RESUMO
We recruited 48 neonates (50 vancomycin treatment episodes) in a prospective study to validate a model-informed precision dosing (MIPD) software. The initial vancomycin dose was based on a population pharmacokinetic model and adjusted every 36-48 h. Compared with a historical control group of 53 neonates (65 episodes), the achievement of a target trough concentration of 10-15 mg/L improved from 37% in the study to 62% in the MIPD group (P = 0.01), with no difference in side effects.
Assuntos
Antibacterianos , Vancomicina , Vancomicina/farmacocinética , Vancomicina/administração & dosagem , Vancomicina/uso terapêutico , Humanos , Recém-Nascido , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Estudos Prospectivos , Masculino , Feminino , SoftwareRESUMO
AIMS: C-reactive protein (CRP) is used to determine the effect of antibiotic treatment on sepsis in neonates/infants. We aimed to develop pharmacokinetic-pharmacodynamic (PKPD) model of meropenem and CRP in neonates/infants and evaluate its predictive performance of CRP dynamics. METHODS: Data from neonates/infants treated with meropenem in 3 previous studies were analysed. To the previously developed meropenem PK models, the addition of turnover, transit or effect compartment, delay differential equation PD models of CRP as a function of meropenem concentration or its cumulative area under the curve (AUC) were evaluated. The percentage of neonates/infants (P0.1 , P0.2 ) in whom the ratio of the fifth day CRP to its peak value was predicted with an error of <0.1 (<0.2) was calculated. RESULTS: A total of 60 meropenem treatment episodes (median [range] gestational age 27.6 [22.6-40.9] weeks, postnatal age 13 [2-89] days) with a total of 351 CRP concentrations (maximum value 65.5 [13-358.4] mg/L) were included. Turnover model of CRP as a function of meropenem cumulative AUC provided the best fit and included CRP at the start of treatment, use of prior antibiotics, study and causative agent Staphylococcus aureus or enterococci as covariates. Using meropenem population predictions and data available at 0, 24, 48, 72 h after the start of treatment, P0.1 (P0.2 ) was 36.4, 36.4, 60.6 and 66.7% (70.0, 66.7, 72.7 and 78.7%), respectively. CONCLUSION: The developed PKPD model of meropenem and CRP as a function of meropenem cumulative AUC incorporating several patient characteristics predicts CRP dynamics with an error of <0.2 in most neonates/infants.
Assuntos
Proteína C-Reativa , Sepse , Humanos , Lactente , Recém-Nascido , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteína C-Reativa/análise , Idade Gestacional , Meropeném , Sepse/tratamento farmacológicoRESUMO
AIMS: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the haemodynamic response to dobutamine in critically ill neonates. METHODS: Alleles in the known genetic single nucleotide polymorphisms in ß1- and ß2-adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. RESULTS: Twenty-six neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on ß1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8-60.7) beats/min per AUC of 100 µg L-1 h, P = .0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C > T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2-42.9) mL kg-1 min-1 per AUC of 100 µg L-1 h, P = .0095 and 33.2 (12.1-54.3) mL kg-1 min-1 per AUC of 100 µg L-1 h, P = .0025, respectively. CONCLUSION: In critically ill neonates, ß1-AR Arg389Gly and GNAS c.393C > T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.
Assuntos
Dobutamina , Farmacogenética , Estado Terminal , Dobutamina/farmacologia , Feminino , Frequência Cardíaca/genética , Humanos , Recém-Nascido , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
AIMS: To describe the pharmacokinetics (PK) and concentration-related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. METHODS: Dosing, plasma concentration and haemodynamic monitoring data from a dose-escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5-20 µg kg-1 min-1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. RESULTS: Twenty-eight neonates with median (range) gestational age of 30.4 (22.7-41.0) weeks and birth weight (BW) of 1618 (465-4380) g were included. PK data were adequately described by 1-compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h-1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. CONCLUSION: In the postnatal transitional period, PK of dobutamine was described by a 1-compartmental linear model, CL related to BW and PMA. A concentration-response relationship with haemodynamic variables has been established.
Assuntos
Dobutamina , Função Ventricular Esquerda , Débito Cardíaco , Dobutamina/farmacologia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Volume SistólicoRESUMO
OBJECTIVES: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations. DESIGN: A prospective single group open-label pharmacokinetics study. SETTINGS: Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia. PATIENTS: Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery. INTERVENTIONS: Milrinone at a dose of 0.73 µg/kg/min for 3 hours followed by 0.16 µg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected. MEASUREMENTS AND MAIN RESULTS: Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 µg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 µg/kg/min for 3 hours followed by 0.15 µg/kg/min (postmenstrual age < 27 wk) or 0.20 µg/kg/min (postmenstrual age ≥ 27 wk). CONCLUSIONS: Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.
Assuntos
Cardiotônicos/administração & dosagem , Cardiotônicos/farmacocinética , Permeabilidade do Canal Arterial/cirurgia , Milrinona/administração & dosagem , Milrinona/farmacocinética , Complicações Pós-Operatórias/prevenção & controle , Cardiotônicos/sangue , Ecocardiografia , Feminino , Humanos , Hipotensão/induzido quimicamente , Recém-Nascido , Recém-Nascido Prematuro , Ligadura , Masculino , Milrinona/sangue , Complicações Pós-Operatórias/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Síndrome , Taquicardia/induzido quimicamenteRESUMO
BackgroundWe aimed to determine the genetic relatedness between Staphylococcus epidermidis colonizing breast milk (BM) and BM-fed neonates during the first month of life.MethodsS. epidermidis was isolated from the stool and skin swabs of 20 healthy term and 49 preterm neonates hospitalized in the neonatal intensive care unit and from the BM of mothers once a week and typed by multilocus variable-number tandem-repeat analysis. Virulence-related genes were determined by PCR.ResultsThe gut (95%) and skin (100%) of term neonates were colonized with strains genetically similar to those in BM and carrying mecA and IS256 at low rate (both <6.7%). In preterm neonates, colonization with strains genetically similar to those in BM was low on the skin (34.7%) and in the gut in the first week of life (14.3%), but the prevalence of mecA (>90.6%) and IS256 (>61.7%) was high. By the fourth week, in the gut of preterm neonates the prevalence of mecA (73.8%) and IS256 (18.4%) decreased, but colonization with strains genetically similar to those in BM increased (83.7%).ConclusionDuring early life, the skin and gut of preterm neonates is colonized with S. epidermidis that is distinct from strains found in BM, but gradually the gut is enriched with strains genetically similar to those in BM, as in term neonates.
Assuntos
Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Leite Humano/microbiologia , Pele/microbiologia , Staphylococcus epidermidis/crescimento & desenvolvimento , Fatores Etários , Proteínas de Bactérias/genética , Desenvolvimento Infantil , DNA Bacteriano/genética , Fezes/microbiologia , Feminino , Genótipo , Idade Gestacional , Hospitalização , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Repetições Minissatélites , Fenótipo , Gravidez , Staphylococcus epidermidis/genética , Staphylococcus epidermidis/patogenicidade , Nascimento a Termo , Virulência/genéticaRESUMO
AIM: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. METHODS: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission. RESULTS: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001). CONCLUSION: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.
Assuntos
Dor Crônica/diagnóstico , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Medição da Dor/estatística & dados numéricos , Europa (Continente) , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Estudos Prospectivos , Respiração ArtificialRESUMO
Mutations in the gene for adenosine triphosphate-binding cassette transporter subfamily A member 3 (ABCA3) have been reported in infants and children with surfactant deficiency and interstitial lung disease. We report a case of siblings found to be compound heterozygotes for two novel ABCA3 gene mutations but developing very different course of lung disease. The index case is a baby girl with severe interstitial lung disease that manifested on the first days of life. Her 4-year-old brother carrying the same mutations has no signs of lung disease so far. Our findings suggest the contribution of other genetic, epigenetic and environmental factors to discordant phenotype observed in patients carrying the same mutations in the ABCA3 gene. The clinical course of the index case suggests benefit of combined medical therapy in treating infants with ABCA3 deficiency.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Heterozigoto , Doenças Pulmonares Intersticiais/genética , Mutação , Fenótipo , Irmãos , Pré-Escolar , Feminino , Marcadores Genéticos , Humanos , Recém-Nascido , MasculinoRESUMO
UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Europa (Continente) , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Resultado do TratamentoRESUMO
Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C(max)) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V(ss)) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V(ss) of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C(max) with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.
Assuntos
Antibacterianos/administração & dosagem , Doenças do Prematuro/tratamento farmacológico , Modelos Estatísticos , Software , Tienamicinas/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/microbiologia , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/microbiologia , Recém-Nascido de muito Baixo Peso , Infusões Intravenosas , Masculino , Meropeném , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Sepse/tratamento farmacológico , Sepse/microbiologia , Tienamicinas/sangue , Tienamicinas/farmacocinéticaRESUMO
AIM: To identify recent changes in short-term outcome and care for very preterm infants in Estonia. METHODS: Comparison of two population-based cohort of very preterm infants born alive at 22-31 gestational weeks. In 2007-2008, data were recorded prospectively in a neonatal register. For the cohort born in 2002-2003, the same variables were extracted retrospectively from the hospital records. Infants were followed up to discharge or death. RESULTS: The cohort of 2007-2008 contained a higher proportion of infants born by caesarean section and of infants who received antenatal corticosteroids, maternal antibiotics, or surfactant therapy than the earlier cohort. A higher proportion of infants was admitted for care in 2007-2008 (98% vs. 94%; p = 0.013). During the study period, survival until discharge increased (85% vs. 78%; p = 0.041), although the length of hospital stay was unchanged. The use of mechanical ventilation, inotropes, and postnatal antibiotics decreased. Neonatal morbidity remained unchanged, except for a decrease in severe periventricular/intraventricular haemorrhage. CONCLUSION: The outcome for very preterm infants in Estonia has improved since 2002. With proactive perinatal management and less invasive neonatal care, survival until discharge increased without concomitant increases in neonatal morbidity and the length of hospital stay.
Assuntos
Recém-Nascido Prematuro , Assistência Perinatal/métodos , Taxa de Sobrevida/tendências , Estudos de Coortes , Estônia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different Km (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15 mg/L) provided a better fit than the model with equal Km (15 mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4 mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00-8.12%)), followed by total gentamicin (0.20% (0.00-4.10%)), C1a (0.11% (0.00-7.57%)), and C1 (0.04% (0.00-1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4 mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.
Assuntos
Antibacterianos , Gentamicinas , Taxa de Filtração Glomerular , Humanos , Recém-Nascido , Rim , CinéticaRESUMO
BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.
Assuntos
Antibacterianos , Estudos de Equivalência como Asunto , Unidades de Terapia Intensiva Neonatal , Sepse/tratamento farmacológico , Vancomicina , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Europa (Continente) , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Sepse/mortalidade , Espanha , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Vancomicina/administração & dosagem , Vancomicina/efeitos adversosRESUMO
BACKGROUND: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low-birthweight (ELBW) neonates at risk of early onset sepsis (EOS). METHODS: A subgroup analysis was carried out of ELBW neonates recruited into a two-center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end-point (need for change of antibiotics within 72 h and/or 7 day all-cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period. RESULTS: In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end-point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age <26 weeks was lower in the ampicillin group. Ampicillin treatment was associated with a higher colonization rate by Klebsiella pneumoniae, including ampicillin-resistant strains. CONCLUSION: Preliminary data indicate an urgent need for adequately powered studies of early antibiotic therapy in the subpopulation of ELBW neonates at risk of EOS.
Assuntos
Ampicilina/administração & dosagem , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Unidades de Terapia Intensiva Neonatal , Infecções por Klebsiella/tratamento farmacológico , Penicilinas/administração & dosagem , Sepse/tratamento farmacológico , Idade de Início , Antibacterianos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Incidência , Mortalidade Infantil/tendências , Recém-Nascido , Intestinos/microbiologia , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/isolamento & purificação , Masculino , Estudos Prospectivos , Fatores de Risco , Sepse/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. METHODS: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. RESULTS: In 14 neonates (GA of 32-42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. CONCLUSIONS: We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.
Assuntos
Ampicilina/farmacocinética , Antibacterianos/farmacocinética , Recém-Nascido , Sepse Neonatal/tratamento farmacológico , Ampicilina/administração & dosagem , Ampicilina/sangue , Ampicilina/líquido cefalorraquidiano , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Modelos Epidemiológicos , Idade Gestacional , Humanos , Testes de Sensibilidade Microbiana , Modelos Estatísticos , Estudos ProspectivosRESUMO
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.
Assuntos
Meropeném/uso terapêutico , Sepse Neonatal/tratamento farmacológico , Padrão de Cuidado , Feminino , Humanos , Lactente , Masculino , Meropeném/efeitos adversos , Segurança , Resultado do TratamentoRESUMO
BACKGROUND: About 10-20% of neonates with suspected or proven early onset sepsis (EOS) fail on the empiric antibiotic regimen of ampicillin or penicillin and gentamicin. We aimed to identify clinical and laboratory markers associated with empiric antibiotic treatment failure in neonates with suspected EOS. METHODS: Maternal and early neonatal characteristics predicting failure of empiric antibiotic treatment were identified by univariate logistic regression analysis from a prospective database of 283 neonates admitted to neonatal intensive care unit within 72 hours of life and requiring antibiotic therapy with penicillin or ampicillin and gentamicin. Variables, identified as significant by univariate analysis, were entered into stepwise multiple logistic regression (MLR) analysis and classification and regression tree (CRT) analysis to develop a decision algorithm for clinical application. In order to ensure the earliest possible timing separate analysis for 24 and 72 hours of age was performed. RESULTS: At 24 hours of age neonates with hypoglycaemia < or = 2.55 mmol/L together with CRP values > 1.35 mg/L or those with BW < or = 678 g had more than 30% likelihood of treatment failure. In normoglycaemic neonates with higher BW the best predictors of treatment failure at 24 hours were GA < or = 27 weeks and among those, with higher GA, WBC < or = 8.25 x 10(9) L(-1) together with platelet count < or = 143 x 10(9) L(-1). The algorithm allowed capture of 75% of treatment failure cases with a specificity of 89%. By 72 hours of age minimum platelet count < or = 94.5 x 10(9) L(-1) with need for vasoactive treatment or leukopaenia < or = 3.5 x 10(9) L(-1) or leukocytosis > 39.8 x 10(9) L(-1) or blood glucose < or = 1.65 mmol/L allowed capture of 81% of treatment failure cases with the specificity of 88%. The performance of MLR and CRT models was similar, except for higher specificity of the CRT at 72 h, compared to MLR analysis. CONCLUSION: There is an identifiable group of neonates with high risk of EOS, likely to fail on conventional antibiotic therapy.
Assuntos
Antibacterianos/uso terapêutico , Sepse/tratamento farmacológico , Pré-Escolar , Estônia/epidemiologia , Seguimentos , Humanos , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Valor Preditivo dos Testes , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Sepse/classificação , Sepse/epidemiologia , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: Staphylococcus haemolyticus is a common colonizer and cause of late-onset sepsis (LOS) in preterm neonates. By describing genetic relatedness, we aimed to determine whether mother's breast milk (BM) is a source of S. haemolyticus colonizing neonatal gut and skin and/or causing LOS. METHODS: S. haemolyticus was isolated from stool and skin swabs of 49 BM-fed preterm neonates admitted to neonatal intensive care unit, 20 healthy BM-fed term neonates and BM of mothers once a week and typed by multilocus variable number tandem repeat analysis and multilocus sequence typing. Virulence-related genes were determined by polymerase chain reaction. RESULTS: Compared with term neonates, S. haemolyticus colonized more commonly gut (35% vs. 89.9%; P < 0.001) and skin (50% vs. 91.8%; P < 0.001) of preterm neonates and mothers' BM (15% vs. 38.8%). Isolates from preterm compared with term neonates and their mothers carried more commonly the mecA gene (83.5% vs. 5.4%; P < 0.001) and IS256 (52.4% vs. 2.7%; P < 0.001) and belonged to clonal complex 29 (89.1% vs. 63%; P = 0.014). Only 7 (14.3%) preterm and 3 (15%) term neonates were colonized in gut or on skin with multilocus variable number tandem repeat analysis types indistinguishable from those in BM. Most frequent multilocus variable number tandem repeat analysis types belonged to sequence type 3 or 42, comprised 71.1%-78.4% of isolates from preterm neonates/mothers and caused all 7 LOS episodes. LOS-causing strain colonized the gut of 4/7 and the skin of 5/7 neonates, but not BM, before onset of LOS. CONCLUSIONS: S. haemolyticus colonizing gut and skin or causing LOS in preterm neonates rarely originate from BM but are mecA-positive strains adapted to hospital environment.
Assuntos
Trato Gastrointestinal/microbiologia , Leite Humano/microbiologia , Pele/microbiologia , Staphylococcus haemolyticus/classificação , Staphylococcus haemolyticus/genética , Técnicas de Tipagem Bacteriana , Aleitamento Materno , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Estudos Longitudinais , Masculino , Mães , Tipagem de Sequências Multilocus , Sepse Neonatal/microbiologia , Estudos Prospectivos , Infecções Estafilocócicas/microbiologiaRESUMO
The purpose of this work was to develop and validate an HPLC-MS/MS method suitable for quantifying two important cardiovascular drugs, milrinone and dobutamine, in neonatal and paediatric patients' blood plasma samples. Sufficiently low LLOQ levels were required to obtain adequate pharmacokinetic data for the evaluation of optimal dosing. Since the specifics of the patient group set some restrictions on the available sample volume, the method was designed to use only 20⯵L of plasma for the analysis. Analytes were separated chromatographically in a biphenyl column using a conventional water-methanol-formic acid eluent with the addition of ammonium fluoride. The latter provided a significant signal enhancement in positive ion mode detection for both analytes allowing the LLOQ to reach below 1â¯ng/mL. Matrix matched calibration was linear in the range of 1-300â¯ng/mL, between-run accuracy remained within 107-115%, and precision within 4.8-7.4% for both analytes over the calibration range (including LLOQ level). Dobutamine degradation in plasma samples was prevented by the usage of ascorbic acid. The method was applied to plasma samples of neonates from two pharmacokinetic/pharmacodynamics studies (nâ¯=â¯38).
RESUMO
OBJECTIVE: We aimed to determine factors associated with gut colonization of preterm neonates with coagulase-negative staphylococci (CoNS) from maternal milk (MM). STUDY DESIGN: CoNS isolated from weekly collected stool and MM of hospitalized preterm (n = 49) and healthy term neonates (n = 20) were genotyped. Colonization-related factors were determined by Cox proportional hazards regression. RESULT: Gut colonization with mecA-negative Staphylococcus epidermidis from MM was less prevalent (40.8% vs. 95%) and delayed (median age 15.5 vs. 2 days) in preterm compared with term neonates. Enhanced colonization was associated with higher intake of CoNS from MM (hazard ratio (95% confidence interval) 1.006 (1.00-1.01) for 106 colony-forming units), lower proportion of mecA-positive predominant NICU strains in gut (0.09 (0.01-0.49) for 1%) and lower incidence of late-onset CoNS sepsis (5% vs. 34% in those without colonization). CONCLUSION: Enteral feeding with larger proportion of unpasteurized MM and limiting spread of predominant strains may promote colonization with CoNS from MM.