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Rehospitalizations and Direct Medical Costs
for cSSSI: Linezolid Versus Vancomycin
C. Daniel Mullins, PhD; H. Keri Yang, PhD, MPH; Eberechukwu Onukwugha, PhD, MS; Debra F. Eisenberg, PhD, MS;
Daniela E. Myers, MPH; David B. Huang, MD, PhD; and Thomas P. Lodise, PharmD, PhD
ABSTRACT
Background: Patients hospitalized for complicated skin and skin
structure infections (cSSSIs) are at risk for rehospitalization and
high postdischarge costs.
Objectives: To compare rehospitalization rates and total direct
medical costs among cSSSI patients treated with linezolid or
vancomycin after hospital discharge.
Study Design: Two administrative claims databases were pooled
to identify adult patients (aged 18-64 years) hospitalized for cSSSI
and treated with linezolid or vancomycin. Patients with infective
endocarditis, meningitis, bone/joint/device/implant infections,
necrotizing fasciitis, or gangrene were excluded.
Methods: Unadjusted rehospitalization rates and total direct
medical costs within 42 days after discharge were compared
between linezolid and vancomycin users in the full sample and a
propensity score–matched sample. Multivariable regression analyses examined results after adjusting for confounders. Sensitivity
analyses examined outcomes at 30 and 180 days.
Results: Among 7260 patients hospitalized with cSSSIs, 42.6%
(n = 3093) received linezolid and 57.4% (n = 4167) received
vancomycin. While demographic and clinical characteristics were
similar, vancomycin users had higher baseline comorbidities and
longer length of stay during index hospitalizations. Multivariable
regression indicated that linezolid was associated with 40% and
41% lower rates of all-cause rehospitalizations in the full and
matched samples, respectively, and 45% lower rates of cSSSIrelated rehospitalizations in both samples. Linezolid was associated with cost savings of $1420 and $1708 per patient in the full
and matched samples, respectively.
Conclusions: Among commercially insured patients treated with
either linezolid or vancomycin following hospital discharge for a
cSSSI, linezolid was associated with significantly lower rehospitalization rates and total direct medical costs.
Am J Pharm Benefits. 2013;5(6):258-267
C
omplicated skin and skin structure infections (cSSSIs) are infections that involve deeper layers of the
skin, including the muscle and fascia. In the United
States, there are an estimated 14 million outpatient (ie, physician offices, emergency and outpatient departments) healthcare visits for suspected Staphylococcus aureus skin and soft
tissue infections.1 Treatment of cSSSIs is complicated and often involves both surgery and intravenous antibiotics.2 Once
considered a disease predominated by Streptococcus pyogenes, it is now estimated that more than half of all cSSSIs are
due to Staphylococcus aureus, many of which are methicillin
resistant.3-9 In a study of 11 emergency departments in the
United States, approximately 76% of purulent (ie, containing
pus) skin and soft tissue infections in adults were caused by
S aureus.10 Of these infections, 78% were caused by methicillin-resistant S aureus (MRSA); overall, MRSA caused 59% of
skin and soft tissue infections. Given the increasing ubiquity
of cSSSIs due to MRSA, 2 commonly prescribed empiric antibiotics are vancomycin and linezolid.11,12
Both linezolid and vancomycin are approved by the US
Food and Drug Administration (FDA) for the treatment of
cSSSIs caused by Gram-positive bacteria. These antibiotics
are approved for patients with similar clinical characteristics,
including patients with deep soft tissue infections, surgical/
traumatic wound infections, major abscesses, cellulitis, and
infected ulcers and burns. The Infectious Diseases Society
of America practice guidelines recommend both intravenous
vancomycin and oral or intravenous linezolid 600 mg twice
daily as first-line therapy for cSSSIs.13 To date, vancomycin
and linezolid have been evaluated in a number of comparator-controlled cSSSI trials. Overall, the efficacy and safety
of vancomycin versus linezolid for cSSSI due to MRSA have
been comparable.14-16 Most recently, similar clinical and microbiologic success rates were found in a comparative clinical trial that assessed linezolid versus vancomycin for the
management of noncellulitis cSSSI due to MRSA.17
258 The American Journal of Pharmacy Benefits • November/December 2013
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Rehospitalizations and Direct Medical Costs
While clinical trials have established the safety and
efficacy of linezolid relative to vancomycin for cSSSI,
many important questions remain. Patients enrolled
in clinical trials may not be fully reflective of the diverse patient populations that use the drugs in clinical
practice. Therefore, practice-level analyses are needed
to ascertain the real-world effectiveness of linezolid
relative to vancomycin in patients with cSSSIs. In addition, the primary outcomes assessed in cSSSI clinical trials center on clinical and microbiologic success
rates at predefined times such as 1 to 2 weeks after
the completion of therapy (ie, test-of-cure visit). To
fully understand the clinical and economic implications of one therapy relative to another for cSSSIs, it
is necessary to make a comprehensive assessment of
real-world outcomes including healthcare utilization
and rehospitalization and costs, in time frames beyond
those typically seen in clinical trials. Such a comprehensive assessment, which examines healthcare utilization
and costs across treatment groups, informs the decisionmaking processes of public and private insurers/payers
and ultimately leads to increased patient health/utility
and lower overall medical costs for the patient or society.
Our previous study reported that patients who were
treated with linezolid versus vancomycin after hospital
discharge had lower rates of repeat hospitalization across
an array of infection types; however, the prior study did
not provide cost savings estimates.18 The current study
aims to build upon our prior work using updated data
from 2 administrative claims data sets (HealthCore Integrated Research Database and IMS PharMetrics database).
This time, we examined both rehospitalization rates and
total direct medical costs for patients treated with linezolid and patients treated with vancomycin following
hospital discharge for a cSSSI from the perspective of a
commercial insurer in the United States.
METHODS
Study Design
This was a retrospective observational, comparative
effectiveness drug study (Figure 1). The study design and
analysis reflected the perspective of private insurers. The
cSSSI cases were identified based on eligible hospitalizations occurring between January 1, 2007, and September
30, 2009. The index date was defined as the discharge
date of the qualifying hospitalization. We examined
baseline comorbidities, prior hospitalizations, and prior
infections in the preindex period, which was defined as
180 days prior to the index hospitalization. A primary
postindex period of 42 days (sensitivity analyses at 30
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PRACTICAL IMPLICATIONS
Complicated skin and skin structure infection (cSSSI) patients are at risk for
rehospitalizations, which contribute to potentially avoidable wasteful healthcare spending. This study compared rehospitalization rates and total direct
medical costs among cSSSI patients treated with either linezolid or vancomycin after hospital discharge. At a primary end point of 42 days, compared
with vancomycin, linezolid was associated with:
■
■
■
Significantly lower rates of all-cause rehospitalizations (13% vs 22%;
P <.01).
Significantly lower rates of cSSSI-related rehospitalizations (8% vs 15%;
P <.01).
Significantly lower total direct medical costs (mean cost savings of
$1420 per patient).
and 180 days) from the discharge date of the qualifying
hospitalization was used for comparing rehospitalizations and total costs, in accordance with our prespecified
analysis plan. During the stage of developing our analysis
plan, 42 days was specified as the primary end point for
the analysis because based on the literature and clinical
insight, most infections should resolve within a maximum
of 6 weeks (ie, 42 days).
Study Cohort
The study population consisted of adult patients (aged
18-64 years) with a hospitalization related to cSSSI within
either the HealthCore Integrated Research Database or the
IMS PharMetrics database based on International Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) codes used to define cSSSI. The codes used
for the analyses are available in the eAppendix (available at www.ajpblive.com). Inclusion criteria required that
patients be treated with either linezolid or vancomycin
within 7 days of their hospital discharge. The following
patients were excluded: patients who were enrolled in
Medicare (because of unobserved Medicare claims data);
patients who received oral vancomycin (because there is
no systemic absorption of oral vancomycin, it is not used
for treating cSSSIs); patients who had fewer than 3 days of
linezolid oral therapy, in order to focus on those patients
who experienced a therapeutic effect (there was no minimum day requirement for intravenous therapy because
therapeutic drug levels are achieved after 1 dose); and
patients with index hospitalizations longer than 30 days.
In addition, patients with infections of the musculoskeletal system (codes 015.xx, 324.1, 376.03, 711.xx, 715.90,
715.98, 719.06, 722.9, 722.93, 726.65, 727.05, 727.09, 730.
xx), endocarditis (code 424.9x), meningitis (codes 320.2,
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■ Mullins • Yang • Onukwugha • Eisenberg
Figure 1. Study Design Schematic
Patients must get study drugs
within 7 days
180-day preindex period
Index
hospitalization
180-day postindex period
Last date
of follow-up
Admission date
of the index hospitalization
Study index date = discharge date
of the index hospitalization
Outcomes were assessed
at 30, 42, and 180 days
320.7, 320.8x), necrotizing fasciitis (codes 728.86, 729.4),
gangrene (code 785.4), or prosthetic implant/device infections (codes 919.7, 996.6x, 999.3x) during the index
hospitalization were excluded. These exclusion criteria
were developed to facilitate a comparative study of linezolid versus vancomycin based on the FDA-approved
linezolid indication for cSSSI.17
Outcomes and Study Variables
The following outcomes were captured after discharge:
all-cause rehospitalization and rehospitalization related to
a cSSSI infection and total medical costs, which included
index drug (ie, linezolid or vancomycin) costs; other drug
costs; and inpatient, outpatient, and other costs such as
laboratory and diagnostic costs. In accordance with our
prespecified analysis plan, main analyses examined the
outcomes at 42 days, while sensitivity analyses focused
on the outcomes at 30 and 180 days following discharge.
The covariate of interest was receipt of linezolid (vs
vancomycin) as the index drug. The following potential
confounders were examined and controlled for in multivariable regression models: sex, age at index discharge,
Charlson Comorbidity Index (CCI) score, length of stay of
the index hospitalization, presence of bacteremia during
the index hospitalization, presence of sepsis during the
index hospitalization, use of other anti-MRSA antibiotics
in the preindex period, presence of any infection-related
hospitalization or infection-related outpatient physician
visit in the preindex period, and presence of any all-cause
hospitalization in the preindex period. The effect of CCI
260 The American Journal of Pharmacy Benefits • November/December 2013
score was modeled using an ordered categorical measure
(no comorbidity, 1 comorbidity, 2 comorbidities, 3 or
more comorbidities) in both the rehospitalization and cost
regression models. The rehospitalization and cost regression models included a continuous (linear) measure of
age. The cost regression model also included a quadratic
term to capture the nonlinear effect of age. Length of stay
was dichotomized at the median value (5 days) in the rehospitalization regression model and was log-transformed
in the cost regression model. All other variables entered
as binary indicators of the factor described.
Analyses
A P value of .05 was used to determine statistical significance in hypothesis testing, and a P value of .10 was
used in covariate selection. Descriptive analyses examined various characteristics of the study cohort. The χ2
and t statistics were used to test for significant differences
in categorical and continuous variables, respectively,
between linezolid and vancomycin users. A correlation
matrix including all study variables was used to identify
potential multicollinearity problems. Multivariable logistic
regression analyses were used to estimate the adjusted
odds of rehospitalization for linezolid versus vancomycin
users. Prior to model specification, normality tests combined with quantile-quantile plots confirmed the suitability of the gamma distribution for the cost data. Following
estimation of model parameters using a generalized linear model with a gamma distribution, the modified Park
test19 confirmed the appropriateness of the gamma family
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Rehospitalizations and Direct Medical Costs
distribution for this analysis. A generalized linear model
with log link was used to examine differences in total direct medical costs between linezolid versus vancomycin,
after controlling for covariates. The covariates from the
generalized linear model with gamma distribution provided input data for calculating the marginal effect (ie,
the covariate-adjusted incremental cost for linezolid users
compared with vancomycin users). The 95% confidence
interval (CI) on the adjusted incremental cost was defined
using the 5th and 95th percentiles of bootstrapped replicates (1000 runs).
To address the potential for selection bias, we ran the
aforementioned multivariable analyses in a propensity
score–matched sample as well as in the full sample. The
propensity score–matched sample was created by estimating the propensity of receiving linezolid as the index
drug and then using a greedy algorithm macro written
by Jon Kosanke and Erik Bergstralh of the Mayo Clinic
College of Medicine to match cases with controls.20 The
algorithm used a caliper width of 0.2 of the standard deviation (SD) of the logit of the propensity score, which is
a function of the predicted propensity score, to conduct
a 1-to-1 match. The following baseline characteristics
were candidate variables for the regression model that
estimated the propensity score: sex, age, length of stay
of the index hospitalization, bacteremia during the index
hospitalization, sepsis during the index hospitalization,
CCI score, cancer at baseline, transplant, primary immunodeficiency disorders, human immunodeficiency virus,
renal insufficiency, diabetes, hospitalization in the preindex period, and anti-MRSA antibiotics use in the preindex
period; a forward selection approach was used to obtain
the final set of variables for the regression equation. After the propensity score–matched sample was created,
we compared the distribution of the propensity score
between matched linezolid and vancomycin patients,
examined standardized differences in observed baseline
patient characteristics, and conducted individual variable
and joint distribution significance testing.
RESULTS
Descriptive Analyses
The demographic and clinical characteristics of patients treated with linezolid versus vancomycin are shown
in Table 1. Of the 7260 patients with a cSSSI-related hospitalization in the full sample, 43% (n = 3093) initially
received linezolid and 57% (n = 4167) initially received
vancomycin after discharge. While patient characteristics
were similar, those treated with vancomycin after discharge had more baseline comorbidities, longer hospital
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stays, and higher rates of bacteremia during the index
hospitalization relative to the linezolid users. The propensity score–matched sample consisted of 5920 patients
with equal numbers in each treatment group and with no
significant differences in examined baseline characteristics (Table 1).
Results of bivariate rehospitalization comparisons are
displayed in Figure 2. Unadjusted rehospitalization rates
were lower for linezolid users compared with vancomycin users at each postdischarge time point assessed. At
42 days after discharge, treatment with linezolid versus
vancomycin was correlated with significantly lower rates
of all-cause rehospitalizations (13% vs 22%; P <.01) and
cSSSI-related rehospitalizations (8% vs 15%; P <.01). Similarly, compared with vancomycin, linezolid use was associated with lower rates of all-cause and cSSSI-related
rehospitalizations at day 30 (11% vs 19% and 7% vs 13%)
and day 180 (24% vs 36% and 12% vs 21%), respectively.
The differences were statistically significant in all cases
(P <.01).
Results of the unadjusted mean costs by cost category
for patients treated with linezolid versus vancomycin are
displayed in Figure 3. Index drug costs at 42 days after discharge were significantly higher for those treated
with linezolid versus vancomycin ($1634 vs $375; P <.01);
however, unadjusted total direct medical costs, inclusive
of index drug costs, were significantly lower among patients treated with linezolid versus vancomycin ($6258 vs
$10,066; P <.01). Similar results were found at 30 and 180
days after discharge (Figure 3).
Multivariable Regression Analyses
All-Cause Rehospitalization. After controlling for
covariates (age, sex, CCI score, bacteremia, sepsis, length
of stay during the index hospitalization, hospitalization
or use of other anti-MRSA antibiotics in the preindex period), the use of linezolid versus vancomycin was associated with a lower odds of rehospitalization; linezolid use
was associated with 40% lower odds of rehospitalization
for any reason within 42 days of initial discharge (odds
ratio [OR] = 0.60, 95% CI, 0.53-0.69; Table 2, full sample).
Additional factors correlated with the odds of all-cause
rehospitalization within 42 days included more comorbidities at baseline (OR = 1.35, 95% CI, 1.14-1.60 for CCI
score of 1; OR = 1.95, 95% CI, 1.59-2.38 for CCI score
of 2; OR = 2.55, 95% CI, 2.16-3.01 for CCI score of >3);
having an index hospitalization longer than the median
of 5 days (OR = 1.30, 95% CI, 1.13-1.48); and having an
all-cause hospitalization in the preindex period (OR =
1.68, 95% CI, 1.47-1.90). The results were similar when
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■ Mullins • Yang • Onukwugha • Eisenberg
Table 1. Cohort Characteristics by Study Drug
Full Sample
Matched Sample
Vancomycin
(n = 4167)
Linezolid
(n = 3093)
P
Vancomycin
(n = 2960)
Linezolid
(n = 2960)
P
Male, n (%)
2115 (50.8)
1628 (52.6)
.11
1516 (51.2)
1546 (52.2)
.44
Age, y, mean ± SD
47.0 (11.1)
45.5 (11.5)
<.01
46.0 (11.0)
46.0 (11.0)
.53
Characteristics
Demographics
a
Baseline comorbidities, n (%)
CCI score
<.01
.42
0
2010 (48.2)
1808 (58.5)
1665 (56.3)
1702 (57.5)
1
872 (20.9)
556 (18.0)
581 (19.6)
552 (18.7)
2
462 (11.1)
273 (8.8)
299 (10.1)
272 (9.2)
>3
823 (19.8)
456 (14.7)
415 (14.0)
434 (14.7)
Cancer
486 (11.7)
280 (9.1)
<.01
259 (8.8)
275 (9.3)
.47
HIV
22 (0.5)
43 (1.4)
<.01
22 (0.7)
20 (0.7)
.76
257 (6.2)
141 (4.6)
<.01
121 (4.1)
141 (4.8)
.21
1056 (25.3)
649 (21.0)
<.01
649 (21.9)
648 (21.9)
.97
Bacteremia during the index hospitalization, n (%)
162 (3.9)
79 (2.6)
<.01
59 (2.0)
79 (2.7)
.08
Sepsis during the index hospitalization, n (%)
228 (5.5)
158 (5.1)
.5
138 (4.7)
153 (5.2)
.37
Length of stay of the index hospitalization, days, mean ± SD
6.4 (4.6)
6.1 (4.2)
<.01
6.0 (4.0)
6.0 (4.0)
.78
2117 (50.8)
1249 (40.4)
<.01
1252 (42.3)
1237 (41.8)
.92
Hospitalization
1102 (26.5)
613 (19.8)
<.01
650 (22.0)
603 (20.4)
.13
Outpatient physician visit
2962 (71.1)
2232 (72.2)
.31
2106 (71.2)
2121 (71.7)
.67
Hospitalization or outpatient physician visit
3215 (77.2)
2368 (76.6)
.55
2256 (76.2)
2256 (76.2)
>.99
768 (18.4)
464 (15.0)
<.01
453 (15.3)
457 (15.4)
.89
Outpatient physician visit
2140 (51.4)
1684 (54.5)
<.01
1544 (52.2)
1596 (53.9)
.18
With anti-MRSA antibiotics use
1364 (32.7)
1228 (39.7)
<.01
1087 (36.7)
1104 (37.3)
.65
Renal insufficiency
Diabetes
Index hospitalization
a
Baseline utilization, n (%)
With an inpatient admission
With an infection-related:
With a cSSSI infection-related:
Hospitalization
CCI indicates Charlson Comorbidity Index; cSSSI, complicated skin and skin structure infection; HIV, human immunodeficiency virus; MRSA, methicillin-resistant Staphylococcus
aureus; SD, standard deviation.
a
Baseline period: 180 days prior to the admission date for the first qualifying hospitalization.
examining all-cause rehospitalizations for linezolid versus
vancomycin within 30 days (OR = 0.58, 95% CI, 0.50-0.67)
or 180 days after discharge (OR = 0.65, 95% CI, 0.58-0.73).
Table 2 (matched sample) further documents that
linezolid was associated with reduced odds of repeat
hospitalization in the subset of propensity score–matched
patients. After controlling for covariates, using linezolid
as initial treatment was associated with a 41% lower likelihood of rehospitalization for any reason within 42 days
of initial discharge (OR = 0.59, 95% CI, 0.51-0.68). The
results were similar when examining all-cause rehospitalizations within 30 days (OR = 0.56, 95% CI, 0.48-0.65) or
180 days after discharge (OR = 0.66, 95% CI, 0.59-0.74).
262 The American Journal of Pharmacy Benefits • November/December 2013
cSSSI-Related Rehospitalization. After controlling
for covariates, the use of linezolid compared with vancomycin was associated with a 45% lower likelihood of
a cSSSI-related rehospitalization within 42 days of initial
discharge (OR = 0.55, 95% CI, 0.47-0.64; Table 2, full
sample). Individuals with 2 or more index comorbidities (OR = 1.57, 95% CI, 1.24-2.00 for CCI score of 2;
OR = 1.92, 95% CI, 1.58-2.34 for CCI score of >3), an
index hospitalization longer than the median of 5 days
(OR = 1.21, 95% CI, 1.03-1.41), and any all-cause hospitalization in the preindex period (OR = 1.34, 95% CI,
1.15-1.56) had greater odds of rehospitalization with an
ICD-9-CM code for cSSSI infection within 42 days of
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Rehospitalizations and Direct Medical Costs
Figure 2. Unadjusted Rehospitalization Rates for Patients Treated With Linezolid Versus Vancomycin
Patients with an all-cause rehospitalization
by period and index drug
P <.01
P <.01
50
P <.01
36
40
30
22
19
20
24
13
11
10
P <.01
P <.01
P <.01
40
Percentage of All
Percentage of All
50
Patients with a cSSSI-related rehospitalization
by period and index drug
30
21
20
10
0
15
13
12
8
7
0
30 days
42 days
30 days
180 days
180 days
42 days
Period
Period
Linezolid
Vancomycin
cSSSI indicates complicated skin and skin structure infection.
Figure 3. Unadjusted Mean Costs by Cost Category for Patients Treated With Linezolid Versus Vancomycina
Unadjusted Mean Costs
25,000
Ptotal <.01
20,000
$14,875
15,000
Ptotal <.01
Ptotal <.01
10,000
$7964
$10,066
$6258
$5256
5000
0
Pindex <.01
Pindex <.01
Linezolid
Vancomycin
30-Day Costs
Other
a
$22,705
Inpatient
Linezolid
Pindex <.01
Vancomycin
Linezolid
42-Day Costs
Outpatient
Other (nonindex) drugs
Vancomycin
180-Day Costs
Index drugs
P total compares the mean total costs for linezolid and vancomycin patients. P index compares the mean index drug costs for linezolid and vancomycin patients.
discharge. The likelihood of having a cSSSI-related rehospitalization within 30 and 180 days was similar to that
at 42 days after discharge. Linezolid use was associated
with a 49% reduction in the odds of rehospitalization at
30 days (OR = 0.51, 95% CI, 0.43-0.61) and a 42% reduction at 180 days (OR = 0.58, 95% CI, 0.51-0.67) compared
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with vancomycin use following discharge after index
hospitalization.
Table 2 (matched sample) shows that linezolid was
associated with reduced odds of a cSSSI-related rehospitalization in the subset of propensity score–matched
patients. After controlling for covariates, using linezolid
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■ Mullins • Yang • Onukwugha • Eisenberg
Table 2. Association Between Linezolid Use and Odds of Postdischarge Rehospitalization and Incremental Cost
Full Sample
OR
Variable
95% CI
Adjusted OR
Matched Sample
95% CI
a
Rehospitalization for Linezolid vs Vancomycin
OR
95% CI
95% CI
Adjusted ORa
Rehospitalization for Linezolid vs Vancomycin
Any all-cause
rehospitalization within:
30 days
0.52
0.45-0.59
0.58
0.50-0.67
0.56
0.48-0.65
0.56
0.48-0.65
42 days
0.53
0.47-0.61
0.60
0.53-0.69
0.59
0.52-0.68
0.59
0.51-0.68
180 days
0.58
0.52-0.64
0.65
0.58-0.73
0.67
0.60-0.76
0.66
0.59-0.74
30 days
0.48
0.40-0.56
0.51
0.43-0.61
0.51
0.42-0.61
0.51
0.42-0.61
42 days
0.51
0.44-0.59
0.55
0.47-0.64
0.55
0.46-0.65
0.55
0.46-0.65
180 days
0.54
0.47-0.61
0.58
0.51-0.67
0.59
0.51-0.68
0.58
0.50-0.67
Any cSSSI-related
rehospitalization within:
Incremental Cost Savings for
Linezolid vs Vancomycin
Incremental Cost Savings for
Linezolid vs Vancomycin
MEa
95% CI
Adjusted MEb
95% CI
MEa
95% CI
Adjusted MEa
95% CI
30 days
$1154
$1123-$1184
$1003
$970-$1036
$920
$896-$945
$1254
$1211-$1297
42 days
$1622
$1580-$1665
$1420
$1368-$1472
$1268
$1235-$1301
$1708
$1647-$1769
180 days
$3336
$3249-$3423
$2539
$2436-$2641
$2333
$2272-$2394
$3157
$3031-$3284
Total medical and
drug cost within:
CI indicates confidence interval; cSSSI, complicated skin and skin structure infection; ME, marginal effect; MRSA, methicillin-resistant Staphylococcus aureus; OR, odds ratio.
a
Controlling for index drug, sex, age, Charlson Comorbidity Index score in preindex period, length of stay of the index hospitalization more than 5 days (the median), bacteremia during
index hospitalization, sepsis during index hospitalization, any use of other anti-MRSA antibiotics in the preindex period, any infection-related hospitalization or infection-related outpatient
physician visit in the preindex period, and any all-cause hospitalization in the preindex period.
b
The ME estimate calculates the incremental cost for linezolid users compared with vancomycin users.
c
Controlling for index drug, sex, age and age2, Charlson Comorbidity Index score in preindex period, logarithm of the length of stay of the index hospitalization, bacteremia during the
index hospitalization, sepsis during the index hospitalization, any use of other anti-MRSA antibiotics in the preindex period, any infection-related hospitalization or infection-related
outpatient physician visit in the preindex period, and any all-cause hospitalization in the preindex period.
as initial treatment was associated with a 45% lower likelihood of cSSSI-related rehospitalization within 42 days of
initial discharge (OR = 0.55, 95% CI, 0.46-0.65). The results were similar when examining cSSSI-related rehospitalization within 30 days (OR = 0.51, 95% CI, 0.42-0.61) or
180 days after discharge (OR = 0.58, 95% CI, 0.50-0.67).
Total Direct Medical Costs
After controlling for covariates, linezolid versus vancomycin use was associated with a mean cost savings
of $1420 (95% CI, $1368-$1472) per patient within 42
days of discharge in the full sample and with a mean
cost savings of $1708 (95% CI, $1647-$1769) per patient
in the propensity score–matched sample (Table 2). The
estimated cost savings over a 30-day postindex period
were $1003 (95% CI, $970-$1036) in the full sample and
$1254 (95% CI, $1211-$1297) in the propensity score–
matched sample. The estimated cost savings over a 180day postindex period were $2539 (95% CI, $2436-$2641)
264 The American Journal of Pharmacy Benefits • November/December 2013
in the full sample and $3157 (95% CI, $3031-$3284) in the
propensity score–matched sample.
DISCUSSION
Several studies have evaluated the economic effect
of linezolid compared with vancomycin in the treatment
of skin and skin structure infections, including cSSSIs,
and these are described in the medical literature.14,21-29
In these studies, linezolid compared with vancomycin
therapy was generally associated with a decrease in intravenous therapy days14,23,25 and length of stay.14,21,23-25
Linezolid therapy appeared to either decrease costs25-27
or at least be cost neutral29 compared with vancomycin
for the treatment of cSSSIs, including those caused by
MRSA.
Although clinical trials have established the efficacy
of linezolid relative to vancomycin for cSSSI, there is
still a major need for clinical and economic comparative
data in the diverse patient populations that use these
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Rehospitalizations and Direct Medical Costs
drugs in clinical practice. For cSSSIs that require hospitalization, rehospitalization rates and postdischarge costs
are significant concerns from both a public health and
a payer perspective. Unfortunately, these data are not
well captured from cSSSI registration trials. According to
the CMS, 20% of all readmissions occur within 30 days
of discharge and 76% of these readmissions may be preventable.30 Beyond the clear public health implications,
these potentially preventable high readmission rates are
particularly concerning given the recent nosocomial infection policy initiative within the Centers for Medicare
and Medicaid Services; it will refuse to pay for additional
costs associated with selected nosocomial infections that
are “reasonably preventable.”31
In light of the need for real-world comparative effectiveness data, this study compared rehospitalization rates
and total direct medical costs among commercially insured
adult patients with cSSSIs treated with either linezolid or
vancomycin after hospital discharge. Data were compared
across 2 large national administrative claims databases.
The results of the rehospitalization analyses indicated that
receipt of linezolid was associated with an approximate
40% lower odds of a rehospitalization; the exact estimate
of lower odds varied from 35% to 49% according to length
of follow-up (30, 42, and 180 days postdischarge) and
whether all-cause or cSSSI-related rehospitalizations were
examined. These results are similar to our previous administrative claims analysis that pooled 21 unique infection types.18 In that study of 11,018 hospitalized patients,
linezolid was associated with a lower OR of repeat infection-related hospitalization in patients with pneumonia, S
aureus, and skin infections. For patients with skin infections, linezolid was associated with a reduction of 27%
in the odds of infection-related hospitalization relative to
vancomycin. When we examined the full sample of 21
infection types, the number needed to treat with linezolid
instead of vancomycin to avoid a rehospitalization was
14. For the current study, the number needed to treat with
linezolid versus vancomycin was 11 or 15 to avoid a repeat hospitalization, depending on whether the analysis
considers all-cause or cSSSI-related hospitalizations.
Although rehospitalization costs were not calculated,
we did examine the rates of rehospitalization and saw
that linezolid use was associated with significantly lower
rates. The current study also showed that use of linezolid versus vancomycin as the index drug for patients
hospitalized with cSSSI may be associated with significantly lower total costs of care (including rehospitalization costs) compared with postdischarge vancomycin.
The current study also showed an adjusted lower total
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direct cost savings per patient between $1003 and $2539
for patients treated with linezolid versus patients treated
with vancomycin. In the multivariable regression analysis that controlled for potential confounders, these lower
total direct medical costs were consistent at 30, 42, and
180 days. These results are similar to those published by
McKinnon and colleagues.26 Using data from a clinical
trial comparing linezolid with vancomycin for the treatment of cSSSIs due to suspected or proven MRSA, the
mean ± SD cost for intent-to-treat population patients
(n = 717) treated with linezolid versus vancomycin was
$4865 ± $4367 versus $5738 ± $5190, respectively (difference, $873; P = .02); in the MRSA population it was $4881
± $3987 versus $6006 ± $5039, respectively (difference,
$1125; P = .04). A separate administrative claims database study by McKinnon and colleagues showed similar
findings.22 In a cSSSI subgroup, mean ± SD healthcare
costs were greater for patients receiving vancomycin
compared with those receiving linezolid (vancomycin,
$9244 ± $14,244; linezolid, $7794 ± $16,910; P = .12),
and the rate of relapse or rehospitalization was lower for
patients receiving linezolid compared with those receiving vancomycin (OR = 0.70, 95% CI, 0.35-1.40).22
The findings in this study should be interpreted in
the context of a number of important limitations of
observational studies. First, this study reflects nonrandom assignment based upon real-world clinical use of
linezolid versus vancomycin. Thus, selection bias may
impact the reported findings. Furthermore, we utilized
administrative claims data, which are collected for payment purposes rather than research. Therefore, the
presence of a claim for a drug does not guarantee the
actual administration of the drug; the data do not capture the dispensing of a drug sample; and data may be
missing if all the claims are not submitted by providers. Second, this administrative claims database study
lacked patient clinical information (eg, incision and
drainage procedures), including mortality. Instead of
culture results, ICD-9-CM codes were used to determine
the presence of infection. Furthermore, administrative
claims data do not allow us to look at the specific type
of infection, bacterial etiology (eg, methicillin-sensitive
Staphylococcus aureus versus MRSA), and antimicrobial
susceptibility of the cultured bacteria. Third, we were
not able to control for unobservable patient, provider,
and insurance benefit design characteristics that would
further impact selection bias regarding prescription of
linezolid or vancomycin, or for confounding by indication. Selection bias may be a particular issue if linezolid is prescribed to patients with certain demographic
Vol. 5, No. 6 • The American Journal of Pharmacy Benefits 265
■ Mullins • Yang • Onukwugha • Eisenberg
characteristics or higher socioeconomic status because
of the greater cost and patient cost sharing for linezolid.
However, to limit the impact of selection bias, we controlled for certain observable characteristics including
age, sex, CCI score, bacteremia during the index hospitalization, length of stay of the index hospitalization,
and any use of other anti-MRSA antibiotics in the preindex period. We also replicated our analyses in a subset of patients who were matched using a propensity
score–matching algorithm, and the results were similar
for those analyses. Finally, information regarding the
antibiotics received during the index hospitalization
was not available. In addition to the described limitations, it is important not to extend the findings beyond
our study population of nonelderly patients with private insurance, because they are not necessarily representative of all nonelderly, privately insured patients in
the United States.
The strength of this study is the large number of
patients included in this pooled database (n = 7260).
The data were consistent across different definitions of
rehospitalization and total direct medical costs when
evaluated at 30, 42, and 180 days following discharge.
Patients prescribed linezolid after hospital discharge had
significantly lower rates of all-cause and cSSSI-related
rehospitalization, and lower total direct costs compared
with patients receiving vancomycin for cSSSI. In an era
when value-based medical purchasing and reduction in
wasteful spending are major considerations in health
policy, such data provide valuable evidence for hospital
administrators and payers. This is particularly true in infectious diseases, where avoidable readmissions may not
be reimbursed.
CONCLUSION
Among commercially insured patients with a cSSSIrelated hospitalization, the use of linezolid versus vancomycin as the index drug following hospital discharge
was associated with significantly higher antibiotic drug
costs. However, linezolid use was associated with statistically significant lower total direct medical costs, including the index drug costs, compared with vancomycin
use. Furthermore, linezolid was associated with significantly lower rehospitalization rates than vancomycin in
both unadjusted comparisons and multivariable analyses
that controlled for age, sex, CCI score, bacteremia, sepsis, length of stay during the index hospitalization, prior
hospitalization, or use of other anti-MRSA antibiotics in
the preindex period. Results were consistent across the
various postdischarge end points examined and across
266 The American Journal of Pharmacy Benefits • November/December 2013
study samples (ie, full unmatched and propensity score–
matched samples).
Acknowledgments
The authors wish to acknowledge support from Kaloyan Bikov, Diane McNally, and the Pharmaceutical Research Center at the University
of Maryland for data management and analytic support; Christy Fang and
HealthCore Inc, for providing data and analytic support; IMS for providing
data; and Richard Chambers of Pfizer Inc for statistical support. Editorial
support was provided by Lisa Blatt, MA, from the University of Maryland.
Author Affiliations: From Pharmaceutical Health Services Research
(CDM, HKY, EO), University of Maryland, School of Pharmacy, Baltimore, MD; HealthCore Inc (DFE), Wilmington, DE; Pfizer Inc (DEM),
formerly of Pfizer Inc (DBH), Collegeville, PA; Albany College of Pharmacy (TPL), Albany, NY.
Funding Source: This study was sponsored by Pfizer Inc. Drs Mullins and Onukwugha are employees of the University of Maryland, which
received research funding from Pfizer in connection with conducting this
study and development of this manuscript. Dr Yang was an employee
of the University of Maryland when the study was conducted. Dr is
an employee of HealthCore Inc, which received research funding from
Pfizer in connection with conducting this study and development of this
manuscript. Dr Huang is a former employee of Pfizer Inc in connection
with this study and development of this manuscript. Dr was a paid consultant to Pfizer as an employee of Lodise & Lodise LLC in connection
with this study and the development of this manuscript.
Author Disclosures: Dr Mullins has served as a consultant and scientific advisor to Pfizer Inc and has received consulting income and research grants from Pfizer. In addition, he has received consulting income
and/or grant support from Amgen, Bayer, BMS, Cubist, Eisai, Genentech,
GSK, Novartis, NovoNordisk, Otsuka, and sanofi-aventis during the past
3 years. Dr Onukwugha has received consulting fees and research grants
from Pfizer Inc. Dr Eisenberg is a salaried employee of HealthCore Inc.
Ms Myers is a salaried employee and shareholder of Pfizer Inc. Dr Huang
was an employee and shareholder of Pfizer Inc at the time the study was
conducted. Dr Lodise is a consultant for Pfizer, Cubist Pharmaceuticals,
Astellas, and Forest; a speaker for Pfizer, Forest, and Cubist Pharmaceuticals; and has received grant support from Astellas, Cubist, and Pfizer.
Authorship Information: Concept and design (CDM, HKY, DE,
DEM, DBH, TPL); acquisition of data (CDM, DE, DEM); analysis and
interpretation of data (CDM, HKY, EO, DE, DEM, DBH, TPL); drafting of
the manuscript (CDM, EO, DBH); critical revision of the manuscript for
important intellectual content (CDM, EO, DE, DEM, DBH, TPL); statistical analysis (CDM, HKY); provision of study materials or patients (DE);
obtaining funding (CDM, DEM); administrative, technical, or logistic support (CDM, DEM); and supervision (CDM, DEM).
Address correspondence to: C. Daniel Mullins, PhD, Professor,
Pharmaceutical Health Services Research Department, University of
Maryland School of Pharmacy, 220 Arch St, 12th Fl, Baltimore, MD 21201.
E-mail: [email protected].
REFERENCES
1. Hersh AL, Chambers HF, Maselli JH, Gonzales R. National trends in ambulatory
visits and antibiotic prescribing for skin and soft-tissue infections. Arch Intern
Med. 2008;168(14):1585-1591.
2. US Food and Drug Administration. Guidance for industry: acute bacterial skin
and skin structure infections: developing drugs for treatment: draft guidance.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm071185.pdf. Published August 2010. Accessed November 12,
2011.
3. Nichols RL. Optimal treatment of complicated skin and skin structure infections. J Antimicrob Chemother. 1999;44(suppl A):19-23.
4. Wright BM, Eiland EH. Retrospective analysis of clinical and cost outcomes
associated with methicillin-resistant staphylococcus aureus complicated skin
and skin structure infections treated with daptomycin, vancomycin, or linezolid.
http://www.hindawi.com/journals/jpath/2011/347969/. J Pathogens. 2011:1-6.
Accessed November 12, 2011.
5. Jenkins TC, Sabel AL, Sarcone EE, Price CS, Mehler PS, Burman WJ. Skin and
www.ajpblive.com
Rehospitalizations and Direct Medical Costs
soft-tissue infections requiring hospitalization at an academic medical center:
opportunities for antimicrobial stewardship. Clin Infect Dis. 2010;51(8):895-903.
6. Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary
causes of skin and soft tissue infections in North America, Latin America, and
Europe: report from the SENTRY Antimicrobial Surveillance Program (1998-2004).
Diagn Microbiol Infect Dis. 2007;57(1):7-13.
7. Weigelt JA, Lipsky BA, Tabak YP, Derby KG, Kim M, Gupta V. Surgical site infections: causative pathogens and associated outcomes. Am J Infect Control. 2010;
38(2):112-120.
8. Talan DA, Krishnadasan A, Gorwitz RJ, et al; EMERGEncy ID Net Study Group.
Comparison of Staphylococcus aureus from skin and soft-tissue infections in US
emergency department patients, 2004 and 2008. Clin Infect Dis. 2011;53(2):
144-149.
9. Yates C, May K, Hale T, et al. Wound chronicity, inpatient care, and chronic
kidney disease predispose to MRSA infection in diabetic foot ulcers. Diabetes
Care. 2009;32(10):1907-1909.
10. Moran GJ, Krishnadasan A, Gorwitz RJ, et al; EMERGEncy ID Net Study
Group. Methicillin-resistant S. aureus infections among patients in the emergency
department. N Engl J Med. 2006;355(7):666-674.
11. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant
Staphylococcus aureus infections in adults and children: executive summary. Clin
Infect Dis. 2011;52(3):285-292.
12. Liu C, Bayer A, Cosgrove SE, et al; Infectious Diseases Society of America.
Clinical practice guidelines by the infectious diseases society of america for the
treatment of methicillin-resistant Staphylococcus aureus infections in adults and
children [published correction appears in Clin Infect Dis. 2011;53(3):319]. Clin
Infect Dis. 2011;52(3):e18-e55.
13. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue
infections [published corrections appear in Clin Infect Dis. 2005;41(12):1830 and
Clin Infect Dis. 2006;42(8):1219]. Clin Infect Dis. 2005;41(10):1373-1406.
14. Itani KM, Dryden MS, Bhattacharyya H, Kunkel MJ, Baruch AM, Weigelt JA. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated
skin and soft-tissue infections proven to be caused by methicillin-resistant
Staphylococcus aureus. Am J Surg. 2010;199(6):804-816.
15. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus
vancomycin for the treatment of methicillin-resistant Staphylococcus aureus
infections. Clin Infect Dis. 2002;34(11):1481-1490.
16. Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C; Linezolid CSSTI
Study Group. Linezolid versus vancomycin in treatment of complicated skin and
soft tissue infections. Antimicrob Agents Chemother. 2005;49(6):2260-2266.
17. Drugs.com. Zyvox. http://www.drugs.com/pro/zyvox.html. Revised May 2013.
Accessed January 3, 2012.
18. Mullins CD, Hsu VD, Cooke CE, Shelbaya A, Wallace AE, Perencevich EN.
Rehospitalization rates among linezolid versus vancomycin users. Am J Pharm
Benefits. 2011;3(2):e1-e13.
www.ajpblive.com
19. Manning WG, Mullahy J. Estimating log models: to transform or not to transform? J Health Econ. 2001;20(4):461-494.
20. Faries DE, Leon AC, Haro JM, Obenchain RL. Analysis of Observational Health
Care Data Using SAS. Cary, NC: SAS Institute Inc; 2010.
21. Sharpe JN, Shively EH, Polk HC Jr. Clinical and economic outcomes of oral
linezolid versus intravenous vancomycin in the treatment of MRSA-complicated,
lower-extremity skin and soft-tissue infections caused by methicillin-resistant
Staphylococcus aureus. Am J Surg. 2005;189(4):425-428.
22. McKinnon PS, Carter CT, Girase PG, Liu LZ, Carmeli Y. The economic effect of
oral linezolid versus intravenous vancomycin in the outpatient setting: the payer
perspective. Manag Care Interface. 2007;20(1):23-34.
23. Itani KM, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and
duration of intravenous treatment compared with vancomycin for complicated
skin and soft tissue infections due to suspected or proven methicillin-resistant
Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2005;26(6):442-448.
24. Lipsky BA, Itani KM, Weigelt JA, et al. The role of diabetes mellitus in the
treatment of skin and skin structure infections caused by methicillin-resistant
Staphylococcus aureus: results from three randomized controlled trials. Int J Infect
Dis. 2011;15(2):e140-e146.
25. McCollum M, Sorensen SV, Liu LZ. A comparison of costs and hospital length
of stay associated with intravenous/oral linezolid or intravenous vancomycin
treatment of complicated skin and soft-tissue infections caused by suspected or
confirmed methicillin-resistant Staphylococcus aureus in elderly US patients. Clin
Ther. 2007;29(3):469-477.
26. McKinnon PS, Sorensen SV, Liu LZ, Itani KM. Impact of linezolid on economic
outcomes and determinants of cost in a clinical trial evaluating patients with
MRSA complicated skin and soft-tissue infections. Ann Pharmacother. 2006;40(6):
1017-1023.
27. Patanwala AE, Erstad BL, Nix DE. Cost-effectiveness of linezolid and vancomycin in the treatment of surgical site infections. Curr Med Res Opin. 2007;23(1):
185-193.
28. Li JZ, Willke RJ, Rittenhouse BE, Rybak MJ. Effect of linezolid versus vancomycin on length of hospital stay in patients with complicated skin and soft tissue
infections caused by known or suspected methicillin-resistant staphylococci:
results from a randomized clinical trial. Surg Infect (Larchmt). 2003;4(1):57-70.
29. Bounthavong M, Hsu DI, Okamoto MP. Cost-effectiveness analysis of linezolid
vs. vancomycin in treating methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections using a decision analytic model. Int J Clin
Pract. 2009;63(3):376-386.
30. National Priorities Partnership, convened by the National Quality Forum.
Preventing Hospital Readmissions: A $25 Billion Opportunity. http://www.qualityforum.org/NPP/docs/Preventing_Hospital_Readmissions_CAB.aspx. Published
November 2010. Accessed February 1, 2013.
31. Graves N, McGowan JE Jr. Nosocomial infection, the Deficit Reduction Act,
and incentives for hospitals. JAMA. 2008;300(13):1577-1579.
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eAppendix. ICD-9-CM Codes and Descriptions Used for Identification and Inclusion of Patients With Complicated
Skin and Skin Structure Infections
Infection Group
ICD-9-CM Diagnosis Codes
Cellulitis, abscess, mastitis
567.31, 675.10, 675.11, 675.13, 675.14, 675.20, 675.23, 675.24,
681, 681.0, 681.00, 681.01, 681.02, 681.1, 681.10, 681.11, 681.11,
681.9, 682, 682.0, 6821, 682.2, 682.3, 682.4, 682.5, 682.6, 682.7,
682.8, 682.9
Chronic ulcer infection
707.1, 707.10, 707.11, 707.12, 707.13, 707.14, 707.15, 707.19
Postoperative infections
998.5, 998.59, 998.83
Other local infections of skin and subcutaneous tissue
686, 686.0, 686.00, 686.09, 686.8, 686.9, 728.0
Acute lymphadenitis
683
ICD-9 -CM indicates International Classification of Diseases, Ninth Revision, Clinical Modification.
a268 The American Journal of Pharmacy Benefits • November/December 2013
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