Date: October 8th, 2015
Guest Skeptic: Meghan Groth (@EMPharmGirl). Meghan is the emergency medicine pharmacy specialist at the University of Vermont Medical Center in Burlington, Vermont and an adjunct professor of pharmacy at the Albany College of Pharmacy and Health Sciences.
Case: A 26-year-old male presents to your emergency department with complaints of a painful, reddened area on his right arm. He has no significant past medical history, surgical history, or social history, but reports that he has an allergic reaction to penicillin and cephalosporin antibiotics.
On exam, you find an abscess approximately 6cm in diameter with surrounding cellulitis. After performing an incision and drainage, you contemplate sending the patient home with a prescription for antibiotic therapy.
The patient expresses to you that he’s seen cases of MRSA (methicillin-resistant Staphylococcus aureus) reported on the news and is worried this may be involved in his infection.
Background: Skin and soft tissue infections (SSTIs) are a common reason for visits to the emergency department, hospital admissions, and may result in considerable morbidity and mortality.
Classically, it has been thought that beta-hemolytic Streptococci are the causative organisms for cellulitis and Staph species are commonly implicated in cases of skin abscesses.
More recently, MRSA has been recognized as a common cause of SSTIs.
Clinical Question: For patients with uncomplicated skin infections, is clindamycin superior to trimethoprim-sulfamethoxazole?
Reference: Miller LG, et al. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections. NEJM 2015
- Population: Adult and paediatric patients aged six months to 85 years with at least two of the following for 24 hours or more: erythema, swelling/induration, local warmth, purulent drainage, and tenderness to pain/palpation.
- Exclusions: (supplementary index that was three pages long) Body site involvement requiring special management (e.g. perirectal, genital, or hand), human or animal bites, high fever, immunosuppression, diabetes, chronic renal failure, morbid obesity, surgical site infections, or receipt of antibiotics within 14 days that included anti-staphylococcal activity, residence in a long term care facility, cancer, or major surgery in the previous 12 months.
- Intervention: Clindamycin 300 mg PO TID x 10 days (or weight-based paediatric dose)
- Comparison: TMP-SMX 160-800 mg x 10 days BID (or weight-based paediatric dose)
- Primary Outcome: Clinical cure at the test of cure (TOC) visit (7-10 days after completion of antibiotic course).
- Secondary Outcome: Patients were also evaluated at the end of treatment at 30 days post 10 day antibiotic course (day 40) for symptom resolution and for medication-related adverse effects.
Authors’ Conclusions: “We found no significant differences between the efficacy of clindamycin and that of TMP-SMX for the treatment of uncomplicated skin infections in children and adults with few or no major coexisting conditions.”
Quality Check for Randomized Clinical Trials:
- The study population included or focused on those in the ED. No. Patients were recruited from urgent care clinics, emergency departments, and clinics affiliated with the four medical centers involved.
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in the groups to which they were randomized. Yes
- The study patients were recruited consecutively (i.e. no selection bias). Unsure – They did not specifically state consecutive patients so there could be some selection bias.
- The patients in both groups were similar with respect to prognostic factors. No
- All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes – They did a good job of blinding the participants.
- All groups were treated equally except for the intervention. Yes
- Follow-up was complete (i.e. at least 80% for both groups). Yes. Approximately 89% of intention to treat population could be evaluated at TOC visit.
- All patient-important outcomes were considered. No. No mention of trauma-associated SSTI
- The treatment effect was large enough and precise enough to be clinically significant. No
Key Results: 524 patients were enrolled in the study.
- 30% (155/524) were children.
- 53% had cellulitis, 31% had an abscess and 16% had both
- 40% of those cultured had S. aureus
- 77% (167/217) of the S. aureus were MRSA
Primary Outcome: No significant difference in efficacy between clindamycin and TMP-SMX
In the intention to treat population, 80% of clindamycin patients and 78% of TMP-SMX patients had clinical cure at the test of cure (TOC) visit (p=NS).
No significant differences were found in subgroup analysis based on cellulitis, abscess, or mixed cellulitis/abscess, or causative organism.
One-month cure rates were similar between groups, and rates of adverse events were similar between groups. The adverse event rate was about 20% for both groups with the most common adverse event being diarrhoea (easy to smell but hard to spell) in 10% of patients. The discontinuation rate was similar between both groups also at 8%
This was a high-quality randomized, controlled trial of two generically available antibiotics that have been around for a while. However, there are some major points of the study that limit its clinical applicability.
The Infectious Disease Society of America released its latest guideline for the management of skin and soft tissue infections in 2014. In this document, clindamycin is mentioned as an alternative treatment for mild cellulitis, but TMP-SMX is not mentioned at all as a recommended agent.
For patients with mild abscess, no antibiotic treatment is recommended. That is because the treatment of an abscess is typically cold hard steel. However, the IDSA does recommend clindamycin or TMP-SMX as treatment options for moderate abscess. It is likely that these patients with “moderate” abscesses would have been excluded from the present trial due to the severity of infection. Thus, for both cellulitis and abscess, the present study does not reflect the most current recommendations for management of skin and soft tissue infections.
There could also have been a problem with patient selection. Patients in this study were recruited from emergency departments, but also from urgent care clinics and clinics affiliated with the participating institutions. Therefore, some patients represented may not best reflect patients that we see in the emergency department.
They also did not explicitly state that the patients were recruited consecutively. This could have introduced some selection bias by the provider as to who was enrolled in the study. Furthermore, the exclusion criteria outlined in the paper’s supplementary index were extensive, and resulted in a study population that was otherwise pretty healthy. This may be why the cure rates for a less-than-ideal cellulitis agent like TMP-SMX were surprisingly high.
Additionally, the IDSA guidelines recommend a five day treatment duration for cases of uncomplicated cellulitis. The 10-day treatment course used in this study is not congruent with that recommendation, and may not be translatable into everyday practice even if many clinicians use a seven day treatment course rather than five.
While the investigators accounted for comorbidities that may have influenced the results of the study, they did not describe skin and soft tissue infections that may have been secondary to trauma. This particular aspect is addressed in multiple sections of the IDSA treatment guidelines as influencing management. Additionally, patients with trauma-associated SSTI may benefit from a higher dose of TMP-SMX (2 double strength tablets BID) (Cadena J, et al).
The necessity of covering for MRSA in patients with skin abscesses is unclear. In a study by Pallin and colleagues, the addition of TMP-SMX to cephalexin for MRSA coverage in patients with cellulitis without abscess did not improve cure rates (Pallin DJ, et al). Additionally, in patients with abscess, for which MRSA coverage is recommended in the IDSA guidelines, several studies have demonstrated efficacy of antibiotic therapy that lacked MRSA coverage even in patients where MRSA was isolated when cultured (Moran GJ, et al).
However, the authors included culture information in the supplementary index for patients with cellulitis (without abscess) and non-purulent drainage, strangely. This leads me to question first of all the utility of cultures in these patients to begin with, as the skin is not a sterile site. But also wondering what to do with the information obtained from cultures, as it doesn’t necessarily seem like it should be used to change management.
Finally, the authors comment that TMP-SMX has previously thought to be a poor choice for cellulitis, suggesting that their findings would support its use as comparable to clindamycin. This suggestion should be scrutinized, as the results apply to a pretty narrow patient population (that being a patient with nearly zero comorbid conditions, not with an SSTI secondary to trauma).
While this may be an attractive option for patients with multiple drug allergies not able to tolerate first line therapies, it’s important to remember that needlessly starting anti-MRSA antibiotics is not without consequences.
Comment on Authors’ Conclusion Compared to SGEM Conclusion: While TMP-SMX appears to have similar efficacy to clindamycin for uncomplicated SSTIs in this trial, these results are applicable to only a select patient population. Additionally, TMP-SMX does not represent a first line option for uncomplicated cellulitis, and should only be considered after other options have been exhausted.
SGEM Bottom Line: For patients with uncomplicated cellulitis, TMP-SMX may represent an alternative to clindamycin in patients with no major comorbidities.
For patients with mild abscesses, incision and drainage (without antibiotics) is still considered to be the treatment of choice.
Case Resolution: After performing an incision and drainage on the patient’s abscess, you pry further into the patient’s allergic reactions to penicillin and cephalosporin. The patient states he gets stomach upset with cephalosporin, and he thinks that his sister has an allergy to penicillin. After shared decision making, you discuss that therapy with an antibiotic like cephalexin is the first line treatment for his cellulitis, and that GI upset is a common side effect (not an allergy). You discuss that clindamycin or TMP-SMX may be an alternative treatment for him, but that in his case MRSA is likely not necessary. You counsel him that it may take several days to see improvement in his infection, but also provide him with appropriate return precautions.
Clinically Application: TMP-SMX may represent an alternative to clindamycin in patients with uncomplicated SSTIs, but this should be considered only in select patients.
What Do I Tell My Patient? It appears you have an uncomplicated skin infection. We are going to cut it open to release the infection and then send you home on an antibiotic. You should see your primary care provider for follow-up in the next 24-48hrs. It can take a few days to get better but if you are getting worse (more pain, fever, red line up your arm) or you are worried then come back the emergency department to be reassessed. Sometimes a different antibiotic is needed.
Keener Kontest: Last weeks’ winner was Adel Altamimi from Riyadh, Saudi Arabia. Adel knew a dose of ketamine that can be used for rapid sequence intubation is 2mg/kg IV.
Listen to the podcast for this weeks’ question. If you know the answer than send me an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.