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1.
Lancet Infect Dis ; 2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33482143

RESUMEN

BACKGROUND: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule. METHODS: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001). FINDINGS: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001). INTERPRETATION: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease. FUNDING: Wellcome Trust, UK Department of Health, and National Institute for Health Research.

3.
Lancet ; 2020 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-33306989

RESUMEN

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

4.
Emerg Infect Dis ; 26(11): 2651-2659, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33079042

RESUMEN

We performed a systematic review and meta-analysis of the incidence, case-fatality rate (CFR), isolate antimicrobial resistance patterns, and serotype and sequence type distributions for invasive group B Streptococcus (GBS) disease in infants <1-89 days of age in China. We searched the PubMed/Medline, Embase, Wanfang, and China National Knowledge Infrastructure databases for research published during January 1, 2000-March 16, 2018, and identified 64 studies. Quality of included studies was assessed by using Cochrane tools. Incidence and CFR were estimated by using random-effects meta-analyses. Overall incidence was 0.55 (95% CI 0.35-0.74) cases/1,000 live births, and the CFR was 5% (95% CI 3%-6%). Incidence of GBS in young infants in China was higher than the estimated global incidence (0.49 cases/1,000 live births) and higher than previous estimates for Asia (0.3 cases/1,000 live births). Our findings suggest that implementation of additional GBS prevention efforts in China, including maternal vaccination, could be beneficial.

5.
Curr Opin Infect Dis ; 33(6): 517-529, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33044242

RESUMEN

PURPOSE OF REVIEW: Gram-negative bacteria (GNB) are a major cause of infection worldwide and multidrug resistance in infants and children. The major pathogens include Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa and Acinetobacter baumannii. With new antibiotic options limited, immunization is likely to play a critical role in prevention. This review discusses their epidemiology, the current state of vaccine research and potential immunization strategies to protect children. A comprehensive review of the literature, conference abstracts along with web searches was performed to identify current and investigational vaccines against the major GNB in children. RECENT FINDINGS: Phase I--III vaccine trials have been undertaken for the major Gram-negative bacteria but not in infants or children. E. coli is a common infection in immune-competent children, including neonatal sepsis. Several vaccines are in late-phase clinical trials, with some already licensed for recurrent urinary tract infections in women. Klebsiella spp. causes community-acquired and hospital-acquired infections, including sepsis in neonates and immunocompromised children although no vaccine trials have extended beyond early phase 2 trials. P. aeruginosa is a common pathogen in patients with cystic fibrosis. Phase 1--3 vaccine and monoclonal antibody trials are in progress, although candidates provide limited coverage against pathogenic strains. Enterobacter spp. and A. baumannii largely cause hospital-acquired infections with experimental vaccines limited to phase 1 research. SUMMARY: The current immunization pipelines for the most prevalent GNB are years away from licensure. Similar to incentives for new antibiotics, global efforts are warranted to expedite the development of effective vaccines.

6.
Clin Infect Dis ; 2020 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-32989454

RESUMEN

BACKGROUND AND OBJECTIVES: Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in infants <90 days. In this study, the burden of GBS disease and mortality in young infants in England was assessed. METHODS: Using linked hospitalisation records from every National Health Service (NHS) hospital from 1 April 1998 to 31 March 2017, we calculated annual GBS incidence in infants aged <90 days and, using regression models, compared their perinatal factors, rates of hospital-recorded disease outcomes and all-cause infant mortality rates with those of the general infant population. RESULTS: 15,429 infants aged <90 days had a hospital-recorded diagnosis of GBS, giving an average annual incidence of 1.28 per 1000 live births (95% CI 1.26-1.30) with no significant trend over time. GBS-attributable mortality declined significantly from 0.044 (95%CI 0.029-0.065) per 1000 live births in 2001 to 0.014 (95%CI 0.010-0.026) in 2017 (annual percentage change -6.6, 95%CI -9.1 to -4.0). Infants with GBS had higher relative rates of visual impairment (HR 7.0 95% CI 4.1-12.1), cerebral palsy (HR 9.3 95% CI 6.6-13.3), hydrocephalus (HR 17.3 95% CI 13.8-21.6) and NEC (HR 18.8 95% CI 16.7-21.2) compared with those without GBS. CONCLUSIONS: Annual rates of GBS disease in infants have not changed over 19 years. The reduction in mortality is likely multifactorial and due to widespread implementation of antibiotics in at-risk mothers and babies as well as advances in managing acutely unwell infants. New methods for prevention, such as maternal vaccination, must be prioritised.

8.
Clin Infect Dis ; 2020 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-32766850

RESUMEN

BACKGROUND: The true frequency of hospital outbreaks of invasive group B streptococcal (iGBS; Streptococcus agalactiae) disease in infants is unknown. We used whole genome sequencing (WGS) of iGBS isolates collected during a period of enhanced surveillance of infant iGBS disease in the UK and Ireland to determine the number of clustered cases. METHODS: Potentially linked iGBS cases from infants with early (<7 days of life) or late-onset (7-89 days) disease were identified from WGS data (HiSeq 2500 platform, Illumina) from clinical sterile site isolates collected between 04/2014 and 04/2015. We assessed time and place of cases to determine a single-nucleotide polymorphism (SNP) difference threshold for clustered cases. Case details were augmented through linkage to national hospital admission data and hospital record review by local microbiologists. RESULTS: Analysis of sequences indicated a cut-off of ≤5 SNP differences to define iGBS clusters. Among 410 infant iGBS isolates, we identified 7 clusters (4 genetically-identical pairs with 0 SNP differences, one pair with 3 SNP differences, one cluster of 4 cases with ≤1 SNP differences) of which 4 clusters were uncovered for the first time. The clusters comprised 16 cases, of which 15 were late-onset (of 192 late-onset cases with sequenced isolates) and one an early-onset index case. Serial intervals between cases ranged from 0-59 (median 12) days. CONCLUSIONS: Approximately one in 12 late-onset infant iGBS cases were part of a hospital cluster. Over half of clusters were previously undetected, emphasising the importance of routine submission of iGBS isolates to reference laboratories for cluster identification and genomic confirmation.

9.
N Engl J Med ; 383(5): 426-439, 2020 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-32726529

RESUMEN

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).


Asunto(s)
Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio/prevención & control , Adolescente , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Hipoxia/etiología , Inmunoglobulina G/sangre , Lactante , Recién Nacido , Enfermedades del Recién Nacido/prevención & control , Inyecciones Intramusculares , Nanopartículas , Distribución de Poisson , Embarazo , Tercer Trimestre del Embarazo , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/epidemiología , Virus Sincitial Respiratorio Humano/inmunología , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/virología , Vacunación , Proteínas Virales de Fusión/inmunología , Adulto Joven
10.
Vaccine ; 38(35): 5718-5725, 2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32654902

RESUMEN

BACKGROUND: Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants. METHODS: In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM197 protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8). RESULTS: Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose. CONCLUSIONS: DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.

11.
Pediatr Infect Dis J ; 39(10): 949-954, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32502127

RESUMEN

BACKGROUND: Congenital cytomegalovirus infection is the most common nongenetic cause of sensorineural hearing loss in childhood and an important cause of neurodisability. There is no licensed cytomegalovirus (CMV) vaccine and no antenatal treatment for congenital CMV that is routinely recommended in clinical practice in the United Kingdom. OBJECTIVES: To review the published literature for studies that evaluated preventative hygiene-based interventions in pregnancy for their impact on knowledge about CMV prevention, the uptake of preventative behaviors or the acquisition of CMV in pregnancy. SEARCH STRATEGY: Searches were carried out in Medical Literature Analysis and Retrieval System Online and Cumulative Index of Nursing and Allied Health Literature databases. SELECTION CRITERIA: All human studies, limited to women of childbearing age were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the methods and results of included articles. Extracted data were classified using Cochrane guidelines. MAIN RESULTS: Seven studies met the inclusion criteria. These show that preventative measures are acceptable to pregnant women, can impact their behavior and have the potential to reduce CMV in pregnancy. They are limited by several factors; sample size, nonrandomized trial design and interventions that are beyond routine clinical practice. CONCLUSIONS: An effective intervention that changes behavior in pregnancy and reduces the risk of CMV acquisition is needed as part of routine care. There is currently insufficient evidence about the form that this intervention should take. REGISTRATION: PROSPERO registration number: CRD42017069666.

12.
Infect Drug Resist ; 13: 1263-1272, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32425562

RESUMEN

Group B streptococcus (GBS) causes a high burden of neonatal and infant disease globally. Implementing a vaccine for pregnant women is a promising strategy to prevent neonatal and infant GBS disease and has been identified as a priority by the World Health Organisation (WHO). GBS serotype-specific polysaccharide - protein conjugate vaccines are at advanced stages of development, but a large number of participants would be required to undertake Phase III clinical efficacy trials. Efforts are therefore currently focused on establishing serocorrelates of protection in natural immunity studies as an alternative pathway for licensure of a GBS vaccine, followed by Phase IV studies to evaluate safety and effectiveness. Protein vaccines are in earlier stages of development but are highly promising as they might confer protection irrespective of serotype. Further epidemiological, immunological and health economic studies are required to enable the vaccine to reach its target population as soon as possible.

13.
Trials ; 21(1): 329, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32293527

RESUMEN

BACKGROUND: Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin's continued efficacy. METHODS: NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy. DISCUSSION: Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02790996. Registered on 7 April 2016. EudraCT, 2015-000203-89. Entered on 18 July 2016.

14.
PLoS One ; 15(3): e0229380, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32130261

RESUMEN

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS. METHODS AND FINDINGS: NeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.


Asunto(s)
Meropenem/uso terapéutico , Sepsis Neonatal/tratamiento farmacológico , Nivel de Atención , Femenino , Humanos , Lactante , Masculino , Meropenem/efectos adversos , Seguridad , Resultado del Tratamiento
15.
JAMA Netw Open ; 3(2): e1921124, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-32049298

RESUMEN

Importance: High levels of antimicrobial resistance in neonatal bloodstream isolates are being reported globally, including in Asia. Local hospital antibiogram data may include too few isolates to meaningfully examine the expected coverage of antibiotic regimens. Objective: To assess the coverage offered by 3 antibiotic regimens for empirical treatment of neonatal sepsis in Asian countries. Design, Setting, and Participants: A decision analytical model was used to estimate coverage of 3 prespecified antibiotic regimens according to a weighted-incidence syndromic combination antibiogram. Relevant data to parameterize the models were identified from a systematic search of Ovid MEDLINE and Embase. Data from Asian countries published from 2014 onward were of interest. Only data on blood culture isolates from neonates with sepsis, bloodstream infection, or bacteremia reported from the relevant setting were included. Data analysis was performed from April 2019 to July 2019. Exposures: The prespecified regimens of interest were aminopenicillin-gentamicin, third-generation cephalosporins (cefotaxime or ceftriaxone), and meropenem. The relative incidence of different bacteria and their antimicrobial susceptibility to antibiotics relevant for determining expected concordance with these regimens were extracted. Main Outcomes and Measures: Coverage was calculated on the basis of a decision-tree model incorporating relative bacterial incidence and antimicrobial susceptibility of relevant isolates. Data on 7 bacteria most commonly reported in the included studies were used for estimating coverage, which was reported at the country level. Results: Data from 48 studies reporting on 10 countries and 8376 isolates were used. Individual countries reported 51 (Vietnam) to 6284 (India) isolates. Coverage varied considerably between countries. Meropenem was generally estimated to provide the highest coverage, ranging from 64.0% (95% credible interval [CrI], 62.6%-65.4%) in India to 90.6% (95% CrI, 86.2%-94.4%) in Cambodia, followed by aminopenicillin-gentamicin (from 35.9% [95% CrI, 27.7%-44.0%] in Indonesia to 81.0% [95% CrI, 71.1%-89.7%] in Laos) and cefotaxime or ceftriaxone (from 17.9% [95% CrI, 11.7%-24.7%] in Indonesia to 75.0% [95% CrI, 64.8%-84.1%] in Laos). Aminopenicillin-gentamicin coverage was lower than that of meropenem in all countries except Laos (81.0%; 95% CrI, 71.1%-89.7%) and Nepal (74.3%; 95% CrI, 70.3%-78.2%), where 95% CrIs for aminopenicillin-gentamicin and meropenem were overlapping. Third-generation cephalosporin coverage was lowest of the 3 regimens in all countries. The coverage difference between aminopenicillin-gentamicin and meropenem for countries with nonoverlapping 95% CrIs ranged from -15.9% in China to -52.9% in Indonesia. Conclusions and Relevance: This study's findings suggest that noncarbapenem antibiotic regimens may provide limited coverage for empirical treatment of neonatal sepsis in many Asian countries. Alternative regimens must be studied to limit carbapenem consumption.


Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana , Sepsis Neonatal , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Asia/epidemiología , Bacterias/efectos de los fármacos , Toma de Decisiones Clínicas , Árboles de Decisión , Quimioterapia Combinada , Gentamicinas/farmacología , Gentamicinas/uso terapéutico , Humanos , Incidencia , Recién Nacido , Pruebas de Sensibilidad Microbiana , Sepsis Neonatal/tratamiento farmacológico , Sepsis Neonatal/epidemiología , Sepsis Neonatal/microbiología , beta-Lactamas/farmacología , beta-Lactamas/uso terapéutico
16.
PLoS One ; 15(1): e0226817, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31978082

RESUMEN

BACKGROUND: A large proportion of neonates are treated for presumed bacterial sepsis with broad spectrum antibiotics even though their blood cultures subsequently show no growth. This study aimed to investigate PCR-based methods to identify pathogens not detected by conventional culture. METHODS: Whole blood samples of 208 neonates with suspected early onset sepsis were tested using a panel of multiplexed bacterial PCRs targeting Streptococcus pneumoniae, Streptococcus agalactiae (GBS), Staphylococcus aureus, Streptococcus pyogenes (GAS), Enterobacteriaceae, Enterococcus faecalis, Enterococcus faecium, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium, a 16S rRNA gene broad-range PCR and a multiplexed PCR for Candida spp. RESULTS: Two-hundred and eight samples were processed. In five of those samples, organisms were detected by conventional culture; all of those were also identified by PCR. PCR detected bacteria in 91 (45%) of the 203 samples that did not show bacterial growth in culture. S. aureus, Enterobacteriaceae and S. pneumoniae were the most frequently detected pathogens. A higher bacterial load detected by PCR was correlated positively with the number of clinical signs at presentation. CONCLUSION: Real-time PCR has the potential to be a valuable additional tool for the diagnosis of neonatal sepsis.


Asunto(s)
Bacterias/aislamiento & purificación , Infecciones Bacterianas/diagnóstico , Candida/aislamiento & purificación , Candidiasis/diagnóstico , Sepsis Neonatal/microbiología , ARN Ribosómico 16S/genética , Edad de Inicio , Bacterias/genética , Candida/genética , ADN Ribosómico/genética , Diagnóstico Precoz , Enterobacteriaceae/genética , Enterobacteriaceae/aislamiento & purificación , Enterococcus/genética , Enterococcus/aislamiento & purificación , Humanos , Recien Nacido Extremadamente Prematuro , Recién Nacido , Recien Nacido Prematuro , Reacción en Cadena de la Polimerasa Multiplex , Mycoplasma/genética , Mycoplasma/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y Especificidad , Staphylococcus aureus/genética , Staphylococcus aureus/aislamiento & purificación , Streptococcus/genética , Streptococcus/aislamiento & purificación , Ureaplasma/genética , Ureaplasma/aislamiento & purificación
17.
Clin Infect Dis ; 71(5): 1271-1280, 2020 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-31586206

RESUMEN

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy. METHODS: Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months. RESULTS: One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%-27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%-75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%-57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%-72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%-62.6%) maintained immunity at 12 months. CONCLUSIONS: This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection. CLINICAL TRIALS REGISTRATION: EudraCT 2009-011587-11.

19.
J Infect ; 79(6): 521-527, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31733233

RESUMEN

OBJECTIVES: To characterize outbreaks of invasive Group B Streptococcal (iGBS) disease in hospitals. METHODS: Systematic review using electronic databases to identify studies describing iGBS outbreaks/clusters or cross-infection/acquisition in healthcare settings where 'cluster' was defined as ≥2 linked cases. PROSPERO CRD42018096297. RESULTS: Twenty-five references were included describing 30 hospital clusters (26 neonatal, 4 adult) in 11 countries from 1966 to 2019. Cross-infection between unrelated neonates was reported in 19 clusters involving an early-onset (<7 days of life; n = 3), late-onset (7-90 days; n = 13) index case or colonized infant (n = 3) followed by one or more late-onset cases (median serial interval 9 days (IQR 3-17, range 0-50 days, n = 45)); linkage was determined by phage typing in 3 clusters, PFGE/MLST/PCR in 8, WGS in 4, non-molecular methods in 4. Postulated routes of transmission in neonatal clusters were via clinical personnel and equipment, particularly during periods of crowding and high patient-to-nurse ratio. Of 4 adult clusters, one was attributed to droplet spread between respiratory cases, one to handling of haemodialysis catheters and two unspecified. CONCLUSIONS: Long intervals between cases were identified in most of the clusters, a characteristic which potentially hinders detection of GBS hospital outbreaks without enhanced surveillance supported by genomics.


Asunto(s)
Infección Hospitalaria/epidemiología , Brotes de Enfermedades , Sepsis Neonatal/epidemiología , Infecciones Estreptocócicas/epidemiología , Streptococcus agalactiae/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Tipificación de Bacteriófagos , Análisis por Conglomerados , Infección Hospitalaria/microbiología , Monitoreo Epidemiológico , Femenino , Hospitales , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Tipificación Molecular , Sepsis Neonatal/microbiología , Infecciones Estreptocócicas/microbiología
20.
Ann Clin Microbiol Antimicrob ; 18(1): 36, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31727088

RESUMEN

BACKGROUND: Carbapenems are ß-lactam antibiotics which are used to treat severe infections caused by multidrug resistant Enterobacteriacea. The recent emergence and rapid spread of Enterobacteriaceae resistant to carbapenems is a global concern. We undertook a systematic review of the antibiotic susceptibility and genotypic characteristics of carbapenem-resistant Enterobacteriaceae in Chinese neonates. METHODS: Systematic literature reviews were conducted (PubMed/Medline, Embase, Wanfang medical online databases, China National Knowledge Infrastructure (CNKI) database) regarding sepsis caused by carbapenem-resistant Enterobacteriaceae in Chinese neonates aged 0-30 days. RESULTS: 17 studies were identified. Eleven patients in the six studies reported the source of infection. Ten patients (10/11, 90.9%) were hospital-acquired infections. Genotypic data were available for 21 isolates in 11 studies (20 K. pneumoniae, 1 E. coli). NDM-1 was the most frequently reported carbapenem-resistant genotype (81.0%, 17/21). Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli were resistant to many antibiotic classes with the exception of colistin and fosfomycin. Sequence type 105 (ST105) was the most commonly reported K. pneumoniae ST type (30.8%; 4/13), which was from the same hospital in Western China. ST17 and ST20 were the second and third most common K. pneumoniae ST type, 23.1% (3/13) and 15.4% (2/13) respectively. The three strains of ST17 are all from the same hospital in central China. The two strains of ST20, although not from the same hospital, belong to the eastern part of China. CONCLUSIONS: Klebsiella pneumoniae with the NDM-1 genotype was the leading cause of neonatal carbapenem resistant sepsis in China. Hospital acquired infection is the main source of carbapenem resistant sepsis. There is currently no licenced antibiotic regimen available to treat such an infection in China. Improved surveillance, controlling nosocomial infection and the rational use of antibiotics are the key factors to prevent and reduce its spread.


Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos , Infección Hospitalaria/microbiología , Infecciones por Enterobacteriaceae , Sepsis Neonatal , Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Carbapenémicos/uso terapéutico , China/epidemiología , Infección Hospitalaria/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple/genética , Enterobacteriaceae/genética , Enterobacteriaceae/aislamiento & purificación , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/epidemiología , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Genes Bacterianos , Humanos , Lactante , Recién Nacido , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Sepsis Neonatal/microbiología , Resistencia betalactámica/genética , beta-Lactamasas/genética
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