Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial.

BACKGROUND: The available treatment options for Clostridium difficile infection (CDI) are limited by high recurrence rates. Surotomycin was a novel bactericidal cyclic lipopeptide in development to treat CDI that demonstrated non-inferiority to vancomycin in a Phase 2 trial. OBJECTIVES: To assess surotomycin safety and clinical response (non-inferiority versus vancomycin) at the end of treatment (EOT) of CDI. Additionally, to assess surotomycin response over time and sustained response at 30-40 days post-EOT (superiority versus vancomycin). PATIENTS AND METHODS: Patients with CDI were randomized (1:1) to receive twice-daily oral surotomycin 250 mg alternating with twice-daily placebo or four-times-daily oral vancomycin 125 mg for 10 days in this Phase 3, double-blind, multicentre, international trial. Clinical response over time and sustained clinical response were monitored until the end of the trial, through a follow-up period of 30-40 days. Clinical Trial Registration: NCT01598311. RESULTS: A total of 285 and 292 patients with confirmed CDI were randomized to receive surotomycin and vancomycin, respectively. Surotomycin-associated clinical response at EOT was non-inferior to vancomycin (surotomycin/vancomycin: 83.4%/82.1%; difference 1.4%, 95% CI - 4.9, 7.6). Following treatment with surotomycin, both clinical response over time (stratified log-rank test, P = 0.277) and sustained clinical response (63.3%/59.0%; difference 4.3%, 95% CI - 3.6, 12.2) did not demonstrate superiority versus vancomycin at end of trial. Both treatments were generally well tolerated. CONCLUSIONS: Surotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at EOT. Surotomycin did not demonstrate superiority to vancomycin for clinical response over time or sustained clinical response rate.

Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome.

Heterozygous deletions within human chromosome 22q11 are the genetic basis of DiGeorge/velocardiofacial syndrome (DGS/VCFS), the most common deletion syndrome (1 in 4,000 live births) in humans. CRKL maps within the common deletion region for DGS/VCFS (ref. 2) and encodes an SH2-SH3-SH3 adapter protein closely related to the Crk gene products. Here we report that mice homozygous for a targeted null mutation at the CrkL locus (gene symbol Crkol for mice) exhibit defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands and craniofacial structures. We show that the migration and early expansion of neural crest cells is unaffected in Crkol-/- embryos. These results therefore indicate an essential stage- and tissue-specific role for Crkol in the function, differentiation, and/or survival of neural crest cells during development. The similarity between the Crkol-/- phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.

Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression.

Colony-stimulating factor-1 (CSF-1) induces expression of immediate early gene, such as c-myc and c-fos and delayed early genes such as D-type cyclins (D1 and D2), whose products play essential roles in the G1 to S phase transition of the cell cycle. Little is known, however, about the cytoplasmic signal transduction pathways that connect the surface CSF-1 receptor to these genes in the nucleus. We have investigated the signaling mechanism of CSF-1-induced D2 expression. Analyses of CSF-1 receptor autophosphorylation mutants show that, although certain individual mutation has a partial inhibitory effect, only multiple combined mutations completely block induction of D2 in response to CSF-1. We report that at least three parallel pathways, the Src pathway, the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and the c-myc pathway, are involved. Induction of D2 is partially inhibited in Src(-/-) bone marrow-derived macrophages and by Src inhibitor PP1 and is enhanced in v-Src-overexpressing cells. Activation of myc's transactivating activity selectively induces D2 but not D1. Blockade of c-myc expression partially blocks CSF-1-induced D2 expression. Complete inhibition of the MEK/ERK pathway causes 50% decrease of D2 expression. Finally, simultaneous inhibition of Src, MEK activation, and c-myc expression additively blocks CSF-1-induced D2 expression. This study indicates that multiple signaling pathways are involved in full induction of a single gene, and this finding may also apply broadly to other growth factor-inducible genes.

Measles vaccine effectiveness and duration of vaccine-induced immunity in the absence of boosting from exposure to measles virus.

BACKGROUND: It is unknown whether vaccine-induced immunity is lifelong in the absence of periodic exposure to measles virus. After 27 years of no known exposure to measles, an outbreak in Palau in 1993 offered the opportunity to study this issue and the measles vaccine effectiveness. METHODS: Household contacts of a sample of confirmed cases were interviewed for exposure, symptoms and vaccination status verified by records. Serum from symptomatic contacts was tested for measles antibodies. RESULTS: Among 78 contacts 4 of 5 (80%) unvaccinated, 4 of 35 (11%) 1-dose vaccine recipients and none of 38 (0%) > 1-dose recipients developed measles. Effectiveness of 1-dose vaccine was 86% (95% confidence interval, 60 to 95%). An additional dose significantly reduced the risk of measles (P = 0.048). Time since vaccination was not a significant risk factor for developing measles (relative risk, 1.6; 95% confidence interval, 0.3 to 9.4; persons vaccinated > 15 years ago vs. < 5 years ago). CONCLUSIONS: Similar to the estimates previously obtained in the area, measles vaccine effectiveness in Palau was lower than the estimates obtained in the US. A second dose of vaccine further reduced the risk for developing measles. We found no evidence that waning immunity was an important problem in this limited population with no known previous exposure to measles virus. The small number of vaccinated contacts precludes a definitive assessment.

Measles outbreaks in Micronesia, 1991 to 1994.

BACKGROUND: Several islands in Micronesia experienced large measles outbreaks, during 1991 through 1994. Except for Guam, none of the islands had reported measles outbreaks during the previous 20 years. METHODS: To characterize the outbreaks, measles surveillance data, hospital records and death certificates were reviewed. Preoutbreak vaccination coverage rates were assessed by reviewing public health vaccination records. Viral isolates were genetically sequenced to determine the source of transmission. Linear regression analysis was performed to assess the effectiveness of outbreak control measures. RESULTS: Between 1991 and 1994 more than 1300 measles cases and 16 measles-related deaths were reported in Micronesia. Preoutbreak vaccination coverage rates among 2-year-old children were 55 to 94%. Genetic sequencing of the viral isolates and epidemiologic investigations suggested transmission between islands and new importations from outside of Micronesia. The highest attack rates were among children ages < 5 years (20/1000) and 10 to 19 years (38/1000). Compared with attack rates among children ages < 1 and 10 to 19 years, attack rates were lower among those ages 5 to 9 years, in whom 2-dose vaccination coverage rates were highest (P < 0.001). Early and rapid implementation of mass vaccination campaigns was significantly associated with shorter duration of outbreaks (P = 0.049). CONCLUSION: The measles outbreaks in Micronesia show that island populations may be highly susceptible to measles. High two-dose vaccination coverage levels must be maintained to prevent such outbreaks. Early and rapidly implemented mass measles vaccination campaigns were effective in control of island outbreaks. Strengthening public health infrastructure and surveillance is necessary for early identification of outbreaks and rapid implementation of mass campaigns.

Invited commentary: vaccine failure or failure to vaccinate?

PIP: Despite the availability of safe and effective measles vaccines since 1963, measles still accounts for approximately 10% of global mortality from all causes among children aged less than 5 years, an estimated 36.5 million cases and 1 million deaths in 1996. Worldwide in 1996, routine coverage with 1 dose of measles vaccine was 81%, although the African Region of the World Health Organization reports the lowest coverage, at 56%, and the largest proportion of measles cases and deaths. There is an urgent need to strengthen measles control and explore the best ways to achieve that end, especially in areas such as West Africa. However, the data presented by Cisse et al. do not show that the 1995 outbreak of measles in Niakhar, Senegal, was due mainly to the waning of vaccine-induced immunity among school-aged children. Waning immunity therefore cannot be used to justify the introduction of a multidose vaccination schedule as a key strategy for improving measles control in developing countries. The authors explain the basis for their opinions. The immediate objective of any measles control program should be to provide a first dose of measles vaccine to unvaccinated children.^ieng

Effectiveness of the pertussis vaccination program as determined by use of the screening method: United States, 1992-1994.

The screening method was used to evaluate the effectiveness of the pertussis vaccination program in the United States during 1992-1994. The formula VE = 1 - [PCV/(1 - PCV)][(1 - PPV)/PPV] was used (VE = vaccine effectiveness; PCV = proportion of cases vaccinated; PPV = proportion of population vaccinated). Data from the national Supplementary Pertussis Surveillance System and the National Health Interview Survey were used to determine PCV and PPV, respectively. Among children aged 7-18 months, VE for 3 doses of pertussis vaccine was 79% (95% confidence interval, 74%-83%) for preventing culture-confirmed pertussis. Between the ages of 19 and 47 months, VE for > or = 4 doses was 90% (95% confidence interval, 88%-92%). VE estimates appeared lower in epidemic (1993) than non-epidemic years (1992, 1994). VE estimates determined using the screening method were consistent with the previous estimates from the United States. This method will continue to be useful for assessing the effectiveness of the pertussis vaccination program in the United States, where acellular pertussis vaccines are recommended for infants.

Diagnosis of measles with an IgM capture EIA: the optimal timing of specimen collection after rash onset.

The optimal timing for collection of a single serum specimen to diagnose measles by using a monoclonal antibody-capture EIA was evaluated. Results of testing paired serum samples from 166 measles cases with at least 1 IgM-positive specimen were analyzed. Among persons whose second samples were IgM-positive, the seropositivity rate for first samples was 77% when collected within 72 h and 100% when collected 4-11 days after rash onset. Among unvaccinated persons whose first samples were IgM-positive, the rate for IgM positivity of second specimens declined from 100% at 4 days to 94% at 4 weeks after rash onset, then declined further to 63% at 5 weeks. Some previously vaccinated persons became IgM-negative during the third week after rash onset. In general, a single serum specimen collected between 72 h and 4 weeks after rash onset can be used to diagnose most cases of measles with an IgM capture EIA.

Changing epidemiology of pertussis in the United States: increasing reported incidence among adolescents and adults, 1990-1996.

Since 1990, the reported incidence of pertussis has increased in the United States with peaks occurring every 3-4 years. On the basis of analysis of pertussis cases reported to the Centers for Disease Control and Prevention, the incidence remained stable among children aged younger than 5 years, most of whom were protected by vaccination. In contrast to 1990-1993, during 1994-1996, the average incidence among persons aged 5-9 years, 10-19 years, and 20 years or older increased 40%, 106%, and 93%, respectively. Since 1990, 14 states reported pertussis incidences of > or =2 cases per 100,000 population during at least 4 years between 1990 and 1996; seven of these states also reported that a high proportion of cases occurred in persons aged 10 years or older. Analysis of national data on pertussis did not provide sufficient information to fully elucidate the relative importance of multiple possible explanations for the increase in the incidence of pertussis in adolescents and adults. Improvement in diagnosis and reporting of pertussis in this age group, particularly in some states, is an important factor contributing to the overall increase.

An outbreak of Brainerd diarrhea among travelers to the Galapagos Islands.

In 1992, an outbreak of chronic diarrhea occurred among passengers on a cruise ship visiting the Galapagos Islands, Ecuador. Passengers (548) were surveyed, and stool and biopsy specimens from a sample who reported chronic diarrhea were examined. On completed questionnaires, returned by 394 passengers (72%), 58 (15%) reported having chronic diarrhea associated with urgency (84%), weight loss (77%), fatigue (71%), and fecal incontinence (62%). Illness began 11 days (median) after boarding the ship and lasted 7 to >42 months. Macroscopic and histologic abnormalities of the colon were common, but extensive laboratory examination revealed no etiologic agent. No one responded to antimicrobial therapy. Patients were more likely than well passengers to have drunk the ship's unbottled water or ice before onset of illness and to have eaten raw sliced fruits and vegetables washed in unbottled water. Water handling and chlorination on the ship were deficient. Outbreaks of a similar illness, Brainerd diarrhea, have been reported in the United States. Although its etiology remains unknown, Brainerd diarrhea may also occur among travelers.