Transcript Journal Club: Trimethoprim-Sulfamethoxazole verses Placebo for

Journal Club:
Trimethoprim-Sulfamethoxazole
versus Placebo for Uncomplicated
Skin Abscess
Meredith Barlow, M.D.
Eric Tuers, M.D.
11/16/2016
Question:
 56 year old male with history of DM type 1, HTN, and
HLD presents to clinic with large indurated, fluctuant
mass on left lower jaw measuring approximately 2.5cm
in diameter.
 42 year old typically healthy female presents with a
2cm diameter fluctuant indurated mass on the right
anterior chest wall below the breast
 Plan is to I&D the abscesses. Should a course of
antibiotics be added to help improve the outcome?
Background
 The abscess: collections of pus within the dermis and
deeper skin tissues
 Any process leading to a breach in the skin barrier can also
predispose to the development of a skin abscesses
 Increased risk in those with close contact with others who
have active infection with skin abscesses
 S. aureus (either methicillin-susceptible or methicillinresistant S. aureus) occurs in up to 75 percent of abscesses
Background
 Cutaneous abscesses are an important issue because they
are common throughout the world, as well at in our clinics
 Between 1993 – 2005 ER visits for skin and soft tissue
infections in the US increased from 1.2 million to 3.4 million,
mostly due to increased abscesses
 Community acquired MRSA emerged as the most common
pathogen causing purulent skin/soft tissue infections in
many parts of the world
 Trimethoprim – sulfamethoxazole (TMP-SMX) has retained
in vitro activity against MRSA, is one of the most commonly
prescribed antibiotics for MRSA.
Background
 Usual primary treatment is to drain the abscess, and
previous studies did not show a benefit of adjunctive
antibiotics
 Many providers do not prescribe antibiotic coverage for
uncomplicated abscesses as a drained abscess typically
resolves without antibiotics, but may take several days or
even weeks to resolve
 After an initial I and D, some patients will require an
additional surgical drainage procedure to address
accumulations of pus, or will have worsening infection
despite I and D requiring abx.
 So, does the addition of antibiotics alter this?
Article
 Talan, D. et al. Trimethoprim-Sulfamethoxazole versus
Placebo for Uncomplicated Skin Abscess. New
England Journal of Medicine. 374;9 (March 3, 2016).
PICO
 P: Patient/Population/Problem
 I: Variable of Interest
 C: Comparison/Control
 O: Outcome
 T: Type of Question
Type of Question
PICO
 P: Patients age 12 and older with uncomplicated
cutaneous abscesses that get drained.
 I: Cure rate for drained abscess with adjunct treatment
of TMP- SMX
 C: TMP - SMX vs. Placebo
 O: Clinical cure vs. clinical failure
 T: Intervention/Therapy
Purpose and Study Design
 Purpose: To evaluate if 7 days administration of
trimethoprim-sulfamethoxazole 320mg-1600mg (2 tabs
of Bactrim DS) BID vs. placebo in patients with
uncomplicated skin abscesses who underwent I&D and
were treated on an outpatient basis.
 Study Design: Multicenter, double-blind, randomized
trial of 5 US Emergency Departments
P: Population
 Outpatients older than age 12 years, who had an
uncomplicated abscess that was being treated with
drainage
Trial populations
 Trial populations
 Modified intention to treat
 These participants took at least one dose of the active drug or
placebo, and had an in-person or telephone assessment
through the test of cure visit, as well as those who withdrew
from the trial, were lost to follow up before classification, or had
missing or unassigned outcomes
 Per protocol
 Participants who either took >/= 75% total doses of TPM-SMX
or placebo during first 5 days and had an in person test of cure
visit or were determined to have had clinical failure before the
test of cure visit, and received >/= 75% of the doses provided
during the first 48 hours of the treatment period
Trial populations
 FDAGEEP population (FDA Guidance Early End-Point Population)
 Those who received at least one dose of study drug, or
placebo, and completed the follow up evaluation at 48 –
72 hours after the start of trial treatment
 Safety population
 Those who underwent randomization, got the drug or
placebo, and did not return 100% of the doses at the end of
the treatment
I: Variable of Interest
 Response to abscess treatment with I and D with TMP –
SMX at rechecks scheduled at days 3-4, 8-10, and 14-21
(vs response to just I and D).
 Criteria for clinical failure at day 3-4 included:
 Fever attributable to the abscess
 Increase in erythema > 25% from baseline
 Worsening wound swelling or tenderness
 Criteria for clinical failure at day 8-10 included:
 Fever, no decrease in maximal region of erythema from
baseline, no decrease in swelling or tenderness
 Criteria for clinical failure at day 14-21 (test of cure
evaluation) included:
 Fever or more than minimal erythema, swelling, or tenderness
C: Comparison/Control
O: Outcome
Abscess cure rate greater in the TMP-SMX group (80.5%) vs. placebo group
(73.6%) in the mITT-1 group (difference 6.9 percentage points with 95%
confidence interval (2.1-11.7; P=0.005).
Number Needed to Treat
mITT-1
Clinical Cure
Clinical Failure
Total
Bactrim
507
123
630
Placebo
454
163
617
NNT= 1/ARR
ARR= CER-EVR
CER: Control event rate: 454/617= 0.74
EVR: Experimental event rate: 507/630= 0.8
NTT= 1/(0.74-0.8) = 17 (NNT of mITT-1 group)
NNT of per-protocol group: 14
Secondary Outcomes
Adverse Events
 Similar between TMP-SMX and placebo group, and
most adverse events were considered mild.
 Most common adverse event involved GI system
(42.7% vs. 36.1%).
 NO CASES of C. diff-associated diarrhea occurred.
Discussion
 In this trial involving 1265 patients with drained
cutaneous abscess: Patients who received TMP-SMX
(dose 320mg-1600mg BID x7days) had higher cure
rate than those who received placebo.
 Improved secondary outcomes in TMP-SMX group:
Fewer subsequent surgical drainage procedures, new
skin infections, and infections among household
members 6-8 weeks after end of treatment period.
Discussion
 Practice guidelines for abscess drainage is sufficient for
most patients, and adjunctive antibiotics should be given for
patients who: have systemic response syndrome, DM, very
young or very old, infected site with diameter >5cm, and
surrounding cellulitis.
 Participants in this trial generally had small size of skin
abscess measuring 2-3cm.
 HOWEVER MOST PARTICIPANTS HAD TOTAL LESION
SIZE, INCLUDING ASSOCIATED ERYTHEMA, OF
GREATER THAN 5CM AND THUS MET OTHER
GUIDELINE CRITERIA FOR ABX TREATMENT.
Limitations
 Physicians may have been biased against enrolling patients
“perceived as higher risk,” such as those with DM.
Therefore, low inclusion of diabetic patients.
 Higher dose of TMP-SMX (used 2 tabs DS Bactrim BID).
 Some degree of nonadherence, which would bias against
TMP-SMX group, but higher dose of TMP-SMX may have
mitigated against inadequate treatment.
 Abscesses may not have been fully drained in the
beginning.
 Doesn’t give specifics of age range, only over age 12 years.
Critical Appraisal
 Is the question studied by these investigators similar
enough to our question?
 Is the population studied similar to the population we
are interested in?
 What are the flaws in the way the data was collected or
analyzed? How could this affect the validity of the
results?
 Blinding? Reliability of data collected?
Critical Appraisal
 Are the results understandable and compelling?
 Are the results applicable to our patient?
 Can we use this treatment in our practice?
 Will our practice change based on this evidence?
Questions?