Clinical effectiveness of cefiderocol for the treatment of bloodstream infections due to carbapenem-resistant Acinetobacter baumannii during the COVID-19 era: a single center, observational study.

BACKGROUND: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). MATERIALS/METHODS: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). RESULTS: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. CONCLUSIONS: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.

Ceftazidime/avibactam-resistant meropenem-susceptible KPC-producing Klebsiella pneumoniae: Analysis of cases and evaluation of in vitro activity of fosfomycin-containing combinations.

OBJECTIVES: Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations. METHODS: Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested. RESULTS: Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance. CONCLUSIONS: Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

Effect of ceftazidime/avibactam plus fosfomycin combination on 30†day mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae: results from a multicentre retrospective study.

Introduction: The primary outcome of the study was to evaluate the effect on 30 day mortality of the combination ceftazidime/avibactam + fosfomycin in the treatment of bloodstream infections (BSIs) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp). Materials and methods: From October 2018 to March 2021, a retrospective, two-centre study was performed on patients with KPC-Kp BSI hospitalized at Sapienza University (Rome) and ISMETT-IRCCS (Palermo) and treated with ceftazidime/avibactam-containing regimens. A matched cohort (1:1) analysis was performed. Cases were patients receiving ceftazidime/avibactam + fosfomycin and controls were patients receiving ceftazidime/avibactam alone or in combination with in vitro non-active drugs different from fosfomycin (ceftazidime/avibactam ±â€Šother). Patients were matched for age, Charlson comorbidity index, ward of isolation (ICU or non-ICU), source of infection and severity of BSI, expressed as INCREMENT carbapenemase-producing Enterobacteriaceae (CPE) score. Results: Overall, 221 patients were included in the study. Following the 1:1 match, 122 subjects were retrieved: 61 cases (ceftazidime/avibactam + fosfomycin) and 61 controls (ceftazidime/avibactam ±â€Šother). No difference in overall mortality emerged between cases and controls, whereas controls had more non-BSI KPC-Kp infections and a higher number of deaths attributable to secondary infections. Almost half of ceftazidime/avibactam + fosfomycin patients were prescribed fosfomycin without MIC fosfomycin availability. No difference in the outcome emerged after stratification for fosfomycin susceptibility availability and dosage. SARS-CoV-2 infection and ICS ≥ 8 independently predicted 30 day mortality, whereas an appropriate definitive therapy was protective. Conclusions: Our data show that fosfomycin was used in the treatment of KPC-Kp BSI independently from having its susceptibility testing available. Although no difference was found in 30 day overall mortality, ceftazidime/avibactam + fosfomycin was associated with a lower rate of subsequent KPC-Kp infections and secondary infections than other ceftazidime/avibactam-based regimens.

Comparison of clinical features and outcomes in COVID-19 and influenza pneumonia patients requiring intensive care unit admission.

BACKGROUND: Little is known in distinguishing clinical features and outcomes between coronavirus disease-19 (COVID-19) and influenza (FLU). MATERIALS/METHODS: Retrospective, single-centre study including patients with COVID-19 or FLU pneumonia admitted to the Intensive care Unit (ICU) of Policlinico Umberto I (Rome). Aims were: (1) to assess clinical features and differences of patients with COVID-19 and FLU, (2) to identify clinical and/or laboratory factors associated with FLU or COVID-19 and (3) to evaluate 30-day mortality, bacterial superinfections, thrombotic events and invasive pulmonary aspergillosis (IPA) in patients with FLU versus COVID-19. RESULTS: Overall, 74 patients were included (19, 25.7%, FLU and 55, 74.3%, COVID-19), median age 67 years (58-76). COVID-19 patients were more male (p = 0.013), with a lower percentage of COPD (Chronic Obstructive Pulmonary Disease) and chronic kidney disease (CKD) (p = 0.001 and p = 0.037, respectively) than FLU. SOFA score was higher (p = 0.020) and lymphocytes were significantly lower in FLU than in COVID-19 [395.5 vs 770.0 cells/mmc, p = 0.005]. At multivariable analysis, male sex (OR 6.1, p < 0.002), age > 65 years (OR 2.4, p = 0.024) and lymphocyte count > 725 cells/mmc at ICU admission (OR 5.1, p = 0.024) were significantly associated with COVID-19, whereas CKD and COPD were associated with FLU (OR 0.1 and OR 0.16, p = 0.020 and p < 0.001, respectively). No differences in mortality, bacterial superinfections and thrombotic events were observed, whereas IPA was mostly associated with FLU (31.5% vs 3.6%, p = 0.0029). CONCLUSIONS: In critically ill patients, male sex, age > 65 years and lymphocytes > 725 cells/mmc are related to COVID-19. FLU is associated with a significantly higher risk of IPA than COVID-19.

Disseminated fungal infection due to Saprochaete clavata in a kidney transplant recipient.

Saprochaete clavata and Saprochaete capitata are closely related fungal species (family Dipodascaceae, order Saccharomycetales) that are rarely involved in the etiology of systemic infections in humans. In recent years, these yeasts are emerging as cause of life-threatening infections in patients with severe neutropenia and haematological malignancies. Infections by these fungi have been reported mostly from Mediterranean countries. To the best of our knowledge, only 2 cases of infection due to S. capitata have been reported in solid organ transplant recipients and none due to S. clavata. Herein we report a fatal case of S. clavata disseminated infection occurring in a patient with recent kidney transplantation and severe neutropenia. Patient was receiving antifungal echinocandin prophylaxis and the yeast was isolated from the blood and multiple non contiguous sites. Saprochaete spp. should be considered in the differential diagnosis of invasive mycoses in transplant recipients, especially if they are neutropenic and living or travelling in Mediterranean countries.

Risk factors for recurrence in patients with Clostridium difficile infection due to 027 and non-027 ribotypes.

OBJECTIVES: Our objective was to evaluate factors associated with recurrence in patients with 027+ and 027- Clostridium difficile infection (CDI). METHODS: Patients with CDI observed between January and December 2014 in six hospitals were consecutively included in the study. The 027 ribotype was deduced by the presence of tcdB, tcdB, cdt genes and the deletion Δ117 in tcdC (Xpert® C. difficile/Epi). Recurrence was defined as a positive laboratory test result for C. difficile more than 14 days but within 8 weeks after the initial diagnosis date with reappearance of symptoms. To identify factors associated with recurrence in 027+ and 027- CDI, a multivariate analysis was performed in each patient group. Subdistributional hazard ratios (sHRs) and 95% confidence intervals (95%CIs) were calculated. RESULTS: Overall, 238 patients with 027+ CDI and 267 with 027- CDI were analysed. On multivariate analysis metronidazole monotherapy (sHR 2.380, 95%CI 1.549-3.60, p <0.001) and immunosuppressive treatment (sHR 3.116, 95%CI 1.906-5.090, p <0.001) were factors associated with recurrence in patients with 027+ CDI. In this patient group, metronidazole monotherapy was independently associated with recurrence in both mild/moderate (sHR 1.894, 95%CI 1.051-3.410, p 0.033) and severe CDI (sHR 2.476, 95%CI 1.281-4.790, p 0.007). Conversely, non-severe disease (sHR 3.704, 95%CI 1.437-9.524, p 0.007) and absence of chronic renal failure (sHR 16.129, 95%CI 2.155-125.000, p 0.007) were associated with recurrence in 027- CDI. CONCLUSIONS: Compared to vancomycin, metronidazole monotherapy appears less effective in curing CDI without relapse in the 027+ patient group, independently of disease severity.

Assessment of risk factors for candidemia in non-neutropenic patients hospitalized in Internal Medicine wards: A multicenter study.

BACKGROUND: An increasing prevalence of candidemia has been reported in Internal Medicine wards (IMWs). The aim of our study was to identify risk factors for candidemia among non-neutropenic patients hospitalized in IMWs. METHODS: A multicenter case-control study was performed in three hospitals in Italy. Patients developing candidemia (cases) were compared to patients without candidemia (controls) matched by age, time of admission and duration of hospitalization. A logistic regression analysis identified risk factors for candidemia, and a new risk score was developed. Validation was performed on an external cohort of patients. RESULTS: Overall, 951 patients (317 cases of candidemia and 634 controls) were included in the derivation cohort, while 270 patients (90 patients with candidemia and 180 controls) constituted the validation cohort. Severe sepsis or septic shock, recent Clostridium difficile infection, diabetes mellitus, total parenteral nutrition, chronic obstructive pulmonary disease, concomitant intravenous glycopeptide therapy, presence of peripherally inserted central catheter, previous antibiotic therapy and immunosuppressive therapy were factors independently associated with candidemia. The new risk score showed good area under the curve (AUC) values in both derivation (AUC 0.973 95% CI 0.809-0.997, p<0.001) and validation cohort (0.867 95% CI 0.710-0.931, p<0.001). A threshold of 3 leads to a sensitivity of 87% and a specificity of 83%. CONCLUSION: Non-neutropenic patients admitted in IMWs have peculiar risk factors for candidemia. A new risk score with a good performance could facilitate the identification of candidates to early antifungal therapy.

Postural control in patients after a recent vestibular neuritis with hyperhomocysteinemia.

To assess the possible role of hyperhomocysteinemia (HyHcy) in delaying recovery after acute vestibular neuritis. In our retrospective study, 90 subjects were evaluated within 7 days from the beginning of an acute vertigo. All subjects had high plasma levels of homocysteine (Hcy). 46 patients were treated with homocysteine lowering therapy and betahistine for 1 month, while 44 subjects received only betahistine. Subjective symptoms were evaluated with the Dizziness Handicap Inventory (DHI) questionnaire, administered 7 days after the beginning of vertigo and again after 1 month. Moreover, postural control performed at 1 month' control was studied with static stabilometry in a subgroup of 21 non-treated and 20 treated patients. DHI total score decreased significantly more in the subgroup of subjects treated with homocysteine lowering therapy. Moreover, posturographic data were significantly increased in non-treated compared with treated subjects. Our data support the possibility of a role of HyHcy in preventing recovery after a recent vestibular neuritis. A microvascular disorder or the neurotoxic effect of HyHcy have been considered as possible causal factors. Although not conclusive, our data are not inconsistent with the hypothesis of a poorer adaptation in patients with untreated HyHcy.

Clinical experience of anidulafungin for the treatment of patients with documented candidemia.

Candida species are the most common causes of invasive fungal infections in humans, producing infections that range from mucocutaneous disorders to invasive disease that can involve any organ. Here we present our clinical experience with anidulafungin for the treatment of documented nosocomial candidaemia. From february 2009 through January 2010 all patients with documented candidemia treated with anidulafungin in three medical centers in italy were reviewed. Demographics, clinical and microbiological data, and outcome were collected for each patient. Twenty-four patients were included in the study. most patients had a central venous catheter (CVC) or a port-a-cath (100%), had a history of recent surgery (87.5%), or were receiving total parenteral nutrition (79%), broad spectrum antibiotics (83%), steroids or chemotherapy (45.8%). C. albicans (54%) was the most commonly isolated pathogen. CVC was the source of candidemia in 79% of cases. Six patients (25%) developed severe sepsis or septic shock, and five patients had unfavorable outcomes, with an overall mortality rate of 20%. No patients experienced side effects related to anidulafungin therapy. Anidulafungin was effective in the treatment of patients with documented candidemia arising from different sites, and no significant side effects were observed.

Antimicrobial susceptibility, biochemical and genetic profiles of Staphylococcus haemolyticus strains isolated from the bloodstream of patients hospitalized in critical care units.

Staphylococcus haemolyticus strains (n=20), responsible of blood stream infections, were consecutively isolated from patients hospitalized in two different wards at high risk of infection. Strains displayed high rate of resistance to oxacillin (90%). All strains but two with decreased susceptibility (MIC = 4 microg/mL), were sensitive to vancomycin. Ten strains were resistant to teicoplanin. Among the strains susceptible to glycopeptides, three displayed heteroresistance to vancomycin and seven to teicoplanin, when tested by Etest technique with 2 x McFarland inoculum. Biochemical reactions allowed to assign strains to eight biotypes, with 11 strains clustering under two main biotype A and biotype B. Pulsed-field-gel-electrophoresis (PFGE) identified 11 different PFGE-types. Seven strains grouping under the major PFGE-type 1 and three strains clustering in PFGE-type 2, closely correlated to biotype A and biotype B respectively. Seven teicoplanin-resistant isolates clustered in the PFGE-type 1, two in the PFGE-type 2 and one in PFGE-type 5. Therefore, teicoplanin-resistant strains were biochemically and genetically related and clonally distributed, despite different clones of S. haemolyticus circulated in the units during the study period.

The treatment of acute vertigo.

Vertigo and dizziness are very common symptoms in the general population. The aim of this paper is to describe the physical and pharmacological treatment of symptoms characterized by sudden onset of rotatory vertigo. Acute vertigo can be subdivided into two main groups: (1) spontaneous vertigo and (2) provoked vertigo, usually by postural changes, generally called paroxysmal positional vertigo (PPV). Sudden onset of acute vertigo is usually due to acute spontaneous unilateral vestibular failure. It can be also fluctuant as, e.g., in recurrent attacks of Ménière's disease. Pharmacotherapy of acute spontaneous vertigo includes Levo-sulpiride i.v., 50 mg in 250 physiologic solution, once or twice a day, methoclopramide i.m., 10 mg once or twice a day, or triethilperazine rectally, once or twice a day, to reduce neurovegetative symptoms; diazepam i.m., 10 mg once or twice a day, to decrease internuclear inhibition, sulfate magnesium i.v., two ampoules in 500 cc physiological solution, twice a day, or piracetam i.v., one ampoule in 500 cc physiological solution, twice a day, to decrease vestibular damage. At the onset of the acute symptoms, patients must lie on their healthy side with the head and trunk raised 20 degrees. The room must be quiet but not darkened. If the patient is able to swallow without vomiting, it is important to reduce nystagmus and stabilize the visual field with gabapentine, per os, 300 mg twice or three times a day. The first step of the physical therapy of acute vertigo is vestibular electrical stimulation, that is to say, a superficial paravertebral electrical stimulation of neck muscles, aimed to reduce antigravitary failure and to increase proprioceptive cervical sensory substitution. PPV is a common complaint and represents one of the most common entities in peripheral vestibular pathology. While the clinical picture is well known and widely described, the etiopathogenesis of PPV is still a matter of debate. Despite the different interpretation of PPV etiopathogenesis, the maneuvers described by Semont, Epley, or Lempert and their modifications are undoubtedly effective. For this reason the first therapeutic approach in acute provoked vertigo must be by means of one of these kinds of treatments.

Extracorporeal circulation does not induce intra-alveolar release of Endothelin 1, but only a modest overproduction in pulmonary circulation.

OBJECTIVE: To investigate whether ECC may produce regional liberation of inflammatory mediators capable of inducing vascular effects and organ damage. EXPERIMENTAL DESIGN: Comparative study [corrected]. SETTING: Cardiac surgery department in a University hospital. PATIENTS: Fifteen patients undergoing coronary artery bypass grafting (CABG, group A) and ten patients operated for infrarenal abdominal aortic aneurysm (controls, group B) have been studied. MEASURES: Levels of Interleukin 1beta (IL1), Tumor Necrosis Factor alpha (TNF), Interleukin 6 (IL6), and Endothelin 1 (ET1) were measured in pulmonary capillary, arterial, and venous blood and in bronchoalveolar lavages (BAL) before, during and after extracorporeal circulation (ECC) or surgical intervention. RESULTS: TNF-alpha (never >35 pg/ml) and IL1beta (range 20-300 pg/ml) values did not change over time for both groups. IL6 concentrations in all samples of group A increased between five and twenty fold, during and after ECC (from 3-5 pg/ml up to 240 pg/ml, p<0.001). This trend was similar in controls after surgical stress. Endothelin 1 was always undetectable in the BAL fluid, with a modest, but significant increase in pulmonary capillary blood of group A, after ECC, (from 11+/-4 pg/ml to 18+/-5 pg/ml, p<0.001). This increment correlated well with the PVR increase, but was transient and after 24 hours, ET1 values returned to baseline levels. Mean values of ET1 increased also in controls, but not significantly. CONCLUSIONS: ECC may induce ET1 liberation in pulmonary circulation with transient pulmonary vasoconstriction, but wihout intra-alveolar release, or lung damage. Augmented concentrations of IL6 probably express a response to surgical procedure rather than an effect exclusively related to ECC.

Serum-mediated enhancement of TNF-alpha release by human monocytes stimulated with the yeast form of Candida albicans.

The role of serum in the production of tumor necrosis factor-alpha (TNF-alpha) by human monocytes stimulated with yeast-form Candida albicans was studied. Pre-exposure of C. albicans to human pooled serum enhanced both TNF-alpha mRNA and cytokine secretion compared with C. albicans preincubated with medium only. Serum factors involved were >30 kDa, were efficiently inhibited by D-mannose, and recognized both Ca++-dependent and -independent pathways. Preincubation of yeasts with rabbit mannose-binding protein (MBP) resulted in dose-related enhancement of TNF-alpha secretion, through a Ca++-dependent pathway inhibited by D-mannose. TNF-alpha levels were similarly induced in C. albicans preincubated with vitronectin and with serum. Ca++ depletion did not affect cytokine release, while D-mannose supplementation displayed inhibition. The latter effect was abolished after Ca++ depletion. These data call for an involvement of both MBP and vitronectin in the serum-mediated enhancement of TNF-alpha release upon stimulation of monocytes with yeast forms of C. albicans.

Balance of proinflammatory and antiinflammatory cytokines in mice immunized with Escherichia coli and correlation with mortality after lethal challenge.

The balance of proinflammatory and antiinflammatory cytokines, their correlation with endotoxin levels and mortality rate after lethal challenge of Escherichia coli was investigated in mice immunized weekly for 8 weeks with formalin-killed E. coli either untreated or treated with 0.5x minimal inhibitory concentration of aztreonam. Control mice treated in parallel with saline, died within 24 h after challenge with 100x lethal dose (LD50) of viable E. coli O6:K-. Mice immunized with antibiotic-treated bacteria showed a significantly higher survival than mice immunized with untreated E. coli. Cytokines were not detected in the sera of control mice during the entire period of immunization. At 90 min after immunization, mice immunized with antibiotic-treated E. coli showed tumor necrosis factor-alpha (TNF-alpha) levels significantly lower and interleukin (IL)-6 levels significantly higher (P < 0.05) than mice immunized with untreated E. coli, while comparable levels of interferon-gamma (IFN-gamma were measured in both groups. TNF-alpha and IL-10 levels measured 90 min after lethal challenge correlated with the mortality rate observed in each group (r = 0.96 for TNF-alpha and 0.94 for IL-10). IL-6 levels correlated with survival (r = 0.95), while IFN-gamma serum levels did not differ in the two immunized groups, but were significantly higher than those measured in the control mice. IL-4 was detected only after challenge of mice immunized with antibiotic-treated bacteria. Comparable levels of circulating endotoxin were measured after lethal challenge in both control and immunized mice. These data showed that in the presence of a protective immune response the survival of immunized mice was correlated with an early alteration of cytokine expression pattern including enhanced secretion of IL-4, IL-6 and IFN-gamma, and reduced secretion of TNF-alpha and IL-10.

Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli.

The binding capacity and the protective activity of three monoclonal antibodies (MAbs)-ARM 1-4, ARM 1-7 and ARM 2-2-obtained from spleen cells of mice immunised with Escherichia coli O6:K-pre-treated with sub-MIC of aztreonam were studied. The MAbs belonged to IgG1 isotype and showed different reactivity toward protein epitopes of E. coli in an immunoblotting assay. ARM 1-4 recognised epitopes on molecules of 30 kDa and 40 kDa. ARM 1-7 identified an epitope of a molecule of 41 kDa, and ARM 2-2 recognised epitopes of molecules of 15 kDa and 41 kDa. In ELISA the MAbs cross-reacted with E. coli O7:K-, E. coli O111:B4 and E. coli O128:K- with different binding affinity. Furthermore, the MAbs showed complement-dependent bactericidal activity. The MAbs displayed different protective capacities when given to mice 90 min before lethal challenges with 2 x LD50, 4 x LD50 and 8 x LD50 of E. coli strains. In all but one instance (ARM 1-4 versus E. coli O7:K-) it was not possible to correlate protective capacity with binding affinity of a MAb to a given bacterial cell. Therefore, the epitopes recognised by the MAb may be more closely associated with bacterial virulence than in binding to the bacterial cell.

The release of tumor necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) induced THP-1 cells stimulated with smooth lipopolysaccharide is inhibited by MAbs against HLA-DR and CD14 receptors on the effector cell.

Bacterial lipopolysaccharide (LPS) plays a central role in the pathogenesis of gram-negative sepsis and shock. The glycosylphoshatidyl inositol (GPI) anchored glycoprotein CD14 on mononuclear cells binds LPS, especially in the presence of an LPS binding serum protein, activating the production of pro-inflammatory cytokines, i.e. TNF-alpha. However, since GPI anchorage to the cell membrane lacks the intracellular signalling capacity, the existence of at least a second receptor has been postulated. In attempt to identify additional LPS receptors, we used the human myelomonocytic cell line THP-1. This undifferentiated cell line did not respond to LPS in terms of TNF-alpha release, but when induced with 250 U/ml of IFN-gamma for 48 h, the cells released TNF-alpha (174 +/- 58.6 U/ml. L929 cell bioassay) in response to 10 vg/ml of E. coli 0111 LPS, in the absence of serum. Blockade of either HLA-DR or CD14 receptors with specific MAbs did not reduce the amount of cytokine released. However, when both the receptors were sequentially blocked involved on the effector cells a remarkable inhibition of TNF-alpha release was observed (8.6 +/- 1.4). It seems therefore, that HLA-DR receptor may be with CD14 in triggering TNF-alpha release by IFN-gamma, induced THP-1 cells.

High IL-6 serum levels are associated with septic shock and mortality in septic patients with severe leukopenia due to hematological malignancies.

The serum levels of immunoreactive interleukin-6 (IL-6) and tumor necrosis factor (TNF) were analyzed in 14 leukopenic patients with documented sepsis, at 60 min (T0), 24 h (T1), and one week (T3) after the onset of sepsis syndrome. Sera from 10 leukopenic patients without sepsis (controls) were also tested. All septic patients had high IL-6 levels at T0. These levels persisted only in the seven patients who died of septic shock, presenting a 30-fold increase (p<0.001) as compared to the survivors and the controls. At T3, 7 survivors had recovered from sepsis and showed low IL-6 serum levels. The TNF serum concentration always <30 pg/ml in both the subjects and in the controls. The C-reactive protein (CRP) and clinical parameters appeared to be less specifically associated with shock and mortality than IL-6.