title: Ciprofloxacin Therapy for Neonates and Young Infants:A Clinical Pharmacological Perspective including Pharmacokinetics (PK) and Pharmacodynamics (PD)
Creators: name: Hill, H
Publisher: name: University of Liverpool Repository
Year: 2016

description: Abstract Ciprofloxacin Therapy for Neonates and Young Infants: A Clinical Pharmacological Perspective including Pharmacokinetics (PK) and Pharmacodynamics (PD). Severe infection due to Gram-negative bacteraemia increases mortality and long term consequences of morbidity. In Liverpool Women’s NHS FT neonatal unit mortality increased from 20% for the more premature babies to 44%. Ciprofloxacin is a synthetic fluoroquinolone prescribed for suspected or proven Gram-negative infection in many neonatal units throughout Europe (25%). At present this drug is not authorised for this population and is prescribed off label. The optimal drug regimen is unknown resulting in a wide range of regimens (5 to 60 mg/kg/day) prescribed internationally. The TINN Consortium ‘Treat Infection in Neonates’ were funded by a European Union FP7 grant to develop a Paediatric Investigation Plan in line with the EU Paediatric Regulations and European Medicines Agency requirements. This thesis describes a prospective population PK clinical trial as part of the work of TINN, a retrospective clinical outcome study in neonates and infants with late onset Gram-negative sepsis and a framework to facilitate PK-PD research. The pharmacokinetic (PK) clinical trial of ciprofloxacin recruited 64 babies including a minimum of seven recruits representing every four weeks of development. The median post menstrual age in weeks was 35.7 (6.5) (range 24.9 - 47.9). Blood samples (n = 265) were collected at pre-defined informative time points in addition to 165 samples scavenged from clinically indicated blood tests, in total 430. A two compartment model with first-order elimination fitted the data. PK parameters included maximum concentration, clearance, area under the curve (0-tau), apparent volume of distribution and half-life and selected covariates with their inter-individual variability (CV%). Based on adult PD targets the minimum area under the curve /minimum inhibitory concentration (AUC/MIC) ratio 125 was achieved by 85% of this population. Higher AUC24 hour/MIC targets &gt;250 may be required for serious infections yet few (42%) of this population achieved this. The optimal AUC/MIC ratio for neonates is unknown. Clearance increased with post-natal age yet the combined effect of PMA at birth and corrected gestational age had a greater effect on clearance. Clearance reduced by 29% with co-administration of inotropes associated with underlying renal compromise. Monte Carlo simulation demonstrated that the AUC24/MIC 125 was achieved by 90% of neonates &lt;34 weeks PMA administered 7.5 mg/kg/day and 84% of those ≥34 PMA administered 12.5 mg/kg/day. Ciprofloxacin is lipophilic and has good tissue penetration. CSF concentrations achieved a ratio of 0.33 of the serum plasma concentrations. Pharmacodynamic data included a retrospective cohort study over a six year period of neonates with confirmed Gram-negative organisms in blood cultures. Organisms retrieved from the clinical laboratory (n=88) were re-cultured and the MIC ciprofloxacin determined using an E Test. A sub-group were administered ciprofloxacin (n=33); each organism’s MIC was compared with the same neonate’s clinical outcome. Relatively higher MICs within the susceptible range were associated with a greater risk of treatment failure. These data were not statistically significant due to the low incidence of confirmed Gram-negative bacteraemia (1.3%). The clinical implications are that more intensive dosage regimens may be required or a lower clinical breakpoint subject to further PD and safety data. Too few organisms were available to determine if the MIC increased annually but the incidence of ciprofloxacin resistance in surveillance surface swabs was no higher than for gentamicin. To prepare for a future pharmacogenomic study, DNA scavenged from clinical blood samples were compared to a buccal scrape to evaluate whether this less invasive method is reliable. A substantially larger quantity and higher quality of DNA was obtained from scavenged blood. A sub-group were transfused with leukocyte depleted products for their clinical care prior to DNA sampling. The genotyping of allelic polymorphisms were not affected by the donor’s blood sufficiently to affect the genetic fingerprint. This indicates that prior blood transfusions should not be a contra-indication to scavenging blood for pharmacogenetic purposes. The challenges of PK/PD trials in this vulnerable population were explored. The majority were recruited in intensive care and had comorbidity and extreme prematurity. Due to the complexity of critical illness there are limitations to interpreting clinical outcome or safety data from a PK clinical trial design. There were no suspected unexpected serious adverse reactions. Arthralgia was not reported but is difficult to assess in non-weight bearing non-vocal neonates and young infants. A proportionate regulatory model of neonatal PK clinical trials was developed with the Medicines and Health Care Products Regulatory Agency. A framework for pharmacovigilance reporting during critical illness which avoided nuisance reporting was developed. The impact was assessed by an observational case study and review of discharge letters to illustrate the challenge of attributing causality. Individualised therapy may be required in critical illness. The correct dose of an antimicrobial may change daily during the sepsis episode. The inter- and intra-individual variability in parameters is associated with dynamic changes during neonatal development and the effects of critical illness. Further outcome and safety data are required to determine the optimal AUC24/MIC ratio. Paediatric clinical breakpoints specific to each sub-age group of children are required. Individualised therapy may be required to optimise clinical outcome and minimise resistance.