Analysis Of Antimicrobial Use And Its Rationality In Very Low Birth Weight Infants By Real-world Study

BackgroundAntimicrobial overuse is nowadays a global health problem.Due to the special delivery characteristics,vulnerable immune function and immature development,antimicrobial overuse is particularly severe in very-low-birth-weight infant(VLBWI).However,a growing number of studies have shown that overuse of antimicrobial can lead to increase of severe morbidity and mortality.Nowadays,western countries mainly rationalize the antimicrobial use by ’limiting the duration of antimicrobial and selecting sensitive antimicrobial of pathogenic bacteria".But it is scarcely reported with a large sample real world study(RWS)on antimicrobial use in VLBWI in developing countries,which were much heavier burden in antimicrobial use.Besides,most antimicrobial are off-label used in neonates,leading to a severe phenomenon of using beyond the instruction.So,it is not verified in safety and effect for empirical antimicrobial use in neonates nowadays in the real world.Therefore,it is very crucial to deeply describe of the real-world data about antimicrobial overuse,the true infectious pathogens and antimicrobial resistance,and rationally empirical antimicrobial selection.Our study was a real world study that based on the Sino-northern Neonatal Network(SNN)and Chinese Adverse PRognosis of VEry Preterm infants cohort(CARE Preterm)cohort to describe the current situation of antimicrobial overuse in VLBWI of regional multicenter in China,and to explore the relationship between antimicrobial overuse and adverse outcome.Furthermore,we want to explore the optimally empirical antimicrobial by analyze the infectious pathogens and antimicrobial resistance.Lastly,we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in early-onset sepsis(EOS)patients.Our study is aimed to provide real-world evidence for promoting the rational use of antibiotics in VLBWI in NICU.MethodsA population-based prospective cohort study was conducted in all VLBW infants admitted to 21 Grade A tertiary hospitals from Sino-northern Neonatal Network(SNN)database between January 1,2019 and June 30,2021.Antibiotic use was described antibiotic use rate(AUR,calculated as calendar days of antimicrobial therapy divided by total hospital days)and days of therapy(DOT,calculated as an aggregate sum of the days of exposure accounting for each antibiotic)per 1000 patient days(PD).We further describe the pathogens and their antimicrobial resistance(AMR)for neonatal sepsis.Then we explore the associations between higher AUR and adverse outcomes in VLBWI without culture-proven sepsis or necrotizing enterocolitis(NEC).We divided the non-confirmed infective VLBWI by quartile of individual AUR.The composite primary outcome was defined as mortality or severe morbidity,including any of the following:periventricular leukomalacia,bronchopulmonary dysplasia(BPD),and stage 3 or higher retinopathy of prematurity(ROP).Univariate analysis and multivariable regression analysis was used to calculate adjusted odds ratios(aORs)and 95%CIs for the association between AURs and outcomes.For the part three,a prospective,single-center,phase Ⅱ clinical study of piperacillin/tazobactam in neonates with EOS was conducted between June 1,2019,to October 31,2019.The dosing regimen(90 mg·kg-1,q8h)was determined based on a previous piperacillin PPK model in young infants(Cohen-Wolkowiez et al.,2014)using NONMEM v7.4.The pharmacodynamics(PD)target(70%fT>MIC,free drug concentration above MIC during 70%of the dosing interval)attainment was calculated using NONMEM combined with an opportunistic sampling design.The primary outcome was treatment failure rate.The second outcomes were PD target(70%fT>MIC)attainment,duration of piperacillin/tazobactam treatment,length of hospitalization,adverse events and infection-related deaths in the first month of life accompanied by piperacillin/tazobactam treatment.Results1.Among 2403 eligible VLBW infants,2244(93.8%)infants received antibiotics.Total antibiotic use was 562.0DOT/1000Pd and total AUR was 0.48.The median duration of antibiotic course was 13(IQR 7.5;21)days,with 76.4%courses>7 days and 41.2%courses>14 days.The most common antibiotic agent were TGC(69.9%,185.5DOT/1000Pd),penicillins plus enzyme inhibitor(56.4%,117.6DOT/1000Pd)and carbapenems(40.6%,107.3DOT/1000Pd).2.A total of 2001 VLBW infants who received antibiotics without culture-proven sepsis or NEC were included in this study.The overall AUR of eligible VLBW infants was 49%,and the median AUR of each eligible VLBW infant was 48%(IQR 30%,69%).After logistic regression analysis of 4 groups of VLBW infants with different AUR range,infants in the higher quartile AUR(Q3,0.49～0.69)and AUR(Q4,0.70～1.00)had higher odds of BPD(adjusted OR 2.46,95%CI 1.42-4.28,adjusted OR 2.51,95%CI 1.45-4.36 respectively)and composite primary outcome(adjusted OR 2.97,95%Cl 1.99-4.44,adjusted OR 1.85,95%CI 1.23-2.79 respectively)than those in the lowest AUR(Q1).10%increase in the AUR was associated with an increased odds of the primary composite outcome(adjusted OR,1.18,95%CI1.12-1.24)and BPD(adjusted OR 1.11,95%CI 1.04-1.18).3.A total of 126 positive blood cultures were reported in 124 VLBWI(4.5%).The most frequent pathogens were Klebsiella pneumoniae(28 case)and Escherichia coli(22 case).Third-generation cephalosporin resistance rate was 75.0%and 68.2%,respectively.Carbapenems resistance rate was 25%and 0%,respectively.Gram-negative(GN)bacteria accounted for a majority of overall pathogens(58.7%)and the Third-generation cephalosporin resistance rate was 56.8,and the multidrug resistance was 32.4%.While Piperacillin/tazobactam resistance rate was only 6.8%in total GN bacteria.4.A total of 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis.Eight(16.3%)neonates experienced treatment failure clinically.Forty-seven(95.9%)neonates reached their PD target.Eight(16.3%)neonates experienced treatment failure clinically.The mean(SD,range)duration of treatment and length of hospitalization were 100.1(62.2,36.2-305.8)hours and 31(30.5-123)days.There were no obvious adverse events and no infection-related deaths occurred in the first month of life.Conclusion1.We verified the antimicrobial overuse in VLBWI in multicenter of China.The high proportion of antibiotic exposure and excessively prolonged antimicrobial course were the major reason for antibiotic overuse.Besides,antimicrobial overexposure in VLBW infants without culture-proven sepsis or NEC was associated with increased risk of composite primary outcome and BPD.2.Gram-negative(GN)bacteria accounted for a majority of pathogens in VLBWI in multicenter of China and the most frequent pathogens were Klebsiella pneumoniae and Escherichia coli,respectively,which showed the high Third-generation cephalosporin resistance rate.However,the resistance rate to Piperacillin/tazobactam were much lower.Piperacillin/tazobactam can be used as an empirical antibiotic for VLBWI with suspected sepsis.3.A model-based dosing regimen(90 mg·kg-1,q8h)of piperacillin/tazobactam optimized was evaluated clinically and was tolerated well and effective for EOS treatment.The model-based validation method may be helpful to explore the rational and safety use of other empirical antimicrobial in neonate.