Antibiotic regimens for late-onset neonatal sepsis

Korang, Steven Kwasi; Safi, Sanam; Nava, Chiara; Greisen, Gorm; Gupta, Munish; Lausten-Thomsen, Ulrik; Jakobsen, Janus Christian

doi:10.1002/14651858.cd013836.pub2

Cited by 29 publications

(31 citation statements)

References 200 publications

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“…30 However, data in neonates and young infants in many LMIC settings are scarce. 15,31 A limited number of largely retrospective observational studies have shown an increase in mortality particularly in association with resistant Gram negative infections 32–35 , such as those due to organisms producing extended spectrum beta-lactamases (ESBL) 3 -39 and carbapenem resistant organisms (CRO), 40–43 and some suggest an increase in mortality in the absence of appropriate antimicrobial therapy. 32,44–47 A recent large multicentre neonatal sepsis study (BARNARDS) demonstrated high resistance to ampicillin + gentamicin (97% and 70%, respectively) among Gram-negative infections; however, analysis of the influence of antibiotic treatment on outcomes was confounded by country effects, and limited clinical data prevented adjusting for other important confounders.…”

Section: Discussionmentioning

confidence: 99%

“…After initial therapy, 728/2880 (25.3%) who started on Group 1-4 regimens were escalated to a higher group regimen, the majority switching within the first days of treatment (supplement figures [15][16][17]. 258/814 (31.7%) infants escalated from Group 1 (ampicillin/gentamicin) regimens, the majority of which switched to Group 2 (cefotaxime/ceftriaxone-based) regimens (61.6%, n=159) (figure 1c).…”

Section: Antibiotic Switchingmentioning

confidence: 99%

“…Despite this, there is limited high quality evidence generated in LMIC neonatal inpatient settings to guide empiric antibiotic treatment. 4,15 Published observational data largely involve single centre studies reporting non-systematically collected microbiological data, which are rarely accompanied by detailed clinical and antibiotic use data. Global antibiotic use data largely rely on point prevalence surveys, with limited information on patterns of switching and duration.…”

Section: Introductionmentioning

confidence: 99%

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Patterns of antibiotic use, pathogens and clinical outcomes in hospitalised neonates and young infants with sepsis in the NeoOBS global neonatal sepsis observational cohort study

Russell

Stöhr

Plakkal

et al. 2022

Preprint

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Background Neonatal sepsis is a leading cause of child mortality, and increasing antimicrobial resistance threatens progress towards the Sustainable Development Goals. Evidence to guide antibiotic treatment for sepsis in neonates and young infants from randomized controlled trials or observational studies in low- and middle-income countries (LMICs) is scarce. We aimed to describe patterns of antibiotic use, pathogens and outcomes in LMIC hospital settings globally to inform future clinical trials on the management of neonatal sepsis. Methods & Findings Hospitalised infants aged <60 days with clinical sepsis were enrolled during 2018-2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily data was collected on clinical signs, supportive care, antibiotic treatment, microbiology and clinical outcome at 28 days. The study was observational, with no changes to routine clinical practice. 3204 infants were enrolled, with median birth weight 2500g (IQR 1400-3000) and postnatal age 5 days (IQR 2-15). Of 309 enrolled aged 28-60 days, 58.6% (n=181) were ex-preterm and/or a neonate at admission. 2215 (69%) infants had been in hospital since birth. 206 different empiric antibiotic combinations were used, which were structured into 5 groups that were developed from the World Health Organisation (WHO) AWaRe classification. 25.9% (n=814) of infants started a WHO first line regimen (Group 1 Access, penicillin-based regimen) and 13.8% (n=432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2 Low Watch). The largest group (34.0%, n=1068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3 Medium Watch), 18.0% (n=566) started a carbapenem (Group 4 High Watch), and 1.8% (n=57) started a Reserve antibiotic (Group 5, largely colistin-based). Predictors of starting non-WHO recommended regimens included lower birth weight, longer in-hospital stay, central vascular catheter use, previous culture positive sepsis or antibiotic exposure, previous surgery and greater sepsis severity. 728/2880 (25.3%) of initial regimens in Group 1-4 were escalated, mainly to carbapenems, and usually for clinical indications (n=480; 65.9%). 564 infants (17.6%) isolated a pathogen from their baseline blood culture, of which 62.9% (n=355) had a Gram-negative organism, predominantly Klebsiella pneumoniae (n=132) and Acinetobacter spp. (n=72). These leading Gram-negatives were both mostly resistant to WHO-recommended regimens, and also resistant to carbapenems in 32.6% and 71.4% of cases respectively. MRSA accounted for 61.1% of Staphylococcus aureus (n=54) isolates. Overall, 350/3204 infants died (11.3%; 95%CI 10.2-12.5%), with 17.7% case fatality rate among infants with a pathogen in baseline culture (95%CI 14.7-20.1%, n=99/564). Gram-negative infections accounted for 75/99 (75.8%) of pathogen-positive deaths, especially Klebsiella pneumoniae (n=28; 28.3%), and Acinetobacter spp. (n=24; 24.2%). Conclusion A very wide range of antibiotic regimens are now used to treat neonatal sepsis globally. There is common use of higher-level Watch antibiotics, frequent early switching and very infrequent de-escalation of therapy. Future hospital based neonatal sepsis trials will ideally need to account for the multiple regimens used as standard of care globally and include both empiric first line regimens and subsequent switching in the trial design.

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Section: Discussionmentioning

confidence: 99%

Section: Antibiotic Switchingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patterns of antibiotic use, pathogens and clinical outcomes in hospitalised neonates and young infants with sepsis in the NeoOBS global neonatal sepsis observational cohort study

Russell

Stöhr

Plakkal

et al. 2022

Preprint

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“…The authors suggest further RCTs of different antibiotic regimens in late-onset neonatal sepsis are required. 25 Flannery et al the emergence of multidrug-resistant microorganisms requiring Surveillance and prevention is a paediatric research priority. Extended-spectrum β–lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CRE) are increasing and their impact on morbidity and novel antibiotic therapies are required.…”

Section: Treatments and Future Plans In Paediatric And Neonatal Sepsismentioning

confidence: 99%

Paediatric and neonatal sepsis and inflammation

Molloy

Bearer

2022

Pediatr Res

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Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

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“…( 118 - 120 ) A 2021 Cochrane systematic review assessed the effects of different LOI regimens, and similar to the previously discuss EOI Cochrane review, found that all analyzed trials were at high risk for bias and provided low-quality evidence. ( 121 ) Prescribers must therefore balance the risk of suboptimal empiric coverage with excessive coverage; the issue is complicated by a lack of clarity as to whether suboptimal early coverage impacts relevant clinical outcomes. The World Health Organization recommends ampicillin and gentamicin as first line therapy for neonatal sepsis in LMIC, and 3 rd generation cephalosporins as second line.…”

Section: Empiric Therapymentioning

confidence: 99%

Neonatal multidrug-resistant gram-negative infection: epidemiology, mechanisms of resistance, and management

et al. 2021

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Infants admitted to the neonatal intensive care unit, particularly those born preterm, are at high risk for infection due to the combination of an immature immune system, prolonged hospitalization, and frequent use of invasive devices. Emerging evidence suggests that multidrug resistant gram-negative (MDR-GN) infections are increasing in neonatal settings, which directly threatens recent and ongoing advances in contemporary neonatal care. A rising prevalence of antibiotic resistance among common neonatal pathogens compounds the challenge of optimal management of suspected and confirmed neonatal infection. We review the epidemiology of MDR-GN infections in neonates in the United States and internationally, with a focus on extended-spectrum β-lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CRE). We include published single center studies, neonatal collaborative reports, and national surveillance data. Risk factors for and mechanisms of resistance are discussed. Additionally, we discuss current recommendations for empiric antibiotic therapy for suspected infections, as well as definitive treatment options for key multidrug resistant organisms. Finally, we review best practices for prevention and identify current knowledge gaps and areas for future research.

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Antibiotic regimens for late-onset neonatal sepsis

Abstract: Analysis 4.1. Comparison 4: Meropenem versus standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin), Outcome

Cited by 29 publications

References 200 publications

Patterns of antibiotic use, pathogens and clinical outcomes in hospitalised neonates and young infants with sepsis in the NeoOBS global neonatal sepsis observational cohort study

Patterns of antibiotic use, pathogens and clinical outcomes in hospitalised neonates and young infants with sepsis in the NeoOBS global neonatal sepsis observational cohort study

Paediatric and neonatal sepsis and inflammation

Neonatal multidrug-resistant gram-negative infection: epidemiology, mechanisms of resistance, and management

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