a 2-hr i.v. immunoglobulin infusion (400 mg/kg) or a similar saline infusion that was initiated 30 mins before endotoxin challenge. Control animals were challenged with saline alone. RESULTS Compared with untreated control animals, pulse rate increased (p less than .007) and mean arterial pressure and serum bicarbonate concentrations decreased (p less than .02) in both experimental groups, but did not differ between immunoglobulin-treated and saline-treated animals (p greater than .05) at any time after the endotoxin challenge. Geometric mean serum endotoxin concentrations were significantly (p less than .03) lower in the immunoglobulin-treated animals at 60, 120, 180, 240, 300, and 360 mins after the endotoxin challenge. The geometric mean serum tumor necrosis factor level at 1 hr after the endotoxin challenge in the immunoglobulin-treated experimental animals was lower than in saline-treated animals (5.53 vs. 8.47 tumor necrosis factor enzyme-linked immunosorbent assay U/mL), but not significantly so (p greater than .05). Mortality rate was similar in both experimental groups; eight (67%) of 12 saline-treated experimental rabbits and seven (70%) of ten immunoglobulin-treated rabbits died. All untreated control animals survived 24 hrs. CONCLUSIONS In this model of circulatory shock in rabbits, i.v. immunoglobulin: a) does not significantly alter the physiologic responses to endotoxin challenge; b) significantly reduces endotoxin concentrations; c) reduces tumor necrosis factor concentrations, but not significantly; and d) does not improve survival rate.

Meningococcemia is the most frequent cause of septic shock in healthy children. To determine whether polymyxin B (PMB) might improve mortality from meningococcal shock, its protective activity was evaluated in rabbits challenged with an LD90 of meningococcal lipooligosaccharide (LOS) and compared with an LD80 of Escherichia coli O111:B4 lipopolysaccharide (LPS). PMB (5 mg/kg) administered intravenously 30 min before meningococcal LOS challenge had no significant effect on heart rate, mean arterial pressure, serum bicarbonate, serum tumor necrosis factor (TNF) levels, or survival relative to controls. However, PMB premixed with LOS in vitro increased serum bicarbonate levels (P less than .05) and improved 24-h survival (P less than .05). In contrast, PMB given before E. coli LPS challenge increased serum bicarbonate levels, decreased TNF levels, and improved 24-h survival (all, P less than .05). In vitro studies confirmed that PMB at 10 micrograms/ml neutralized E. coli LPS but not meningococcal LOS activity. Thus, pretreatment with PMB apparently protects rabbits against shock induced by E. coli LPS but not by meningococcal LOS.

Background Treatment of severe sepsis is expensive, often encompassing a number of discretionary modalities. The objective of the present study was to assess intercenter variation in resource and therapeutic modality use in patients with severe sepsis. Methods We conducted a prospective cohort study of 1028 adult admissions with severe sepsis from a stratified random sample of patients admitted to eight academic tertiary care centers. The main outcome measures were length of stay (LOS; total LOS and LOS after onset of severe sepsis) and total hospital charges. Results The adjusted mean total hospital charges varied from $69 429 to US$237 898 across centers, whereas the adjusted LOS after onset varied from 15.9 days to 24.2 days per admission. Treatments used frequently after the first onset of sepsis among patients with severe sepsis were pulmonary artery catheters (19.4%), ventilator support (21.8%), pressor support (45.8%) and albumin infusion (14.4%). Pulmonary artery catheter use, ventilator support and albumin infusion had moderate variation profiles, varying 3.2-fold to 4.9-fold, whereas the rate of pressor support varied only 1.92-fold across centers. Even after adjusting for age, sex, Charlson comorbidity score, discharge diagnosisrelative group weight, organ dysfunction and service at onset, the odds for using these therapeutic modalities still varied significantly across centers. Failure to start antibiotics within 24 hours was strongly correlated with a higher probability of 28-day mortality (r 2 = 0.72).

Context. —Sepsis syndrome is a leading cause of mortality in hospitalized patients. However, few studies have described the epidemiology of sepsis syndrome in a hospitalwide population. Objective. —To describe the epidemiology of sepsis syndrome in the tertiary care hospital setting. Design. —Prospective, multi-institutional, observational study including 5-month follow-up. Setting. —Eight academic tertiary care centers. Methods. —Each center monitored a weighted random sample of intensive care unit (ICU) patients, non-ICU patients who had blood cultures drawn, and all patients who received a novel therapeutic agent or who died in an emergency department or ICU. Sepsis syndrome was defined as the presence of either a positive blood culture or the combination of fever, tachypnea, tachycardia, clinically suspected infection, and any 1 of 7 confirmatory criteria. Estimates of total cases expected annually were extrapolated from the number of cases, the period of observation, and the sampling fraction. Results. —From January 4, 1993, to April 2, 1994, 12759 patients were monitored and 1342 episodes of sepsis syndrome were documented. The extrapolated, weighted estimate of hospitalwide incidence (mean±95% confidence limit) of sepsis syndrome was 2.0±0.16 cases per 100 admissions, or 2.8±0.17 per 1000 patient-days. The unadjusted attack rate for sepis syndrome between individual centers differed by as much as 3-fold, but after adjustment for institutional differences in organ transplant populations, variation from the expected number of cases was reduced to 2-fold and was not statistically significant overall. Patients in ICUs accounted for 59% of total extrapolated cases, non-ICU patients with positive blood cultures for 11%, and non-ICU patients with negative blood cultures for 30%. Septic shock was present at onset of sepsis syndrome in 25% of patients. Bloodstream infection was documented in 28%, with gram-positive organisms being the most frequent isolates. Mortality was 34% at 28 days and 45% at 5 months. Conclusions. —Sepsis syndrome is common in academic hospitals, although the overall rates vary considerably with the patient population. A substantial fraction of cases occur outside ICUs. An understanding of the hospitalwide epidemiology of sepsis syndrome is vital for rational planning and treatment of hospitalized patients with sepsis syndrome, especially as new and expensive therapeutic agents become available.

We performed a series of collaborative experiments to clarify the effect of Mg++ on production of toxic-shock-syndrome toxin-1 (TSST-1) in various culture media. TSST-1 production was enhanced by adding ethylenediamine-tetraacetic acid (EDTA) at appropriate concentrations to brain-heart infusion and beef-heart medium. The magnitude of this effect depended both on the number of bacteria used to inoculate the media and on the sampling time. Large inocula prepared in media containing high levels of Mg++ introduced sufficient Mg++ to the growth medium to influence subsequent bacterial multiplication and toxin production. Small inocula of bacteria washed in Mg++-deficient medium before inoculation did not, however, multiply or produce toxin in Mg++-deficient medium. Maximal toxin expression occurred during late logarithmic phase, regardless of Mg++ concentration, and Mg++ appeared to control when late logarithmic stage of growth would be achieved. The toxin-enhancing effect of EDTA was reversed by adding excess Mg++ to treated medium.

Seventy-nine per cent of a series of 48 patients with implanted pacemakers developed arrhythmias during exercise. There were 23 patients without known previous competition, and in 69.5 per cent of them arrhythmias developed during exercise. No serious arrhythmias developed, but there were three cases of repetitive firing or short bursts of ventricular tachycardia, five instances of pacing on the apex of the T wave, and one instance of R-on-T phenomenon. None of these cases of ventricular tachycardia was preceded by spike-on-T or R-on-T stimulation. Based on these observations, recommendations for selection of the proper pacemaker have been made.

We studied the induction of human interleukin-1 (IL-1) production in strains of Staphylococcus aureus isolated from patients with nonmenstrual toxic shock syndrome (TSS). Of the 20 TSS-associated strains studied, 11 produced and nine did not produce TSS toxin-1 (TSST-1). Human monocytes were incubated with dilute staphylococcal supernatants, and IL-1 production was measured in a lymphocyte-activating factor assay. All 20 TSS-associated strains were potent inducers of IL-1, in comparison with none of 10 vaginal isolates of S. aureus from healthy women. TSST-1-positive strains were more potent than TSST-1-negative strains. Nine TSST-1-negative TSS-associated strains were compared with 14 strains of S. aureus from other clinical settings and were found to be significantly more potent inducers of IL-1 (P less than .01). Eight of these nine TSS-associated strains produced at least one staphylococcal enterotoxin. Stimulation of monocytes by products of S. aureus may play a role in the pathogenesis of TSS.

Strains of Staphylococcus aureus isolated from patients with toxic shock syndrome (TSS) make a characteristic protein known as toxic-shock-syndrome toxin-1 (TSST-1), but the role of this protein in the pathogenesis of TSS is not certain. We have purified TSST-1 by using a combination of alcohol precipitation, isoelectric focusing, and gel chromatography. TSST-1 has an isoelectric point of 7.2 and a molecular weight of 23,100, in accordance with previously published determinations for this protein, and is serologically identical to pyrogenic exotoxin C and staphylococcal enterotoxin F. In highly purified form, TSST-1 is a potent inducer of interleukin-1 production by human monocytes, as quantitated in a thymocyte-proliferation assay. This capability is not attributable to contamination by other staphylococcal products or gram-negative endotoxin and can be blocked by hydrocortisone. Many features of TSS suggest that induction of interleukin-1 by TSST-1 in vivo may play a central role in the elaboration of this disease.

A typographical error appeared in "The Relative Role of Bacterial Cell Wall and Capsule in the Induction of Inflammation in Pneumococcal Meningitis" by Elaine Tuomanen et al. (March 1985). The second sentence of the legend for figure 3 on page 538 is incomplete and should appear as follows: . . . concentrations present on 106 cells (hatched bars with stipple, cell wall; cross-hatched bars, capsule), or alternatively at 2 mg/0.2 ml (stippled bars, cell wall; hatched bars, capsule)."

Ces variables exercent leur effet maximal lorsque la concentration de Mg du milieu de culture est limitant et inversement, lorsque du Mg ++ est present en exces, la production de toxine est diminuee, quelle que soit l'action des autres variables

Understanding of the pathogenesis of toxic shock syndrome (TSS) has come from the juxtaposition of epidemiologic, clinical, immunologic, and physiologic studies. A hypothesis has been developed for the pathogenesis of menstrually related TSS. Certain tampon fibers that are highly absorbent for water are also ion exchangers for magnesium ions. The latter ions uniquely affect the production of TSS toxin 1 (TSST-1) by appropriate strains of Staphylococcus aureus, with a marked increase in the amount of toxin when magnesium concentrations are limiting and suppression of toxin production when magnesium is in excess. Many epidemiologic features of TSS could be explained by this hypothesis. The absorbability of highly absorptive fibers is not affected by the addition of small amounts of magnesium sufficient to suppress production of TSST-1; thus absorption is distinguishable from toxin production in vitro. TSST-1 stimulates production of interleukin 1 and of tumor necrosis factor and is highly toxic when absorbed slowly. Like TSST-1, staphylococcal enterotoxins are lethal to rabbits when given by slow injection, and some enterotoxins may be more lethal than TSST-1.

We studied the effect of toxic-shock-syndrome toxin-1 (TSST-1) on production of tumor necrosis factor (TNF) by human monocytes. Adherent mononuclear cells were stimulated with TSST-1 and their supernatants assayed for TNF by using L929 cells in a cytotoxicity assay. TSST-1 stimulated production of TNF over a wide range of concentrations. The cytotoxicity of monocyte supernatants was neutralized by antibody to TNF but not by antibody to interleukin-1 or by normal rabbit serum. TSST-1 and lipopolysaccharide (LPS) had a synergistic effect on monokine production. Monocytes "primed" with TSST-1 produced more interleukin-1 and TNF in response to LPS than did unprimed cells. Treating monocytes with LPS before TSST-1 and co-incubating the two agents with cells for 24 h also enhanced monokine production under some circumstances. These studies suggest a role for TNF in the pathogenesis of toxic shock syndrome, as a consequence of induction by TSST-1 alone or the synergistic effects of several bacterial products.

Since toxic shock syndrome (TSS) was formally defined in 1978, much has been learned about the clinical and epidemiologic features of this disease. Furthermore, a specific staphylococcal protein, known as toxic shock syndrome toxin 1 (TSST-1), has been identified as a putative pathogenic agent. Conditions affecting production of TSST-1 have been discussed during other sessions of this symposium. It is evident, however, that toxins other than TSST-1 must be capable of causing TSS, since not all TSS-associated strains of Staphylococcus aureus produce TSST-1. This issue has also been addressed in detail elsewhere. In this overview, I will focus on mechanisms, proposed and documented, by which the TSS toxins cause disease. As indicated in table 1, TSS may be the consequence of the pathogenic effects of several staphylococcal products acting alone or in concert. Moreover, other microbial products, particularly endotoxin of gram-negative bacilli, have been cited as possible contributors to the pathogenic process. These agents may act either by directly exerting toxic effects on host tissues or by inducing the production and release of a variety of endogenous mediators, which in turn combine to sculpt this complex syndrome. Endogenous mediators likely to be involved (on the basis either of investigations performed to date with TSST-1 or of known activities under other circumstances) are also listed in table 1.

We examined the harbingers of 68 episodes of paroxysmal ventricular tachycardia in 42 patients with documented acute myocardial infarction. Late ventricular premature contractions initiated 46 bouts of paroxysmal ventricular tachycardia, while 17 were engendered by early ventricular premature contractions and five by atrial premature contractions. Paroxysmal ventricular tachycardia related to early ventricular premature contractions tended to last longer and failed to respond to therapy with lidocaine more often than paroxysmal ventricular tachycardia begun by late ventricular or atrial premature contractions. Ventricular fibrillation occurred in six cases of paroxysmal ventricular tachycardia due to early ventricular premature contractions but was absent in paroxysmal ventricular tachycardia related to late ventricular or atrial premature contractions. The "malignant" potential of a given ventricular premature contraction cannot be assessed from its degree of prematurity alone.

We have developed a rabbit model of toxic shock syndrome that uses a subcutaneous infusion pump to administer toxic shock syndrome toxin 1 (TSST-1). A dose of 150 micrograms, infused at a constant rate over a period of 7 days, resulted in a characteristic illness highlighted by fever, conjunctival hyperemia, cachexia, and lethargy. The illness was uniformly fatal, with a mean interval until death of 3.2 +/- 0.4 days. Serial determinations of serum chemistries confirmed the multisystem nature of this illness. Rabbits developed profound hypocalcemia, with levels falling from 15.5 +/- 0.2 to 7.6 +/- 0.4 mg/dl under the influence of TSST-1. Blood urea nitrogen and creatinine rose dramatically, in the setting of oliguria or anuria. Serum glutamicpyruvic transaminase was the most reliable indicator of hepatic dysfunction, with the mean rising from 48 U/liter before administration of TSST-1 to 546 U/liter among rabbits surviving 2 days of the infusion. Creatine phosphokinase also rose dramatically in 10 of 16 rabbits. Rabbits demonstrated relative neutrophilia and lymphopenia as well as an increase in the partial thromboplastin time. Histopathologic examination demonstrated disease of multiple organs, particularly the liver, spleen, and lymph nodes, all of which demonstrated inflammation, thrombosis, hemorrhage, and erythrophagocytosis. The concurrent administration of prednisolone with TSST-1 prevented death in four of four rabbits and greatly lessened the morbidity. Rabbits were not protected from morbidity or mortality by the concurrent administration of polymyxin B. We believe that a constant, subcutaneous infusion of TSST-1 in rabbits provides a reproducible model for studying the pathogenesis of TSS.

We developed a competitive, enzyme-linked immunosorbent assay for the quantitation of toxic shock syndrome toxin 1 (TSST-1). Polyvalent immunoglobulin G from immunized rabbits was used as the capture antibody, and alkaline phosphatase conjugated to purified toxin served as the indicator enzyme. A standard curve was generated with each experiment, from which the concentration of toxin in culture supernatants was extrapolated. The assay was useful for determining toxin concentrations of 0.03 to 0.5 micrograms/ml, which is a substantial, practical improvement over immunodiffusion methods. Staphylococcal enterotoxins A through E were not significantly cross-reactive in the assay, and staphylococcal protein A did not interfere with quantitation of TSST-1. By testing a variety of staphylococcal strains, we found 100% concordance between toxin determinations made with our assay and those made by the investigators from whom the strains were obtained. The competitive, enzyme-linked immunosorbent assay is a highly reproducible, inexpensive means of determining TSST-1 concentrations and may have broad applicability in the field of toxic shock research.

Toxic shock syndrome toxin 1 (TSST-1) is a 22-kDa exotoxin produced by strains of Staphylococcus aureus and implicated in the pathogenesis of toxic shock syndrome. In common with other staphylococcal exotoxins, TSST-1 has diverse immunological effects. These include the induction of interleukin 2 receptor expression, interleukin 2 synthesis, proliferation of human T lymphocytes, and stimulation of interleukin 1 synthesis by human monocytes. In the present study, we demonstrate that TSST-1 binds with saturation kinetics and with a dissociation constant of 17-43 nM to a single class of binding sites on human mononuclear cells. There was a strong correlation between the number of TSST-1 binding sites and the expression of major histocompatibility complex class II molecules, and interferon-gamma induced the expression of class II molecules as well as TSST-1 binding sites on human skin-derived fibroblasts. Monoclonal antibodies to HLA-DR, but not to HLA-DP or HLA-DQ, strongly inhibited TSST-1 binding. Affinity chromatography of 125I-labeled cell membranes over TSST-1-agarose resulted in the recovery of two bands of 35 kDa and 31 kDa that comigrated, respectively, with the alpha and beta chains of HLA-DR and that could be immunoprecipitated with anti-HLA-DR monoclonal antibodies. Binding of TSST-1 was demonstrated to HLA-DR and HLA-DQ L-cell transfectants. These results indicate that major histocompatibility complex class II molecules represent the major binding site for TSST-1 on human cells.