Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis (“flesh-eating disease”). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the ΔmtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.     

The ALS/PDC syndrome of Guam and the cycad hypothesis

There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.     

Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999-2000

OBJECTIVES: To describe the experience of Ontario long-term care facilities that used oseltamivir during influenza outbreaks in 1999/2000. DESIGN: Case series. SETTING: Ten Ontario long-term care facilities for older people and their residents. PARTICIPANTS: Older residents of long-term care facilities. INTERVENTION: Oseltamivir for treatment or prophylaxis during 11 influenza outbreaks in 1999/2000. MEASUREMENTS: Control of outbreaks; pneumonia, hospitalization, and death complicating acute influenza. RESULTS: All outbreaks were due to influenza A//H3N2/Sydney/05/97. One facility elected to use oseltamivir for treatment and amantadine for prophylaxis. The remaining nine facilities (10 outbreaks) recommended oseltamivir for treatment and prophylaxis (after amantadine failure in five and as primary prophylaxis in five). Use of oseltamivir was associated with termination of the outbreak in all eight evaluable outbreaks. Overall, 178/185 (96%) case-residents met the case definition of influenza and had complete data for evaluation. Of these, 63 (35%) were treated with antibiotics, 37 (21%) were diagnosed with pneumonia, 19 (11%) were hospitalized, and 16 (9%) died. Compared with residents receiving no therapy or who became ill while taking amantadine, residents who received oseltamivir within 48 hours of the onset of symptoms were less likely to be prescribed antibiotics, to be hospitalized, or to die (P <.05 for each outcome). These differences persisted and remained statistically significant when corrected for influenza immunization status. A total of 730 residents received oseltamivir prophylaxis for a median of 9 days (range 5-12). Of these, side effects were identified in 30 (4.1%), the most common being diarrhea (12 residents, 1.6%), cough (5, 0.7%), confusion (4, 0.5%) and nausea (4, 0.5%). CONCLUSIONS: Oseltamivir is safe and appears to be effective when used as treatment or prophylaxis to control outbreaks of influenza in older nursing home residents.     

Economic evaluation of oseltamivir phosphate for postexposure prophylaxis of influenza in long-term care facilities

OBJECTIVES: To compare the cost-effectiveness of oseltamivir postexposure prophylaxis during influenza A outbreaks with that of amantadine postexposure prophylaxis or no postexposure prophylaxis in long-term care facilities (LTCFs). DESIGN: Cost-effectiveness analysis based on decision analytic model from a government-payer perspective. SETTING: A Canadian LTCF, with high staff vaccination, at the beginning of influenza season. PARTICIPANTS: Elderly, influenza-vaccinated patients living in a Canadian LTCF. MEASUREMENTS: Incremental costs (or savings) per influenza-like illness case avoided compared with usual care. RESULTS: From a government-payer perspective, this analysis showed that oseltamivir was a dominant strategy because it was associated with the fewest influenza-like illness cases, with cost savings of $1,249 per 100 patients in 2001 Canadian dollars compared with amantadine and $3,357 per 100 patients compared with no prophylaxis. Costs for amantadine dose calculation and hospitalization for adverse events contributed to amantadine being a more-expensive prophylaxis strategy than oseltamivir. Both prophylaxis strategies were more cost-effective than no prophylaxis. CONCLUSION: Despite high influenza vaccination rates, influenza outbreaks continue to emerge in LTCFs, necessitating cost-effective measures to further limit the spread of influenza and related complications. Although amantadine has a lower acquisition cost than oseltamivir, it is associated with more adverse events, lower efficacy, and individualized dosing requirements, leading to higher overall costs and more influenza-like illness cases than oseltamivir. Therefore the use of oseltamivir postexposure prophylaxis is more cost-effective than the current standard of care with amantadine prophylaxis or no prophylaxis.     

Clinical and epidemiologic features of group a streptococcal pneumonia in Ontario,Canada

BACKGROUND: Since the 1960s, group A streptococcus (GAS) has accounted for less than 1% of cases of community-acquired pneumonia. During the past 2 decades there has been a resurgence of invasive GAS infection, but no large study of GAS pneumonia has been performed. METHODS: To determine the clinical and epidemiologic features of GAS pneumonia, we conducted prospective, population-based surveillance of all invasive GAS infection in residents of Ontario from January 1, 1992, through December 31, 1999. RESULTS: Of 2079 cases of invasive GAS infection, 222 (11%) represented GAS pneumonia. The incidence of GAS pneumonia ranged from 0.16 per 100 000 in 1992 to 0.35 per 100 000 in 1999. Most cases were community acquired (81%). Forty-four percent of nursing home-acquired cases occurred during outbreaks. The case fatality rate was 38% for GAS pneumonia, compared with 12% for the entire cohort with invasive GAS infection and 26% for patients with necrotizing fasciitis. The presence of streptococcal toxic shock syndrome (odds ratio, 19; 95% confidence interval, 8.4-42; P =.001) and increasing age (odds ratio per decade, 1.45; 95% confidence interval, 1.2-1.7; P<.001) were associated with fatal outcome. Time to death was rapid, with a median of 2 days despite antimicrobial therapy and supportive measures. CONCLUSIONS: Group A streptococcal pneumonia is a common form of invasive GAS disease but remains an uncommon cause of community-acquired pneumonia. Progression is rapid despite appropriate therapy. The incidence is similar to, and the case fatality rate higher than, that of necrotizing fasciitis.     

Antibodies to capsular polysaccharides of group B Streptococcus in pregnant Canadian women: relationship to colonization status and infection in the neonate.

In a cohort study of 1207 pregnant women in Alberta, Canada, the serotype distributions of vaginal-rectal group B Streptococcus (GBS) isolates were compared with all isolates from neonates with invasive GBS disease identified by population-based surveillance. Serum concentrations of Ia, Ib, II, III, and V capsular polysaccharide (CPS)-specific IgG also were determined, according to serotype of the vaginal-rectal colonizing GBS strain. GBS colonization was detected in 19.5% (235 of 1207) of women. Serotype III accounted for 20.6% (48 of 233) of colonizing strains available for typing but for 37% (27 of 73) of invasive isolates from neonates (P<.01). Maternal colonization with type III was least likely to be associated with moderate concentrations of III CPS-specific IgG. Serotype III GBS is more invasive than other serotypes in this population; this may be due, at least in part, to poor maternal type III CPS-specific antibody response.     

Neonatal group B streptococcal disease: incidence, presentation, and mortality.

OBJECTIVES: To ascertain the incidence, and compare the clinical characteristics, laboratory parameters, and immediate mortality of neonates with early-onset (symptomatic and asymptomatic) and late-onset group B streptococcal (GBS) disease. METHODS: A chart review of 81 neonates with GBS disease (either blood and/or cerebrospinal fluid culture-proven) born between 1995 and 2002 admitted to two tertiary care perinatal centers in Toronto was conducted. Clinical characteristics were compared for (1) asymptomatic early-onset, symptomatic early-onset, and late-onset GBS disease and (2) survivors and non-survivors. RESULTS: The incidence of GBS disease was 1.13/1000 live births. One or more antepartum or intrapartum predisposing factors were recognized in 62% of cases. Early-onset was noted in 65 (80%) neonates (23 asymptomatic and 42 symptomatic). All full-term infants survived. The mortality was 6% and was confined to preterm neonates with early symptomatic disease who presented with shock and had thrombocytopenia. CONCLUSION: Antepartum or intrapartum known predisposing risk factors of GBS disease were lacking in one third of patients. Patients who died were preterm infants in the early symptomatic group.