RESEARCH REPORTS

Infectious Diseases

Treatment of Methicillin-Resistant Staphylococcus aureus Infections

with a Minimal Inhibitory Concentration of 2 µg/mL to Vancomycin:
Old (Trimethoprim/Sulfamethoxazole) versus New (Daptomycin
or Linezolid) Agents

Michelle L Campbell, Dror Marchaim, Jason M Pogue, Bharath Sunkara, Suchitha Bheemreddy,

Pradeep Bathina, Harish Pulluru, Neelu Chugh, Melanie N Wilson, Judy Moshos, Kimberley Ku,

Kayoko Hayakawa, Emily T Martin, Paul R Lephart, Michael J Rybak, and Keith S Kaye

ethicillin-resistant Staphylococcus
M aureus (MRSA) is a serious human
pathogen,1 and vancomycin is consid-
ered the therapeutic option of choice.2 In
recent years, the minimal inhibitory con-
centrations (MICs) to vancomycin have
increased in MRSA isolates in some re-
gions.3-5 Recent data demonstrate high
rates of clinical and bacteriologic fail-
ures, mainly in bloodstream infections
(BSIs), when vancomycin is used to treat
MRSA strains with an MIC to vancomy-
cin of 2 µg/mL or greater.2,3,6-12 There is a
paucity of evidence guiding the treat-
ment of MRSA infections with MICs at
that level; therefore, for infections due to
strains of MRSA with MIC to van-
comycin of 2 µg/mL or greater, other an-
timicrobials are often preferred.1,13 Other
therapeutic options for MRSA include
newer and expensive agents that have
been extensively studied for the treatment
of MRSA, such as daptomycin and line-
zolid, and older inexpensive generic
agents including trimethoprim/sulfa-
methoxazole (TMP/SMX), clindamycin,
and fusidic acid. There are few data from
controlled studies of the efficacy of these
older agents in the treatment of MRSA
infection, and there are even fewer data
Author information provided at end of text.
BACKGROUND: Guidelines recommend that agents other than vancomycin be
considered for some types of infection due to methicillin-resistant Staphylococcus
aureus (MRSA) when the minimum inhibitory concentration (MIC) to vancomycin
is 2 µg/mL or more. Alternative therapeutic options include daptomycin and
linezolid, 2 relatively new and expensive drugs, and trimethoprim/sulfamethox-
azole (TMP/SMX), an old and inexpensive agent.
OBJECTIVE: To compare the clinical efficacy and potential cost savings associated
with use of TMP/SMX compared to linezolid and daptomycin.
METHODS: A retrospective study was conducted at Detroit Medical Center. For
calendar year 2009, unique adults (age >18 years) with infections due to MRSA
with an MIC to vancomycin of 2 µg/mL were included if they received 2 or more
doses of TMP/SMX and/or daptomycin and/or linezolid. Data were abstracted
from patient charts and pharmacy records.
RESULTS: There were 328 patients included in the study cohort: 143 received
TMP/SMX alone, 89 received daptomycin alone, 75 received linezolid alone, and 21
patients received a combination of 2 or more of these agents. In univariate analysis,
patients who received TMP/SMX alone had significantly better outcomes, including
in-hospital (p = 0.003) and 90-day mortality (p < 0.001) compared to patients treated
with daptomycin or linezolid. Patients receiving TMP/SMX were also younger (p <
0.001), had fewer comorbid conditions (p < 0.001), had less severe acute severity of
illness (p < 0.001), and received appropriate therapy more rapidly (p = 0.001). In
multivariate models the association between TMP/SMX treatment and mortality was
no longer significant. Antimicrobial cost savings associated with using TMP/SMX
averaged $2067.40 per patient.
CONCLUSIONS: TMP/SMX monotherapy compared favorably to linezolid and
daptomycin in terms of treatment efficacy and mortality. Use of TMP/SMX instead of
linezolid or daptomycin could potentially significantly reduce antibiotic costs. TMP/
SMX should be considered for the treatment of MRSA infection with MIC of 2 µg/mL
to vancomycin.
KEY WORDS: heterogenous vancomycin-intermediate Staphylococcus aureus,
methicillin-resistant Staphylococcus aureus, minimum inhibitory concentration,
trimethoprim/sulfamethoxazole, vancomycin.
Ann Pharmacother 2012;46:1587-97.
Published Online, 4 Dec 2012, theannals.com, doi: 10.1345/aph.1R211

theannals.com The Annals of Pharmacotherapy n 2012 December, Volume 46 n 1587

Downloaded from aop.sagepub.com by guest on October 11, 2013
ML Campbell et al.
comparing these older agents to newer drugs, such as line-
zolid and daptomycin.
Because of their low cost and familiarity to health care
providers, older antimicrobials are attractive for treatment
of MRSA infection. Clindamycin has maintained very
good in vitro activity against many strains of MRSA. Be-
cause clindamycin is bacteriostatic and is associated with
increased rates of inducible resistance,14 some prescribers
are reluctant to use it as monotherapy for severe invasive
MRSA infections.1 In addition, clindamycin use is a signif-
icant risk factor for Clostridium difficile infections.1 Fu-
sidic acid, which recently has become available only as an
oral formulation in the US, lacks clinical efficacy data for
the treatment of MRSA.15 In addition, rapid emergence of
resistance when fusidic acid is given as monotherapy is a
major concern.16 Additional older therapeutic options such
as rifampin and doxycycline are also disadvantageous be-
cause of toxicity and lack of controlled efficacy data on use
as monotherapy.17
TMP/SMX, despite being used as a therapeutic antimi-
crobial for many years, has not been extensively studied
in controlled trials for treatment of infections due to
MRSA.18 There are also limited data pertaining to the op-
timal dosage to use for specific types of infection. A re-
cent comparative retrospective study of clindamycin and
TMP/SMX for the treatment of mild superficial skin and
soft-tissue infections (SSTIs) did not reveal significant
differences between the efficacy of these agents.19 Anoth-
er trial found TMP/SMX to be noninferior to vancomycin
for the treatment of MRSA bacteremia in a region where
most strains had a vancomycin MIC of 1 µg/mL or less.20
An older study among intravenous drug users with S. au-
reus endocarditis found TMP/SMX to be inferior to van-
comycin, but not among the subgroup of patients with
MRSA infections.18 Recently, TMP/SMX was reported to
be an effective treatment option in the management of os-
teomyelitis due to MRSA among pediatric patients.14 Al-
though TMP/SMX is associated with severe allergic reac-
tions and hyperkalemia, there has been renewed interest
in its use for MRSA infection, particularly SSTIs.14
Southeast Michigan is an endemic region for MRSA
with elevated MICs to vancomycin including van-
comycin-resistant S. aureus.21 Thus, alternatives to van-
comycin are frequently used for treatment of MRSA in-
fections. The aims of this study were to (1) compare
TMP/SMX to daptomycin or linezolid for the treatment
of infection due to MRSA with a vancomycin MIC of 2
µg/mL; (2) analyze potential cost savings associated with
use of TMP/SMX instead of daptomycin or linezolid for
treatment of MRSA infection; and (3) evaluate the sus-
ceptibility trends of MRSA strains within our health sys-
tem against TMP/SMX, daptomycin, and linezolid over a
5-year period.
1588 n The Annals of Pharmacotherapy n 2012 December, Volume 46
Methods
The Detroit Medical Center (DMC) health system is the
largest in Southeast Michigan and consists of 8 hospitals
with over 2200 inpatient beds. The DMC’s antimicrobial
stewardship committee issued practice guidelines in 2007
recommending that clinicians avoid vancomycin for treat-
ment of MRSA infections when the MIC to vancomycin is
2 µg/mL or more. The institutional review boards of DMC
and Wayne State University approved the study.
A retrospective cohort study of outcomes associated
with infections caused by MRSA with vancomycin MIC
of 2 µg/mL during calendar year 2009 was conducted.
Adults (age >18 years) who received 2 or more doses of ei-
ther TMP/SMX or daptomycin or linezolid from 3 days
before to 14 days after the date when the initial MRSA cul-
ture was obtained were included. Patients with coloniza-
tion only in the absence of infection (based on absence of
systemic inflammatory response syndrome criteria22 or
clinically diagnosed by the attending physicians as colo-
nization) were excluded, and only unique patient episodes
were analyzed. When patients received 2 different study
drugs (ie, TMP/SMX, daptomycin, or linezolid), they were
analyzed as a separate group, since both drugs could have
affected the patient’s outcome.
Variables collected from patient charts and pharmacy
records included (1) demographics; (2) comorbidities (in-
cluding Charlson index scores23); (3) microbiologic data;
(4) acute illness indices (including McCabe score24); and
(5) outcomes including in-hospital and 30-day mortality,
length of hospital stay, functional status deterioration in 1
or more activities of daily living25 compared to the status
before the MRSA infection, discharge to a long-term care
facility (LTCF) after being admitted from home, hospital
readmission in the 6 months following hospital discharge,
additional isolation of the same organism 14 days to 3
months following the index culture (ie, bacteriologic fail-
ures), and costs of the antibiotic regimen prescribed. An-
timicrobial costs and use of study drugs within the health
system were obtained from pharmacy records for the years
2005-2009, and use was reported as defined daily doses
(DDDs). To control for confounding in outcomes analyses,
the time to initiation of appropriate therapy was captured.
Because the objective of the study was to analyze the ther-
apeutic impact of TMP/SMX compared with that of dapto-
mycin and linezolid, vancomycin therapy was not consid-
ered to be appropriate therapy. Appropriate therapy was
determined by the in vitro susceptibility results of the path-
ogen to study antimicrobials used for therapy (ie, dapto-
mycin, linezolid, TMP/SMX or other agents with in vitro
activity, but not vancomycin). Time to appropriate therapy
was measured from the time of culture to time of initiation
of appropriate therapy.
theannals.com

An MIC of 2 µg/mL for MRSA to vancomycin is offi-
cially interpreted by Clinical Laboratories Standards Insti-
tute (CLSI) as susceptible,26 and some might argue that
vancomycin should have been considered appropriate ther-
apy in our study. To address this issue, we analyzed multi-
variate models for outcomes both with and without the co-
variate “time to appropriate therapy.” Because many pa-
tients were treated with vancomycin before receiving one
of the study drugs, and because prior treatment with van-
comycin might have impacted the efficacy of some of the
drugs being studied, treatment with vancomycin was cap-
tured from 3 days before to 14 days after the culture date.
Bacteria were identified to the species level, and suscep-
tibilities were determined to predefined antimicrobials, based
on an automated broth microdilution system (MicroScan;
Siemens AG), and in accordance with CLSI criteria and
breakpoints.26 Daptomycin susceptibility was added to the
automated system panel in 2008. Prior to 2008, E-tests
(bioMérieux) were used to determine daptomycin suscepti-
bility and these were performed only on request by the clini-
cian. Antibiograms of unique patient MRSA isolations for
2005-2009 were conducted according to CLSI criteria.26
Statistical analyses were performed by using IBM-SPSS
19 (2011) and Epi Info (version 6.0). Fisher exact and χ2 tests
were used for categorical variables and t-test, 1-way analysis
of variance, and Mann-Whitney tests were used to analyze
continuous variables. All variables with a p value <0.05 in
the univariate analysis were considered for inclusion in the
multivariate analyses. A stepwise selection procedure was
used to select variables for inclusion in the final model. Lo-
gistic regression tests were used for multivariate analyses. For
outcomes, models were constructed with the goal of evaluat-
ing the independent effect of TMP/SMX therapy on clinical
outcomes. The final selected model was tested for confound-
ing. If a covariate affected the β coefficient of a variable in
the model by more than 10%, then the confounding variable
was maintained in the multivariate model. All p values were
2-sided. In addition to examining statistical significance and
confounding, effect modification between variables was eval-
uated by testing appropriate interaction terms for statistical
significance. When effect modification was detected, sub-
group analyses were performed. A χ2 test for trend and
Spearman correlation test were used to analyze trends for
2005-2009 at DMC. Trends and correlations analyzed were
(1) MRSA prevalence; (2) MRSA incidence (per 1000 pa-
tient days); (3) changes in susceptibility rates to study drugs;
(4) drug utilization; and (5) correlation between drug use and
MRSA prevalence, MRSA incidence, and the susceptibility
rates to study drugs.
Results
A total of 328 patients infected with MRSA with van-
comycin MIC of 2 µg/mL during 2009 who received 1 of
theannals.com The Annals of Pharmacotherapy
Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid
the study drugs were included in the study. Of these pa-
tients, 145 had SSTI, 90 had pneumonia, 42 had BSI with-
out an identifiable source, 22 had a catheter-related BSI,
and 11 had a urinary tract infection. Among patients who
received only 1 study drug, 143 received TMP/SMX (130
received the oral formulation and 13 received the intra-
venous formulation), 89 received daptomycin, and 75 re-
ceived linezolid. Twenty-one subjects received both
TMP/SMX and either daptomycin or linezolid.
From 3 days before to 14 days after the culture date,
vancomycin was prescribed for 239 (73%) patients. Van-
comycin was prescribed mostly empirically and was
stopped because of either clinical failure or when an MIC
of 2 µg/mL was reported.
Of the entire cohort, 5 (1.5%) isolates were nonsuscepti-
ble to TMP/SMX. All isolates were susceptible to dapto-
mycin (mean [SD] MIC 0.5 [0.4] µg/mL, median 0.4
[range 0.25- 4]) and linezolid (mean MIC 2.5 [0.9] µg/mL,
median 2.5 [range 0.25- 4]).
After excluding patients with creatinine clearance less
than 30 mL/min, the median trimethoprim dose was 4.7
mg/kg/day (range 1.3-14.9, mean 5.4 [2.6]) and the median
daptomycin dose was 6.3 mg/kg/day (range 2.6-12, mean
6.9 [1.9]). In the group of patients with BSI and creatinine
clearance greater than 30 mL/min, the median daptomycin
dose was 6.7 mg/kg/day (range 3.3-12, mean 7.1 [2]).
CLINICAL OUTCOMES
In bivariate analysis of patients who received TMP/SMX
versus those who received other regimens, TMP/SMX was
associated with favorable outcomes compared to the newer
regimens prescribed. Table 1 displays the univariate com-
parison between the various 4 treatment groups. Notably,
TMP/SMX was prescribed for a different type of patient
population than was daptomycin and linezolid: patients
who were treated with TMP/SMX were younger (mean
[SD] age 48 [5] years vs 56.3 years, p < 0.001), had lower
Charlson index scores (p < 0.001), had a lower severity of
acute illness (as measured by the McCabe score) (p <
0.001), and had lower severity of sepsis levels (p <
0.001).22 In addition, patients treated with TMP/SMX were
more likely to have SSTIs (p < 0.001) and less likely to
have BSI (p < 0.001). Moreover, patients who received
TMP/ SMX had significantly shorter delays in initiation of
appropriate therapy compared to patients who received
daptomycin or linezolid (62 [71.7] vs 93.3 [62.8] hours, p
< 0.001). From 3 days before to 14 days after the culture
date, vancomycin was prescribed significantly less often in
patients who received TMP/SMX versus those who re-
ceived linezolid or daptomycin (90 [55%] vs 149 [91%];
OR 0.12; 95% CI 0.06 to 0.23; p < 0.001).
Multivariate analyses were conducted for patient out-
comes (Table 2). Parameters inserted into the model in-
n 2012 December, Volume 46 n 1589
 Table 1. Univariate Analysis of Patients Treated for MRSA Infections with an MIC of 2 µg/mL to Vancomycin

1590
TMP/SMX plus
Daptomycin or

n
TMP/SMX Daptomycin Linezolid Linezolid
Parameter (n = 143) (n = 89) (n = 75) (n = 21) p Value
ML Campbell et al.

Demographics
male, n (%) 86 (60) 56 (63) 40 (53) 11 (52) 0.57
age, years, mean (SD) 47.6 (18) 57 (17) 56 (16) 55 (14) <0.001
elderly (age ≥65 years), n (%) 26 (18) 26 (29) 18 (24) 4 (19) 0.3
African American, n (%) 102 (71) 57 (64) 42 (56) 16 (76) 0.08
LTCF permanent residence, n (%) 16 (11) 29 (33) 16 (21) 3 (14) 0.001
Background chronic conditions, n (%)
hemodialysis 2 (1) 27 (30) 4 (5) 3 (14) <0.001
ischemic heart disease 16 (11) 23 (26) 26 (35) 3 (14) <0.001

The Annals of Pharmacotherapy

congestive heart failure 19 (13) 31 (35) 25 (33) 7 (33) <0.001

n
peripheral vascular disease 15 (11) 23 (26) 14 (19) 4 (19) 0.02
diabetes mellitus 34 (24) 35 (39) 29 (39) 8 (38) 0.04
chronic renal failurea 17 (12) 49 (55) 25 (33) 6 (29) <0.001
chronic lung diseaseb 38 (27) 31 (35) 52 (69) 9 (43) <0.001
peptic ulcer disease 15 (11) 28 (32) 28 (37) 3 (14) <0.001
neurovascular diseasec 10 (7) 14 (16) 18 (24) 5 (24) 0.003
dementia 8 (6) 8 (9) 13 (17) 1 (5) 0.03
malignancyd 9 (6) 18 (20) 14 (19) 1 (5) 0.002
HIV positive 10 (7) 1 (1) 1 (1) 1 (5) 0.08
Charlson23 combined condition score, mean (SD) 3.1 (3.1) 5.8 (3.9) 6.4 (3.9) 4.4 (3) <0.001

2012 December, Volume 46

Culture body site, n (%)
blood 3 (2) 62 (70) 8 (11) 6 (29) <0.001
respiratory 28 (20) 3 (3) 45 (60) 7 (33) <0.001
urine 17 (12) 3 (3) 2 (3) 0 0.01
wound 94 (66) 16 (18) 18 (24) 7 (33) <0.001
Infectious clinical syndrome, n (%)
catheter-related bloodstream infection 0 16 (18) 3 (4) 3 (14) <0.001
bacteremia without a determined focus 3 (2) 28 (32) 5 (7) 4 (19) <0.001
pneumonia 24 (17) 6 (7) 47 (63) 8 (38) <0.001
urinary tract infection 15 (11) 1 (1) 2 (3) 2 (10) 0.002
skin and soft-tissue infection 95 (66) 33 (37) 12 (16) 5 (24) <0.001
Status on admission, n (%)
dependent functional statuse 33 (23) 41 (46) 35 (47) 5 (24) <0.001
reduced consciousness 22 (15) 29 (33) 22 (29) 4 (19) 0.012
permanent/chronic invasive devicef 35 (25) 62 (70) 57 (76) 14 (67) <0.001

theannals.com
 u

s
Acute illness indices
McCabe score,24 mean (SD) 2.8 (0.5) 2.5 (0.7) 2.3 (0.7) u 2.5 (0.8) <0.001
rapidly fatal state per McCabe score,24 n (%) 4 (5) 5 (10) 6 (13) 1 (17) 0.01
c
high severity of sepsis level,22 n (%) 21 (18) 46 (54) 33 (48) 10 (48) <0.001

theannals.com
necessitates transfer to an ICU, n (%) 18 (14) 18 (23) 31 (55) c 9 (47) <0.001
Additional antimicrobial parameters
o
hours to appropriate therapy,g mean (SD) 61 (72) 90 (58) 97 (68) 76 (73) 0.001
vancomycin use from 3 days before to 14 days after culture,h n (%) 75 (52) 86 (97) 63 (84) c 15 (71) <0.001
Outcomes
o
in-hospital death, n (%) 5 (3.5) 9 (10) 14 (19) l 2 (9.5) 0.003
died within 3 months, n (%) 7 (6) 10 (13) 18 (30) 3 (16) <0.001
functional status deterioration,e n (%) 8 (6) 17 (19) 22 (30) y 9 (43) <0.001
discharged to LTCF,i n (%) 14 (11) 14 (20) 20 (36) 8 (50) <0.001
h
additional hospitalizations,j n (%) 51 (36) 42 (48) 36 (50) 15 (75) 0.005
bacteriologic failure,k n (%) 5 (3.5) 11 (13) 15 (20) p 4 (19) <0.001
total LOS, days, mean (SD) 7 (32) 12 (42) 22 (18) 19 (12) 0.006
LOS from culture to discharge, days, mean (SD) 7 (9) 12 (10) 17 (13) a 18 (12) <0.001
t
LOS from culture to discharge, after excluding the dead, days, mean (SD) 7 (9) 12 (9) 17 (14) 16 (11) <0.001

ICU = intensive care unit; LOS = length of stay; LTCF = long-term care facility; MIC = minimal inhibitory concentration; MRSA = methicillin-resistant S ; TMP/SMX = trimethoprim/sulfa-
methoxazole.
a
Defined as serum creatinine higher than 1.5 mg/dL.
b
Included chronic obstructive pulmonary disease, bronchiectasis, restrictive lung disease, and asthma.
c
Any cerebral stroke in the past (with or without neurologic sequelae).
d
Included active and past malignancy.
e
Measured according to Katz criteria, of being or becoming dependent in 1 or more activities of daily living.25
f
Included permanent devices (eg, tracheotomies, central catheter lines, urinary catheters, external orthopedic devices, gastrostomy) that were in place at least 48 hours before MRSA isolation.
g
Defined as therapy that the isolate displayed susceptibility to per in vitro testing.
h
From 3 days before to 14 days after the culture date.

The Annals of Pharmacotherapy

i
Discharge to an LTCF after being admitted from home.

n
j
Additional hospitalizations within 6 months following MRSA isolation.
k
Additional MRSA isolations with vancomycin MIC of 2 µg/mL 14 days to 3 months following the index culture.

2012 December, Volume 46

1591 n
Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid
 ML Campbell et al.

cluded (1) age older than 55 years, (2) Charlson index

p Value

0.06
0.9

0.7
0.4

0.1

0.7
0.6
combined condition score greater than 4, (3) type of infec-
Readmissionc
tious clinical syndrome (SSTI vs other), (4) level of sepsis
(sepsis syndrome vs severe sepsis, septic shock, or multior-

0.95 (0.6 to 1.9)

1.1 (0.6 to 1.9)
1.3 (0.7 to 2.2)

0.6 (0.4 to 1.1)

1.6 (0.9 to 2.7)

1.1 (0.6 to 2.1)

0.9 (0.5 to 1.4)
(95% CI) gan failure), (5) vancomycin therapy (from 3 days before to

; TMP/SMX = trimethoprim/sulfamethoxazole.
OR

14 days after the culture date), (6) time to initiation of appro-

priate therapy more than 80 hours, and (7) type of MRSA
therapy (TMP/SMX vs daptomycin or linezolid). Outcomes
an MIC of 2 µg/mL to Vancomycin

analyzed included (1) in-hospital mortality, (2) 3-month mor-

p Value

0.004
0.06
0.2

0.8

0.8
0.6

0.8
tality, (3) length of hospital stay from infection to discharge at
Discharge to

more than 10 days (excluding patients who died), (4) func-

LTCFb

2.2 (0.97 to 4.8)

tional status deterioration at time of discharge, (5) discharge

1.7 (0.8 to 3.5)

0.3 (0.1 to 0.7)

1.1 (0.5 to 2.2)

1.2 (0.5 to 2.8)

1.2 (0.6 to 2.3)

0.9 (0.5 to 2.3)

(95% CI)

to an LTCF after being admitted from home; and (6) hospital

OR

readmissions within 6 months following discharge. In multi-

variate analysis, TMP/SMX was associated with a trend to-
ward favorable outcomes (OR <1), although no associations
p Value

<0.001
0.001

reached statistical significance (Table 2). In secondary analy-

0.04

0.08
0.3

0.3

0.9

ses, conducted without the parameter of time to initiation of

Deterioration
Functional
Table 2. Multivariate Analyses of Outcomes of Patients with Infections Caused by MRSA with

appropriate therapy, no significant differences in outcomes

s

Status
u

0.2 (0.07y to 0.4)

c

0.7 (0.3 to 1.5)

2.5 (1.1 too5.9)

3.5 (1.7 to 7.2)

1.7 (0.6 to 4.8)

0.5 (0.3 to 1.1)

0.9 (0.4 to 2.2)

c

were noted, and the association between type of antimicro-

o
(95% CI)
c

bial therapy and outcomes remained insignificant (data not

OR

shown).
a
t

LOS = length of stay; LTCF = long-term care facility; MIC = minimal inhibitory concentration; MRSA = methicillin-resistant S

To study whether TMP/SMX might be considered as a

therapeutic option also for patients with more severe infec-
p Value

<0.001

<0.001
0.06

tions, we performed a subanalysis of those with severe

0.9
0.1

0.5

0.7
a
Prolonged LOS

sepsis or septic shock or multiorgan failure per established

criteria,22 excluding from this analysis patients with sepsis
1.1 (0.5 to 2.1)
1.9 (0.9 to 4.1)

0.2 (0.1 to 0.4)

1.3 (0.7 to 2.4)

2.2 (0.9 to 5.0)

4.2 (2.3 to 7.7)

1.1 (0.6 to 2.2)

(95% CI)

syndrome. Table 3 summarizes the outcomes of these pa-

OR

tients. Both in bivariate and multivariate (data not shown)

analyses, TMP/SMX therapy was not associated with
poorer outcomes.
p Value

0.005

0.025
0.001

One of the potential clinical niches for TMP/SMX treat-

0.7

0.8
0.9

0.5

ment is SSTIs. In the subgroup of 145 SSTI cases,

Mortality
3-Month

TMP/SMX alone was prescribed for 95 patients (median

5.9 (1.7 to 20.2)

0.2 (0.08 to 0.8)

5.8 (2.1 to 15.9)
0.8 (0.3 to 2.1)

0.8 (0.2 to 3.2)

1.1 (0.5 to 2.4)

0.7 (0.3 to 2.0)

trimethoprim dose 4.6 mg/kg/day [range 1.3-12.8]), dapto-

(95% CI)
OR

mycin alone to 33 patients (median dose 6.1 mg/kg/day

[range 2.6-10.1]), linezolid alone to 12 patients, and 5 pa-
tients with SSTI had received TMP/SMX and either dapto-
p Value

mycin or linezolid. In bivariate analysis, TMP/SMX was

0.007
0.88
0.04

0.06

0.98
0.45

0.36

associated with favorable outcomes including in-hospital

Discharge to LTCF after being admitted from home.
In-hospital
Mortality

mortality (none of the patients who received TMP/SMX

More than 10 days, excluding patients who died.
1.02 (0.25 to 4.2)
0.93 (0.4 to 2.5)
3.8 (1.1 to 13.5)

4.0 (1.5 to 10.9)

0.72 (0.3 to 1.7)

died; 4 in the daptomycin group died, OR 0.90; 95% CI

0.3 (0.1 to 1.1)

0.6 (0.2 to 1.8)

(95% CI)

0.83 to 0.99; p = 0.002), 3-month mortality (OR 0.89; 95%

OR

Hospital readmissions within 6 months.

CI 0.81 to 0.99; p = 0.002), length of hospital stay from

culture to discharge after excluding the patients who died
(4.2 [5.6] vs 10.2 [9.6] days, p < 0.001), discharge to LTCF
Skin and soft-tissue infection
Charlson index combined

after being admitted from home (OR 0.3; 95% CI 0.07 to

shock/multiorgan failure
Additional vancomycin

0.9; p = 0.03), and bacteriologic failure (p < 0.001). No-

Severe sepsis/septic

appropriate therapy
condition score >4

Time to initiation of

TMP/SMX therapy
Parameter

tably, among the SSTI group of patients, as was seen in the

Age >55 years

general cohort, TMP/SMX was prescribed for patients

>80 hours

who were younger (p < 0.001), had lower Charlson index

scores (p < 0.001), had less acute severity of illness as
measured by the McCabe score (p = 0.003), had lower in-
b
a

1592 n The Annals of Pharmacotherapy n 2012 December, Volume 46 theannals.com

 Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid

dices of acute sepsis levels (p < 0.001), and had shorter
times until they received appropriate antimicrobial therapy
(p = 0.004). Multivariate analyses for mortality were not
conducted because no patients who received TMP/SMX
died. In multivariate models for the other outcomes there
was no significant association between TMP/SMX therapy
and outcomes, although all ORs remained less than 1 for
TMP/SMX treatment.
ANTIMICROBIAL USE AND SUSCEPTIBILITY
Figure 1 displays the prevalence of MRSA, use in
DDDs for all study drugs, and the susceptibility rates (in
percentages) of MRSA to all study drugs from 2005 to
2009. The incidence of MRSA remained stable during the
study years (mean [SD] 7.5 [0.23] cases per 1000 patient
days, p = 0.7 for trend), despite nonsignificant increments
in TMP/SMX use (mean 15,732 [2990] DDDs per year, p
= 0.94 for trend), daptomycin use (mean 4967 [3131]
DDDs per year, p = 0.2 for trend), and linezolid use (mean
5144 [1482] DDDs per year, p = 0.3 for trend). The sus-
ceptibility rates for MRSA to linezolid (mean 99.9% [0.05]
per year, p = 0.08 for trend) and daptomycin (mean 99.8%
[0.07] per year, p = 0.3 for trend) remained stable during
the study period. Interestingly, the susceptibility rate to
TMP/SMX among MRSA isolates significantly increased
during the 5-year study period, from 97.9% in 2005 to
98.7% in 2009 (p = 0.05 for trend).
ANTIMICROBIAL COSTS
The mean (SD) antibiotic costs per patient and mean num-
ber of treatment days for patients treated with daptomycin (n
= 89) were $2486 (2576) and 12.3 (11.5) days and for pa-
tients treated with linezolid (n = 75), $1670 (1414) and 9.6
(8.3) days. Among patients who received TMP/SMX (n =
143), the mean number of treatment days was 5.5 (5.8) and
the mean antibiotic cost was $27 (44) per patient. The differ-
ence in cost between the TMP/SMX group and the other
groups was statistically significant (p < 0.001).
There were 161 patients (49% of the entire cohort) who
had an isolate that was susceptible to TMP/SMX but were
treated with daptomycin or with linezolid. If these patients
had been treated with TMP/SMX for the same number of
days that they received daptomycin or linezolid, the total
cost savings would have been $332,844.20, for an average
of $2067.40 per patient.
Discussion
In the past 2 years, 2 pivotal clinical practice guidelines
have been published by the Infectious Diseases Society of
America and related professional societies: treatment guide-
lines for MRSA infections1 and therapeutic guidelines for
vancomycin use.2 Both guidelines noted a commonly en-
countered gap in current scientific knowledge, pertaining to
the preferred management of MRSA infections when the iso-
late’s vancomycin MIC is 2 µg/mL or more. Recent publica-
tions questioned whether vancomycin should even be consid-
ered a first-line option to treat these types of pathogens.11,12
Unfortunately, as depicted in this study, prescribers are reluc-
tant to use TMP/SMX for severe MRSA infections and pre-
fer to use drugs that are more expensive, even though their
superiority over TMP/SMX has never been established or
even formally investigated.
This study analyzed a large cohort of patients in South-
east Michigan infected with MRSA with an MIC to van-
comycin of 2 µg/mL. Despite the retrospective design of

Table 3. Bivariate Subanalysis of Outcomes of Patients with Severe Infectionsa Caused by

MRSA with an MIC of 2 µg/mL to Vancomycin
TMP/SMX plus
TMP/SMX, Daptomycin, Linezolid, Daptomycin or
n (%) n (%) n (%) Linezolid, n (%)
Parameter (n = 21) (n = 46) (n = 33) (n = 10) p Value

In-hospital mortality 2 (9.5) 9 (19.6) 9 (27.3) 2 (20) 0.5

3-Month mortality 3 (19) 10 (24) 13 (45) 3 (30) 0.2
Prolonged LOSb 7 (37) 17 (46) 16 (67) 6 (75) 0.1
Functional status deterioration 4 (19) 15 (33) 15 (45) 5 (50) 0.2
Discharge to LTCFc 3 (18) 10 (32) 6 (29) 4 (50) 0.4
Readmissionsd 9 (43) 29 (64) 16 (49) 7 (78) 0.15

LOS = length of stay; LTCF = long-term care facility; MRSA = methicillin-resistant Staphylococcus aureus; TMP/SMX= trimethoprim/sulfamethoxa-
zole.
a
Defined as infections with severe sepsis or septic shock or multiorgan failure per established criteria,22 and excluding those with sepsis syndrome.
b
More than 10 days, excluding patients who died.
c
Discharge to LTCF after being admitted from home.
d
Hospital readmissions within 6 months.

theannals.com The Annals of Pharmacotherapy n 2012 December, Volume 46 n 1593

ML Campbell et al.

the study, with its inherent biases, the data suggest noninfe-
riority of TMP/SMX compared to daptomycin or linezolid.
Multivariate models controlling for confounders that might
bias the impact of the MRSA therapeutics on outcomes
suggested that TMP/SMX was at least as appropriate as
the newer agents. Several outcomes were analyzed, and all
multivariate models failed to show that TMP/SMX therapy
was associated with poor outcomes. Since the possibility
of conducting a prospective comparative randomized con-
trolled trial in the near future between these on-patent
drugs and TMP/SMX is low, this study, with its inherent
limitations, provides important information.
These analyses provide data pertaining to a commonly
encountered clinical scenario in many parts of the world.
Ideally, TMP/SMX might be used more frequently for
MRSA infections as an alternative to daptomycin and line-
zolid, particularly for SSTIs and pneumonia. Even though
MRSA with a vancomycin MIC of 2 µg/mL is endemic in
southeast Michigan, vancomycin is still frequently used as
the empiric agent of choice. More than 70% of patients in-
cluded in this study were treated with vancomycin before
receiving an alternative agent.
Reduced use of daptomycin and linezolid might translate
into reductions in the emergence of resistance to these 2
agents, which has been described.27,28 The potential cost re-
ductions associated with generic TMP/SMX are large. For
2009 alone at DMC, if patients had been treated with
TMP/SMX instead of linezolid or daptomycin, savings of
greater than $330,000 in antibiotic costs alone might have
been achieved.
The susceptibilities of daptomycin and linezolid re-
mained stable, and TMP/SMX susceptibilities improved
within DMC during the 5-year study period. This is partic-
ularly notable in light of the fact that DMC’s internal prac-
tice guidelines since 2007 recommend that clinicans avoid
vancomycin use for treatment of MRSA infections when
the MIC to vancomycin is 2 µg/mL or more. Thus, despite
increased use of the 3 study antimicrobials, the drugs re-
main extremely active versus most MRSA strains at DMC.
This is in concordance with a recent comprehensive sys-
tematic review that reported prolonged TMP/SMX use
was not associated with increments in antibiotic resis-
tance29 and low rates of resistance to daptomycin and li-
nezolid even in hospitals where these agents are used fre-
quently.30
Treatment of SSTIs is a niche where TMP/SMX use
should be promoted, even in some cases of severe infec-
tions and among inpatients with relatively high levels of
acute illness.14 SSTI is the most common infectious clini-
cal syndrome caused by MRSA, and using TMP/SMX

Figure 1. Prevalence and incidence of MRSA, coupled with the rate of susceptibility to and level of use for TMP/SMX, daptomycin, and linezolid, De-
troit Medical Center, 2005-2009. X axis: prevalence of MRSA unique patient isolations at Detroit Medical Center and incidence. Y axis (left): level of
use (in DDDs) for study drugs. Y axis (right): rate of susceptibility for study drugs. DDD = defined daily dose; MRSA = methicillin-resistant Staphylo-
coccus aureus; TMP/SMX = trimethoprim/sulfamethoxazole.

1594 n The Annals of Pharmacotherapy n 2012 December, Volume 46 theannals.com


for this indication will reduce the burden of daptomycin
and linezolid use.14 In addition, the availability of both
parenteral and oral TMP/SMX preparations enables a
natural step-down in treatment and early hospital dis-
charge when the patient stabilizes and is ready for hospi-
tal discharge. The lack of availability of the parenteral
preparation of TMP/SMX in some countries hopefully
will be rectified.
The significance and true risk of TMP/SMX-associated
nephrotoxicity, interaction with warfarin,31 and other ad-
verse events (eg, hyperkalemia)32 should be further ex-
plored, particularly when TMP/SMX therapy is being con-
sidered for prolonged durations. TMP/SMX is appropriate,
has a low cost, and should be considered as a viable treat-
ment alternative for MRSA infection, even in some severe
disease states. Increased use of TMP/SMX will likely re-
duce the emergence of resistance to and the costs associat-
ed with daptomycin and linezolid therapy.
Michelle L Campbell BA, Research Assistant, Division of Infec-
tious Diseases, Detroit Medical Center, Wayne State University,
Harper University Hospital, Detroit, MI
Dror Marchaim MD, Infection Control Fellow, Division of Infectious
Diseases, Detroit Medical Center, Wayne State University, Harper
University Hospital
Jason M Pogue PharmD, Pharmacist, Department of Pharmacy
Services, Sinai-Grace Hospital, Detroit Medical Center, Detroit, MI
Bharath Sunkara MD, Research Assistant, Division of Infectious
Diseases, Detroit Medical Center, Wayne State University, Harper
University Hospital
Suchitha Bheemreddy MD, Research Assistant, Division of In-
fectious Diseases, Detroit Medical Center, Wayne State University,
Harper University Hospital
Pradeep Bathina MBBS, Research Assistant, Division of Infec-
tious Diseases, Detroit Medical Center, Wayne State University,
Harper University Hospital
Harish Pulluru MBBS, Research Assistant, Division of Infectious
Diseases, Detroit Medical Center, Wayne State University, Harper
University Hospital
Neelu Chugh MBBS, Research Assistant, Division of Infectious
Diseases, Detroit Medical Center, Wayne State University, Harper
University Hospital
Melanie N Wilson BS, Research Assistant, Division of Infectious
Diseases, Detroit Medical Center, Wayne State University, Harper
University Hospital
Judy Moshos MT, Infection Preventionist, Sinai-Grace Hospital,
Detroit Medical Center
Kimberley Ku BS, Research Assistant, Division of Infectious Dis-
eases, Detroit Medical Center, Wayne State University, Harper Uni-
versity Hospital
Kayoko Hayakawa MD PhD, Infection Control Fellow, Division of
Infectious Diseases, Detroit Medical Center, Wayne State Universi-
ty, Harper University Hospital
Emily T Martin MPH PhD, Department of Pharmacy Practice,
Wayne State University, Detroit, MI
Paul R Lephart PhD, Technical Director, Department of Clinical Mi-
crobiology, University Laboratories, Detroit Medical Center, Detroit
Receiving Hospital, Detroit, MI
Michael J Rybak PharmD MPH FCCP BCPS, Professor of Phar-
macy and Medicine Director, Anti-Infective Research Laboratory,
Eugene Applebaum College of Pharmacy and Health Sciences,
Wayne State University
Keith S Kaye MD MPH, Professor of Medicine, Corporate Direc-
tor, Infection Prevention, Epidemiology and Antimicrobial Steward-
ship, Detroit Medical Center, Wayne State University, University
Health Center
theannals.com The Annals of Pharmacotherapy
Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid
Correspondence: Dr. Marchaim, drormc@hotmail.com
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1R211
Conflict of interest: Dr. Rybak is a speaker, consultant or received
grant support from Astellas, Cubist, Forest, and Rib-X Pharmaceu-
ticals; Dr. Kaye is a speaker and consultant and receives grant sup-
port from Cubist and Pfizer.
Dr. Kaye is supported by the National Institute of Allergy and Infec-
tious Diseases (NIAID); DMID Protocol Number: 10-0065.
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1596 n The Annals of Pharmacotherapy n 2012 December, Volume 46
EXTRACTO
Staphylococcus aureus Resistante a Meticilina con una
Concentración Mínima Inhibitoria de 2 µg/mL Para Vancomicina:
Agentes Viejos (Trimetoprim/Sulfametoxazol) Contra Agentes
Nuevos (Daptomicina o Linezolida)
ML Campbell, D Marchaim, JM Pogue, B Sunkara, S Bheemreddy, P Bathina,
H Pulluru, N Chugh, MN Wilson, J Moshos, K Ku, K Hayakawa, ET Martin,
PR Lephart, MJ Rybak, y KS Kaye
Ann Pharmacother 2012;46:1587-97.
TRASFONDO: Las guías recomiendan que se consideren otros agentes en
lugar de vancomicina para algunos tipos de infecciones causadas por
Staphylococcus aureus resistente a meticilina (MRSA) cuando la MIC
para vancomicina es ≥2 µg/mL. Las opciones terapéuticas alternativas
incluyen daptomicina y linezolida, 2 fármacos relativamente nuevos y
caros; y trimetoprim /sulfametoxazol (TMP/SMX), un agente viejo y
barato.
OBJETIVOS: Este estudio está dirigido a comparar la eficacia clínica y los
ahorros potenciales en el costo asociados con el uso de TMP/SMX
comparado a linezolida y daptomicina.
MÉTODOS: Un estudio retrospectivo fue llevado a en el Centro Médico de
Detroit. Para el año calendario de 2009, pacientes adultos (>18 años) con
infecciones causadas por MRSA con un MIC para vancomicina de 2
µg/mL fueron incluidos si recibieron ≥2 dosis de TMP/SMX y/o
daptomicina y/o linezolida. Los datos fueron obtenidos de los historiales
del paciente y de farmacia.
RESULTADOS: Hubo 328 pacientes incluidos en el estudio cohorte, 143
recibieron TMP/SMX sola, 89 recibieron daptomicina sola, 75
recibieron linezolida sola y 21 pacientes recibieron una combinación con
≥2 de estos agentes. En análisis univariado, pacientes que recibieron
TMP/SMX sola tuvieron mejores resultados significativamente,
incluyendo hospitalización (p = 0.003) y mortalidad de 90 días (p <
0.001) comparado a pacientes tratados con daptomicina o linezolida.
Pacientes en TMP/SMX eran también más jóvenes (p < 0.001), y tenían
menos condiciones co-mórbidas (p < 0.001), enfermedad aguda menos
severa (p < 0.001), y recibieron la terapia apropiada más temprano (p =
0.001). En modelos multivariados la asociación entre el tratamiento con
TMP/SMX y la mortalidad no fue significativa. La economía en costo
de antimicrobiales asociada con el uso de TMP/SMX promedió $2,067
por paciente.
CONCLUSIONES: TMP/SMX compara favorablemente con linezolida y
daptomicina en términos de eficacia del tratamiento y mortalidad. El uso
de TMP/SMX en lugar de linezolida o daptomicina puede
potencialmente reducir significativamente los costos de los antibióticos.
El uso de TMP/SMX debe considerarse para el tratamiento de
infecciones MRSA con MIC de 2 µg/mL para vancomicina.
Traducido por Sonia I Lugo
RÉSUMÉ
Traitement des Infections à Staphylococcus aureus Résistant à la
Méthicilline Présentant une Concentration Minimale Inhibitrice de la
Vancomycine de 2 µg/mL ou plus: Anciens
(Triméthoprime/Sulfaméthoxazole) vs Nouveaux Agents
(Daptomycine ou Linézolide)
ML Campbell, D Marchaim, JM Pogue, B Sunkara, S Bheemreddy, P Bathina,
H Pulluru, N Chugh, MN Wilson, J Moshos, K Ku, K Hayakawa, ET Martin,
PR Lephart, MJ Rybak, et KS Kaye
Ann Pharmacother 2012;46:1587-97.
HISTORIQUE: Les lignes directrices de traitement mentionnent que
d’autres agents que la vancomycine peuvent être utilisés pour le
traitement de certains types d’infection à Staphylococcus aureus résistant
à la méthicilline (SARM) lorsque la concentration minimale inhibitrice
(CMI) de la vancomycine est de 2 µg/mL ou plus. Ces alternatives
thérapeutiques sont: le triméthoprime/sulfaméthoxazole (TMP/SMX),
un vieil agent peu dispendieux et la daptomycine ou le linézolide, 2
agents relativement nouveaux et dispendieux.
theannals.com
 Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid

OBJECTIF: Cette étude vise à comparer l’efficacité clinique et le potentiel
d’économies liés à l’utilisation du TMP/SMX comparativement à la
daptomycine ou au linézolide.
MÉTHODOLOGIE: Une étude rétrospective a été faite au Detroit Medical
Center. Dans l’année 2009, les patients adultes de plus de 18 ans
présentant une infection à SARM avec une CMI de vancomycine de 2
µg/mL ou plus ont été inclus, s’ils avaient reçu 2 doses ou plus de
TMP/SMX, de daptomycine ou de linézolide. Les données ont été
recueillies à partir des dossiers des patients ou des dossiers de la
pharmacie.
RÉSULTATS: Des 328 patients inclus dans la cohorte, 143 ont reçu du
TMP/SMX seul, 89 ont reçu de la daptomycine seule, 75 ont reçu du
linézolide seul et 21 patients ont reçu une association de 2 ou plus de ces
agents. Dans une analyse de univariance, chez les patients qui ont reçu
du TMP/SMX seul, on observait des mesures de résultats
significativement meilleures, incluant la mortalité à l’hôpital (p = 0.003)
et à 90 jours (p > 0.001), comparativement aux patients traités par la
daptomycine ou le linézolide. Les patients ayant reçu le TMP/SMX
étaient plus jeunes (p < 0.001), présentaient moins de comorbidité (p <
0.001), une infection moins aiguë et moins grave (p < 0.001), et ont reçu
une thérapie appropriée plus rapidement (p = 0.001). Dans des modèles
multivariés, l’association entre le traitement par le TMP/SMX et la
mortalité n’était plus significative. Les économies de coûts liés à
l’antibiothérapie lors d’infection par le SARM sont de l’ordre de $2067
par patient lorsque le TMP/SMX est utilisé.
CONCLUSIONS: L’association TMP/SMX se compare favorablement au
linézolide et à la daptomycine quant à l’efficacité et la mortalité.
L’utilisation du TMP/SMX à la place du linézolide ou de la daptomycine
peut potentiellement réduire significativement les coûts de
l’antibiothérapie. Le TMP/SMX devrait être considéré comme une
option de traitement des infections à SARM lorsque la concentration
minimale inhibitrice de la vancomycine est de 2 µg/mL ou plus.
Traduit par Denyse Demers

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theannals.com The Annals of Pharmacotherapy n 2012 December, Volume 46 n 1597