2.3 | Interventions (Figure 1)
2.3.1 | The method of infusing vancomycin
The patients were randomly assigned in a 1:1 ratio to receive either the standard care, consisting of IIV (dose was given every 6 h at 40 mg.kg-1per day) 6,7. Alternately, CIV was given as a maintenance infusion (20 mg/kg) over the remaining 23 h after a loading dose of 20 mg.kg-1 infused over 1 h and which was started immediately after the loading infusion was complete (the same dose was given at 40 mg.kg-1 per day).
2.3.2 |Experimental materials, instrumentation, and chromatographic conditions13
The ultra-high-performance liquid chromatography (UPLC) was used to detect the plasma concentration of vancomycin in the children included in the study.
2.3.3 | The index of PK/PD
In the IIV group: trough and peak concentrations were measured immediately before the fifth dose or 30 min after the fifth dose6,7,12. In the CIV group, 500 μl of venous blood was taken to determine the plasma concentration at 24, 36, 48 h after the first administration, and the mean value of the three consecutive data (and there was no statistical difference before and after the difference) was used as the steady-state concentration of vancomycin which was called the plateau concentration.
AUC0–24 h/MIC: Besides the MIC values based on the measured values, the AUC0–24 h/MIC was calculated as follows:
Lin trap = (Cmax + Cmin)/2 × Tinfusion
Log trap= [(Cmax - Cmin) × (Tau-Tinfusion)]/ln(Cmax/Cmin)
AUC0–Tau = (Lin trap) + ( Log trap)
AUC0–24h= (AUC0-Tau) × (24/Tau)
Tinfusion: drip time of vancomycin; Tau: administration period; Cmax: Peak concentration; Cmin: trough concentration.
2.3.4 | Index of clinical prognosis
The outcome of treatment was classified as cured14 if the patients with cleared blood cultures demonstrated clinical improvement, the disappearance of symptoms, and signs, and normal laboratory tests at the time of initiation of vancomycin therapy. When gram-positive infection resulted in worsened clinical symptoms, signs, or laboratory results often leading to death, the outcome was a treatment failure14.
The following blood tests were performed for all the patients at or before randomization: full blood examination; urea, creatinine, cystatin C (CysC), β2-microglobulin (β2-MG), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1); C-reactive protein (CRP), procalcitonin (PCT), cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10). Some tests like the full blood examination; C-reactive protein and procalcitonin were repeated every 24, and 72 h for the first week then weekly thereafter during the vancomycin therapy, and others were repeated every 72 h for the first week before administration. The blood culture of all the patients was examined before admission or administration. If new infections were suspected upon re-examining the blood cultures on the 3rd and 7thday, the culture would be notified as positive (Figure 1).
The brainstem auditory evoked potentials were monitored at a drug concentration higher than 15 mg.L-1 to evaluate the hearing impairment15. Other possible drug-related adverse effects were observed throughout the trial including liver injury, rash, and Red man syndrome (RMS).