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Linezolid mean daily dose and body height were associated with mortality in vancomycin-resistant Enterococcus bloodstream infection.
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Increasing the mean linezolid daily dose was protective in shorter patients.
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A trough concentration >12.2 mg/l was a risk factor for thrombocytopenia.
Abstract
Objectives
We analyzed the risk factors affecting linezolid treatment outcome in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI).
Methods
We conducted a multicenter observational study of patients who received linezolid 600 mg every 12 hours for VRE BSI. The primary outcome was 28-day mortality. The estimated area under the concentration-time curve and trough concentration were calculated. Multivariable logistic regression was used for the outcome analysis.
Results
A total of 170 patients were included: 114 (67.1%) survived and 56 (32.9%) did not. A total of 26 (18.2%) isolates showed a linezolid minimum inhibitory concentration (MIC) of ≤1 mg/l, 113 (79.0%) of 2 mg/l, and 4 (2.8%) of 4 mg/l. The univariable analysis showed that the linezolid MIC and concentration-time curve/MIC were not associated with mortality (P = 0.95 and P = 0.42, respectively). After adjusting for underlying comorbidity and disease severity, the linezolid dose per body weight (LDBW), body height, and interaction between them were independent risks for mortality. Marginal analysis showed that increasing the LDBW was protective in patients with a body height <160 cm. A trough concentration of >12.2 mg/l was a risk factor for thrombocytopenia.
Conclusion
The LDBW and body height were interactively associated with clinical outcomes of linezolid treatment for VRE BSI.
Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review and meta-analysis.
Despite the high mortality rate of VRE BSI, there are limited treatment options for VRE because of the low susceptibility of enterococci to many antibiotics [
]. Although it is not Food and Drug Administration-approved for VRE BSI, the off-label use of daptomycin for the treatment of VRE infection is increasing [
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis.
], the heterogenicity in the treatment groups and selection bias make the findings inconclusive. A study of the largest cohort by Britt et al. found an opposite result that linezolid was associated with a higher mortality than daptomycin [
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
]. Given the inconsistent results and retrospective design of previous studies, there is no consensus for the selection between linezolid and daptomycin for treatment of VRE infection. Knowing the factors affecting the outcomes of linezolid treatment is essential for selecting the appropriate treatment.
Only a few studies have described the risk factors associated with linezolid treatment outcomes of VRE BSI [
Risk factors associated with failure of linezolid therapy in vancomycin-resistant Enterococcus faecium bacteremia: a retrospective cohort study in a Referral Center in Mexico.
Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial.
], and none have analyzed the effects of pharmacodynamic (PD) parameters or linezolid dosage. Although the PD index for linezolid efficacy supports the standard dosage of linezolid 600 mg every 12 hours for VRE infection [
], the variability in clinical conditions, body size, and creatinine clearance can influence drug pharmacokinetics (PK) and may be associated with treatment failure and antibiotic resistance [
]. In addition, when the minimum inhibitory concentration (MIC) of VRE isolates is >1 mg/l, the same dose is less effective and tends to result in resistance.
In this study, we hypothesized that the PD parameters and dosage of linezolid would correlate with clinical outcomes. Because hemodialysis influences the drug PK of linezolid [
], in this study, we included only patients not under renal replacement therapy to ensure a more homogeneous population and the ability to predict the PD parameter. In this observational study, we aimed to identify the factors, especially PD parameters and linezolid dosage, that affect the linezolid treatment outcomes of VRE BSI.
Patients and methods
Study population, selection, and definition
We performed an observational study to evaluate risk factors associated with linezolid treatment outcome of VRE BSI. The study was conducted at the National Taiwan University Hospital (NTUH), NTUH Yun-Lin Branch, and NTUH Hsin-Chu Branch. The participants were enrolled between January 2010 and December 2021. The patients with VRE BSI were prospectively identified per institution routine. For the specific purpose of the study, the subsample was extracted and analyzed in retrospect. The inclusion criteria were patients who had at least one set of blood culture growth of VRE and received linezolid as initial treatment. Patients who received hemodialysis or peritoneal dialysis were excluded to minimize their influence on the PK and PD. Patients who survived for more than 7 days but did not receive follow-up blood cultures received linezolid for less than 72 hours or received linezolid after the VRE BSI had cleared were excluded from the microbiologically evaluable cohort [
We collected demographic, comorbidities, and clinical data from electronic medical records. The linezolid dose per body weight (LDBW) was defined as the daily linezolid dose divided by body weight, and all participants in the study received linezolid at the dose of 600 mg every 12 hours. The area under the concentration-time curve (AUC24) and trough concentration (Cmin) in the study were estimated based on formula of a previous PK study, in which the daily dose (mg/day) = drug clearance × AUC24, drug clearance = 0.0258 × creatinine clearance + 2.03, and AUC24 = 18.2 × Cmin + 134.4 [
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
]. We defined combinations with β-lactams as the use of penicillin, cephalosporin, or carbapenem, along with linezolid treatment. We defined immunosuppressive agent use as antineoplastic agents or other immunosuppressive agents within 6 weeks or prednisolone 20 mg/day for over 2 weeks or 30 mg/day for over 1 week. Primary BSI was defined as unknown infection focus.
The primary outcome was all-cause 28-day mortality [
]. The secondary outcomes included overall in-hospital mortality, microbiological failure, clinical failure, and thrombocytopenia. Microbiological failure was defined as persistent VRE bacteremia over 4 days after the onset of VRE BSI or mortality within 7 days [
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
]. Patients who received linezolid for at least 72 hours and patients with VRE isolates available for antimicrobial susceptibility testing were selected for sensitivity analysis of the primary outcome.
Microbiological identification and antimicrobial susceptibility
Blood cultures were performed in the clinical microbiology laboratory. Enterococcus spp. was identified using VITEK 2 identification system before 2017 and matrix-assisted laser desorption ionization-time of flight mass spectrometry after 2017. The susceptibility of linezolid was obtained using Sensititre GPN3F MIC test systems. The MIC interpretation break points were according to Clinical and Laboratory Standards Institute criteria [
Continuous variables were shown as the mean and SD and compared using Student's t-test. For categorical variables, percentages were calculated and compared using Pearson chi-squared test or Fisher's exact test. We performed a stepwise multivariable logistic regression, which included variables with P ≤0.2 in the univariable analysis. After the selection using the Akaike information criterion method, the variables with P ≤0.05 were determined as statistically significant. The interaction between LDBW and body height on mortality was examined using the marginal effects analysis. The statistical analyses were performed by using Stata software (v. 16; StataCorp, College Station, TX, USA).
Results
A total of 1425 episodes of VRE bacteremia were identified during the study period; 170 patients who had received linezolid without renal replacement therapy met the inclusion criteria (Figure 1). There were 133 patients enrolled in NTUH, 19 in NTUH Yun-Lin Branch, and 18 in NTUH Hsin-Chu Branch. One VRE isolate was Enterococcus casseliflavus, and the others were E. faecium. Among the enrolled patients, 131 patients met the criteria for a microbiologically evaluable cohort and 143 VRE isolates were available for MIC testing.
The baseline and clinical characteristics of the enrolled patients with VRE BSI are summarized in Table 1. Among the 170 included patients, the mean (SD) age was 69.6 (14.2) years, and the mean Pitt bacteremia score was 2.5 (2.3) points (Table 1). All patients received linezolid 600 mg every 12 hours. The LDBW (mg/kg) was 21.5 mg/kg. The mean interval to linezolid initiation from the onset of infection was 3.0 days (2.0). Most patients had multiple underlying comorbidities; the mean Charlson score was 4.1 (2.7), and 80 (47.1%) had an underlying malignancy. Primary BSI was the major infection focus (49.8%). A total of 26 (18.2%) isolates showed a linezolid MIC of ≤1 mg/l, 113 (79.0%) of 2 mg/l, and 4 (2.8%) of 4 mg/l. On day 28, 114 (67.1%) patients had survived and 56 (32.9%) had not. A total of 26 (19.9%) patients had microbiological failure.
Table 1Baseline characteristics, clinical characteristics, and univariable logistic regression of risk factors for 28-day mortality.
Data are mean values (SD) for continuous variables and n (%) for categorical variables. Student's t-test was used to compare continuous variables and Pearson's chi-square test or Fisher's exact test was used to compare categorical variables.
Among the 131 patients with an evaluable microbiological outcome.
26 (19.9)
6 (6.5)
20 (51.3)
<0.001
15.1 (5.3-42.6)
Abbreviations: AUC24, area under the curve; MIC, minimum inhibitory concentration.
a Data are mean values (SD) for continuous variables and n (%) for categorical variables. Student's t-test was used to compare continuous variables and Pearson's chi-square test or Fisher's exact test was used to compare categorical variables.
b 143 isolates were available for MIC testing.
c Among the 131 patients with an evaluable microbiological outcome.
The baseline demographics and clinical characteristics of the survivors and nonsurvivors are summarized in Table 1. The survivors had a higher proportion of male patients (70.2% vs 46.4%; P = 0.003). The nonsurvivors had a higher proportion of patients with diabetes mellitus (50.0% vs 32.5%; P = 0.03), higher Pitt bacteremia score (3.5 vs 2.1; P < 0.001), and lower platelet count (× 104 cells/µl; 12.9 vs 23.5; P <0.001). Microbiological failure was significantly associated with 28-day mortality (P <0.001). The univariable analysis showed that the linezolid MIC and LDBW were not associated with mortality (P = 0.95 and P = 0.85, respectively). The AUC24/MIC and time to linezolid initiation did not differ significantly between survivors and nonsurvivors (P = 0.42 and P = 0.22, respectively).
We performed a stepwise multivariable logistic regression analysis to adjust for the differences in the baseline characteristics between survivors and nonsurvivors (Table 2). The mean linezolid daily dose (adjusted odds ratio [aOR], 0.02; P = 0.002), body height (aOR, 0.55; P = 0.001), and the interaction between them (aOR, 1.02; P = 0.002) were independent risks for mortality after adjusting for diabetes mellitus, platelet count, and Pitt bacteremia score.
Table 2Multivariable logistic regression analysis of the risk of 28-day mortality.
Odds ratio (95% confidence interval)
P-value
LDBW (mg/kg)
0.02 (0.002-0.23)
0.002
Body height (cm)
0.55 (0.39-0.77)
0.001
LDBW (mg/kg) × body height (cm)
1.02 (1.01-1.04)
0.002
Diabetes mellitus
3.76 (1.52-9.29)
0.004
Platelet count (× 104 cells/µL)
0.92 (0.89-0.96)
<0.001
Pitt bacteremia score
1.48 (1.21-1.80)
<0.001
Abbreviations: LDBW, linezolid dose per body weight.
Marginal analysis of risk factors associated with mortality
To examine further the interaction between LDBW and body height on 28-day mortality, we performed a marginal analysis; the results are shown in Figure 2. In patients whose body height was <160 cm, a higher LDBW was associated with better survival.
Figure 2Marginal analysis of the interaction between body height and LDBW for mortality.
We selected 162 patients who had received linezolid for at least 72 hours for the sensitivity analysis. The 28-day mortality was 51/162 (31.5%). A multivariable logistic regression analysis performed on the sensitivity analysis cohort showed that LDBW (aOR, 0.02; P = 0.002), body height (aOR, 0.55; P = 0.001), and the interaction between them (aOR, 1.03; P = 0.002) remained significantly associated with mortality (Supplementary Table S1).
We also selected 143 patients with VRE isolates available for antimicrobial susceptibility testing for the sensitivity analysis. The 28-day mortality was 48/143 (33.6%). The analysis revealed that LDBW (aOR, 0.05; P = 0.03), body height (aOR, 0.61; P = 0.007), and the interaction between them (aOR, 1.02; P = 0.03) were significantly associated with mortality (Supplementary Table S2).
Secondary outcomes
Among the secondary outcomes, the overall in-hospital mortality rate was 72/170 (42.4%), the microbiological failure rate was 16/131 (19.9%), and the clinical failure rate was 60/170 (35.3%). The AUC24/MIC and LDBW (mg/kg) were not significantly associated with overall in-hospital mortality, microbiological failure, or clinical failure.
Among patients without thrombocytopenia before linezolid treatment, the thrombocytopenia rate after linezolid therapy was 30/148 (20.3%). The optimal cut-off point of Cmin for predicting thrombocytopenia after linezolid therapy was determined using the Youden index from the receiver operating characteristic curve. The cut-off point for Cmin was 12.2 mg/l (sensitivity = 0.72, specificity = 0.53, AUC of the receiver operating characteristic curve = 0.62). A Cmin >12.2 mg/l was a risk factor for thrombocytopenia (OR [odds ratio], 2.35; 95% confidence interval [CI], 1.04-5.31; P = 0.04). Other risk factors for thrombocytopenia were the Pitt bacteremia score (OR, 1.30; 95% CI, 1.12-1.50) and ventilator use (OR, 7.24; 95% CI, 3.44-15.23).
Discussion
Linezolid is one of the limited choices for treating VRE BSI [
In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains.
Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis.
]. It is essential to know the factors affecting the linezolid treatment outcomes. In this observational study, after adjusting for the underlying disease and bacteremia severity, we found that the independent risk factors associated with 28-day mortality were LDBW and body height.
Studies focused on linezolid to treat VRE BSI are limited [
Risk factors associated with failure of linezolid therapy in vancomycin-resistant Enterococcus faecium bacteremia: a retrospective cohort study in a Referral Center in Mexico.
Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial.
Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial.
Risk factors associated with failure of linezolid therapy in vancomycin-resistant Enterococcus faecium bacteremia: a retrospective cohort study in a Referral Center in Mexico.
], early studies did not explore the effect of linezolid dosing on the clinical outcome. In the current study, we found that both bacteremia severity, as measured by Pitt bacteremia score, and the mean dose of linezolid were associated with 28-day mortality.
Linezolid and daptomycin are the main treatments available for VRE and their effectiveness has been compared [
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
]. The representative study by Britt et al. reported that linezolid for VRE BSI was associated with a higher mortality and treatment failure than daptomycin [
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
]. However, the cohort studies in Taiwan have consistently shown greater survival benefit and microbiological eradication for linezolid over daptomycin [
Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis.
], our findings in the current study suggest that body size may influence linezolid treatment outcomes. In our study, body height and LDBW were related to mortality. The marginal analysis showed that increasing the LDBW was a protective factor for patients with a body height <160 cm but was a risk factor for those who were taller. Taiwanese people are shorter and slimmer than people in Western countries [
NCD Risk Factor Collaboration (NCD-RisC) Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants.
]. Furthermore, taller people with lower body weight were more likely to be malnourished, resulting in higher mortality. A possible reason for the effect of body height is its influence on body surface area [
]. However, the mechanism to explain the effect of body height on linezolid treatment outcome has not been studied thoroughly and warrants further exploration.
Body weight is another crucial factor that alters the PK of linezolid [
Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a phase I pharmacokinetic and pharmacodynamic study.
Linezolid concentrations in plasma and subcutaneous tissue are reduced in obese patients, resulting in a higher risk of underdosing in critically ill patients: a controlled clinical pharmacokinetic study.
Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a phase I pharmacokinetic and pharmacodynamic study.
Linezolid concentrations in plasma and subcutaneous tissue are reduced in obese patients, resulting in a higher risk of underdosing in critically ill patients: a controlled clinical pharmacokinetic study.
Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a phase I pharmacokinetic and pharmacodynamic study.
Linezolid concentrations in plasma and subcutaneous tissue are reduced in obese patients, resulting in a higher risk of underdosing in critically ill patients: a controlled clinical pharmacokinetic study.
]. These previous studies have focused mainly on the PK and PD of linezolid for treatment of methicillin-resistant Staphylococcus aureus rather than VRE infection and have used Monte Carlo simulation to evaluate PD target attainment with small sample sizes [
Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a phase I pharmacokinetic and pharmacodynamic study.
Linezolid concentrations in plasma and subcutaneous tissue are reduced in obese patients, resulting in a higher risk of underdosing in critically ill patients: a controlled clinical pharmacokinetic study.
]. In our study, a fixed linezolid daily dose of 600 mg every 12 hours was given to all patients whose body weight differed. We found that LDBW, which is determined by body weight, was associated with 28-day mortality in patients with VRE BSI treated with linezolid.
The AUC/MIC predicts linezolid efficacy, and the AUC increases proportionally with the mean linezolid dose [
]. However, the AUC24/MIC was not associated with clinical or microbiological outcomes in our analysis. A possible explanation is that although the estimated AUC24 was calculated in the current study, various clinical conditions may confound the real AUC24. However, we did not perform monitoring of the therapeutic drug level.
The susceptibility break point of linezolid for VRE is at an MIC of 2 mg/l [
In vitro activities of tedizolid and linezolid against Gram-positive cocci associated with acute bacterial skin and skin structure infections and pneumonia.
]. However, a previous PK study showed that the recommended linezolid dosage of 600 mg every 12 hours did not reach an AUC/MIC >100 in patients with VRE isolated at an MIC >1 mg/l [
], which is 2 mg/l for the VRE isolates. Our study did not find that an MIC >1 mg/l in VRE isolates predicted mortality or microbiological failure. This may reflect the finding that most of the VRE isolates had an MIC of 2 mg/l and may be because of the small sample size in our study.
Thrombocytopenia is a common severe adverse event in linezolid therapy [
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
], and Cmin is an important factor for predicting thrombocytopenia. A target Cmin (mg/l) ranging from 7 to 22.1 was recommended in previous PK studies as the threshold for preventing thrombocytopenia [
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
]. In the current study, we used the Youden index to find the Cmin cut-off for predicting thrombocytopenia. Consistent with a therapeutic drug level monitoring study of linezolid in Taiwanese adult patients [
], a Cmin value >12.2 mg/l was significantly associated with thrombocytopenia after linezolid treatment in our analysis.
There are several limitations to our study. First, given its observational nature, unmeasured confounders may have interfered with the multivariable regression analysis despite our endeavors to minimize these factors using the multivariable regression analysis. Second, although the study included a large sample size compared with other studies of linezolid-treated VRE BSI cohorts, it was still small. The participants enrolled in our study were predominantly older men. The linezolid MIC was 2 mg/l in most of our VRE isolates. Patients who were receiving hemodialysis or peritoneal dialysis were excluded from our study. Therefore, the conclusions should be generalized to other populations with caution. Third, the blood culture and laboratory follow-up were determined by the primary care physician, which may have contributed to misclassification bias. However, we used a hard end point, mortality, as the primary end point to avoid possible misclassification bias.
In conclusion, we found that the interaction between the mean daily dose of linezolid and body height was associated with mortality in patients who received linezolid for treatment of VRE BSI. A higher Cmin was found to be a risk factor for thrombocytopenia. The platelet count should be closely monitored during linezolid therapy. Further investigations are required to evaluate the effects of body size and the MIC on the effectiveness and risks associated with linezolid therapy. This information is essential for identifying the optimal linezolid dosing and timing for combination therapy when treating individual patients with VRE BSI.
Declaration of competing interest
The authors have no competing interests to declare.
Funding
This work was partially supported by the Ministry of Science and Technology, Taiwan (110-2628-B-002-059, 110-2326-B-002-003-MY3, and 111-2314-B-002-209); the Ministry of Health and Welfare, Taiwan (MOHW110-TDU-B-211-124002); and NTUH (NTUH 110-S4901).
Ethical approval
The research ethics committee of NTUH (201606064RINB) approved the study. The committee waived the requirement for written informed consent because the study had an observational design with minimal risk to source patients and did not include sensitive populations or topics.
Acknowledgments
The authors thank the Third Core Facility at the NTUH for technical assistance and facility support.
CRediT authorship contribution statement
JT Wang, YC Chuang, YC Chen, and SC Chang conceived and designed the study. JL Yang, CY Lin, HS Huang, and YC Chuang collected the data. ST Huang, JT Wang, and YC Chuang performed data analysis and interpretation. ST Huang and YC Chuang wrote the manuscript. YC Chuang revised the article critically for important intellectual content and final approval of the version to be submitted. All authors read and approved the final manuscript.
Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review and meta-analysis.
Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients.
Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis.
Risk factors associated with failure of linezolid therapy in vancomycin-resistant Enterococcus faecium bacteremia: a retrospective cohort study in a Referral Center in Mexico.
Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial.
Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains.
Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants.
Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a phase I pharmacokinetic and pharmacodynamic study.
Linezolid concentrations in plasma and subcutaneous tissue are reduced in obese patients, resulting in a higher risk of underdosing in critically ill patients: a controlled clinical pharmacokinetic study.
In vitro activities of tedizolid and linezolid against Gram-positive cocci associated with acute bacterial skin and skin structure infections and pneumonia.
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