Pharmacokinetics/pharmacodynamics:
Vancomycin is water-soluble, has a limited plasma protein binding capacity 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, are 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, and Clostridium spp. by 0.39–6 mg/mL.[1]
Pharmacokinetic studies demonstrate variability, which is only in part explained by weight, age, or creatinine level.[1-4] 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 may provide no additional monitoring value.[1]
Because vancomycin activity against S. aureus is primarily exposure-dependent, the 24-hour area under the concentration-time curve (AUC0-24) divided by the MIC (AUC0-24/MIC) is a better predictor of efficacy. In adults with S. aureus MIC values less than 1 mg/ml, trough concentrations >10 mg/ml result in AUC0-24/MIC values >400.[1]
In neonates, an RCT [5] compared intermittent intravenous (IV) dosing using the British Neonatal Formulary (BNF) dosage guideline 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 level for intermittent IV dosing was 10 to 20 mg/L and steady-state level for continuous IV 15 to 25mg/L. Target concentrations at the first steady-state level was higher for continuous IV compared with intermittent IV (45/53 (85%) vs 21/51 (41%); p <0.001). Fewer dose adjustments were required in the continuous IV. The mean daily dose required to achieve target concentrations was lower with continuous IV (40.6 vs 60.6 mg/kg/day; p=0.01). No nephrotoxicity or red man syndrome occurred in either group. Conclusion: Continuous infusion of vancomycin achieves target concentrations more reliably at a lower total daily dose. [LOE II]
There are few case reports of vancomycin cerebrospinal fluid concentrations with reported CSF penetration rates ranging from 7 to 42%.[1]
For peak-trough dosing of intermittent vancomycin, dosing has typically been designed to achieve a peak concentration 20-40 mg/L and a trough 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. [22] Peak concentrations >40 mg/L are rarely reported except in infants with impaired renal function. [23] Patients with renal failure and other special subpopulations, such as patients exposed to ECMO or indomethacin, need to be monitored more closely. [23]
Multiple studies of vancomycin use have found that previously recommended dosing regimens often do not achieve designated therapeutic ranges.[24] Overall, population pharmacokinetic models contain sufficient levels of unexplained variability to warrant continued TDM for post hoc dose adjustment to achieve a given pharmacodynamic target concentration.[24] However, an external validation analysis across multiple population pharmacokinetic models found that most models led to ‘acceptable’ vancomycin concentrations in neonates.[25] The ANMF has adapted the documented regimen of Roberts et al 2014.[24]
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 limit the duration of antibiotics where possible.[6, 7]
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