3 | Results
3.1 | Baseline Characteristics (Table 1)
As showed in Table 1, the 90 patients (63.3% males; average age 2.4 years, range 1 month–14 years) included 63 children younger than 3 years. The median time of hospitalization was 16 days in the CIV group and 17 days in the IIV group. The median therapy time was 9.5 days for CIV and 13 days for IIV. According to the scoring system of pediatric critical cases, 9 of the CIV group and 11 of the IIV group were extremely critical patients defined by a score lower than 70. The CIV group had no significant difference (P > 0.05) in terms of the baseline parameters like age, gender, and hospitalization time compared to the IIV group.
The most common diagnoses were that of pneumonia (35 of 90, 38.9%) and sepsis (35 of 90, 38.9%), central nervous system infections (11 of 90, 12.2%), skin and soft tissue infection (9 of 90, 10%). 26.7% of patients (24 of 90) had one more underlying diseases, such as hemopoietic system malignant or tumor (12/90, 13.3%), intracranial hemorrhage (4/90, 4.4%), congenital heart diseases (4/90, 4.4%), genetic metabolic diseases (3/90, 3.3%), surgical diseases (2/90, 2.2%), endocrine and rheumatic diseases (2/90, 2.2%), epilepsy (1/90, 1.1%), bronchopulmonary dysplasia (1/90, 1.1%).
A positive blood culture result was found in the case of 42(42/90, 46.7%) patients (Table 2) , indicating infection byStaphylococcus aureus (19/42, 45.2%), Streptococcus pneumonia (9/42, 21.4%), Streptococcus agalactiae (GBS) (4/42, 9.5%), and Enterococcus spp. (3/42, 7.1%). The blood cultures were repeated on the 7th day for two infants in the IIV group and three infants in the CIV group with gram-positive bacteremia which did not turn negative on the 3rd day. The baseline characteristics such as the days of medication and the positive rate of bacterial culture were similar between both the groups.
3.2 | Attainment of the target level in PK/PD
The average drug concentration at 24, 36, 48 h in the CIV group were 8.96 mg.L-1 (IQR 5.32, 11.70), 16.1 mg.L-1 (IQR 9.59, 19.30) and 19.50 mg.L-1 (IQR 12.98, 25.0), respectively. The plateau concentration in the CIV group was 15.22 mg.L-1 (IQR 10.07, 17.18). The median of the trough and peak concentration in the IIV group were 6.25 mg.L-1 (median 6.25 mg.L-1; IQR 3.73, 11.07) and 17.91 mg.L-1 (IQR 7.09,88.31). The higher target levels were achieved with the same dosing regimen of 40 mg.kg-1.d-1 in the CIV group (median 15.22 mg.L-1; IQR 10.07, 17.18) compared to that in the IIV group (median 6.25 mg.L-1; IQR 3.73, 11.07) (P < 0.05) (Figure 2) .
The proportion of patients who achieved target concentrations (therapeutic drug monitoring concentration of vancomycin is up to 10 mg.L-1) was 26% (13 of 50) in the IIV group compared to 75% (30 of 40) in the CIV group (P < 0.01). In the CIV group, a higher proportion of blood concentration up to 15 mg.L-1 was found compared to that in the IIV group (72.5% VS 28.0%, P < 0.05).
Among all the patients, 46.7% (42 of 90) with the minimum inhibitory concentration (MIC) of vancomycin showed a median of AUC0–24h/MIC ratio of 429.60 (220.92, 769.20) and 391.45 (251.45, 898.16) in the CIV and IIV groups (P = 0.582) (Figure 2). Based on the studies and guidelines of treatment of S. aureus bacteremia and pneumonia3, the bacteria were found to be cleared quickly and improved the clinical symptoms quickly when the AUC0–24 h/MIC ratio ≥ 400. The proportion of patients with AUC0–24 h/MIC ≥ 400 between the two groups was 52.9% (9/17) and 48.0% (12/25), respectively, and there was no statistical significance (P = 0.753).
3.3 |Drug-related adverse effects
The serum creatinine and urea levels were determined between the time points before the initial dosing and the 1st, 3rd, 7th, and 14thday after vancomycin treatment in all the patients in both two groups. The data showed that (Figure 3) there was no increase in the creatinine, urea, KIM-1, CysC, β2-MG in the blood and NGAL levels at the end compared to that at the start of the treatment in both the groups. In the CIV group, the β2-MG in the urine had higher baseline parameters at the start of treatment. However, there was no significant difference (P > 0.05) at the end of the trial compared to the IIV group. No patients in each of the groups had an increased creatinine level >1.5 times the baseline creatinine. Vancomycin was well-tolerated, with no documented vancomycin-related adverse effects in either group.
Supratherapeutic concentrations were found in 12.5% (5 of 40) and 12.0% (6 of 50) patients in the CIV and IIV groups. However, none of them had hearing impairment such as high-frequency sensorineural hearing loss during hospitalization and later follow-up. About 23.3% (21 of 90) patients had a liver injury, including 20.0% (8/40) and 26.0% (13/50) patients in the CIV and IIV group, respectively. However, combining the clinical characteristics of the patients and comparing the liver function before and after treatment, showed no parallel relationship between the degree of liver damage and the duration of treatment with vancomycin and the increase in the concentration of vancomycin. In addition, one patient in the CIV group developed the Red man syndrome.
3.4 |Clinicalprognoses
The body temperature of the two groups during the treatment showed a downward trend. The CIV group could return to normal body temperature after about 3.43 days, while the IIV group regained the normal body temperature in 3.96 days. There was no significant difference in the time required for regaining the normal body temperature between the CIV and IIV groups (P = 0.405). There was no significant difference in the clinical indices such as CRP, PCT, and cytokines in either group (Figure 4), suggesting that the therapeutic effect was achieved irrespective of the methods of infusion of vancomycin.