1110. In Vivo Pharmacodynamics of Vancomycin Against Staphylococci in Young Infants

Abstract Background Coagulase-negative staphylococci are the predominant pathogen causing late onset sepsis in young infants, however, the pharmacodynamic target for vancomycin therapy is unknown. This study aimed to determine the pharmacodynamic target of vancomycin in young infants with staphylococcal infections. Methods Retrospective data were collected for infants aged 0-90 days with methicillin-resistant Staphylococcus aureus (MRSA or coagulase-negative staphylococci (CoNS) bacteraemia over a 4-year period at the Royal Children’s Hospital Melbourne, Australia. Vancomycin broth microdilution minimum inhibitory concentrations (MIC) were determined. A published pharmacokinetic model was externally validated using the study dataset and a time-to-event pharmacodynamic model developed using non-linear mixed effects modelling, with the event being the first negative blood culture. Simulations were performed to determine the 24-hour trough vancomycin concentration correlating with a 90% probability target attainment (PTA) of the area under the curve in the first 24-hours (AUC0-24) exceeding the identified target. Results Thirty infants, 28 with CoNS and two with MRSA bacteraemia, who had 165 vancomycin concentrations determined were included. The vancomycin broth microdilution MIC was determined for 24 CoNS and one MRSA isolate, both with a median MIC of 1 mg/L (CoNS range 0.5 to 4). An AUC0-24 ≥3 00 mg/L·h was associated with a 7.8-fold increase in the chance of bacteriological cure for all staphylococci at any time point compared to an AUC0-24 < 300 mg/L·h (hazard ratio 95% CI: 3.21-18.8). The 24-hour trough concentrations associated with a 90% PTA of achieving this target were > 13-16 mg/L and > 8-12 mg/L for 6 and 12-hourly dosing, respectively. Conclusion Our study found that an AUC0-24 ≥ 300 mg/L·h was associated with a 7.8-fold increase in bacteriological cure in young infants with staphylococcal bloodstream infections. Disclosures All Authors: No reported disclosures


Session: P-62. PK/PD Studies
Background. ECMO is a life-saving tool utilized in critically ill patients that require respiratory and/or cardiac support. ECMO may also affect the pharmacokinetics (PK) of certain medications, including some antibiotics. Cefepime is a widely used antibiotic in this population due to its broad spectrum activity but limited data are available to guide dosing in patients requiring ECMO.
Methods. This was a prospective, single-center study of 6 critically ill adult patients requiring ECMO and receiving cefepime 2g q8h as a 3h infusion. After obtaining informed consent, 4-6 blood samples within the dosing interval were collected to determine cefepime concentrations. Population PK was conducted in Pmetrics using R. Final MAP Bayesian parameter estimates were used to simulate free time above MIC (%ƒT >MIC) for various cefepime dosing regimens. The target pharmacodynamic exposure was 70% fT >MIC.
Conclusion. These are the first data describing cefepime PK and exposure attainment in critically ill patients receiving ECMO. Cefepime 2g q8h (3h infusion) achieved target pharmacodynamic exposure up to the susceptibility breakpoint of 8 mg/L in all 6 patients, including 2 with concomitant CVVHDF. Additional studies are warranted to define cefepime PK in patients on ECMO across a robust range of CrCL to guide dosing. Disclosures

In Vivo Pharmacodynamics of Vancomycin Against Staphylococci in Young Infants
Amanda Gwee, MBBS, FRACP, DTMH, PhD 1 ; Stephen Duffull, PHD 2 ; Derek Zhu, PhD 2 ; 1 The Royal Children's Hospital, Melbourne, Victoria, Parkville, Victoria, Australia; 2 University of Otago, Dunedin, Otago, New Zealand Session: P-62. PK/PD Studies Background. Coagulase-negative staphylococci are the predominant pathogen causing late onset sepsis in young infants, however, the pharmacodynamic target for vancomycin therapy is unknown. This study aimed to determine the pharmacodynamic target of vancomycin in young infants with staphylococcal infections.

Methods.
Retrospective data were collected for infants aged 0-90 days with methicillin-resistant Staphylococcus aureus (MRSA or coagulase-negative staphylococci (CoNS) bacteraemia over a 4-year period at the Royal Children's Hospital Melbourne, Australia. Vancomycin broth microdilution minimum inhibitory concentrations (MIC) were determined. A published pharmacokinetic model was externally validated using the study dataset and a time-to-event pharmacodynamic model developed using non-linear mixed effects modelling, with the event being the first negative blood culture. Simulations were performed to determine the 24-hour trough vancomycin concentration correlating with a 90% probability target attainment (PTA) of the area under the curve in the first 24-hours (AUC 0-24 ) exceeding the identified target.
Results. Thirty infants, 28 with CoNS and two with MRSA bacteraemia, who had 165 vancomycin concentrations determined were included. The vancomycin broth microdilution MIC was determined for 24 CoNS and one MRSA isolate, both with a median MIC of 1 mg/L (CoNS range 0.5 to 4). An AUC 0-24 ≥3 00 mg/L·h was associated with a 7.8-fold increase in the chance of bacteriological cure for all staphylococci at any time point compared to an AUC 0-24 < 300 mg/L·h (hazard ratio 95% CI: 3.21-18.8). The 24-hour trough concentrations associated with a 90% PTA of achieving this target were > 13-16 mg/L and > 8-12 mg/L for 6 and 12-hourly dosing, respectively.
Conclusion. Our study found that an AUC 0-24 ≥ 300 mg/L·h was associated with a 7.8-fold increase in bacteriological cure in young infants with staphylococcal bloodstream infections. Disclosures.