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The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi.

ABSTRACT: The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice, and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin with ceftriaxone as first-line treatment, assessing outcome and adverse events.This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi, from 2010 to 2013. Infants <60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge.Three-hundred forty-eight infants were included in analyses. Outcome in the benzylpenicillin and gentamicin and ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae were 14.5% and 11.2%, respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% versus 5%, P = 0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge, 11 more infants had died, and 17 more children were found to have sequelae.Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long-term follow-up as many poor outcomes occurred after hospital discharge.

SUBMITTER: Molyneux EM

PROVIDER: S-EPMC5466153 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi.

Molyneux Elizabeth M EM Dube Queen Q Banda Francis M FM Chiume Msandeni M Singini Isaac I Mallewa Macpherson M Schwalbe Edward C EC Heyderman Robert S RS

The Pediatric infectious disease journal 20171201 12

<h4>Background</h4>The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative ...[more]

PMID: 28263245

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Project description:BackgroundInfant gut microbiota is highly malleable, but the long-term longitudinal impact of antibiotic exposure in early life, together with the mode of delivery on infant gut microbiota and resistome, is not extensively studied.MethodsTwo hundred and eight samples from 45 infants collected from birth until 2 years of age over five time points (week 1, 4, 8, 24, year 2) were analysed. Based on shotgun metagenomics, the gut microbial composition and resistome profile were compared in the early life of infants divided into three groups: vaginal delivery/no-antibiotic in the first 4 days of life, C-section/no-antibiotic in the first 4 days of life, and C-section/antibiotic exposed in first 4 days of life. Gentamycin and benzylpenicillin were the most commonly administered antibiotics during this cohort's first week of life.ResultsNewborn gut microbial composition differed in all three groups, with higher diversity and stable composition seen at 2 years of age, compared to week 1. An increase in microbial diversity from week 1 to week 4 only in the C-section/antibiotic-exposed group reflects the effect of antibiotic use in the first 4 days of life, with a gradual increase thereafter. Overall, a relative abundance of Actinobacteria and Bacteroides was significantly higher in vaginal delivery/no-antibiotic while Proteobacteria was higher in C-section/antibiotic-exposed infants. Strains from species belonging to Bifidobacterium and Bacteroidetes were generally persistent colonisers, with Bifidobacterium breve and Bifidobacterium bifidum species being the major persistent colonisers in all three groups. Bacteroides persistence was dominant in the vaginal delivery/no-antibiotic group, with species Bacteroides ovatus and Phocaeicola vulgatus found to be persistent colonisers in the no-antibiotic groups. Most strains carrying antibiotic-resistance genes belonged to phyla Proteobacteria and Firmicutes, with the C-section/antibiotic-exposed group presenting a higher frequency of antibiotic-resistance genes (ARGs).ConclusionThese data show that antibiotic exposure has an immediate and persistent effect on the gut microbiome in early life. As such, the two antibiotics used in the study selected for strains (mainly Proteobacteria) which were multiple drug-resistant (MDR), presumably a reflection of their evolutionary lineage of historical exposures-leading to what can be an extensive and diverse resistome. Video Abstract.

Project description:ImportanceYoung febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach.ObjectiveTo assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections.Design, setting, and participantsProspective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.ExposureRNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections.Main outcomes and measuresBacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores.ResultsOf 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43).Conclusions and relevanceIn this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

Project description:The goal of this work was to study the phenotypic susceptibility and resistance determinants of N. gonorrhoeae isolates to beta-lactam antimicrobials (benzylpenicillin and ceftriaxone). A total of 522 clinical isolates collected in Russia in 2015-2017 were analysed for susceptibility using the agar dilution method. DNA loci involved in antimicrobial resistance were identified using DNA microarray analysis and sequencing. Resistance to benzylpenicillin remained high, with 7.7% of isolates resistant (MICpen > 1 mg/L) and 47.5% of isolates showing intermediate susceptibility (MICpen = 0.12-1 mg/L). The most frequent resistance determinant (72.4% isolates) was the Asp345 insertion in penA, both as a single mutation and in combination with other mutations, particularly with the substitution Leu421Pro in ponA (39.0%). Mutations affecting the influx and efflux of drugs were also found, including amino acid substitutions in PorB (26.8% isolates) and delA in the promoter region of mtrR (22.8%). The accumulation of mutations in chromosomal genes (penA, pon, porA, and mtrR) led to a stepwise increase in MICpen to values characteristic of intermediate resistance. The presence of blaTEM plasmids was found in 25 isolates (4.8%), resulting in a strong increase in resistance to penicillin (MICpen > 16 mg/L) compared with the chromosomal mutations; 23 plasmids were of the African type with TEM-1 beta-lactamase, and two plasmids were of the Toronto/Rio type with TEM-135 beta-lactamase. Only three isolates were found with reduced susceptibility to ceftriaxone, with MICcef = 0.12-0.25 mg/L. Sequencing of penA did not reveal mutations associated with resistance to third-generation cephalosporins, and the gene structure was non-mosaic. The majority of isolates (21 of 25) carrying the blaTEM plasmid also contained the conjugative plasmid with tetM (resistance to tetracyclines), consistent with previously reported data that the presence of the conjugative plasmid facilitates the transfer of other plasmids associated with antimicrobial resistance.

Project description:ImportanceClinicians often risk stratify young febrile infants for invasive bacterial infections (IBIs), defined as bacteremia and/or bacterial meningitis, using complete blood cell count parameters.ObjectiveTo estimate the accuracy of individual complete blood cell count parameters to identify febrile infants with IBIs.Design, setting, and participantsPlanned secondary analysis of a prospective observational cohort study comprising 26 emergency departments in the Pediatric Emergency Care Applied Research Network from 2008 to 2013. We included febrile (≥38°C), previously healthy, full-term infants younger than 60 days for whom blood cultures were obtained. All infants had either cerebrospinal fluid cultures or 7-day follow-up.Main outcomes and measuresWe tested the accuracy of the white blood cell count, absolute neutrophil count, and platelet count at commonly used thresholds for IBIs. We determined optimal thresholds using receiver operating characteristic curves.ResultsOf 4313 enrolled infants, 1340 (31%; 95% CI, 30% to 32%) were aged 0 to 28 days, 2412 were boys (56%), and 2471 were white (57%). Ninety-seven (2.2%; 95% CI, 1.8% to 2.7%) had IBIs. Sensitivities were low for common complete blood cell count parameter thresholds: white blood cell count less than 5000/µL, 10% (95% CI, 4% to 16%) (to convert to 109 per liter, multiply by 0.001); white blood cell count ≥15 000/µL, 27% (95% CI, 18% to 36%); absolute neutrophil count ≥10 000/µL, 18% (95% CI, 10% to 25%) (to convert to × 109 per liter, multiply by 0.001); and platelets <100 × 103/µL, 7% (95% CI, 2% to 12%) (to convert to × 109 per liter, multiply by 1). Optimal thresholds for white blood cell count (11 600/µL), absolute neutrophil count (4100/µL), and platelet count (362 × 103/µL) were identified in models that had areas under the receiver operating characteristic curves of 0.57 (95% CI, 0.50-0.63), 0.70 (95% CI, 0.64-0.76), and 0.61 (95% CI, 0.55-0.67), respectively.Conclusions and relevanceNo complete blood cell count parameter at commonly used or optimal thresholds identified febrile infants 60 days or younger with IBIs with high accuracy. Better diagnostic tools are needed to risk stratify young febrile infants for IBIs.

Dataset Information

The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi.

Publications

The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi.

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