Epidermidis Sepsis Research Articles

Modulation of S. epidermidis-induced innate immune responses in neonatal whole blood.

Coagulase-negative staphylococci (CoNS) such as Staphylococcus epidermidis are highly prevalent pathogens for sepsis in neonates. The interaction between host, environment and pathogenic factors of S. epidermidis are still poorly understood. Our objective was to address the role of several pathogenic factors of S. epidermidis on neonatal cytokine responses and to characterize the influence of three immunomodulatory drugs. We performed an ex-vivo model of S. epidermidis sepsis by assessment of blood cytokine production in neonatal whole blood stimulation assays (ELISA). S. epidermidis strains with different characteristics were added as full pathogen to umbilical cord blood cultures and the influence of indomethacin, ibuprofen and furosemide on neonatal immune response to S. epidermidis was evaluated (Flow cytometry). Stimulation with S. epidermidis sepsis strains induced higher IL-6 and IL-10 expression than stimulation with colonization strains. Biofilm formation in clinical isolates was associated with increased IL-10 but not IL-6 levels. In contrast, stimulation with mutant strains for biofilm formation and extracellular virulence factors had no major effect on cytokine expression. Notably, addition of ibuprofen or indomethacin to S. epidermidis inoculated whole blood resulted in mildly increased expression of TNF-α but not IL-6, while frusemide decreased the production of pro-inflammatory cytokines, i.e. IL-6 and IL-8. The virulence of sepsis strains is coherent with increased cytokine production in our whole-blood in-vitro sepsis model. Biofilm formation and expression of extracellular virulence factors had no major influence on readouts in our setting. It is important to acknowledge that several drugs used in neonatal care have immunomodulatory potential.

The role of Staphylococcus epidermidis in neonatal sepsis: Guarding angel or pathogenic devil?

Neonatal late-onset sepsis (LOS) is a serious problem in neonatal intensive care. Coagulase-negative staphylococci, especially Staphylococcus epidermidis, have emerged as the predominant pathogen of LOS in very low birth weight (VLBW) infants, accounting for up to 77.9% of neonatal LOS in industrialized countries and 46.5% in some developing regions. VLBW neonates with indwelling medical devices are most susceptible for S. epidermidis sepsis, the incidence rate of which is approximately 25%. However, S. epidermidis primarily plays a commensal role on human host and is of evolutionary importance to newborns, by inhibiting virulent pathogens and educating the innate immune system. Recent advances in molecular microbiology show that S. epidermidis is a bacterial species equipped with remarkable genetic flexibility, and can employ a multitude of mechanisms to become adapted to the changing environment. Extrinsic factors in the neonatal ward, such as the interruption of skin barrier by medical devices and the selective pressure due to antibiotics, contribute to the conversion of S. epidermidis from a member of the skin microflora to an infectious agent. Furthermore, neonates are predisposed for S. epidermidis infections due to their distinct immunological characteristics. A better understanding of the dichotomy of S. epidermidis and the underlying mechanisms may inspire new anti-infectious strategies.

Staphylococcus epidermidisandStaphylococcus aureustrigger different interleukin-8 and intercellular adhesion molecule-1 in lung cells: implications for inflammatory complications following neonatal sepsis

Staphylococci are a major contribution for neonatal sepsis, which is the main risk factor for bronchopulmonary dysplasia. This study investigated the expression of pro-inflammatory mediators in endothelial and respiratory cells from newborns exposed to staphylococci. Human vascular endothelial cells and small airway epithelial cells were incubated with neonatal blood isolates of Staphylococcus epidermidis (n = 14) and Staphylococcus aureus (n = 14). The extracellular release of IL-8, IL-10, sICAM-1, ICAM-1 mRNA and the expression of membrane bound ICAM-1 were assessed by ELISA, RT-PCR and immunofluorescence microscopy. Staphylococcus epidermidis induced higher levels of IL-8 (mean 38.5 ng/mL) and ICAM-1 mRNA (mean ratio 1.037) in the small airway epithelial cells than S. aureus (IL-8 mean 22.2 ng/mL, p < 0.01 and ICAM-1 mRNA mean ratio 0.715, p < 0.01). In the endothelial cells, ICAM-1 remained more integrated in the cell membranes after exposure to S. epidermidis compared with S. aureus, which induced disintegration and release of soluble ICAM-1 into the supernatants. Staphylococcus epidermidis induced a higher chemoattractive response than S. aureus. A persistent transmigration of granulocytes into the lung tissue in neonatal S. epidermidis sepsis might contribute to the development of bronchopulmonary dysplasia.

Clinical Outcomes in Patients with ADAMTS13-Deficient Thrombotic Thrombocytopenic Purpura (TTP) Who Received Platelet Transfusions (PT).

Case reports describe neurological complications, acute renal failure and death in patients with TTP following PT; these observations have led to recommendations to avoid PT. The Oklahoma TTP-HUS Registry enrolled 254 consecutive patients with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 12-31-2006 for whom plasma exchange treatment (PEX) was requested; ADAMTS13 activity was measured in 235 (93%) patients immediately before their first PEX; 44 (19%) patients had ADAMTS13 activity <10%. To avoid selection bias, the 19 patients without ADAMTS13 measurements were also included; 9 died before a sample was obtained. We excluded 11 of the 63 patients because of alternative etiologies or subsequent diagnoses (drug-associated TTP-HUS (5), sepsis (4), cancer (1), post-BMT (1)). The initial episodes of 52 patients were analyzed (42 with ADAMTS13 <10%; 10 not measured). 26 (50%) patients received PT; 23 (88%) only before the first PEX. 13 patients had 1 PT; 9 had 2–3, and 4 had 4–14. 17 (65%) patients received PT for an indication such as central venous catheter placement or hemorrhage, 5 (19%) only because of thrombocytopenia, and 4 (15%) had multiple PT for both reasons.PatientsPT (n=26)No PT (n=26)PAge* (years)40410.649Female (%)69%88%0.090Race (% black)35%38%0.773Severe neurologic abnormalities**46%50%0.789Platelet count† (/μL)11,00013,0000.058Hematocrit† (%)21220.339LDH† (U/L)163912260.045Creatinine† (mg/dL)1.31.00.156Acute renal failure§8%4%1.000Death (30 days)27%12%0.159*median; **seizure, stroke, coma, focal abnormalities anytime during the course; †most abnormal values at diagnosis ± 7 days, median; §defined by ↑ Cr ≥ 0.5 mg/dL x 2 days or Cr ≥4.0 and dialysis.There were no clinically important differences between the groups of patients who did or did not receive PT. 22 of 26 (85%) patients who received PT had no adverse events in <24 hours. Although there was no difference in the overall occurrence of severe neurologic abnormalities, 2 patients who received PT had new neurologic events <24 hours after a PT (stroke, seizure). Patients who received PT had a higher but not significantly different mortality. 7 patients who received PT died; 3 died 9, 12, and 72 hours after PT; autopsies were performed in 2 of these 3 patients documenting systemic microvascular thrombosis; another patient died 6 hours after PT from intrathoracic hemorrhage due to subclavian line placement. The other 3 patients died 14, 18, and 18 days after PT from S. epidermidis sepsis, respiratory failure, and stroke. 3 patients who had not received PT died; 2 died immediately after diagnosis before PEX could begin; autopsies in both documented systemic microvascular thrombosis. 1 patient died of enterococcal sepsis 11 days after diagnosis.Conclusions:1.PT are commonly given to patients with TTP, most often before the diagnosis is established and PEX is begun.2.Although PT may be followed by severe complications or death, the relation of PT to these adverse events is uncertain.3.It is prudent to avoid PT in patients with TTP; however in patients with overt hemorrhage or who require a high risk invasive procedure, PT may be appropriate supportive care.

Phenotypic and genotypic characterisation of blood isolates of coagulase-negative staphylococci in the newborn.

Coagulase-negative staphylococci (CNS) are the leading cause of late-onset sepsis in newborns (>72 h of age). Our aim was to determine whether phenotypic and/or genotypic differences existed between blood isolates of CNS regarded as inducers of sepsis or as contaminants. Ninety-seven bloodisolates of CNS recovered from newborns at the neonatal intensive care unit, Orebro, Sweden in 1983-1997 were analysed. Twenty-nine of them (30%) were classified as sepsis isolates and 68 (70%) as contaminants. The most prevalent species was Staphylococcus epidermidis (n=59). Staphylococcus haemolyticus (n=16) was most often isolated from newborns with the lowest gestational age and birth weight. Biochemical typing using the Phene Plate system (PhP) and genotyping using pulsed-field gel electrophoresis (PFGE) showed that the S. epidermidis isolates regarded as inducers of sepsis (n=16) were more homogeneous than isolates considered contaminants (n=37). One main genotypic group, representing seven (44%) isolates, was identified among the sepsis isolates. Phenotypically the S. epidermidis sepsis isolates comprised three major clusters. In contrast, among the S. epidermidis contaminants, eight genotypic groups and two phenotypic clusters were identified. The dominating genotypic group among the sepsis isolates of S. epidermidis may represent strains with higher invasive capacity.

Molecular characterization and LD 50 identify virulent isolates of Staphylococcus epidermidis from adult sepsis

Staphylococcus epidermidis plays an important role in infections of patients with implanted prosthetic devices. The exact clinical significance of recovered S. epidermidis from clinical specimens is difficult to assess, as they are inhabitants of the normal skin. In this study, 11 adults with clinical sepsis and blood cultures that grew only S. epidermidis were the host population. Bacterial virulence in vivo was determined by using the mouse LD 50 assay where the intravenous lethality was determined for each patient isolate. Bacterial dose (CFU × 10 9) that produced lethality in 50% of the animals at 12 h was the value used for comparison. Restriction fragment length polymorphism (RFLP) analysis of chromosomal DNA by pulsed-field gel electrophoresis (PFGE) was used for identification of individual strains and their clonal organization. Confirmation of species assignment was done by RFLP analysis of 16S + 23S rRNA gene regions (ribotyping). Plasmid profile analysis was also conducted. Four of 11 blood isolates from adults with S. epidermidis sepsis had indistinguishable or closely related DNA patterns and were considered clone A. The same clone was previously seen to account for the majority of sepsis in a neonatal intensive care unit. There were significant differences in virulence characteristics of the S. epidermidis isolates. Clone A isolates produced lethality by LD 50 in mice at a dose averaging 2.35; clone B isolate at a dose of 2.54, and the remaining isolates, representing six distinct clones, were lethal to mice at significantly larger doses (3.51-5.17, average 4.16). These data suggest that individual clones of S. epidermidis isolated from septic adults have detectable differences in virulence as defined by an animal bioassay, and the more virulent clone is widespread.

Opsonic antibodies to Staphylococcus epidermidis: in vitro and in vivo studies using human intravenous immune globulin.

Staphylococcus epidermidis is a major cause of nosocomial infections, including sepsis in premature infants. Intravenous immune globulin (IVIG) has been used to prevent neonatal sepsis, but efficacy has varied in different clinical trials. The role of IgG antibody in immunity to S. epidermidis was studied using an opsonophagocytic assay and a lipid-emulsion-induced lethal model of neonatal S. epidermidis sepsis. Opsonic antibody to S. epidermidis varied between IVIG preparations and between lots: Lots with > or = 90% opsonic activity promoted bacterial clearance from blood and significantly enhanced survival when compared with lots with < or = 50% opsonic activity. Absorption of IVIG with S. epidermidis removed in vitro opsonic and in vivo protective activity. These studies suggest that opsonic antibody may play an important role in S. epidermidis immunity in immunocompromised patients, such as premature infants. Standard IVIG, however, may not provide therapy effective in preventing S. epidermidis infections, as many IVIG lots contain insufficient levels of opsonic S. epidermidis antibody.

Aerobes isolated in fecal microflora of infants in the intensive care nursery: Relationship to human milk use and systemic sepsis

Background: Staphylococcus epidermidis is a leading cause of nosocomial sepsis in the intensive care nursery. The relationship between rates of gastrointestinal colonization and the incidence of systemic sepsis with S. epidermidis in hospitalized neonates is under investigation. Methods: In this study, we enrolled 46 infants consecutively admitted to the intensive care nursery (mean standard deviation, birth weight 1300 ± 337 gm, gestational age 29.4 ± 2.2 weeks). At the time of enrollment, infants had been fed enterally for at least 1 week (28 were fed formula and 18 received their own mothers' frozen milk). Stool samples were collected when infants were 2 to 3 weeks of age (16.3 ± 7.4 days). Results: Aerobic stool flora were present in 65% of all patients. Human milk use was associated with a significant increase in the presence of aerobic stool flora (78% vs 46%, p = 0.035), as well as more frequent isolation of S. epidermidis. The incidence of S. epidermidis sepsis was 33% in those infants whose stool specimens grew S. epidermidis and 3.5% in those whose stool specimens did not ( p < 0.01). Conclusions: These findings suggest the gastrointestinal tract as a possible site of entry for S. epidermidis in the hospitalized preterm infant. In addition, frozen human milk may be a vehicle for gastrointestinal S. epidermidis colonization.

Staphylococcus epidermidis-associated enterocolitis

Nineteen infants (mean +/- SD gestational age 30 +/- 2 weeks, birth weight 1.28 +/- 0.53 kg) with Staphylococcus epidermidis bacteremia were found on retrospective chart review to have had signs and symptoms of acute enterocolitis. This S. epidermidis-associated enterocolitis constituted 37% of the 51 cases of enterocolitis and 23% of the 81 cases of S. epidermidis sepsis during the study period. S. epidermidis-associated enterocolitis was relatively mild compared with other forms of enterocolitis. Although abdominal radiographs showed markedly abnormal bowel gas patterns with distended bowel loops and bowel wall edema, only one infant had pneumatosis intestinalis and none had portal venous or free intraperitoneal gas. Only three infants had neutropenia, and five had thrombocytopenia. None of these infants required surgical intervention. Although bloody stools often persisted for weeks, none of the neonates had prolonged feeding intolerance or development of a stricture. We conclude that S. epidermidis infection is commonly associated with a mild form of enterocolitis in the neonate and that this association should be considered when selecting antibiotics for therapy.

Staphylococcus epidermidis sepsis in surgical patients.

We examined 58 surgical patients with two or more blood cultures positive for Staphylococcus epidermidis to determine factors associated with risk, mortality, and invasive sepsis. Bacterial sepsis was associated with gastrointestinal (GI) operations, total parenteral nutrition, and a regimen of two or more parenteral antibiotics. Mortality was 46% overall and significantly increased with age greater than 50 years, GI operations, other gram-positive sepsis, recurrent sepsis (positive blood culture 24 hours or more after the first blood culture), and the presence of organisms sensitive to three or less antibiotics. Antibiotic therapy appropriate for more than 50% of the S epidermidis organisms cultured from each patient resulted in significant reduction in mortality. Staphylococcus epidermidis should be considered a significant pathogen in critically ill surgical patients. Invasive S epidermidis sepsis can be recognized and requires specific antibiotic therapy.

The Prevalence of High-Level Methicillin Resistance in Multiply Resistant Hospital Staphylococci

This study was prompted by observing in the summer of 1975, five lethal septicemias caused by methicillin resistant staphylococci. Among the 17 initial S. aureus strains, only 36% were killed at 250 micrograms per ml of methicillin. One phage type of S. aureus predominated (85, group III). Methicillin resistance was found in 17 of 102 S. aureus and in 28 off 102 S. epidermidis septicemias; the mortality among methicillin resistant S. aureus cases was 52.9%, corresponding to 39.3% for S. epidermidis sepsis. Antibiograms revealed methicillin resistance in 59/400 S. aureus and 94/400 S. epidermidis isolates. Cross-resistance to other drugs was common. It is concluded that the emergence of methicillin and gentamicin-tobramycin resistance among hospital staphylococci represents a serious, persistent problem. Certain microbiologic characteristics of these resistant strains differ from results heretofore reported by others.