Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscesses?

Background: It is well documented that the number of visits to the ED for abscesses is on the rise in the US, with methicillin-resistant Staphylococcus aureus (MRSA) being the most common cause of purulent skin and soft-tissue infections. The primary treatment for cutaneous abscesses is incision and drainage (I&D). The prescription of antibiotics after this procedure is not straightforward. On one hand there is increased cost and possibly increased side effects, but on the other hand maybe antibiotics will increase eradication and improve treatment. What is known is that I&D alone will result in resolution in >80% of cases. So this begs the question, should we be empirically prescribing Trimethoprim-Sulfamethoxazole for uncomplicated skin abscesses after I&D?

What Article are we Reviewing?

Talan DA et al. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. NEJM 2016; 374 (9): 823 – 32. [Epub ahead of print]

What They Did:

• Multicenter, double-blind, Randomized Controlled Trial of 5 US EDs with >1200 patients
• Determine whether trimethoprim-sulfamethoxazole (320mg and 1600mg BID x7d) would be superior to placebo in outpatients in uncomplicated abscesses status post incision and drainage
• Only enrolled participants who had a lesion with purulent drainage that had been present for <1 week and measured ≥2cm in diameter (measured from the borders of the induration if lesion fluctuant or abscess cavity on ultrasound if lesion not fluctuant)

Key Exclusion Criteria:

• Suspected osteomyelitis or septic arthritis
• Diabetic foot, decubitus, or ischemic ulcer
• Mammalian bite
• IVDU
• Long-term care residence
• Incarceration
• Immunodeficiency (i.e. ANC <500/mm³)
• Immunosuppressive drugs
• Active chemotherapy
• Known AIDS
• Creatinine clearance <50mL/min
• Taking warfarin, phenytoin, or methotrexate
• Pregnant or lactating

Definitions:

• Modified Intention-to-Treat: Participants who 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 final classification, or had missing or unassigned outcomes
• Per-Protocol: Participants who either took ≥75% of the total doses of study drug or placebo during first 5 days and had an in-person test-of-cure 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
• Uncomplicated Abscess: Cutaneous lesion suspected of being an abscess based on physical exam or ultrasound that was found to have purulent drainage on surgical exploration
• Complicated Abscess: Infections involving deeper soft tissues, requiring significant surgical intervention, such as infected ulcers, burns, and major abscesses or a significant underlying disease state that complicates the response to treatment

Outcomes:

• Primary: Clinical Cure of Abscess:
  • Test-of-cure Visit = 7 – 14d after treatment period
  • Extended Follow–up Visit = 42 – 56d after treatment period
• Secondary:
  • Composite cure (i.e. resolution of all symptoms and signs of infection, or improvement such that no additional antibiotic therapy or surgical drainage procedure was necessary)
  • Surgical drainage procedures
  • Changes in erythema size
  • Invasive infections (sepsis, bacteremia, endocarditis, osteomyelitis, septic arthritis, necrotizing fasciitis, or pneumonia)
  • Skin infections at the same site and at a different site
  • Hospitalizations
  • Similar infection in household contacts
  • Days missed from normal activities
  • Days missed from work or school
  • Days analgesics were used

Results:

• 45.3% of participants had wound cultures positive for MRSA
• Median Length, Width, and Depth of Abscesses:
  • 2.5 x 2.0 x 1.5cm
• Median Length and Width of Erythema
  • 6.5 x 5.0cm
• Clinical Cure of Abscess in Modified Intention-to-Treat Population:
  • Trimethoprim-Sulfamethoxazole: 507/630 patients (80.5%)
  • Placebo: 454/617 patients (73.6%)
  • Absolute Difference: 6.9% (2.1 – 11.7%)
  • NNT = 14
• Clinical Cure of Abscess in Per-Protocol Population:
  • Trimethoprim-Sulfamethoxazole: 487/524 patients (92.9%)
  • Placebo: 457/533 patients (85.7%)
  • Absolute Difference: 7.2% (3.2 – 11.2%)
  • NNT = 14
• Secondary Outcomes (7 – 14 Days after Treatment):

 

• Adverse Events:
  • Most events were mild (Most commonly GI Side Effects)
  • No treatment-associated serious or life-threatening adverse events
  • GI Side Effects with Trimethoprim-Sulfamethoxazole: 42.7%
  • GI Side Effects with Placebo: 36.1%

Strengths:

• Multicenter, double-blinded, randomized clinical trial
• Before initiation of trial, trial personnel underwent standardized training on the general technique and trial-specific procedures for I&D
• 97.4% of the MRSA isolates tested were susceptible to trimethoprim-sulfamethoxazole

Limitations:

• There was a moderate degree of nonadherence with only 64.7% of the study population determined to be 100% adherent and another 17.2% were 76 – 99% adherent. But this is probably what happens in everyday practice. This could bias the results against trimethoprim-sulfamethoxazole.
• This study provided a power of 90% to detect a between-group difference of 7.5%, which was not met by this study in any of its trial populations. The key to understanding this issue is to recall the difference between a superiority study and a non-inferiority study. This was a superiority study and hence a statistical difference can be found even if the observed delta is less than the delta used to power the study. Because the 95% CI did not cross zero, statistical significance was found. One has to determine, however, what is clinically significant as the threshold for clinical significance was not defined. Because the effect size was not huge, Dr. Talan and co-authors suggest that collaborative decision making with the patient should be used.
• Physicians may have been biased against enrolling some patients perceived as being at higher risk (i.e. diabetic patients)

Discussion:

• Cure rate of uncomplicated abscesses is >80% without antibiotics. Does it make sense then to give empiric trimethoprim-sulfamethoxazole to all patients after I&D?
• Although not shown in this study, trimethoprim-sulfamehtoxazole can cause serious complications such as C. difficile colitis, renal, and electrolyte problems, drug interactions, and Stevens-Johnson syndrome.
• Increased antibiotic use may promote bacterial resistance and an endpoint that was not discussed in this trial.
• Practice guidelines for abscess treatment state that drainage is sufficient for many patients, but primarily through expert opinion, recommend adjunctive antibiotics for patients who have certain clinical or demographic characteristics, including systemic inflammatory response syndrome, diabetes, very young or very old age, an infected site with a diameter of more than 5cm and surrounding cellulitis.
• The majority of abscesses in this trial were small, mostly measuring 2 – 3 cm, but the majority had associated cellulitis measuring more than 5cm.

Author Conclusion: “In settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo.”

Expert Peer Review/Questions:

Gillian Schmitz, MD
Twitter: @GillianMD1
Associate Clinical Professor of Emergency Medicine
University of Texas Health Science Center at San Antonio

1. Do you think the practice of empiric trimethoprim-sulfamethoxazole will increase resistance in the future?

MRSA has remained universally susceptible to TMP-SMX so far. There is a theoretical concern that overuse of TMP-SMX may cause resistance. We have already seen TMP-SMX resistance in E Coli, presumably secondary to antibiotic use in animal food and overuse in hyper-endemic resistant environments. The risk of resistance to MRSA is somewhat decreased, and considered minimal risk by some, in that we are targeting our use on specific subset of patients that have a known purulent bacterial infection (as opposed to liberal use of antibiotics in viral infections, bronchitis, etc.) That being said, less than 50% of patients in this study grew out MRSA. Although antibiotic use is probably not indicated in those with sterile abscesses, it is not cost efficient to culture every abscess to determine which ones are MRSA. Antibiotic stewardship and resistance is always a concern from a public health standpoint, but is hard to implement in the care of an individual patient. (What would you want if you or your child had an abscess?) I like the approach of partnering with the patient and utilizing the “watch and wait” strategy. From my experience, most patients start having less pain and some clinical improvement within 48-72 hours. I think it is a reasonable approach to give patients a prescription on their initial visit but suggest only filling it if their symptoms worsen, or do not clinically improve within 48-72 hours.

2. Although this study showed that trimethoprim-sulfamethoxazole had “mild” side effects, what are your thoughts on this with routine prescriptions?

I was surprised that there were not more cases of C. diff or other more serious side effects. Any study is at risk of some sampling bias and it’s possible that these 1200 patients had a lower incidence of side effects than the general population would if treated. We also don’t know what happened to the group lost to follow up. Additionally, as pointed out earlier, less than 65% of patients were 100% compliant with antibiotics use. Perhaps the risk of adverse events and more serious side effects would increase if antibiotic use became standard and patients became more compliant with antibiotic therapy.

But, at least for now, this is relatively reassuring that there were not more frequent serious side effects. Until more data is available, it seems the potential benefit outweighs the risk.

3. What strategy would you implement at this point in treatment of abscesses after I&D, in areas where MRSA is prevalent?

I think the key to emphasize here is ensuring adequate drainage of the abscess cavity in the first place. This study has some bias in that providers were all trained in proper technique for this study and made relatively large incisions. The treatment after incision and drainage becomes less relevant, and I suspect failure rates would be higher, if adequate drainage is not achieved in the first place.

Assuming adequate drainage is performed, I will implement the “wait and see “ approach and offer antibiotics to patients if their symptoms worsen, or do not clinically improve, within 48-72 hours. For patients who have had multiple abscesses in the past, however, I am more likely to recommend TMP-SMX at the onset as this study suggests in their secondary outcome what we found in earlier studies, a decreased recurrence rate of new lesion development in the group who had antibiotics.

I would also emphasize adequate hygiene with daily washing of the wound in shower/ bath, frequent hand washing with soap especially after dressing changes, washing linens and towels in hot water, and keeping wound covered to minimize spread to other sites or household contacts until healing has occurred.

Clinical Take Home Point: In uncomplicated abscesses, TMP-SMX confers some benefit compared to placebo in clinical cure rate after incision and drainage. The 7% absolute difference between groups was statistically significant, but there is no standard for defining what is clinically significant with abscess drainage and 85% of patients improved with incision and drainage alone in the group who finished the protocol. Although the effect size was small with TMP-SMX, the drug itself is cheap and the side effects in this study were mild. A cost analysis favors antibiotic use as the cost of the TMP-SMX is considerably lower than the cost of repeat visits. There is a theoretical risk of increased resistance with higher rate of antibiotic use.

One strategy would be a “wait and see” approach, reserving antibiotics for the subset of patients who are not clinically improving after incision and drainage. In other words provide a prescription for trimethoprim-sulfamethoxazole, with the specific instructions that if symptoms of infection have not improved at 48 hours then start taking the antibiotic.

References:

1. Talan DA et al. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. NEJM 2016; 374 (9): 823 – 32. [Epub ahead of print] 

For More Thoughts on This Topic Checkout:

• Ryan Radecki at EMLit of Note: Are Antibiotic Back in Favor for Abscesses?
• Bryan Hayes at ALiEM: Sulfamethoxazole-Trimethoprim for Skin and Soft Tissue Infections: 1 or 2 Tablets BID?
• Rory Spiegel at EM NERD: The Case of the Pragmatic Wound
• Aaron Arredondo on CORE EM: TMP-SMX vs. Placebo in the Treatment of Superficial Abscesses
• Ken Milne At The SGEM: SGEM#164 – Cuts Like a Knife – But you Might Also Need Antibiotics for Uncomplicated Skin Abscesses

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