How to use vancomycin optimally in neonates: remaining questions

Abstract

In neonates, vancomycin, a narrow-spectrum antibiotic, is the first choice of treatment of late-onset sepsis predominantly caused by Gram-positive bacteria (coagulase-negative staphylococci and enterococci). Although it has been used for >50 years, prescribing the right dose and dosing regimen remains a challenge in neonatal intensive care units for many reasons including high pharmacokinetic variability, increase in the minimal inhibition concentration against staphylococci, lack of consensus on dosing regimen and way of administration (continuous or intermittent), duration of treatment, use of therapeutic drug monitoring, limited data on short- and long-term toxicity, risk of mutant selection and errors of administration linked to concentrated formulations. This article highlights and discusses future research directions, with specific attention given to dosing optimization of vancomycin, including the advantages of modeling and simulation approaches.

Keywords:

• continuous infusion
• dosing optimization
• formulation
• modeling and simulation
• neonates
• nephrotoxicity
• ototoxicity
• pharmacokinetics
• therapeutic drug monitoring
• vancomycin

Financial & competing interests disclosure

All authors receive support from the European Commission for their work in pediatric pharmacology: FP7 Treat infection in neonates TINN1 (grant agreement no. 223614), FP7 Treat infection in neonates TINN2 (grant agreement no. 260908), FP7 Global research in paediatrics GRIP (grant agreement no. 261060), NeoVanc (grant agreement no 602041). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Vancomycin is frequently used to treat neonatal infections due to resistant staphylococci. It is primarily administered as an intermittent infusion, but optimal dosage remains to be validated.

• Continuous infusion in the neonate is currently under investigation, as it is reported to be more safe and effective in older patients, but may be difficult to use in neonates.

• Drug dosage should be based on the covariates identified, as unexplained pharmacokinetic (PK) variability is high.

• PK/PD target has to be increased as methicillin-resistant Staphylococcus aureus sensitivity decreases. Neonates may require different PK/PD targets compared to adults because of age-specific risk factors for infection.

• As selection of resistant mutants increases with long exposure at too low doses, optimal treatment duration should be evaluated.

• Formulations adjusted to the neonate are required in order to avoid administration errors linked to highly concentrated products. In addition, the ‘bacteriological efficacy’ of generics should be evaluated.

• Consensus on initial dosing regimen of vancomycin adapted to significant covariates and PK/PD target is required.

• Continuous infusion and intermittent administrations should be compared in terms of feasibility but also efficacy and safey.

Notes