TMP-SMX vs. Vancomycin for Severe Infections Caused by MRSA
TMP-SMX vs. Vancomycin for Severe Infections Caused by MRSA
We evaluated 782 patients with clinically significant MRSA isolates, of whom 252 were included. The main reasons for exclusion were previous treatment with trimethoprim-sulfamethoxazole or vancomycin for more than 48 hours or inability to provide informed consent, related mostly to severity of sepsis (Figure). Inclusion was based on microbiologically documented inclusion criteria in 245 (97%) patients: 91 (36%) with bacteraemia and 154 (61%) with MRSA isolated from other clinical samples. Patients' mean age was 65.8 (SD 17) years, and all infections were healthcare associated (218 (87%) hospital acquired). Characteristics of patients and infections were mostly balanced between groups; the exception was bacteraemia, which was more common in the vancomycin group ( Table 1 ). Appropriate empirical antibiotic treatment was infrequent. Surgical interventions and catheter extraction, when indicated, were performed in similar proportions in the two study groups. Vancomycin trough concentrations were available for 97/117 (82.9%) patients in the vancomycin arm (≥10 μg/mL in 80 (83%) patients and ≥15 μg/mL in 65 (67%) patients). Isolates' minimum inhibitory concentration to vancomycin was 2 μg/mL in 12/77 (16%) of patients in the vancomycin arm and lower in the remaining patients. All isolates were susceptible to trimethoprim-sulfamethoxazole (disk zone ≤10 mm). The median duration of treatment with assigned antibiotics in the per protocol population was 17 (95% confidence interval 12 to 22) days with trimethoprim-sulfamethoxazole (n=110) and 14 (13 to 15) days with vancomycin (n=96). Potentially effective antibiotics against MRSA (mainly rifampin) were added throughout the treatment course for 14/135 (10%) patients in the trimethoprim-sulfamethoxazole arm and 8/117 (7%) patients in the vancomycin arm (P=0.32).
(Enlarge Image)
Flow of patients through study. BMT=bone marrow transplant; MRSA=meticillin resistant Staphylococcus aureus
We found no significant difference in treatment failure at day 7 between trimethoprim-sulfamethoxazole and vancomycin (risk ratio 1.38, 95% confidence interval 0.96 to 1.99) ( Table 2 ) . The failure rate with trimethoprim-sulfamethoxazole was 51/135 (38%) compared with 32/117 (27%) with vancomycin, and the 95% confidence interval for the difference fell outside the lower limit of the 15% predefined for non-inferiority (−1.2% to 21.5%). Of the components comprising the composite outcome, the advantage to vancomycin emerged from higher bacteraemia persistence at day 7 and lack of improvement in SOFA score at day 7 with trimethoprim-sulfamethoxazole. We observed similar results in the per protocol population of patients completing seven days' treatment (risk ratio 1.24, 0.82 to 1.89; absolute difference 9.9%, −3.1% to 22.5%) and for patients with bacteraemia (risk ratio 1.40, 0.91 to 2.16). Restricting the analysis to patients in the vancomycin group whose isolates' minimum inhibitory concentrations were below 2 μg/mL resulted in a larger risk ratio in favour of vancomycin (1.64, 0.99 to 2.68).
All cause 30 day mortality did not differ significantly between groups. However, among patients with bacteraemia, mortality was nearly twice as high with trimethoprim-sulfamethoxazole—14/41 (34%) versus 9/50 (18%) with vancomycin (risk ratio 1.90, 0.92 to 3.93). Among non-bacteraemic patients, mortality rates were low (5/94 (5%) v 4/67 (6%)) and not significantly different (risk ratio 0.89, 0.25 to 3.2).
We found no significant differences with regard to the pre-defined secondary outcomes ( Table 2 ). Persistence of bacteraemia was slightly more common with vancomycin at 48 hours and with trimethoprim-sulfamethoxazole at seven days. There was no significant difference in length of hospital admission for patients discharged alive. Adverse events were reported with similar frequency. Renal failure at day 7 and day 30 was slightly more common with vancomycin, but this was not statistically significant ( Table 3 ).
Variables significantly associated with the primary outcome on univariate analysis were included in the multivariable analysis. McCabe score, presence of nasogastric tube or urine catheter at onset of infection, white blood count, and albumin concentrations were associated with treatment failure but correlated with other included variables and were not entered into the regression analysis. Other significant variables are shown in Table 4 . On multivariable analysis, allocation to trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). Other independent risk factors were bacteraemia and mechanical ventilation at infection onset; surgery in the 30 days before infection was inversely associated with treatment failure.
Results
We evaluated 782 patients with clinically significant MRSA isolates, of whom 252 were included. The main reasons for exclusion were previous treatment with trimethoprim-sulfamethoxazole or vancomycin for more than 48 hours or inability to provide informed consent, related mostly to severity of sepsis (Figure). Inclusion was based on microbiologically documented inclusion criteria in 245 (97%) patients: 91 (36%) with bacteraemia and 154 (61%) with MRSA isolated from other clinical samples. Patients' mean age was 65.8 (SD 17) years, and all infections were healthcare associated (218 (87%) hospital acquired). Characteristics of patients and infections were mostly balanced between groups; the exception was bacteraemia, which was more common in the vancomycin group ( Table 1 ). Appropriate empirical antibiotic treatment was infrequent. Surgical interventions and catheter extraction, when indicated, were performed in similar proportions in the two study groups. Vancomycin trough concentrations were available for 97/117 (82.9%) patients in the vancomycin arm (≥10 μg/mL in 80 (83%) patients and ≥15 μg/mL in 65 (67%) patients). Isolates' minimum inhibitory concentration to vancomycin was 2 μg/mL in 12/77 (16%) of patients in the vancomycin arm and lower in the remaining patients. All isolates were susceptible to trimethoprim-sulfamethoxazole (disk zone ≤10 mm). The median duration of treatment with assigned antibiotics in the per protocol population was 17 (95% confidence interval 12 to 22) days with trimethoprim-sulfamethoxazole (n=110) and 14 (13 to 15) days with vancomycin (n=96). Potentially effective antibiotics against MRSA (mainly rifampin) were added throughout the treatment course for 14/135 (10%) patients in the trimethoprim-sulfamethoxazole arm and 8/117 (7%) patients in the vancomycin arm (P=0.32).
(Enlarge Image)
Flow of patients through study. BMT=bone marrow transplant; MRSA=meticillin resistant Staphylococcus aureus
We found no significant difference in treatment failure at day 7 between trimethoprim-sulfamethoxazole and vancomycin (risk ratio 1.38, 95% confidence interval 0.96 to 1.99) ( Table 2 ) . The failure rate with trimethoprim-sulfamethoxazole was 51/135 (38%) compared with 32/117 (27%) with vancomycin, and the 95% confidence interval for the difference fell outside the lower limit of the 15% predefined for non-inferiority (−1.2% to 21.5%). Of the components comprising the composite outcome, the advantage to vancomycin emerged from higher bacteraemia persistence at day 7 and lack of improvement in SOFA score at day 7 with trimethoprim-sulfamethoxazole. We observed similar results in the per protocol population of patients completing seven days' treatment (risk ratio 1.24, 0.82 to 1.89; absolute difference 9.9%, −3.1% to 22.5%) and for patients with bacteraemia (risk ratio 1.40, 0.91 to 2.16). Restricting the analysis to patients in the vancomycin group whose isolates' minimum inhibitory concentrations were below 2 μg/mL resulted in a larger risk ratio in favour of vancomycin (1.64, 0.99 to 2.68).
All cause 30 day mortality did not differ significantly between groups. However, among patients with bacteraemia, mortality was nearly twice as high with trimethoprim-sulfamethoxazole—14/41 (34%) versus 9/50 (18%) with vancomycin (risk ratio 1.90, 0.92 to 3.93). Among non-bacteraemic patients, mortality rates were low (5/94 (5%) v 4/67 (6%)) and not significantly different (risk ratio 0.89, 0.25 to 3.2).
We found no significant differences with regard to the pre-defined secondary outcomes ( Table 2 ). Persistence of bacteraemia was slightly more common with vancomycin at 48 hours and with trimethoprim-sulfamethoxazole at seven days. There was no significant difference in length of hospital admission for patients discharged alive. Adverse events were reported with similar frequency. Renal failure at day 7 and day 30 was slightly more common with vancomycin, but this was not statistically significant ( Table 3 ).
Variables significantly associated with the primary outcome on univariate analysis were included in the multivariable analysis. McCabe score, presence of nasogastric tube or urine catheter at onset of infection, white blood count, and albumin concentrations were associated with treatment failure but correlated with other included variables and were not entered into the regression analysis. Other significant variables are shown in Table 4 . On multivariable analysis, allocation to trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). Other independent risk factors were bacteraemia and mechanical ventilation at infection onset; surgery in the 30 days before infection was inversely associated with treatment failure.
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