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Background
This bacterial organism may cause meningitis, an inflammation of the coverings of the brain. This infection may also lead to sepsis, a blood borne infection by the bacteria. It is highly contagious and may spread to other people who have had close or prolonged contact with a patient with meningitis. Anyone in close contact is considered at increased risk for acquiring the infection and should receive antibiotics to prevent the disease.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE Up to 2% in epidemics
0.5-5/100,000 for endemic disease, worldwide in distribution
Asymtomatic carriage of Neisseria meningitidis and Neisseria lactamica in relation to Streptococcus pneumoniae and Haemophilus influenzae colonization in healthy children: apropos of 1400 children sampled.Bakir M, Yagci A, Ulger N, Akbenlioglu C, Ilki A, Soyletir G.
Department of Pediatrics, Marmara University, School of Medicine, Istanbul, Turkey.
Eur J Epidemiol 2001;17(11):1015-8 Abstract quote Meningococcal disease is one of the most important causes of morbidity and mortality among children in many parts of the world. Main reservoir of carriage and site of meningococcal dissemination appears to be the upper respiratory tract.
Colonization of Neisseria meningitidis and lactamica and factors affecting this carriage were determined in a group of healthy children aged 0-10 years. Meningococcus and N. lactamica carriage were detected in 17 (1.23%) and 245 (17.7%) of 1382 subjects, respectively. Number (%) of serogroups for meningococci was 1 (6), 5 (29), 0 (0), 1 (6), 1 (6), and 9 (53) for A, B, C, D, W135, and Y, respectively. Having more than three household members, elementary school attendance, pharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae were associated with carriage of meningococci, whereas age less than 24-month was associated with carriage of N. lactamica.
There was a reverse carriage rate between N. meningitidis and N. lactamica by age which may suggest a possible protective role of N. lactamica against meningococcal colonization among pre-school children.
GEOGRAPHY Infants and young children (for endemic disease)
Refugees, household contacts of case patients, military personnel, college freshmen (who live in dormitories)Exposure to active and passive tobacco smoke.
Day-care and meningococcal disease in young children.Grein T, O'Flanagan D.
European Programme for Intervention Epidemiology Training, Saint Maurice, France.
Epidemiol Infect 2001 Dec;127(3):435-41 Abstract quote The Republic of Ireland has the highest incidence of meningococcal disease in Europe with 40% of all cases occurring in children under the age of 5 years.
Attending day-care increases the risk of certain infections, including Haemophilus influenzae type b (Hib) meningitis. The risk of meningococcal disease associated with day-care is not known. We conducted a case-control study among pre-school children with 130 laboratory-confirmed cases and 390 controls, matched on age, gender and place of residence, to determine if day-care attendance was a risk factor for meningococcal disease. Multivariate analysis showed that day-care attenders had a lower risk of disease than non-attenders (OR 0.3, 95% CI 0.1-0.7) whereas the number of adults in a household, and household crowding were independent risk factors for disease.
Asymptomatic carriers of Neisseria meningitidis are the main source of transmission and these carriers are usually adults. Regular day-care attendance may reduce this risk by removing children from close and prolonged contact with adults.
DISEASE ASSOCIATIONS CHARACTERIZATION PREGNANCY
Disseminated neisserial infection in pregnancy: the empress may have a change of clothing.Mitchell SR, Katz P.
Department of Internal Medicine, Georgetown University Hospital, Washington, D.C.
Obstet Gynecol Surv 1989 Nov;44(11):780-8 Abstract quote A case of disseminated neisserial disease during pregnancy with good perinatal outcome is presented along with two examples of disseminated N. meningitidis from endocervical site.
Upon close review, it is clear that the biological similarities of both N. gonorrhoeae and N. meningitidis may outweigh their differences. The two organisms may behave in clinically indistinguishable fashion and probably justify a more cautious approach to the clinical syndromes we have considered the inviolate domain of the gonococcus.
The management of disseminated neisserial disease in pregnancy should include prompt empiric parenteral therapy while aggressive diagnostic confirmation of the organism is pursued. In addition, neonatal conjunctivitis caused by a Gram-negative diplococci should be treated parenterally until clinical response and identity of the organism is confirmed.
PATHOGENESIS CHARACTERIZATION COMPLEMENT
Host defense against Neisseria meningitidis requires a complement-dependent bactericidal activity.Nicholson A, Lepow IH.
Science 1979 Jul 20;205(4403):298-9 Abstract quote Some individuals, with severe or recurrent infection with Neisseria species, have been identified as lacking a component in the terminal attack sequence of complement (complement components 5 to 9).
The relevance of the terminal attack sequence to various phases of host defense was tested with the use of the C-11 strain of meningococci and human serum genetically deficient in complement component 8 (C8-D). The C8-D serum was comparable to normal serum in supporting ingestion and intracellular killing by leukocytes but was not bactericidal in the fluid phase unless reconstituted with C8.
Thus, serum complement-dependent bactericidal activity may be especially critical for the host's defense against invasive Neisseria species.
CYTOKINES
Interaction of Neisseria meningitidis with human meningeal cells induces the secretion of a distinct group of chemotactic, proinflammatory, and growth-factor cytokines.Christodoulides M, Makepeace BL, Partridge KA, Kaur D, Fowler MI, Weller RO, Heckels JE.
Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, United Kingdom.
Infect Immun 2002 Aug;70(8):4035-44 Abstract quote The interactions of Neisseria meningitidis with cells of the leptomeninges are pivotal events in the progression of bacterial leptomeningitis. An in vitro model based on the culture of human meningioma cells was used to investigate the role of the leptomeninges in the inflammatory response.
Following challenge with meningococci, meningioma cells secreted specifically the proinflammatory cytokine interleukin-6 (IL-6), the CXC chemokine IL-8, the CC chemokines monocyte chemoattractant protein 1 (MCP-1) and regulated-upon-activation, normal-T-cell expressed and secreted protein (RANTES), and the cytokine growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). A temporal pattern of cytokine production was observed, with early secretion of IL-6, IL-8, and MCP-1 followed by later increases in RANTES and GM-CSF levels. IL-6 was induced equally by the interactions of piliated and nonpiliated meningococci, whereas lipopolysaccharide (LPS) had a minimal effect, suggesting that other, possibly secreted, bacterial components were responsible.
Induction of IL-8 and MCP-1 also did not require adherence of bacteria to meningeal cells, but LPS was implicated. In contrast, efficient stimulation of RANTES by intact meningococci required pilus-mediated adherence, which served to deliver increased local concentrations of LPS onto the surface of meningeal cells. Secretion of GM-CSF was induced by pilus-mediated interactions but did not involve LPS. In addition, capsule expression had a specific inhibitory effect on GM-CSF secretion, which was not observed with IL-6, IL-8, MCP-1, or RANTES.
Thus, the data demonstrate that cells of the leptomeninges are not inert but are active participants in the innate host response during leptomeningitis and that there is a complex relationship between expression of meningococcal components and cytokine induction.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS GENERAL Improved rate of isolation of Neisseria meningitidis by direct plating of pharyngeal swabs.
Cunningham R, Matthews R, Lewendon G, Harrison S, Stuart JM.
Plymouth Public Health Laboratory, Derriford Hospital, Plymouth, United Kingdom.
J Clin Microbiol 2001 Dec;39(12):4575-6 Abstract quote Culturing of pharyngeal swabs for Neisseria meningitidis is an important clinical and epidemiological tool. Routine methods include direct plating onto solid medium or later plating in the laboratory.
A comparison of these methods used with 490 high school students found a significantly higher carriage rate with direct plating (11.8 versus 6.1%; P < 0.001).
Detection of meningococcal carriage by culture and PCR of throat swabs and mouth gargles.Jordens JZ, Williams JN, Jones GR, Heckels JE.
Public Health Laboratory, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
J Clin Microbiol 2002 Jan;40(1):75-9 Abstract quote The standard method for detecting meningococcal carriage is culture of throat swabs on selective media, but the levels of carriage determined depend heavily on the skills of the individuals taking the swab and interpreting the cultures.
This study aimed to determine the most sensitive detection method for meningococcal carriage. Throat swabs and saline mouth gargles, obtained from 89 university students, were processed in parallel by conventional culture and TaqMan ctrA PCR. Carriage of meningococci, as detected by the combined methods, was 20%. The sensitivities of throat swab culture, throat swab PCR, gargle culture, and gargle PCR were 72, 56, 56, and 50%, respectively, and the probabilities that these techniques would correctly identify the absence of carriage (negative predictive value [NPV]) were 93.4, 89.9, 89.9, and 88.8%. Culturing both throat swabs and gargles increased the NPV to 98.6%. The further addition of throat swab PCR increased this to 100%.
Testing gargles by both culture and PCR was as sensitive as testing throat swabs by both methods, suggesting that gargles may be a suitable alternative for large-scale screening studies when throat swabs are difficult to obtain, although they required more lengthy laboratory processing. PCR was a useful adjunct to culture for detecting nasopharyngeal carriage, but it failed to detect some nongroupable strains.
For maximum sensitivity, a combination of techniques was required. This study indicates the confidence with which health care professionals involved in meningococcal screening can regard laboratory results.
CSF CULTURE
Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment.Kanegaye JT, Soliemanzadeh P, Bradley JS.
Division of Emergency Medicine, Children's Hospital and Health Center and Department of Pediatrics, University of California San Diego, San Diego, California 92123, USA.
Pediatrics 2001 Nov;108(5):1169-74 Abstract quote OBJECTIVE: Despite the lack of evidence defining a time interval during which cerebrospinal fluid (CSF) culture yield will not be affected by previous antibiotic therapy, recent publications cite a "minimum window" of 2 to 3 hours for recovery of bacterial pathogens after parenteral antibiotic administration. We conducted a retrospective review of children with bacterial meningitis to describe the rate at which parenteral antibiotic pretreatment sterilizes CSF cultures.
METHODS: The medical records of pediatric patients who were discharged from a tertiary children's hospital during a 5-year period with the final diagnosis of bacterial meningitis or suspected bacterial meningitis were reviewed. The decay in yield of CSF cultures over time was evaluated in patients with lumbar punctures (LP) delayed until after initiation of parenteral antibiotics and in patients with serial LPs before and after initiation of parenteral antibiotics.
RESULTS: The pathogens that infected the 128 study patients were Streptococcus pneumoniae (49), Neisseria meningitidis (37), group B Streptococcus (21), Haemophilus influenzae (8), other organisms (11), and undetermined (3). Thirty-nine patients (30%) had first LPs after initiation of parenteral antibiotics, and 55 (43%) had serial LPs before and after initiation of parenteral antibiotics. After >/=50 mg/kg of a third-generation cephalosporin, 3 of 9 LPs in meningococcal meningitis were sterile within 1 hour, occurring as early as 15 minutes, and all were sterile by 2 hours. With pneumococcal disease, the first negative CSF culture occurred at 4.3 hours, with 5 of 7 cultures negative from 4 to 10 hours after initiation of parenteral antibiotics. Reduced susceptibility to beta-lactam antibiotics occurred in 11 of 46 pneumococcal isolates. Group B streptococcal cultures were positive through the first 8 hours after parenteral antibiotics. Blood cultures were positive in 74% of cases without pretreatment and in 57% to 68% of cases with negative CSF cultures.
CONCLUSIONS: The temptation to initiate antimicrobial therapy may override the principle of obtaining adequate pretreatment culture material. The present study demonstrates that CSF sterilization may occur more rapidly after initiation of parenteral antibiotics than previously suggested, with complete sterilization of meningococcus within 2 hours and the beginning of sterilization of pneumococcus by 4 hours into therapy. Lack of adequate culture material may result in inability to tailor therapy to antimicrobial susceptibility or in unnecessarily prolonged treatment if the clinical presentation and laboratory data cannot exclude the possibility of bacterial meningitis.
POLYMERASE CHAIN REACTION
Polyclinique de Dermatologie et Vénéréologie, Hôpital Universitaire de Genève, Rue Micheli-du-Crest 24, 1211 Genève 14, Switzerland.
BACKGROUND: Chronic meningococcemia (CM) is a diagnostic challenge. Skin lesions are frequent but in most cases nonspecific. Polymerase chain reaction (PCR)-based diagnosis has been validated in blood and cerebrospinal fluid for acute Neisseria meningitidis infection, in patients in whom routine microbiologic tests have failed to isolate the bacteria. In 2 patients with CM, we established the diagnosis by a newly developed PCR-based approach performed on skin biopsy specimens.
OBSERVATIONS: Two patients presented with fever together with systemic and cutaneous manifestations suggestive of CM. Although findings from blood cultures remained negative, we were able to identify N meningitidis in the skin lesions by a newly developed PCR assay. In 1 patient, an N meningitidis strain of the same serogroup was also isolated from a throat swab specimen. Both patients rapidly improved after appropriate antibiotherapy.
CONCLUSIONS: To our knowledge, we report the first cases of CM diagnosed by PCR testing on skin biopsy specimens. It is noteworthy that, although N meningitidis-specific PCR is highly sensitive in blood and cerebrospinal fluid in acute infections, our observations underscore the usefulness of PCR performed on skin lesions for the diagnosis of chronic N meningitidis infections. Whenever possible, this approach should be systematically employed in patients for whom N meningitidis infection cannot be confirmed by routine microbiologic investigations.
Evaluation of a diagnostic polymerase chain reaction assay for Neisseria meningitidis in North America and field experience during an outbreak.Pollard AJ, Probe G, Trombley C, Castell A, Whitehead S, Bigham JM, Champagne S, Isaac-Renton J, Tan R, Guiver M, Borrow R, Speert DP, Thomas E.
Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, British Columbia's Research Institute for Child and Family Health, Vancouver, Canada
Arch Pathol Lab Med 2002 Oct;126(10):1209-15 Abstract quote CONTEXT: Meningococcal infection has a high public profile because of its dramatic presentation, high fatality rate, and propensity to occur in outbreaks and clusters of cases. Use of a diagnostic polymerase chain reaction (PCR) assay could enhance laboratory confirmation of cases and guide the public health response in North America.
OBJECTIVE: To assess the performance of a PCR assay for the diagnosis of meningococcal disease after its implementation in a North American setting and to evaluate sensitivity and specificity of the assay for the detection of prevalent bacterial isolates.
DESIGN: Laboratory evaluation of the sensitivity and specificity of a PCR assay for Neisseria meningitidis and observational study of a series of cases comparing molecular diagnosis against the criterion standard of conventional laboratory diagnostic tests.
SETTING: A Canadian province with a population of 4 million people.
PATIENTS: Children and adults presenting with suspected meningococcal disease in British Columbia.
MAIN OUTCOME MEASURES: The sensitivity and specificity of the PCR assay when compared against standard laboratory methods. RESULTS: The PCR assay correctly identified all of 38 Canadian isolates of Neisseria meningitidis and correctly assigned the serogroup to each isolate. None of 57 other gram-positive or gram-negative bacteria or yeasts were detected by the PCR assay. In a clinical evaluation, for diagnosis of meningococcal disease, the PCR assay had a sensitivity and specificity of 91% and 76%, respectively, against conventional methods of diagnosis. Use of the PCR assay increased the laboratory confirmation of clinically suspected cases by 36%. During an outbreak, the PCR assay allowed serogroup determination in 3 of 7 cases, aiding in the public health decision to launch an immunization campaign.
CONCLUSIONS: The PCR assay is more sensitive than conventional methods for the diagnosis of meningococcal disease, and enhanced surveillance may help direct the public health response to the changing epidemiology of disease in North America.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS SEPSIS
Pathogenesis, Therapy, and Prevention of Meningococcal Sepsis.Stephens DS, Zimmer SM.
Department of Medicine, Emory University School of Medicine, H-153 Emory University Hospital, 1364 Clifton Road, NE, Atlanta, GA 30322, USA.
Curr Infect Dis Rep 2002 Oct;4(5):377-386 Abstract quote Neisseria meningitidis (meningococcus), an exclusive pathogen of humans, is the cause of sepsis (meningococcemia) and meningitis, often in otherwise healthy individuals.
Several hundred thousand cases of meningococcal disease occur worldwide each year, a number that is frequently accentuated by epidemic outbreaks. In recent years, significant advances, fueled by new molecular approaches and genome sequencing projects, have improved our understanding of the pathogenesis of meningococcal disease and have led to progress in the development of the next generation of meningococcal vaccines. However, the mortality of meningococcal disease remains 10% to 15% for all cases, and is up to 40% in patients with severe sepsis.
This review summarizes current knowledge of the pathogenesis, therapy, and prevention of meningococcal disease with emphasis on meningococcal sepsis.
WATERHOUSE-FRIDERICHSEN
Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis.Agraharkar M, Fahlen M, Siddiqui M, Rajaraman S.
Department of Medicine, Nephrology Division, University of Texas Medical Branch, Galveston, TX 77555-0562, USA.
Am J Kidney Dis 2000 Aug;36(2):396-400 Abstract quote Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis (BRCN) are rare complications of meningococcal sepsis associated with high mortality rates.
We describe a 20-year-old man who presented with a 1-day history of fever, chills, malaise, and vomiting. He collapsed in the emergency room, requiring mechanical ventilation and intravenous vasopressors for resuscitation. He was noted to be anuric, and computed tomography showed adrenal hemorrhage and BRCN. Blood cultures later confirmed Neisseria meningitidis sepsis, and a biopsy confirmed renal cortical infarction. The patient was treated aggressively with intravenous antibiotics, corticosteroids, and immunoglobulins, in addition to plasmapheresis, dialysis, and supportive measures. He recovered his adrenal function and was discharged from the hospital, but he remains dialysis dependent.
To our knowledge, this is the first reported case of concomitant Waterhouse-Friderichsen syndrome and BRCN in a patient with meningococcal sepsis.
PROGNOSIS/
TREATMENTCHARACTERIZATION PROGNOSTIC FACTORS ACTH LEVELS
Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease.De Kleijn ED, Joosten KF, Van Rijn B, Westerterp M, De Groot R, Hokken-Koelega AC, Hazelzet JA.
Erasmus Medical Center, Department of Pediatrics, Sophia Children's Hospital, Rotterdam, The Netherlands.
Pediatr Infect Dis J 2002 Apr;21(4):330-6 Abstract quote OBJECTIVES: To study the correlation between serum concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in relation to severity of disease in children with meningococcal sepsis.
METHODS: Subjects were children with meningococcal sepsis, admitted to the pediatric intensive care unit. Clinical data, laboratory values and blood samples were selected. Arterial cortisol, ACTH, interleukin 6 and tumor necrosis factor alpha concentrations were measured on admission and studied for their relation to severity of disease (sepsis, septic shock/survivors, septic shock/nonsurvivors).
RESULTS: Seventy-two patients fulfilled the criteria for meningococcal sepsis. Sixty-two of these children with positive blood cultures of Neisseria meningitidis, who were not treated with corticosteroids before admission, were included. Fifty of the 62 patients had septic shock. Twelve of those children (24%) died. The median age of the subjects was 2.6 years (range, 0.3 to 16.1 years). Cortisol values were significantly lower in non-survivors (median, 654 nmol/l) than in survivors (median, 2184 nmol/l) (P < 0.01). ACTH values were significantly higher in children who died (median, 1271 ng/l) than in survivors (85 ng/l) (P < 0.01). The median cortisol:ACTH ratio decreased significantly depending on the disease severity categories.
CONCLUSIONS: Low serum cortisol concentrations in combination with high ACTH concentrations are associated with poor outcome in children with severe meningococcal disease.
TREATMENT ANTIBIOTIC THERAPY
Ceftriaxone: an update of its use in the management of community-acquired and nosocomial infections.Lamb HM, Ormrod D, Scott LJ, Figgitt DP.
Adis International Limited, 41 Centorian Drive, PB 65901, Mairangi Bay, Auckland 10, New Zealand.
Drugs 2002;62(7):1041-89 Abstract quote Ceftriaxone is a parenteral third-generation cephalosporin with a long elimination half-life which permits once-daily administration. It has good activity against Streptococcus pneumoniae, methicillin-susceptible staphylococci, Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp. Although active against Enterobacteriaceae, the recent spread of derepressed mutants which hyperproduce chromosomal beta-lactamases and extended-spectrum beta-lactamases has diminished the activity of all third-generation cephalosporins against these pathogens necessitating careful attention to sensitivity studies.
Extensive data from randomised clinical trials confirm the efficacy of ceftriaxone in serious and difficult-to-treat community-acquired infections including meningitis, pneumonia and nonresponsive acute otitis media. Ceftriaxone also has efficacy in other community-acquired infections including uncomplicated gonorrhoea, acute pyelonephritis and various infections in children. In the nosocomial setting, extensive data also confirm the efficacy of ceftriaxone with or without an aminoglycoside in serious Gram-negative infections, pneumonia, spontaneous bacterial peritonitis and as surgical prophylaxis.
Outpatient use of ceftriaxone, either as part of a step-down regimen or parenterally, is a distinguishing feature of the data gathered on the agent over the last decade. The review focuses on new applications of the drug and its use in infections in which the causative pathogens or their resistance patterns have changed over the past decade. Ceftriaxone has a good tolerability profile, the most common events being diarrhoea, nausea, vomiting, candidiasis and rash. Ceftriaxone may cause reversible biliary pseudolithiasis, notably at higher dosages of the drug (>/=2 g/day); however, the incidence of true lithiasis is <0.1%. Injection site discomfort or phlebitis can occur after intramuscular or intravenous administration.
CONCLUSIONS: As a result of its strong activity against S. pneumoniae, ceftriaxone holds an important place, either alone or as part of a combination regimen, in the treatment of invasive pneumococcal infections, including those with reduced beta-lactam susceptibility. Its once-daily administration schedule allows simplification of otherwise complex regimens in a hospital setting and has also contributed to its popularity as a parenteral agent in an ambulatory setting. These properties, together with a well characterised tolerability profile, mean that ceftriaxone is likely to retain its place as an important third-generation cephalosporin in the treatment of serious community-acquired and nosocomial infections.
Prevalence of moderate penicillin resistant invasive Neisseria meningitidis infection in Scotland, 1994-9.Kyaw MH, Bramley JC, Clark S, Christie P, Jones IG, Campbell H.
Scottish Centre for Infection and Environmental Health, Glasgow, UK.
Epidemiol Infect 2002 Apr;128(2):149-56 Abstract quote We examined the serological characteristics of 774 invasive meningococcal isolates collected through an active laboratory-based surveillance system in Scotland from 1994 to 1999. Of these, 72-73% of isolates were tested for susceptibility to several antimicrobial agents.
Meningococci with high-level resistance to sulphadiazine had a prevalence of 10% and incidence of 0.22 per 100,000 population. High-level resistance to penicillin and other antibiotics was not detected. The prevalence of moderate penicillin resistant meningococci was 8.3%. There was no increase in moderate penicillin resistant meningococcal isolates during the study period, but there were temporal and geographic variations.
The estimated incidence of moderate penicillin resistant meningococci was 0.15 per 100,000 population. High and low incidence of moderate penicillin resistant meningococci appeared to correlate with the number of doses of penicillin prescribed in some geographic locations. The majority of moderate penicillin resistant isolates belonged to serogroups B (52.2%) and C (39.2%). However, the prevalence of moderate penicillin resistance in serogroup W135 was substantially higher (51.7%) than serogroups B (7.8%) and C (7.6%). Serogroup W135 accounted for a higher proportion of moderate penicillin resistance (8.7%) than disease (1%). There was no predominant penicillin resistant serotype/subtype within any serogroup.
Constant surveillance is necessary to monitor the emergence and spread of resistance and to guide appropriate public health interventions in preventing drug resistant meningococci.
BACTERICIDAL/
PERMEABILITY-INCREASING PROTEIN
Bactericidal/permeability-increasing protein--lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia.Giroir BP, Scannon PJ, Levin M.
Children's Meical Center, Dallas, TX 75235, USA.
Crit Care Med 2001 Jul;29(7 Suppl):S130-5 Abstract quote OBJECTIVES: To review the scientific rationale for the clinical use of recombinant bactericidal permeability-increasing protein (rBPI21) and to discuss the results, implications, and lessons learned during the clinical development of rBPI21 for adjunctive treatment of children with severe meningococcemia.
DATA SOURCES: The published medical literature.
STUDY SELECTION: Of the phase I/II and phase III trials in humans, preclinical experimental studies were selected. Data from these sources are presented in the context of the authors' experiences as principal investigators in the phase I/II and/or phase III clinical trials.
DATA EXTRACTION AND DATA SYNTHESIS: Bactericidal permeability-increasing protein and N-terminal fragments of bactericidal permeability-increasing protein, such as rBPI21, bind and neutralize endotoxin and are potently bactericidal against both smooth and rough forms of Gram-negative bacteria, including Neisseria meningitidis. Based on these properties and compelling preclinical data indicating that administration of rBPI21 reduced mortality in several models of sepsis, we initiated clinical trials by using rBPI21 as adjunctive therapy for children with severe meningococcemia. Data from the phase III, randomized, placebo-controlled trial indicate that rBPI21 reduces clinically significant morbidities and improves the functional outcome of children with severe meningococcemia. No statistically significant benefit in mortality was demonstrated; however, because of the rare incidence of disease and the rapidity of death in this study, the trial was substantially underpowered to detect a statistically significant mortality advantage. Before the completion of the trial, the probability that the study might have been underpowered to detect a significant reduction in mortality was recognized. An attempt at selecting a previously unvalidated composite end point to increase the meaningful event rate for the primary end point proved unsuccessful. Significant improvements were seen in other prospectively defined outcome variables that suggest an overall substantial benefit of therapy with rBPI21 in children with severe meningococcemia.
CONCLUSIONS: As the largest therapeutic trial conducted in pediatric critical care, the phase III trial of rBPI21 demonstrates important principles that can influence the design of future trials targeting rare, life-threatening diseases.
ANTI-ENDOTOXIN ANTIBODY
Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group.Derkx B, Wittes J, McCloskey R.
Academic Medical Center, University of Amsterdam, Emma Children's Hospital AMC, Department of Pediatrics, The Netherlands.
Clin Infect Dis 1999 Apr;28(4):770-7 Abstract quote Meningococcal septic shock has a rapid onset and characteristic skin hemorrhages that allow bedside diagnosis. Initial plasma endotoxin levels are high and correlate closely with clinical outcome. In a double-blind, randomized, placebo-controlled trial (planned, n = 270; actual, n = 269), we compared the effectiveness of HA-1A (6 mg/kg of body weight iv; maximum, 100 mg), a human monoclonal antibody to endotoxin, and placebo in reducing the 28-day all-cause mortality rate among children with a presumptive clinical diagnosis of meningococcal septic shock.
Treatment groups were well balanced for baseline characteristics and prespecified prognostic variables. In this trial no significant benefit of HA-1A could be demonstrated. The 28-day mortality rates in the intention-to-treat analysis were as follows: placebo, 28%; HA-1A, 18%; reduction in mortality, 33% (P = .11, per Fisher's exact test, two-tailed; odds ratio = 0.59; 95% confidence interval for the difference, 0.31-1.05). A
ll patients tolerated HA-1A well, and no antibodies to HA-1A were detected.
PROPHYLAXIS
Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of serogroup B Neisseria meningitidis.Simmons G, Jones N, Calder L.
Auckland Healthcare Public Health Protection, Auckland, New Zealand.
J Antimicrob Chemother 2000 Jun;45(6):909-11 Abstract quote The efficacy of ceftriaxone in eliminating nasopharyngeal carriage of Neisseria meningitidis was compared with that of rifampicin during an epidemic of serogroup B meningococcal disease in Auckland, New Zealand.
Household contacts of cases had a throat swab taken and were randomized to treatment. Carriers had a repeat swab taken 6 days later to determine efficacy of treatment.
Ceftriaxone (98.2%) was equivalent to rifampicin (97.6%) in eliminating serogroup B N. meningitidis. It is cheaper than rifampicin and has the advantage of full compliance and fewer contraindications, but its acceptability by patients may limit its use as a first-line prophylactic agent.
VACCINE
Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants.Rennels MB, Edwards KM, Keyserling HL, Reisinger K, Blatter MM, Quataert SA, Madore DV, Chang I, Malinoski FJ, Hackell JG, Paradiso PR.
Center for Vaccine Development and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, USA.
Pediatr Infect Dis J 2001 Feb;20(2):153-9 Abstract quote BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC).
METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4.
RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster.
CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.
Combinations of protein polysaccharide conjugate vaccines for intranasal immunization.Ugozzoli M, Mariani M, Del Giudice G, Soenawan E, O'Hagan DT.
Chiron Corporation, Emeryville, California, USA.
J Infect Dis 2002 Nov 1;186(9):1358-61 Abstract quote The ability of 2 mutants of heat-labile Escherichia coli enterotoxin (LTK63 and LTR72) to enhance the immunogenicity of 2 protein polysaccharide conjugate vaccines, Neisseria meningitidis group C (MenC) and Haemophilus influenzae type B (Hib), both of which are conjugated to the nontoxic mutant of diphtheria toxin (CRM197), after intranasal (inl) immunization in mice was evaluated. In addition, the question of whether combining both vaccines in a single formulation with heat-labile E. coli enterotoxin mutants reduced the response to either vaccine was investigated.
The results showed that potent serum antibody responses against MenC and Hib could be elicited by inl immunization in combination with the mucosal adjuvants. Moreover, IgA mucosal responses were induced only in animals immunized through the inl route. Finally, the coadministration of 2 conjugate vaccines simultaneously did not adversely affect the responses against either.
These studies support the rationale for developing mucosal vaccines, based on combining protein polysaccharide conjugates with heat-labile E. coli enterotoxin mutants, for infants and young children.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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