A Prospective Cohort Study of Factors Associated with Empiric Antibiotic De-escalation in Neonates Suspected with Early Onset Sepsis (EOS).
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SUBMITTER: Ain Ibrahim N
PROVIDER: S-EPMC7222079 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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A Prospective Cohort Study of Factors Associated with Empiric Antibiotic De-escalation in Neonates Suspected with Early Onset Sepsis (EOS).
Ain Ibrahim Nazedah N Makmor Bakry Mohd M Mohd Tahir Nurul Ain NA Mohd Zaini Nur Rashidah NR Mohamed Shah Noraida N
Paediatric drugs 20200601 3
<h4>Background</h4>Prolonged empiric antibiotic use, resulting from diagnostic uncertainties, in suspected early onset sepsis (EOS) cases constitutes a significant problem. Unnecessary antibiotic use increases the risk of antibiotic resistance. Furthermore, prolonged antibiotic use increases the risk of mortality and morbidity in neonates. Proactive measures including empiric antibiotic de-escalation are crucial to overcome these problems.<h4>Methods</h4>This was a prospective cohort study condu ...[more]
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Project description:BackgroundEarly administration of antibiotics in sepsis is associated with improved patient outcomes, but safe and generalizable approaches to de-escalate or discontinue antibiotics after suspected sepsis events are unknown.MethodsWe used a modified Delphi approach to identify safety criteria for an opt-out protocol to guide de-escalation or discontinuation of antibiotic therapy after 72 hours in non-ICU patients with suspected sepsis. An expert panel with expertise in antimicrobial stewardship and hospital epidemiology rated 48 unique criteria across 3 electronic survey rating tools. Criteria were rated primarily based on their impact on patient safety and feasibility for extraction from electronic health record review. The 48 unique criteria were rated by anonymous electronic survey tools, and the results were fed back to the expert panel participants. Consensus was achieved to either retain or remove each criterion.ResultsAfter 3 rounds, 22 unique criteria remained as part of the opt-out safety checklist. These criteria included high-risk comorbidities, signs of severe illness, lack of cultures during sepsis work-up or antibiotic use prior to blood cultures, or ongoing signs and symptoms of infection.ConclusionsThe modified Delphi approach is a useful method to achieve expert-level consensus in the absence of evidence suifficient to provide validated guidance. The Delphi approach allowed for flexibility in development of an opt-out trial protocol for sepsis antibiotic de-escalation. The utility of this protocol should be evaluated in a randomized controlled trial.
| S-EPMC9495406 | biostudies-literature
Project description:Abstract Background Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. We conducted a randomized controlled trial (NCT03517007) of an opt-out protocol to decrease unnecessary antibiotics in selected patients with suspected sepsis. Methods We evaluated non-ICU adults remaining on broad-spectrum antibiotics with negative blood cultures at 48-96 hours at ten U.S. hospitals during September 2018-May 2020. A 23-item safety check excluded patients with ongoing signs of infection, concerning or inadequate microbiologic data, or high-risk conditions (Figure 1). Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted by a pharmacist or physician to encourage antibiotic discontinuation or de-escalation using opt-out language, discuss rationale for continuing antibiotics, working diagnosis, and de-escalation and duration plans. Hurdle models separately compared the odds of antibiotic continuation and DOT distributions among those who continued antibiotics. Components of the De-Escalating Empiric Therapy: Opting-OUt of Rx in Selected patients with Suspected Sepsis (DETOURS) Trial Protocol Results Among 9606 screened, 767 (8%) were enrolled (Figure 2). Common reasons for exclusion were antibiotics given prior to blood culture (35%), positive culture from non-blood sites (26%), and increased oxygen requirement (21%). Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval [0.47, 0.98]). DOT distributions among those who continued antibiotics were similar (ratio of means 1.06 [0.88-1.26], Figure 3). Fewer intervention patients were exposed to extended-spectrum agents (38% vs. 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was not safe (31%). Safety outcomes such as mortality, readmission, sepsis relapse, C. difficile, and length of stay did not differ. DETOURS Trial Flow Diagram Flow of participants through the DETOURS Trial. Observed Days of Antibiotic Therapy Among Intervention and Control Subjects in the DETOURS Trial Post-enrollment days of antibiotic therapy among 767 DETOURS Trial participants in 10 US acute care hospitals within 30 days after enrollment. Dark pink color indicates percent overlap between intervention (purple) and control (light pink) groups. Conclusion In this patient-level randomized trial of a stewardship intervention, the opt-out de-escalation protocol targeting selected patients with suspected sepsis resulted in more antibiotic discontinuations but did not affect safety events. Disclosures Rebekah W. Moehring, MD, MPH, UpToDate, Inc. (Other Financial or Material Support, Author Royalties) Michael Z. David, MD PhD, GSK (Board Member) Michael Klompas, MD, MPH, UpToDate (Other Financial or Material Support, Chapter Author)
| S-EPMC8643792 | biostudies-literature
Project description:SettingNobel Medical College and Teaching Hospital, Biratnagar, Nepal.ObjectiveTo determine the pattern of antimicrobial resistance and hospital exit outcomes in neonates with suspected sepsis in a tertiary neonatal intensive care unit (NICU).DesignThis hospital-based cohort study was conducted to follow patients from January to December 2019. All identified cases of suspected sepsis were enlisted from hospital records.ResultsSepsis was suspected in 177 (88%) of the 200 cases admitted in the NICU; 52 (29%) were culture-positive. Pseudomonas was the predominant organism isolated (n = 40; 78%), followed by coagulase negative staphylococcus (n = 12, 23%). Nine (17%) of the 52 isolates were resistant to the Access and Watch group of antibiotics, including some resistance to Reserve group drugs such as imipenem and linezolid. Most treated cases (n = 170, 96%) improved, although 7 (4%) left against medical advice.ConclusionMost of the pathogens were resistant to WHO Access and Watch antibiotics and occasional resistance was observed to Reserve group drugs. Most sepsis was caused by Gram-negative bacilli. Improving turnaround times for antibiotic sensitivity testing using point-of-care testing, and a greater yield of culture-positive results are needed to enhance the management of neonatal sepsis.
| S-EPMC8575386 | biostudies-literature
Project description:BackgroundSepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis.MethodsThe study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia).ResultsA total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support.ConclusionsOur findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.
| S-EPMC7788923 | biostudies-literature
Project description:BackgroundLate onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies.MethodsThe PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics.DiscussionThe study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals.Trial registrationClinicaltrials.gov, NCT04152980 , Registered November 6th, 2019.
| S-EPMC8603542 | biostudies-literature
Project description:Context: The incidence of early-onset neonatal infection has greatly decreased, but a new diagnostic approach is needed to avoid overdiagnosis and overtreatment. The aim of this study was to assess the potential impact of an algorithm incorporating umbilical-cord-blood procalcitonin (PCT) level on neonatal antibiotics prescription rate as compared with current practice. Material and methods: We conducted a prospective study in three maternity wards in France. All term and preterm neonates with the usual risk factors for neonatal group B Streptococcus infection were eligible for umbilical-cord-blood PCT testing. We compared the proportion of neonates who were exposed early to antibiotics (before 6 days of life) to that of neonates for whom antibiotics prescription would be indicated according to the PCT-based algorithm. Results: Among the 3,080 neonates included, 1 neonate presented with certain infection and 38 neonates with probable infection. The global antibiotics prescription rate was 4.6% [95% confidence interval (CI), 4.1-5]. With the PCT-based algorithm, the potential decrease in prescription rate would be 1.8% (95% CI, 1.3-2.3), corresponding to a 39% (95% CI, 37.3-40.7) relative reduction in antibiotics exposure (p < 0.05). Conclusion: These results suggest that the umbilical-cord-blood PCT-based algorithm could significantly help the clinicians in their antibiotic prescription decision to decrease neonatal antibiotics exposure as compared with current practice. If validated in a larger interventional randomized study, this approach could help clinicians stratify the risk of early-onset neonatal infection and initiate early antibiotics treatment in newborns at high risk of infection while limiting the deleterious effects of useless prescriptions in non-infected newborns.
| S-EPMC7181674 | biostudies-literature
Project description:BackgroundPremature, very low birth weight (VLBW) neonates are at risk for early-onset sepsis and receive ampicillin and gentamicin post-birth. Antimicrobial stewardship supports short-course antibiotics, but how long antibiotic concentrations remain therapeutic post-last dose is unknown.MethodsUsing Monte Carlo simulations (NONMEM 7.3), we analyzed antibiotic exposures in a retrospective cohort of 34 689 neonates (<1500 g, 22-27 weeks of gestation). Therapeutic exposure for ampicillin and gentamicin was evaluated relative to the minimum inhibitory concentration (MIC) for common pathogens (MIC 0.25-8 mcg/mL for group B streptococcus [GBS] and Escherichia coli). Post-discontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to time when concentration decreased below MIC.ResultsNeonates had a median (range) gestational age of 26 (22-27) weeks and BW, 790 g (400-1497) . All ampicillin dosing regimens (50-100 mg/kg every 8-12 hours for 2-6 doses) achieved therapeutic exposures > MIC range. After the last dose, the PDAE mean (95% confidence interval [CI]) ranged from 34 to 50 hours (17-79) for E. coli (MIC 8) and 82 to 104 hours (95% CI: 39-122) for GBS (MIC 0.25); longer PDAE occurred with higher dose, shorter interval, and longer course. Short-course ampicillin (2 doses, 50 mg/kg every 12 hours) provided PDAE 34 hours for E. coli and 82 hours for GBS. Single-dose 5 mg/kg gentamicin provided PDAE > MIC 2 for 26 hours.ConclusionsIn VLBW neonates, ampicillin exposure remains therapeutic long after the last dose. Short-course ampicillin provided therapeutic exposures throughout the typical blood culture incubation period.
| S-EPMC8163059 | biostudies-literature
Project description:BackgroundEmpiric Gram-negative antibiotics are frequently changed in response to new information. To inform antibiotic stewardship, we sought to identify predictors of antibiotic changes using information knowable before microbiological test results.MethodsWe performed a retrospective cohort study. Survival-time models were used to evaluate clinical factors associated with antibiotic escalation and de-escalation (defined as an increase or decrease, respectively, in the spectrum or number of Gram-negative antibiotics within 5 days of initiation). Spectrum was categorized as narrow, broad, extended or protected. Tjur's D statistic was used to estimate the discriminatory power of groups of variables.ResultsIn 2019, 2 751 969 patients received empiric Gram-negative antibiotics at 920 study hospitals. Antibiotic escalation occurred in 6.5%, and 49.2% underwent de-escalation; 8.8% were changed to an equivalent regimen. Escalation was more likely when empiric antibiotics were narrow-spectrum (HR 19.0 relative to protected; 95% CI: 17.9-20.1), broad-spectrum (HR 10.3; 95% CI: 9.78-10.9) or extended-spectrum (HR 3.49; 95% CI: 3.30-3.69). Patients with sepsis present on admission (HR 1.94; 95% CI: 1.91-1.96) and urinary tract infection present on admission (HR 1.36; 95% CI: 1.35-1.38) were more likely to undergo antibiotic escalation than patients without these syndromes. De-escalation was more likely with combination therapy (HR 2.62 per additional agent; 95% CI: 2.61-2.63) or narrow-spectrum empiric antibiotics (HR 1.67 relative to protected; 95% CI: 1.65-1.69). Choice of empiric regimen accounted for 51% and 74% of the explained variation in antibiotic escalation and de-escalation, respectively.ConclusionsEmpiric Gram-negative antibiotics are frequently de-escalated early in hospitalization, whereas escalation is infrequent. Changes are primarily driven by choice of empiric therapy and presence of infectious syndromes.
| S-EPMC10182731 | biostudies-literature
Project description:IntroductionClinicians commonly escalate empiric antibiotic therapy due to poor clinical progress without microbiology guidance. When escalating, they should take account of how resistance to an initial antibiotic affects the probability of resistance to subsequent options. The term "escalation antibiogram" (EA) has been coined to describe this concept. One difficulty when applying the EA concept to clinical practice is understanding the uncertainty in results and how this changes for specific patient subgroups.MethodsA Bayesian model was developed to estimate antibiotic resistance rates in Gram-negative bloodstream infections based on phenotypic resistance data. The model generates a series of "credible" curves to fit the resistance data, each with the same probability of representing the true rate given the inherent uncertainty. To avoid overfitting, an integrated penalisation term adaptively smooths the curves given the level of evidence.ResultsRates of resistance to empiric first-choice and potential escalation antibiotics were calculated for the whole hospitalised population based on 10,486 individual bloodstream infections, and for a range of specific patient groups, including ICU (intensive care unit), haematolo-oncology, and paediatric patients. The model generated an expected value (posterior mean) with 95% credible interval to illustrate uncertainty, based on the size of the patient subgroup. For example, the posterior means of piperacillin/tazobactam resistance rates in Gram-negative bloodstream infection are different between patients on ICU and the general hospital population: 27.3% (95% CI 18.1-37.2 vs. 13.4% 95% CI 11.0-16.1) respectively. The model can also estimate the probability of inferiority between two antibiotics for a specific patient population. Differences in optimal escalation antibiotic options between specific patient groups were noted.ConclusionsEA analysis informed by our Bayesian model is a useful tool to support empiric antibiotic switches, providing an estimate of local resistance rates, and a comparison of antibiotic options with a measure of the uncertainty in the data. We demonstrate that EAs calculated for the whole hospital population cannot be assumed to apply to specific patient group.
| S-EPMC11343932 | biostudies-literature
Project description:BackgroundFosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.ObjectivesTo generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.MethodsThe NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed.ResultsIn total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio.ConclusionsThrough this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant's PMA, PNA and weight.
| S-EPMC8212774 | biostudies-literature