Treatment and Epidemiology of Third-Generation Cephalosporin-Resistant Urinary Tract Infections.

BACKGROUND AND OBJECTIVES: Limited data are available on the contemporary epidemiology, clinical management, and health care utilization for pediatric urinary tract infection (UTI) due to third-generation cephalosporin-resistant Enterobacterales (G3CR) in the United States. The objective is to describe the epidemiology, antimicrobial treatment and response, and health care utilization associated with G3CR UTI. METHODS: Multisite, matched cohort-control study including children with G3CR UTI versus non-G3CR UTI. UTI was defined as per American Academy of Pediatrics guidelines, and G3CR as resistance to ceftriaxone, cefotaxime, or ceftazidime. We collected data from the acute phase of illness to 6 months thereafter. RESULTS: Among 107 children with G3CR UTI and 206 non-G3CR UTI with documented assessment of response, the proportion with significant improvement on initial therapy was similar (52% vs 57%; odds ratio [OR], 0.81; 95% confidence interval [CI], 0.44-1.50). Patients with G3CR were more frequently hospitalized at presentation (38% vs 17%; OR, 3.03; 95% CI, 1.77-5.19). In the follow-up period, more patients with G3CR had urine cultures (75% vs 53%; OR, 2.61; 95% CI, 1.33-5.24), antimicrobial treatment of any indication (53% vs 29%; OR, 2.82; 95% CI, 1.47-5.39), and subspecialty consultation (23% vs 6%; OR, 4.52; 95% CI, 2.10-10.09). In multivariate analysis, previous systemic antimicrobial therapy remained a significant risk factor for G3CR UTI (adjusted OR, 1.91; 95% CI, 1.06-3.44). CONCLUSIONS: We did not observe a significant difference in response to therapy between G3CR and susceptible UTI, but subsequent health care utilization was significantly increased.

Profile of the Pediatric Infectious Disease Workforce in 2015.

BACKGROUND: Almost 20 years have elapsed since the last workforce survey of pediatric infectious disease (PID) subspecialists was conducted in 1997-1998. The American Academy of Pediatrics Section on Infectious Diseases in collaboration with the Pediatric Infectious Diseases Society sought to assess the status of the current PID workforce. METHODS: A Web-based survey conducted in 2015 collected data on demographics, practice patterns, and job satisfaction among the PID workforce, and identified factors related to job placement among recent fellowship graduates. RESULTS: Of 946 respondents (48% response rate), 50% were female. The average age was 51 years (range, 29-88 years); 63% were employed by an academic center/hospital, and 85% provided direct patient care; and 18% were not current PID practitioners. Of the 138 (21%) respondents who had completed a PID fellowship within the previous 5 years, 83% applied for <5 PID positions; 43% reported that their first position was created specifically for them; 47% had 1 job offer, and 41% had 2 or 3 job offers; 82% were employed within 6 months; and 74% remained at the institution of their first job. Respondents who were practicing PID full-time or part-time (n = 778) indicated desiring more focused training in immunodeficiencies (31%), transplant-related care (31%), and travel/tropical medicine (28%). Overall, 70% of the respondents would "definitely" or "probably" choose PID again. CONCLUSIONS: Most respondents were satisfied with their career choice in PID. Most of the recent fellowship graduates were employed within 6 months after training. We identified potential areas in which the PID community can focus efforts to maintain the pipeline and improve satisfaction among its physicians.

Cost-benefit analysis of hospital based postpartum vaccination with combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap).

OBJECTIVE: To assess the economic benefits associated with hospital-based postpartum Tdap (combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccination. METHODS: A decision tree model was constructed to calculate the potential cost-benefit of this strategy from both a health care system and a societal perspective. Probabilities and costs were derived from published literature, data reported to Centers for Disease Control and Prevention, and recommendations from expert panels. The maternal vaccination protection period for infants was defined as 7 months, and 10 years of waning immunity following Tdap for birth mothers was estimated in the model. All cost estimates were inflated to year 2012 US dollars and discounted at a 3% annual discount rate. RESULTS: In the base case from a societal perspective, the expected costs per vaccinated and unvaccinated mother were estimated at $129.27 and $187.97, respectively, suggesting an expected net benefit of $58.70 per vaccinated mother. The overall societal benefits in the cohort of 3.6 million U.S. birth mothers ranged from $52.8-126.8 million, depending on the vaccination coverage level. If including direct medical costs only, the strategy would not generate net savings from a health care system perspective. Annual incidence of pertussis in birth mothers and Tdap efficacy exhibited substantial impact on the model as shown in one-way and two-way sensitivity analyses. CONCLUSIONS: Although postpartum Tdap vaccination is not cost-beneficial from a health care system perspective in the base case, this strategy is likely to generate net benefits from a societal perspective.

Cost-benefit analysis of in-hospital influenza vaccination of postpartum women.

OBJECTIVE: To estimate the potential economic benefits associated with hospital-based postpartum influenza vaccination. METHODS: We constructed a decision analysis model to estimate the potential cost benefit of this strategy from both a societal perspective and a third-party perspective. We included a hypothetical cohort of 1.47 million U.S. postpartum women, assuming an influenza season beginning September 1 and ending April 30. Probabilities and costs were derived from published literature, Centers for Disease Control and Prevention data, and expert recommendations. We used one-way and two-way sensitivity analyses. All cost estimates were inflated to year 2010 U.S. dollars and discounted at a 3% annual discount rate. RESULTS: From the societal perceptive, the expected costs per vaccinated and unvaccinated mother were $328.45 and $341.02 respectively, resulting in an expected net benefit of $12.57 per vaccinated mother. The overall savings in the cohort were predicted to range from $3.69 to $14.75 million, depending on the vaccination coverage rate. This strategy would be cost-beneficial, holding all other variables to the base case, if the annual maternal influenza attack rate is more than 2.8%, influenza vaccine efficacy is more than 47%, or if vaccine acquisition and administration cost per dose are less than $32.78. The strategy would not generate net savings from the third-party perspective. Sensitivity analyses were robust, but disease incidence and vaccine efficacy were important drivers. CONCLUSION: Our model suggests that postpartum influenza vaccination is a cost-beneficial approach for prevention of maternal and infantile influenza from a societal perspective. LEVEL OF EVIDENCE: III.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine.

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) has proven highly effective in preventing diseases caused by Streptococcus pneumoniae; however, in some regions, serotype coverage is limited. A recently licensed 13-valent PCV (PCV13) was developed to provide additional coverage globally. Children previously vaccinated with PCV7 could benefit from supplemental vaccination with PCV13 to provide protection against the 6 additional serotypes in PCV13. This open-label study evaluated the immunogenicity and safety of administering PCV13 to healthy children previously vaccinated with PCV7. METHODS: Children between 15 months and 2 years of age (group 1) received 2 doses of PCV13; children between 2 and 5 years (group 2) received 1 dose. Antibodies (immunoglobulin G) against the polysaccharide antigens in PCV13 were measured before vaccination and 1 month after the final dose. Solicited local and systemic adverse events (AEs) were collected for 7 days postvaccination. Unsolicited and serious AEs were collected throughout. RESULTS: A total of 284 subjects (group 1: n = 109; group 2: n = 175) had blood available for testing. Antipneumococcal immunoglobulin G geometric mean fold rises ranged from 2- to 19-fold for the PCV7 serotypes and from approximately 2- to 124-fold for the 6 additional serotypes. Additionally, postvaccination titers in excess of 0.35 µg/mL, the serologic correlate of immunity against pneumococcus for children, occurred in ≥98% of subjects in both groups for 12 of the 13 serotypes in PCV13. Slightly lower percentage of subjects, 94.5% and 92% of subjects in group 1 and group 2, respectively, had postvaccine titers for serotype 3 exceeding the serologic correlate of immunity. Reactogenicity was typically mild and self-limited, and unsolicited AEs reported were generally consistent with common childhood illnesses. CONCLUSION: PCV13 was safe and immunogenic when administered to children who had previously received PCV7, and can be used for supplemental vaccination to provide additional protection against the 6 additional serotypes.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers.

BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were generally somewhat lower. PCV13 also elicited functional opsonophagocytic activity comparable with that elicited by PCV7. For the 6 additional serotypes in PCV13, PCV13 elicited binding and functional antibody levels notably greater than those in PCV7 recipients. After PCV13 immunization, concordance between antipolysaccharide and opsonophagocytic responses was noted for all 13 serotypes. The PCV13 toddler dose resulted in higher immune responses compared with infant-series doses. Safety and tolerability were comparable; reactogenicity was generally mild. CONCLUSIONS: PCV13 will be as effective as PCV7 in the prevention of pneumococcal disease caused by the 7 common serotypes and could provide expanded protection against the 6 additional serotypes. The PCV13 safety profile was comparable to that of PCV7.

Paralytic syndromes in children: epidemiology and relationship to vaccination.

Acute flaccid paralysis is a standard outcome for detection of poliomyelitis globally and an ongoing potential vaccine-associated adverse event concern for polio, influenza, and meningococcal vaccines. No systematic population-based data on the epidemiologic and clinical features of this condition, or its potential association with immunization, have been reported from the United States. The present retrospective cohort study of acute flaccid paralysis in the Southern and Northern California Kaiser Permanente Health Care Plans was conducted using computerized diagnosis data and medical record review of potential cases among children aged 1 month to <15 years and diagnosed from January 1, 1992 through December 31, 1998. In all, 3297 potential cases were identified; of these, 2682 cases (81%) did not meet the case definition, and of the remaining 615 cases, 245 (7% of the total) were included. The incidence of disease was 1.4 per 100,000 children/year (95% confidence interval = 1.2-1.6); predicting approximately 844 children/year in the United States. Disease incidence did not vary with season or sex, varied inversely with age, and declined 28% during the study period. No cases of vaccine-associated acute flaccid paralysis were identified. In nonendemic countries, ongoing acute flaccid paralysis surveillance is often conducted, because of the risk of poliovirus importation, but this practice may be difficult to justify, given low disease incidence and breadth of clinical presentation.

The Bordetella type III secretion system effector BteA contains a conserved N-terminal motif that guides bacterial virulence factors to lipid rafts.

The Bordetella type III secretion system (T3SS) effector protein BteA is necessary and sufficient for rapid cytotoxicity in a wide range of mammalian cells. We show that BteA is highly conserved and functionally interchangeable between Bordetella bronchiseptica, Bordetella pertussis and Bordetella parapertussis. The identification of BteA sequences required for cytotoxicity allowed the construction of non-cytotoxic mutants for localization studies. BteA derivatives were targeted to lipid rafts and showed clear colocalization with cortical actin, ezrin and the lipid raft marker GM1. We hypothesized that BteA associates with the cytoplasmic face of lipid rafts to locally modulate host cell responses to Bordetella attachment. B. bronchiseptica adhered to host cells almost exclusively to GM1-enriched lipid raft microdomains and BteA colocalized to these same sites following T3SS-mediated translocation. Disruption of lipid rafts with methyl-beta-cyclodextrin protected cells from T3SS-induced cytotoxicity. Localization to lipid rafts was mediated by a 130-amino-acid lipid raft targeting domain at the N-terminus of BteA, and homologous domains were identified in virulence factors from other bacterial species. Lipid raft targeting sequences from a T3SS effector (Plu4750) and an RTX-type toxin (Plu3217) from Photorhabdus luminescens directed fusion proteins to lipid rafts in a manner identical to the N-terminus of BteA.

Update on adolescent immunization: pertussis, meningococcus, HPV, and the future.

Since January 2005, new vaccines against pertussis, meningococcal disease, and human papillomavirus (HPV) infection have been licensed. The target recipients are adolescents and preadolescents, who are at higher risk of these infections than other age groups. Routinely scheduled visits for 11- to 12-year-olds will allow for immunization against these and other diseases and give us an opportunity to provide anticipatory guidance against high-risk behaviors.

Shift in the epidemiology of pertussis infection: an indication for pertussis vaccine boosters for adults?

Pertussis vaccination of young children has been effective in reducing the overall disease burden due to Bordetella pertussis in many countries. However, the disease has not been eliminated, although humans are the only known host of this pathogen. In fact, in some countries, the number of reported cases has increased dramatically from their nadir and epidemics routinely occur. In areas where >80% of children <2 years of age have been vaccinated, the burden of disease has shifted from elementary school-aged children (who are presumably protected by vaccination) to young infants (<6 months of age) and individuals >11 years of age. With the recent availability of acellular pertussis vaccines for older children to adults, consideration of a change in current vaccination policy is necessary in order to provide better disease control.

PEDIARIX: clinical trials.

PEDIARIX is the first pentavalent combination vaccine licensed for use in infants in the USA. This vaccine is indicated for the prevention of diphtheria, tetanus, pertussis, hepatitis B and poliovirus. This article reviews the available data regarding the vaccine's immunogenicity and safety.

A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.

BACKGROUND: A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS: One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS: The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS: Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

Pertussis: persistent pathogen, imperfect vaccines.

Routine use of pertussis vaccines has diminished the incidence of this disease but has not eliminated the pathogen. Pertussis remains a significant cause of disease in both very young infants and in the adolescent and adult populations. Acellular pertussis vaccines have fewer adverse reactions compared with whole-cell pertussis vaccines. Although efficacious against severe disease, current vaccines may not be as efficacious against milder forms of infection. New methodologies for understanding disease pathogenesis, immune responses and vaccine development are needed to effectively interrupt continued transmission of this pathogen.

Heptavalent pneumococcal vaccine conjugated to outer membrane protein of Neisseria meningitidis serogroup b and nasopharyngeal carriage of Streptococcus pneumoniae in infants.

BACKGROUND: Streptococcus pneumoniae (Sp) is an important bacterial pathogen in children. Nasopharyngeal (NP) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease. METHODS: NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine (PCV) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis (vaccine serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F). The vaccine was administered at 2, 4, 6, and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV and evaluated over the first 15 months of life. RESULTS: Overall, Sp was isolated in 86/367 (23%) of NP cultures and 49% of infants. Serotype 23F was significantly less prevalent in the PCV group (1.9%) than the control group (16.1%) (P<0.05). Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype. We noted, however, decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes (76 and 52% reduction, respectively), but this did not reach statistical significance (P=0.3). Adjustment for age, daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups. CONCLUSION: We did not show a significant effect of this heptavalent PCV on NP carriage. Further study of this issue, including a larger population size, is needed.

Clinical evaluation of a DTaP-HepB-IPV combined vaccine.

OBJECTIVE: To provide an overview of prelicensure clinical data for a new pediatric vaccine that combines diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliovirus vaccines into a single injection (DTaP-HepB-IPV combined vaccine; Pediarix, GlaxoSmithKline Biologicals, Rixensart, Belgium). METHODS: The safety and immunogenicity of DTaP-HepB-IPV combined vaccine have been evaluated extensively in clinical trials in infants. To date, DTaP-HepB-IPV combined vaccine has been administered to more than 7,000 infants as a 3-dose primary series during the first year of life. RESULTS: Studies show that DTaP-HepB-IPV combined vaccine is generally safe, well tolerated, and has not caused any significant serious adverse events. The rates of solicited and unsolicited reports of adverse reactions following vaccination were similar between groups receiving DTaP-HepB-IPV combined vaccine and comparator groups receiving the vaccine components separately. DTaP-HepB-IPV combined vaccine induces immunogenicity (as measured by seroprotection or vaccine response rates to each of the vaccine components [diphtheria, tetanus, 3 pertussis antigens, hepatitis B, and poliovirus types 1, 2, and 31) similar to licensed vaccine components administered separately. CONCLUSION: In prelicensure clinical studies, DTaP-HepB-IPV combined vaccine was safe and immunogenic when given to infants as a primary 3-dose series. As a single injection of multiple vaccine components, DTaP-HepB-IPV combined vaccine may provide a safe and effective alternative to the current multiple-injection immunization regimen.