Ampicillin-Induced Neurotoxicity in Very-Low-Birth-Weight Neonates

Cl, Shaffer; Am, Davey; Jl, Ransom; Brown, YL; P, Gál

doi:10.1345/aph.17228

Cited by 32 publications

(20 citation statements)

References 16 publications

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“…14,31 Although a limited number of neurotoxic adverse events (including seizure, encephalopathy, and tremor) related to amoxicillin treatment have been reported, the role of epileptogenic drugs, such as penicillins, may be underestimated in neonates, as seizure detection in these patients is challenging. 32 It was striking that, despite the advice of the Dutch Pediatric Formulary (75 mg/kg/day amoxicillin in three doses in term neonates <1 week PNA and 2,000 g BW),…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Bijleveld

Mathôt

Lee

et al. 2017

Clin Pharma and Therapeutics

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The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N 5 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.58C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.08C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ To date, there are no data on the effect of moderate hypothermia on the pharmacokinetics (PK) of amoxicillin in term neonates. Only few studies have been performed to evaluate the PK of this antibiotic in noncooled (pre)term neonates. WHAT QUESTION DID THIS STUDY ADDRESS? þ To our knowledge, this is the first prospective study evaluating and describing the PK of amoxicillin during all phases of controlled hypothermia in newborns, e.g., the hypothermic, rewarming, and normothermic phases.WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ A description of the PK properties of amoxicillin in term newborns with hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia receiving hypothermia treatment. Gestational age (GA), postnatal age (PNA), urine output, and body temperature were significant covariates on amoxicillin clearance (Cl). HOW THIS MIGHT CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE þ Based on the newly developed PK-model, we advise an amoxicillin dosing regimen of 50 or 75 mg/kg/24h in three doses for patients with GA 36 or GA 38-42 weeks, respectively.Term neonates who experience a severe hypoxic-ischemic insult during birth and develop encephalopathy are treated with hypothermia.1,2 This improves long-term outcomes and reduces mortality rates.2-9 These patients may suffer from early-onset sepsis with Streptococcus agalactiae (incidence rate 0.43% (95% confidence interval (CI) 0.37-0.49)), while Listeria monocytogenes should also be considered.10 Because asphyxia due to infection is difficult to distinguish from asphyxia without infection, antibiotics, such as amoxicillin, are frequently used.11 For efficacy, as a surrogate marker, the time that the nonprotein-bound concentration in blood exceeds the minimum inhibitory concentration (T>MIC) should be at least 40-50% in these patients.12 Although b-lactam antibiotics such as amoxicillin are considered safe due to the wide therapeutic range, excessive accumulation can lead to the development of adverse drug events, such as seizures and crystalluria. 13Despi...

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Bijleveld

Mathôt

Lee

et al. 2017

Clin Pharma and Therapeutics

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“…Amp-induced neurotoxicity may perhaps be amid the etiologies of late-onset autism due to alterations in gut microbiota and the induction of propioni bacteria 11 . Disturbances in the gut flora can induce oxidative stress which in turn can increase the neurotoxic effect of the drug and can remarkably affects the brain in rodent models of autism 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Antibiotics can also disturb normal flora to allow the overgrowth of propionic acid producing bacteria which in turn has been associated with the development of autism 10 . Ampicillin-induced neurotoxicity has also been described in the literature in very low birth weight neonates 11 . A recent study by El-Ansary 12 has shown ampicillininduced neurotoxicity that might induce autistic traits in animal model of autism.…”

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confidence: 91%

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2017

IJPSR

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Improper diet can affects the brain and can increase the risk for mental disorders and neurodegenerative diseases like autism. Dietary modification can sometime be helpful to children with autism. The present study examined the effects of a high lipid diet on orally administered ampicillin -induced neurotoxic rats and compared with propionic acid models of autism. Forty young male western albino rats were divided into four equal groups. The first group served as the control; the second group was given an oral neurotoxic dose of propionic (PA) (250 mg/kg body weight/day) for three days. The third group received an orogastric dose of ampicillin (50mg/kg for three weeks) with a standard diet. Groups 4 was given an orogastric dose of ampicillin and fed with high-lipid diets, for 10 weeks. The possible effects of ampicillin (Amp) in presence of high lipid diet on selected neurotransmitters (5HT, DA, NA, glutamate and glutamine) and a cytokine IL-6 were tested and compared with the neurotoxic effect of propionic acid (PA). The results show a significant improvement of the neurotoxic effect of ampicillin when rats were fed with high lipid diet. INTRODUCTION:Autism is a complex neuro developmental disorder caused by interaction between genetic and environmental factors 1 . Although autism is behaviourally defined and its biochemical defects are still not well understood, however children with autism show higher rates of in vivo lipid metabolism than healthy controls 2, 3 . Foods and nutrients can impact the symptoms of autism as the foods eaten by the child can have a direct effect on brain.

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“…Neurotoxicity in association with the use of ampicillin has been reported [41]. The combination of ampicillin and cefotaxime has been associated with a greater mortality than the combination of ampicillin and gentamicin in neonates with sepsis [42].…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

Pacifici

Labatia

Mulla

et al. 2008

Eur J Clin Pharmacol

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Sepsis is common in neonates and a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic during the first week of life, with penicillins being the most frequently administered antibiotics. The clearance (Cl), serum half-life (t(A1/2)) and volume of distribution (Vd) of penicillins are different in the neonate than in the adult. As such, the pharmacokinetics of penicillins need be studied in neonates in order to optimise therapy in this age class with these drugs. The aim of this study was to review the published data on the pharmacokinetics of penicillins in the neonate in order to provide a critical analysis of the literature and, consequently, a useful tool in the hands of the physician. The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines. An initial search was performed with the keywords "pharmacokinetics", "penicillins" and "neonates". Secondly, other searches were performed using the keywords "pharmacokinetics" and "neonates", followed by the name of a single antibiotic. The search included articles up to 2007. There have been few pharmacokinetic studies on the use of penicillins in neonates. The results from those few studies that have been carried out suggest that the Cl is reduced and t(A1/2) prolonged in the neonate as compared with the more mature infant. There is little variation in Vd during the first week of life. In the premature neonate, Cl is reduced compared to the full-term infant. As postnatal age proceeds, the Cl of penicillins increases. More pharmacokinetic studies are required to provide a sound scientific basis for planning a dosage regimen with penicillins in the neonate

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Ampicillin-Induced Neurotoxicity in Very-Low-Birth-Weight Neonates

Cited by 32 publications

References 16 publications

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

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Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

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