Special Comments - Neonatal Intensive Care Drug Manual

Pharmacokinetics/pharmacodynamics:
Vancomycin is water-soluble, has limited plasma protein binding and is mainly eliminated renally by glomerular filtration, although its elimination is further modulated by renal tubular transport.[1]
Vancomycin is active against Gram-positive bacteria. Staphylococcus epidermis, including methicillin-resistant strains, is inhibited by vancomycin concentrations of 1–4 mg/mL; Staphylococcus pyogenes, Streptococcus pneumoniae, and Streptococcus viridans are susceptible to 2 mg/mL; Bacillus spp. are inhibited by 2 mg/mL, Corynebacterium spp. by 0.04–3.1 mg/mL and Clostridium spp. by 0.39–6 mg/mL.[1]
Pharmacokinetic studies demonstrate variability that is only in part explained by weight, age or creatinine.[1-4] These studies report that current dosage regimens typically achieve therapeutic target ranges for CoNS, MSSA and MRSA with MIC ≤1 microg/mL 50 to 60% of the time.[2] This variability necessitates the use of therapeutic drug monitoring (TDM) of trough concentrations to ensure effectiveness and avoid nephrotoxicity. In contrast, the quantification of peak concentrations provides no additional monitoring value.[1]
Because vancomycin activity is primarily time-dependent, the 24 hour area under the curve (AUC0–24) divided by the MIC (AUC0–24/MIC) is a better predictor of efficacy. In adults with MIC values less than 1 mg/ml, trough concentrations >10 mg/mL result in AUC0-24/MIC values of >400.[1]
The elimination half life of vancomycin has been reported to range from 3.5 to 10 hours, decreasing with increasing gestation and postnatal age, and significantly longer in infants with a patent ductus arteriosus and with indomethacin treatment. [19]
In neonates, an RCT [5] compared intermittent intravenous (IV) dosing using the British National Formulary (BNF) dosage guidance [15 mg/kg/dose: <29 weeks 24-hourly; 29 to 35 weeks 12-hourly; 36 to 44 weeks 8-hourly; >44 weeks 6-hourly] versus continuous IV [loading dose of 15 mg/kg over 1 hour then continuous infusion: S creatinine <40 micromol/L, cGA ≥40 = 50 mg/kg/day; S creatinine <40 micromol/L, cGA <40 = 40 mg/kg/day; S creatinine 40–60 micromol/L, cGA All = 30 mg/kg/day; S creatinine >60 micromol/L, cGA All = 20 mg/kg/day). The target trough concentration for intermittent IV dosing was 10 to 20 mg/L and steady state concentration for continuous IV 15 to 25 mg/L. Target concentrations at the first steady state concentration were higher for continuous IV compared with intermittent IV (45/53 (85%) vs 21/51 (41%); p <0.001)). Fewer dose adjustments and a lower total daily dose were required to achieve target concentrations with continuous IV compared to intermittent IV. No nephrotoxicity or red man syndrome occurred in either group. [LOE II]
There are few case reports of vancomycin cerebrospinal fluid concentrations with reported CSF penetration rates ranging from 7 to 42%.[1]
Efficacy: Clinical trials of vancomycin in newborn infants are largely underpowered so the relative efficacy of various antibiotic strategies is unclear. Concerns regarding the potential for antibiotic resistance developing result in recommendations to avoid the use of prophylactic antibiotics and reduce the duration of antibiotic therapy where possible.[6, 7]
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