Ampicillin-Associated Seizures

Hodgman, Tudy; Dasta, Joseph F.; Armstrong, Deborah K.; Visconti, James A.; Reilley, Thomas E.

doi:10.1097/00007611-198410000-00031

Cited by 19 publications

(12 citation statements)

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“…The underprediction of concentrations >100 mg/L have been taken into account in the proposed dosing regimen. Simulations based on our final PK model demonstrated that 50 mg/kg/day and 75 mg/kg/day amoxicillin in three doses (GA 36-37 and 38-42 weeks, respectively) for 7 days results in adequate concentrations (T>MIC 100%) in the case of infections with Streptococcus agalactiae and Listeria monocytogenes (MIC 0.25 mg/L and 1.0 mg/ L, respectively), while avoiding nontoxic peak levels (<140 mg/ L) regardless of variation in the significant covariates on Cl (GA, PNA, TEMP, UO) 14,30,31 This is due to the wide therapeutic range of amoxicillin. The proposed dosage regimen is comparable to the dosage regimen of 20 mg/kg every 8 h advised for patients with GA>34 weeks by Pullen et al…”

Section: Discussionmentioning

confidence: 99%

“…with only one peak level and one middose level measured. 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%

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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%

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Bijleveld

Mathôt

Lee

et al. 2017

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

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“…We performed a sensitivity analyses by dichotomizing C maxss as ≤140 µg/mL versus >140 µg/mL based on a prior seizure thresholds in adults. (16) Finally, we report the cumulative C maxxss and AUC 24 reached on the first day of a new seizure. We calculated the median PNA at which seizures were first diagnosed and compared cumulative C maxss and cumulative AUC 24 to the values registered at the same PNA in infants who did not experience seizures using Wilcoxon rank sum tests.…”

Section: Methodsmentioning

confidence: 99%

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

Hornik

Benjamin

Smith

et al. 2016

The Journal of Pediatrics

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Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design Retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. All infants 24–41 weeks gestational age, 500–5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. Using a 1-compartment pharmacokinetic model and her data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure and seizures as documented in the EHR. Results We identified 131,723 infants receiving 134,041 courses of ampicillin for 653,506 infant-days of exposure. The median daily dose was 200 mg/kg/day (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss [Odds ratio (OR) = 1.10, (95% confidence interval (CI) 1.03, 1.17] and AUC24 [OR = 1.11, (95% CI 1.05, 1.18)] were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

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“…Meningitis patients have shown ampicillin CSF concentrations ranging from 11 to 136 percent of serum concentrations, with a normal range of 4 -10 percent. 4 Penicillin CSF concentrations were usually below 10 percent of the serum concentration, with a normal value below 1 percent." However, this effect on the blood-CSF barrier was unpredictable, because the incidence of seizures does not consistently correlate with high intravenous penicillin dosing in meningitis.e High intravenous penicillin doses in treatment of bacterial endocarditis and gram-negative bacterial septicemia have been associated with myoclonic-type seizures.…”

Section: Case Reportsmentioning

confidence: 99%

Populations at Risk for Penicillin-Induced Seizures

Barrons

Murray²,

Richey³

1992

Ann Pharmacother

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Pharmacokinetic parameters explain patient populations most at risk; a guideline equation has been recommended to allow clinicians to make appropriate dose adjustments based on creatinine clearance. Physicians and pharmacists must recognize the populations most at risk for high-dose, penicillin-induced neurotoxicities; monitor these patients at least during the first 72 hours, and reduce or discontinue therapy when appropriate.

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Ampicillin-Associated Seizures

Cited by 19 publications

References 0 publications

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

Populations at Risk for Penicillin-Induced Seizures

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