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

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- Methods

zolid and daptomycin.
Because of their low cost and familiarity to health care The Detroit Medical Center (DMC) health system is the
providers, older antimicrobials are attractive for treatment largest in Southeast Michigan and consists of 8 hospitals
of MRSA infection. Clindamycin has maintained very with over 2200 inpatient beds. The DMC’s antimicrobial
good in vitro activity against many strains of MRSA. Be- stewardship committee issued practice guidelines in 2007
cause clindamycin is bacteriostatic and is associated with recommending that clinicians avoid vancomycin for treat-
increased rates of inducible resistance,14 some prescribers ment of MRSA infections when the MIC to vancomycin is
are reluctant to use it as monotherapy for severe invasive 2 µg/mL or more. The institutional review boards of DMC
MRSA infections.1 In addition, clindamycin use is a signif- and Wayne State University approved the study.
icant risk factor for Clostridium difficile infections.1 Fu- A retrospective cohort study of outcomes associated
sidic acid, which recently has become available only as an with infections caused by MRSA with vancomycin MIC
oral formulation in the US, lacks clinical efficacy data for of 2 µg/mL during calendar year 2009 was conducted.
the treatment of MRSA.15 In addition, rapid emergence of Adults (age >18 years) who received 2 or more doses of ei-
resistance when fusidic acid is given as monotherapy is a ther TMP/SMX or daptomycin or linezolid from 3 days
major concern.16 Additional older therapeutic options such before to 14 days after the date when the initial MRSA cul-
as rifampin and doxycycline are also disadvantageous be- ture was obtained were included. Patients with coloniza-
cause of toxicity and lack of controlled efficacy data on use tion only in the absence of infection (based on absence of
as monotherapy.17 systemic inflammatory response syndrome criteria22 or
TMP/SMX, despite being used as a therapeutic antimi- clinically diagnosed by the attending physicians as colo-
crobial for many years, has not been extensively studied nization) were excluded, and only unique patient episodes
in controlled trials for treatment of infections due to were analyzed. When patients received 2 different study
MRSA.18 There are also limited data pertaining to the op- drugs (ie, TMP/SMX, daptomycin, or linezolid), they were
timal dosage to use for specific types of infection. A re- analyzed as a separate group, since both drugs could have
cent comparative retrospective study of clindamycin and affected the patient’s outcome.
TMP/SMX for the treatment of mild superficial skin and Variables collected from patient charts and pharmacy
soft-tissue infections (SSTIs) did not reveal significant records included (1) demographics; (2) comorbidities (in-
differences between the efficacy of these agents.19 Anoth- cluding Charlson index scores23); (3) microbiologic data;
er trial found TMP/SMX to be noninferior to vancomycin (4) acute illness indices (including McCabe score24); and
for the treatment of MRSA bacteremia in a region where (5) outcomes including in-hospital and 30-day mortality,
most strains had a vancomycin MIC of 1 µg/mL or less.20 length of hospital stay, functional status deterioration in 1
An older study among intravenous drug users with S. au- or more activities of daily living25 compared to the status
reus endocarditis found TMP/SMX to be inferior to van- before the MRSA infection, discharge to a long-term care
comycin, but not among the subgroup of patients with facility (LTCF) after being admitted from home, hospital
MRSA infections.18 Recently, TMP/SMX was reported to readmission in the 6 months following hospital discharge,
be an effective treatment option in the management of os- additional isolation of the same organism 14 days to 3
teomyelitis due to MRSA among pediatric patients.14 Al- months following the index culture (ie, bacteriologic fail-
though TMP/SMX is associated with severe allergic reac- ures), and costs of the antibiotic regimen prescribed. An-
tions and hyperkalemia, there has been renewed interest timicrobial costs and use of study drugs within the health
in its use for MRSA infection, particularly SSTIs.14 system were obtained from pharmacy records for the years
Southeast Michigan is an endemic region for MRSA 2005-2009, and use was reported as defined daily doses
with elevated MICs to vancomycin including van- (DDDs). To control for confounding in outcomes analyses,
comycin-resistant S. aureus.21 Thus, alternatives to van- the time to initiation of appropriate therapy was captured.
comycin are frequently used for treatment of MRSA in- Because the objective of the study was to analyze the ther-
fections. The aims of this study were to (1) compare apeutic impact of TMP/SMX compared with that of dapto-
TMP/SMX to daptomycin or linezolid for the treatment mycin and linezolid, vancomycin therapy was not consid-
of infection due to MRSA with a vancomycin MIC of 2 ered to be appropriate therapy. Appropriate therapy was
µg/mL; (2) analyze potential cost savings associated with determined by the in vitro susceptibility results of the path-
use of TMP/SMX instead of daptomycin or linezolid for ogen to study antimicrobials used for therapy (ie, dapto-
treatment of MRSA infection; and (3) evaluate the sus- mycin, linezolid, TMP/SMX or other agents with in vitro
ceptibility trends of MRSA strains within our health sys- activity, but not vancomycin). Time to appropriate therapy
tem against TMP/SMX, daptomycin, and linezolid over a was measured from the time of culture to time of initiation
5-year period. of appropriate therapy.

1588 n The Annals of Pharmacotherapy n 2012 December, Volume 46 theannals.com

 Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid

An MIC of 2 µg/mL for MRSA to vancomycin is offi- the study drugs were included in the study. Of these pa-
cially interpreted by Clinical Laboratories Standards Insti- tients, 145 had SSTI, 90 had pneumonia, 42 had BSI with-
tute (CLSI) as susceptible,26 and some might argue that out an identifiable source, 22 had a catheter-related BSI,
vancomycin should have been considered appropriate ther- and 11 had a urinary tract infection. Among patients who
apy in our study. To address this issue, we analyzed multi- received only 1 study drug, 143 received TMP/SMX (130
variate models for outcomes both with and without the co- received the oral formulation and 13 received the intra-
variate “time to appropriate therapy.” Because many pa- venous formulation), 89 received daptomycin, and 75 re-
tients were treated with vancomycin before receiving one ceived linezolid. Twenty-one subjects received both
of the study drugs, and because prior treatment with van- TMP/SMX and either daptomycin or linezolid.
comycin might have impacted the efficacy of some of the From 3 days before to 14 days after the culture date,
drugs being studied, treatment with vancomycin was cap- vancomycin was prescribed for 239 (73%) patients. Van-
tured from 3 days before to 14 days after the culture date. comycin was prescribed mostly empirically and was
Bacteria were identified to the species level, and suscep- stopped because of either clinical failure or when an MIC
tibilities were determined to predefined antimicrobials, based of 2 µg/mL was reported.
on an automated broth microdilution system (MicroScan; Of the entire cohort, 5 (1.5%) isolates were nonsuscepti-
Siemens AG), and in accordance with CLSI criteria and ble to TMP/SMX. All isolates were susceptible to dapto-
breakpoints.26 Daptomycin susceptibility was added to the mycin (mean [SD] MIC 0.5 [0.4] µg/mL, median 0.4
automated system panel in 2008. Prior to 2008, E-tests [range 0.25- 4]) and linezolid (mean MIC 2.5 [0.9] µg/mL,
(bioMérieux) were used to determine daptomycin suscepti- median 2.5 [range 0.25- 4]).
bility and these were performed only on request by the clini- After excluding patients with creatinine clearance less
cian. Antibiograms of unique patient MRSA isolations for than 30 mL/min, the median trimethoprim dose was 4.7
2005-2009 were conducted according to CLSI criteria.26 mg/kg/day (range 1.3-14.9, mean 5.4 [2.6]) and the median
Statistical analyses were performed by using IBM-SPSS daptomycin dose was 6.3 mg/kg/day (range 2.6-12, mean
19 (2011) and Epi Info (version 6.0). Fisher exact and χ2 tests 6.9 [1.9]). In the group of patients with BSI and creatinine
were used for categorical variables and t-test, 1-way analysis clearance greater than 30 mL/min, the median daptomycin
of variance, and Mann-Whitney tests were used to analyze dose was 6.7 mg/kg/day (range 3.3-12, mean 7.1 [2]).
continuous variables. All variables with a p value <0.05 in
the univariate analysis were considered for inclusion in the CLINICAL OUTCOMES
multivariate analyses. A stepwise selection procedure was
used to select variables for inclusion in the final model. Lo- In bivariate analysis of patients who received TMP/SMX
gistic regression tests were used for multivariate analyses. For versus those who received other regimens, TMP/SMX was
outcomes, models were constructed with the goal of evaluat- associated with favorable outcomes compared to the newer
ing the independent effect of TMP/SMX therapy on clinical regimens prescribed. Table 1 displays the univariate com-
outcomes. The final selected model was tested for confound- parison between the various 4 treatment groups. Notably,
ing. If a covariate affected the β coefficient of a variable in TMP/SMX was prescribed for a different type of patient
the model by more than 10%, then the confounding variable population than was daptomycin and linezolid: patients
was maintained in the multivariate model. All p values were who were treated with TMP/SMX were younger (mean
2-sided. In addition to examining statistical significance and [SD] age 48 [5] years vs 56.3 years, p < 0.001), had lower
confounding, effect modification between variables was eval- Charlson index scores (p < 0.001), had a lower severity of
uated by testing appropriate interaction terms for statistical acute illness (as measured by the McCabe score) (p <
significance. When effect modification was detected, sub- 0.001), and had lower severity of sepsis levels (p <
group analyses were performed. A χ2 test for trend and 0.001).22 In addition, patients treated with TMP/SMX were
Spearman correlation test were used to analyze trends for more likely to have SSTIs (p < 0.001) and less likely to
2005-2009 at DMC. Trends and correlations analyzed were have BSI (p < 0.001). Moreover, patients who received
(1) MRSA prevalence; (2) MRSA incidence (per 1000 pa- TMP/ SMX had significantly shorter delays in initiation of
tient days); (3) changes in susceptibility rates to study drugs; appropriate therapy compared to patients who received
(4) drug utilization; and (5) correlation between drug use and daptomycin or linezolid (62 [71.7] vs 93.3 [62.8] hours, p
MRSA prevalence, MRSA incidence, and the susceptibility < 0.001). From 3 days before to 14 days after the culture
rates to study drugs. date, vancomycin was prescribed significantly less often in
patients who received TMP/SMX versus those who re-
Results ceived linezolid or daptomycin (90 [55%] vs 149 [91%];
OR 0.12; 95% CI 0.06 to 0.23; p < 0.001).
A total of 328 patients infected with MRSA with van- Multivariate analyses were conducted for patient out-
comycin MIC of 2 µg/mL during 2009 who received 1 of comes (Table 2). Parameters inserted into the model in-

theannals.com The Annals of Pharmacotherapy 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 tients treated with linezolid (n = 75), $1670 (1414) and 9.6
times until they received appropriate antimicrobial therapy (8.3) days. Among patients who received TMP/SMX (n =
(p = 0.004). Multivariate analyses for mortality were not 143), the mean number of treatment days was 5.5 (5.8) and
conducted because no patients who received TMP/SMX the mean antibiotic cost was $27 (44) per patient. The differ-
died. In multivariate models for the other outcomes there ence in cost between the TMP/SMX group and the other
was no significant association between TMP/SMX therapy groups was statistically significant (p < 0.001).
and outcomes, although all ORs remained less than 1 for There were 161 patients (49% of the entire cohort) who
TMP/SMX treatment. had an isolate that was susceptible to TMP/SMX but were
treated with daptomycin or with linezolid. If these patients
ANTIMICROBIAL USE AND SUSCEPTIBILITY had been treated with TMP/SMX for the same number of
days that they received daptomycin or linezolid, the total
Figure 1 displays the prevalence of MRSA, use in cost savings would have been $332,844.20, for an average
DDDs for all study drugs, and the susceptibility rates (in of $2067.40 per patient.
percentages) of MRSA to all study drugs from 2005 to
2009. The incidence of MRSA remained stable during the Discussion
study years (mean [SD] 7.5 [0.23] cases per 1000 patient
days, p = 0.7 for trend), despite nonsignificant increments In the past 2 years, 2 pivotal clinical practice guidelines
in TMP/SMX use (mean 15,732 [2990] DDDs per year, p have been published by the Infectious Diseases Society of
= 0.94 for trend), daptomycin use (mean 4967 [3131] America and related professional societies: treatment guide-
DDDs per year, p = 0.2 for trend), and linezolid use (mean lines for MRSA infections1 and therapeutic guidelines for
5144 [1482] DDDs per year, p = 0.3 for trend). The sus- vancomycin use.2 Both guidelines noted a commonly en-
ceptibility rates for MRSA to linezolid (mean 99.9% [0.05] countered gap in current scientific knowledge, pertaining to
per year, p = 0.08 for trend) and daptomycin (mean 99.8% the preferred management of MRSA infections when the iso-
[0.07] per year, p = 0.3 for trend) remained stable during late’s vancomycin MIC is 2 µg/mL or more. Recent publica-
the study period. Interestingly, the susceptibility rate to tions questioned whether vancomycin should even be consid-
TMP/SMX among MRSA isolates significantly increased ered a first-line option to treat these types of pathogens.11,12
during the 5-year study period, from 97.9% in 2005 to Unfortunately, as depicted in this study, prescribers are reluc-
98.7% in 2009 (p = 0.05 for trend). 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
ANTIMICROBIAL COSTS
even formally investigated.
The mean (SD) antibiotic costs per patient and mean num- This study analyzed a large cohort of patients in South-
ber of treatment days for patients treated with daptomycin (n east Michigan infected with MRSA with an MIC to van-
= 89) were $2486 (2576) and 12.3 (11.5) days and for pa- 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- ductions associated with generic TMP/SMX are large. For
riority of TMP/SMX compared to daptomycin or linezolid. 2009 alone at DMC, if patients had been treated with
Multivariate models controlling for confounders that might TMP/SMX instead of linezolid or daptomycin, savings of
bias the impact of the MRSA therapeutics on outcomes greater than $330,000 in antibiotic costs alone might have
suggested that TMP/SMX was at least as appropriate as been achieved.
the newer agents. Several outcomes were analyzed, and all The susceptibilities of daptomycin and linezolid re-
multivariate models failed to show that TMP/SMX therapy mained stable, and TMP/SMX susceptibilities improved
was associated with poor outcomes. Since the possibility within DMC during the 5-year study period. This is partic-
of conducting a prospective comparative randomized con- ularly notable in light of the fact that DMC’s internal prac-
trolled trial in the near future between these on-patent tice guidelines since 2007 recommend that clinicans avoid
drugs and TMP/SMX is low, this study, with its inherent vancomycin use for treatment of MRSA infections when
limitations, provides important information. the MIC to vancomycin is 2 µg/mL or more. Thus, despite
These analyses provide data pertaining to a commonly increased use of the 3 study antimicrobials, the drugs re-
encountered clinical scenario in many parts of the world. main extremely active versus most MRSA strains at DMC.
Ideally, TMP/SMX might be used more frequently for This is in concordance with a recent comprehensive sys-
MRSA infections as an alternative to daptomycin and line- tematic review that reported prolonged TMP/SMX use
zolid, particularly for SSTIs and pneumonia. Even though was not associated with increments in antibiotic resis-
MRSA with a vancomycin MIC of 2 µg/mL is endemic in tance29 and low rates of resistance to daptomycin and li-
southeast Michigan, vancomycin is still frequently used as nezolid even in hospitals where these agents are used fre-
the empiric agent of choice. More than 70% of patients in- quently.30
cluded in this study were treated with vancomycin before Treatment of SSTIs is a niche where TMP/SMX use
receiving an alternative agent. should be promoted, even in some cases of severe infec-
Reduced use of daptomycin and linezolid might translate tions and among inpatients with relatively high levels of
into reductions in the emergence of resistance to these 2 acute illness.14 SSTI is the most common infectious clini-
agents, which has been described.27,28 The potential cost re- 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

 Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid

for this indication will reduce the burden of daptomycin Correspondence: Dr. Marchaim, drormc@hotmail.com
and linezolid use.14 In addition, the availability of both Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1R211
parenteral and oral TMP/SMX preparations enables a Conflict of interest: Dr. Rybak is a speaker, consultant or received
grant support from Astellas, Cubist, Forest, and Rib-X Pharmaceu-
natural step-down in treatment and early hospital dis- ticals; Dr. Kaye is a speaker and consultant and receives grant sup-
charge when the patient stabilizes and is ready for hospi- port from Cubist and Pfizer.
tal discharge. The lack of availability of the parenteral Dr. Kaye is supported by the National Institute of Allergy and Infec-
preparation of TMP/SMX in some countries hopefully tious Diseases (NIAID); DMID Protocol Number: 10-0065.
will be rectified.
The significance and true risk of TMP/SMX-associated References
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Judy Moshos MT, Infection Preventionist, Sinai-Grace Hospital, VISA (hVISA). Intern Med J 2005;35(suppl 2):S136- 40.
Detroit Medical Center doi: 10.1111/j.1444-0903.2005.00986.x
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Kayoko Hayakawa MD PhD, Infection Control Fellow, Division of
Infectious Diseases, Detroit Medical Center, Wayne State Universi- Clin Infect Dis 2011;52:975-81. doi: 10.1093/cid/cir124
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Emily T Martin MPH PhD, Department of Pharmacy Practice, not explain poorer outcomes in patients with Staphylococcus aureus bac-
Wayne State University, Detroit, MI teremia and high vancomycin minimum inhibitory concentrations. J In-
Paul R Lephart PhD, Technical Director, Department of Clinical Mi- fect Dis 2011;204:340-7. doi: 10.1093/infdis/jir270
crobiology, University Laboratories, Detroit Medical Center, Detroit 12. Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos
Receiving Hospital, Detroit, MI MJ. Daptomycin versus vancomycin for bloodstream infections due to
Michael J Rybak PharmD MPH FCCP BCPS, Professor of Phar- methicillin-resistant Staphylococcus aureus with a high vancomycin
macy and Medicine Director, Anti-Infective Research Laboratory, minimum inhibitory concentration: a case-control study. Clin Infect Dis
Eugene Applebaum College of Pharmacy and Health Sciences,
2012;54:51-8. doi: 10.1093/cid/cir764
Wayne State University
13. Weston A, Boucher HW. Daptomycin for methicillin-resistant Staphylococ-
Keith S Kaye MD MPH, Professor of Medicine, Corporate Direc-
tor, Infection Prevention, Epidemiology and Antimicrobial Steward- cus aureus bloodstream infection and elevated vancomycin minimum in-
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theannals.com The Annals of Pharmacotherapy n 2012 December, Volume 46 n 1595

ML Campbell et al.

14. Messina AF, Namtu K, Guild M, Dumois JA, Berman DM. Trimethoprim- EXTRACTO
sulfamethoxazole therapy for children with acute osteomyelitis. Pediatr In-
Staphylococcus aureus Resistante a Meticilina con una
fect Dis J 2011;30:1019-21. doi: 10.1097/INF.0b013e31822db658
Concentración Mínima Inhibitoria de 2 µg/mL Para Vancomicina:
15. Craft JC, Moriarty SR, Clark K, et al. A randomized, double-blind phase
Agentes Viejos (Trimetoprim/Sulfametoxazol) Contra Agentes
2 study comparing the efficacy and safety of an oral fusidic acid loading-
dose regimen to oral linezolid for the treatment of acute bacterial skin Nuevos (Daptomicina o Linezolida)
and skin structure infections. Clin Infect Dis 2011;52(suppl 7):S520-6. ML Campbell, D Marchaim, JM Pogue, B Sunkara, S Bheemreddy, P Bathina,
doi: 10.1093/cid/cir167 H Pulluru, N Chugh, MN Wilson, J Moshos, K Ku, K Hayakawa, ET Martin,
16. Farrell DJ, Castanheira M, Chopra I. Characterization of global patterns PR Lephart, MJ Rybak, y KS Kaye
and the genetics of fusidic acid resistance. Clin Infect Dis 2011;52(suppl 7): Ann Pharmacother 2012;46:1587-97.
S487-92. doi: 10.1093/cid/cir164 TRASFONDO: Las guías recomiendan que se consideren otros agentes en
17. Maor Y, Hagin M, Belausov N, Keller N, Ben-David D, Rahav G. Clini- lugar de vancomicina para algunos tipos de infecciones causadas por
cal features of heteroresistant vancomycin-intermediate Staphylococcus Staphylococcus aureus resistente a meticilina (MRSA) cuando la MIC
aureus bacteremia versus those of methicillin-resistant S. aureus bac- para vancomicina es ≥2 µg/mL. Las opciones terapéuticas alternativas
teremia. J Infect Dis 2009;199:619-24. incluyen daptomicina y linezolida, 2 fármacos relativamente nuevos y
18. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxa- caros; y trimetoprim /sulfametoxazol (TMP/SMX), un agente viejo y
zole compared with vancomycin for the treatment of Staphylococcus au- barato.
reus infection. Ann Intern Med 1992;117:390-8. OBJETIVOS: Este estudio está dirigido a comparar la eficacia clínica y los
19. Frei CR, Miller ML, Lewis JS 2nd, et al. Trimethoprim-sulfamethoxa- ahorros potenciales en el costo asociados con el uso de TMP/SMX
zole or clindamycin for community-associated MRSA (CA-MRSA) skin comparado a linezolida y daptomicina.
infections. J Am Board Fam Med 2010;23:714-9. MÉTODOS: Un estudio retrospectivo fue llevado a en el Centro Médico de
20. Goldberg E, Paul M, Talker O, et al. Co-trimoxazole versus vancomycin Detroit. Para el año calendario de 2009, pacientes adultos (>18 años) con
for the treatment of methicillin-resistant Staphylococcus aureus bac- infecciones causadas por MRSA con un MIC para vancomicina de 2
teremia: a retrospective cohort study. J Antimicrob Chemother 2010;65:5. µg/mL fueron incluidos si recibieron ≥2 dosis de TMP/SMX y/o
21. Zhu W, Murray PR, Huskins WC, et al. Dissemination of an Enterococcus daptomicina y/o linezolida. Los datos fueron obtenidos de los historiales
Inc18-like vanA plasmid associated with vancomycin-resistant Staphylo- del paciente y de farmacia.
coccus aureus. Antimicrob Agents Chemother 2010;54:4314-20. RESULTADOS: Hubo 328 pacientes incluidos en el estudio cohorte, 143
doi: 10.1128/AAC.00185-10 recibieron TMP/SMX sola, 89 recibieron daptomicina sola, 75
22. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: recibieron linezolida sola y 21 pacientes recibieron una combinación con
international guidelines for management of severe sepsis and septic shock: ≥2 de estos agentes. En análisis univariado, pacientes que recibieron
2008. Crit Care Med 2008;36:296-327. TMP/SMX sola tuvieron mejores resultados significativamente,
23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of incluyendo hospitalización (p = 0.003) y mortalidad de 90 días (p <
classifying prognostic comorbidity in longitudinal studies: development 0.001) comparado a pacientes tratados con daptomicina o linezolida.
Pacientes en TMP/SMX eran también más jóvenes (p < 0.001), y tenían
and validation. J Chronic Dis 1987;40:373-83.
menos condiciones co-mórbidas (p < 0.001), enfermedad aguda menos
24. Bion JF, Edlin SA, Ramsay G, McCabe S, Ledingham IM. Validation of severa (p < 0.001), y recibieron la terapia apropiada más temprano (p =
a prognostic score in critically ill patients undergoing transport. Br Med J 0.001). En modelos multivariados la asociación entre el tratamiento con
(Clin Res Ed) 1985;291:432- 4. TMP/SMX y la mortalidad no fue significativa. La economía en costo
25. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of ill- de antimicrobiales asociada con el uso de TMP/SMX promedió $2,067
ness in the aged. The Index of ADL: a standardized measure of biologi- por paciente.
cal and psychosocial function. JAMA 1963;185:914-9. CONCLUSIONES: TMP/SMX compara favorablemente con linezolida y
26. Performance standards for antimibrobial susceptibility testing. Nine- daptomicina en términos de eficacia del tratamiento y mortalidad. El uso
teenth informational supplement. Approved standard M100-S19. Wayne, de TMP/SMX en lugar de linezolida o daptomicina puede
PA: CLSI, 2009. potencialmente reducir significativamente los costos de los antibióticos.
27. Sanchez Garcia M, De la Torre MA, Morales G, et al. Clinical outbreak El uso de TMP/SMX debe considerarse para el tratamiento de
of linezolid-resistant Staphylococcus aureus in an intensive care unit. infecciones MRSA con MIC de 2 µg/mL para vancomicina.
JAMA 2010;303:2260- 4. doi: 10.1001/jama.2010.757
Traducido por Sonia I Lugo
28. van Hal SJ, Paterson DL, Gosbell IB. Emergence of daptomycin resistance
following vancomycin-unresponsive Staphylococcus aureus bacteraemia in
a daptomycin-naive patient: a review of the literature. Eur J Clin Microbiol RÉSUMÉ
Infect Dis 2011;30:603-10. doi: 10.1007/s10096-010-1128-3
Traitement des Infections à Staphylococcus aureus Résistant à la
29. Sibanda EL, Weller IV, Hakim JG, Cowan FM. Does trimethoprim-sul-
Méthicilline Présentant une Concentration Minimale Inhibitrice de la
famethoxazole prophylaxis for HIV induce bacterial resistance to other an-
Vancomycine de 2 µg/mL ou plus: Anciens
tibiotic classes? Results of a systematic review. Clin Infect Dis 2011;52:
1184-94. doi: 10.1093/cid/cir067 (Triméthoprime/Sulfaméthoxazole) vs Nouveaux Agents
30. Hayakawa K, Marchaim D, Vidaillac C, et al. Growing prevalence of
(Daptomycine ou Linézolide)
vancomycin-resistant Enterococcus faecalis in the region with the high- ML Campbell, D Marchaim, JM Pogue, B Sunkara, S Bheemreddy, P Bathina,
est prevalence of vancomycin-resistant Staphylococcus aureus. Infect H Pulluru, N Chugh, MN Wilson, J Moshos, K Ku, K Hayakawa, ET Martin,
Control Hosp Epidemiol 2011;32:922- 4. doi: 10.1086/661599 PR Lephart, MJ Rybak, et KS Kaye
31. Fischer HD, Juurlink DN, Mamdani MM, Kopp A, Laupacis A. Hemor- Ann Pharmacother 2012;46:1587-97.
rhage during warfarin therapy associated with cotrimoxazole and other HISTORIQUE: Les lignes directrices de traitement mentionnent que
urinary tract anti-infective agents: a population-based study. Arch Intern d’autres agents que la vancomycine peuvent être utilisés pour le
Med 2010;170:617-21. doi: 10.1001/archinternmed.2010.37 traitement de certains types d’infection à Staphylococcus aureus résistant
32. Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani à la méthicilline (SARM) lorsque la concentration minimale inhibitrice
MM. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients (CMI) de la vancomycine est de 2 µg/mL ou plus. Ces alternatives
receiving inhibitors of the renin-angiotensin system: a population-based thérapeutiques sont: le triméthoprime/sulfaméthoxazole (TMP/SMX),
study. Arch Intern Med 2010;170:1045-9. un vieil agent peu dispendieux et la daptomycine ou le linézolide, 2
doi: 10.1001/archinternmed.2010.142 agents relativement nouveaux et dispendieux.

1596 n The Annals of Pharmacotherapy n 2012 December, Volume 46 theannals.com

 Treatment of MRSA with TMP/SMX vs Daptomycin or Linezolid

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

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