Baseline Characteristic and Outcome of COVID-19 Patients
Among 368 patients hospitalized from Feb 11 to Mar 23, eight (2.17 %) received intravenous vancomycin treatment. TDM was conducted for all eight patients based on the clinical requirement (Table 1 and Table S1). The median age was 64.5 (57-81) years, including six males and two females (Table 1 and Table S1). Seven (87.5 %) patients had a clear etiology, including four cases with Enterococcus faecium pneumonia, and three with Staphylococcus haemolyticus bacteremia. The rest one received empirical vancomycin treatment for pneumonia. At baseline, each of them was on invasive mechanical ventilation. During the therapeutic process, 5 (62.5 %) were on Extracorporeal Membrane Oxygenation (ECMO), and 4 (50 %) were on hemodyalisis. The baseline creatinine concentration and eGFR were 91.04 (31.67-188.67) µmol/L and 92.33 (31.7-193.99) mL/min, respectively. Seven out of 8 have basic diseases. The initial vancomycin dosage was 1000 mg every 12 hours (1000 mg Q12 h) in six patients, 500mg per 8 hours (500 mg Q8 h) in one and 1000 mg every 24 h (1000 mg Qd) in the last patient. Five of them were also administered vancomycin through nasogastric tube feeding. The median treatment duration (including nasal administration) was 18.6 (5-39) days. All 7 culture confirmed infection turned negative after vancomycin treatment. Among patients who did not receive hemodialysis at baseline, 50 % (2/4) experienced AKI, including 1 initiated hemodialysis 4 days after vancomycin treatment.
Vancomycin Concentration Determination by UPLC-MS/MS
Vancomycin concentrations were detected by UPLC-MS/MS (supplement results). The ion channels of vancomycin and demethylvacomycin (IS) were m/z 725.5/144.2, and 718.4/144.2, respectively. As shown in Supplement Figure 1 (Figure S1), vancomycin and IS were eluted at about 1.7 min. The endogenous substances in the blank serum did not interfere with vancomycin and IS (Figure S1A and S1B). The compounds eluted from healthy donors (Figure S1C and S1D) were similar to those from COVID-19 patient’s samples (Figure S1E and S1F). The calibration curve range was 1-100 mg/L, and met the clinical requirement.
TDM of Vancomycin in COVID-19 Patients
A total of 63 time spots were monitored, including 36 troughs and 27 peaks (Table S1). Out of the 36 trough samples, nine had concentrations less than 10 mg/L and 5 have concentrations greater than 20 mg/L. Of the 27 peak samples, seven had concentrations more than 40 mg/L, and 4 less than 20 mg/L. The mean trough concentration was 13.79±6.61 (4.63-34.2) mg/L (n=36) and the peak concentration was 30.97±9.71 (17-49.9) mg/L (n=27) (Figure 1A). For patients with available samples on peak or trough, 28.6 % (2/7)) patients had at least one trough concentration less than 10 mg/L, and 80.0 % (4/5) of the patients had at least one peak concentration greater than 40mg/L. Of which, patient No.1 and 2 patients were continuously monitored for 16 days, and thus, more samples were collected from them than from the others, who had one to four samples (Table S1). For No.1, five samples showed trough concentrations beyond the normal range (10-20mg/L) and two samples showed higher peak concentration (>40 mg/L) (Figure 1B). For patient No.2, 10 samples (50 %) were out of normal range, including 7 at trough and 3 at peak (Figure 1C).
Furthermore, we examined the data from the first test of each patient, and found that 66.7% (4/6) of peak concentrations were higher than the upper limit of 40 mg/L with a mean of 37.19 (17-49.9) mg/L. Furthermore, 55.6% (5/9) of the trough concentrations were also beyond the recommended range (10-20 mg/L) with a mean of 15.59 (4.63-26.6) mg/L (Figure 1D).
Dose Adjustment Dependent on Drug Concentration
Four out of eight (50 %) patients had normal concentrations at the first detection; one (patient No. 5) had a little higher peak concentration (41.3 mg/L at peak (Table S1). Dose adjustment of intravenous vancomycin was made for the other three (37.5%) patients (No.1, 2 and 4) according to their serum drug concentrations. After dose adjustments, the peak concentrations (27.37 (17.8-41.7) mg/L) were basically returned to normal range. Significant difference (P < 0.05) was detected in peak concentrations before and after dose adjustment (Figure 1E).
The curve of concentration for vancomycin, GFR, and creatinine from three patients with dose adjustments was shown in Figure 2（Figure 2A for Patient No.1, 2B for Patient No.2, 2C for Patient No.4）. Patient No.1 (Figure 2A) was initiated with intravenous vancomycin at 1000 mg per 12 h to treat Staphylococcus haemolyticus. On day 5, at first detection, Ctrough was 6.8 mg/L lower than 10 mg/L. The intravenous dose was then increased to 1000 mg Q8 h. He was also given nasal vancomycin at 250 mg Q12 h from day 7. Cpeak was 47.7 and 41.9 mg/L on day 7 and day 8, respectively. Intravenous dose was decreased to 1000 mg Q12 h on day 8, and Ctrough was 4.63 mg/L and 6.7 mg/L on day 11 and day 13, respectively. Intravenous dose was further adjusted to 500 mg Q6 h on day 13. Since then, optimal drug concentration was detected with 90% (9/10) of samples on trough spots and 100% (9/9) on peak spots. However, he met the criteria of grade 1 AKI on day 28 and then stopped intravenous vancomycin.
Patient No. 2 (Figure 2B) was initiated with intravenous vancomycin at 1000 mg Q12 h to treat Enterococcus faecalis bacteremia. He present with renal dysfunction and was on hemodialysis since baseline. At first detection on day3, Cpeak was 33 mg/L and intravenous dose was adjusted to 1000mg Q8h according to improved eGFR. However, Cpeak rised to 46.6 mg/L on day 4, then on the same day intravenous vancomycin was stopped. He also received nasal vancomycin from day 5 to day 39. From day 5 to day 12, Cpeak and Ctrough gradually returned to normal. He was given 1000mg Q24h of vancomycin intravenously on day 10 and stopped on day 12, when both Cpeak and Ctrough exceeded the expected range. From day 15 to day 33, Ctrough was 5.9-13.1 mg/L and Cpeak was 17.8-30.9 mg/L, although the patient was on nasal vancomycin alone.
Patient No.4 (Figure 2C) was initiated with intravenous vancomycin at 500mg Q8h to treat Enterococcus faecium pneumonia. On day 4 and 5, Ctrough was 26.6 mg/L and 25.5 mg/L, respectively. After that, vancomycin administration was paused till day 10, when the patient was given intravenous vancomycin at 500mg Q8h and nasal vancomycin at 250mg Q6h. On day 12, Ctrough and Cpeak were 19.5 mg/L and 41.7 mg/L, respectively. Intravenous vancomycin was stopped on day 13, after the blood culture results were negative.
Population PK and pharmacokinetic / pharmacodynamic (PK/PD) analysis
The PK parameters of vancomycin were shown in Table 2. CL and Q were 4.3 L/h and 4.1 L/h, and V1 and V2 were 2.0 L and 56.7 L respectively. Half-life for distribution phase and elimination phase was 10 min and 19 h, respectively. Hemodialysis and serum creatinine level were covariates on the CL. Both of them were consistent with the power model. The CL in patients with hemodialysis decreased by 58% compared to those in patient without hemodialysis. IIV of CL was removed because it was close to zero after adding hemodialysis and serum creatinine level as the covariates. ECMO did not have significant effect on vancomycin PK parameters. As shown in Figure 3A, individual predictions were close to observations. The correlation coefficient reached 0.81. Most of conditional weighted residuals distributed evenly across zero horizontal line (Figure 3B), indicating that the model estimates were reliable and stable.
The AUC0-24 of vancomycin was shown in Table 1. The mean ± SD were 622±218 h·mg/L, and coefficient of variation was 35%. If the vancomycin dose was higher, or the drug was given more frequent, the AUC0-24 would increase. For example, in patient No.1, AUC0-24 changed from 871 to 740 h·mg/L when the dosage changed from 1g Q8h IV+0.25g NS (day 5-7) to 1g Q12h IV+0.25g NS (day 8-11). The AUC0-24 changed from 596 to 945 h·mg/L when the dosage changed from 1g Q12h IV (day0-2) to 1g Q8h IV (day3) in patient No. 2.
AUC0-24/MIC of vancomycin was shown in Table 1. The mean±SD was 848±566 h·mg/L, and coefficiency of variation was 67%. The maximum and minimum of AUC0-24/MIC were 1738 and 244 h·mg/L, respectively. Although AUC0-24/MIC for 3 patients was less than 400, the microbiological effects were all successful. There was no correlation between AUC0-24/MIC and microbiological effect (R2 = 0.01). AUC0-24 had a positive correlation with the grade of AKI. AUC0-24 = 675 h·mg/L was the best critical value for differentiating AKI occurrence. When AUC0-24 ≥ 675 h·mg/L, 2 of 3 patients (67%) had AKI. Meanwhile, When AUC0-24 < 675 h·mg/L, only 1 of 5 patients (20%) had AKI (p=0.19).