The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis.
A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%).
Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB�
The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively.
For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively.
IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes).
In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.
| Identifer | oai:union.ndltd.org:ADTP/266393 |
| Date | January 2009 |
| Creators | Sherwin, Catherine M. T, n/a |
| Publisher | University of Otago. Dunedin School of Medicine |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Catherine M. T Sherwin |
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