by Dr Geoffrey Modest
Given the emergence of methicillin-resistant Staphylococcus aureus (MRSA), there are concerns about what empiric therapy to prescribe for skin infections, including cellulitis. A recent article in JAMA assessed the utility of adding trimethoprim-sulfamethoxazole (TMP-SMX) to cephalexin in treating uncomplicated cellulitis (see doi:10.1001/jama.2017.5653).
Details:
— 5 US emergency departments participated in an outpatient double-blind study of 500 patients >12 years old with cellulitis but without wound, purulent drainage, or abscess, seen from 2009-2012.
— Median age 40, 58% male, 57% white/35% black/1% Asian, symptom duration 3 days, 20% with a history of fever in the week prior to enrollment, 56% of infections were in the lower extremity/24% upper extremity/9% trunk abdomen or back/6% head or neck/4% groin or buttocks, 11% diabetics; mean length and width of erythema was 13 x 10 cm
— Bedside ultrasound was used to exclude abscess
— patients were randomized to cephalexin 500 mg 4 times a day plus TMP-SMX 160 mg/800 mg twice a day for 7 days, vs cephalexin plus placebo for 7 days
— primary outcome was clinical cure, defined as an absence of fever, increase in erythema >25%, swelling, or tenderness at days 3-4; no decrease in erythema, swelling, or tenderness at days 8-10; and the presence of no more than minimal erythema, swelling, or tenderness at days 14-21.
Results:
— in a per-protocol analysis, which was limited to those patients who had a physical follow-up at 14-21 days after enrollment and took to at least 75% of medication doses: clinical cure at 14-21 days occurred in 182 (83.5%) of those assigned to cephalexin plus TMP-SMX, versus 165 (85.5%) in those on cephalexin alone, nonsignificant
— in the modified intention-to-treat population (participants took at least one dose of study medication, had an in-person or telephone assessment at the test of cure visit, and included those who withdrew from the trial or were lost to follow-up), clinical cure occurred in 189 of 248 patients (76.2%) in the combination group and 171 (69.0%) in the cephalexin group, a difference of 7.3% (-1.0% to 15.5%) p=0.07, almost but not quite significant. However in the more specific modified intention-to-treat analysis including those who took at least one dose of medications and had an in-person follow-up evaluation at any time during the study (ie, not including those who were lost to follow-up etc), the clinical cure rates were 83.8% in those on combined therapy and 82.8% of those with cephalexin alone, nonsignificant
— Adverse events, including the secondary outcome of overnight hospitalization, recurrent skin infections, and similar skin infections in household contacts through weeks 7-9, did not differ significantly. However, one patient on TMP-SMX did have acute-on-chronic kidney injury that resolved.
— 36 patients had treatment failure with cephalexin plus TMP-SMX: 10 (28%) were found to have an abscess the time of clinical failure and 9 (25%) developed an opening of the skin and purulent drainage
— 60 patients overall had treatment failure with clinical evidence of infection and had material available for culture: 41 (68%, and 10% of the per-protocol population) had MRSA, 8 (13%) had MSSA, and 3% streptococcal species, with no difference between treatment groups in the proportion having MRSA during follow-up.
— Post hoc subgroup analyses showed no difference between the groups if the patients had a history of fever or not, had diabetes, or by the size of the erythema.
Commentary:
— cellulitis is a common outpatient issue, and a difficult one because it is usually impossible to find the causative organism. b-hemolytic strep is often considered the cause, and the 2014 guidelines from the Infectious Diseases Society of America suggest choosing an antibiotic against Streptococci if there is no evidence of systemic signs of infection, penetrating trauma, evidence of MRSA elsewhere, or injection drug use. However, it is common for clinicians to cover MRSA infection in patients with cellulitis, given how widespread these infections are and how standard antibiotic therapy as with cephalosporins do not cover these MRSA infections.
— it is not so surprising that TMP/SMX does not add much to the treatment of cellulitis overall, since it does not provide much coverage for b-hemolytic strep, the presumed major causative organism
— One concern with this type of ED-based study is the higher likelihood of lower levels of medication adherence. They found that of the patients who took at least one dose of medications, only 52% were 100% adherent to the full regimen and 25% took 76-99% of their doses. This nonadherence was 3-fold higher in the cephalexin only group, for unclear reasons. But, the per-protocol analysis (ie those who took the meds) showed no difference between the outcomes of the treatment groups. I should add that some in this per-protocol group might have taken as little as 75% of their prescribed antibiotics, and this seems to me to be an arbitrary number. Which brings up the issue that some of these patients, in their most aggressively treated group, may actually have had insufficient antibiotic therapy. It would have been useful to have more granular data here assessing outcomes by finer gradations of medication adherence.
— Of note, of 36 patients who had treatment failure in the combined antibiotic group, over half had an abscess or skin opening/purulent discharge; and 71% of 28 in those on cephalexin alone. 10% of the patients who had clinical failure but had taken at least 75% of medication doses did have MRSA, which does suggest that even in patients with no clinical or ultrasound evidence of an abscess, there might well be MRSA (though, again, was this MRSA created or selected-for by taking insufficient quantities of antibiotics to cure the infection??) And this number is likely to be higher in many clinical settings, where cellulitis is defined exclusively clinically and without the use of ultrasound. It is somewhat reassuring that the treatment failures were similar in that both treatment groups had MRSA, though it seems that the numbers were too low to draw definitive conclusion.
–clearly from this study, there is a fine line between cellulitis and abscess formation. Even many of those who did not have an ultrasound-detectable abscess at the initiation of the study ultimately did develop fluid collections or skin opening with purulent discharge. And the proportion of patients with unknown fluid collections in our health center, for example, is undoubtedly higher than in this study since we do not have a bedside ultrasound machine (which limits the generalizability of this study in these settings). Again, it would have been interesting to have more granular data about the baseline characteristics of those who developed abscess/purulent discharge in this study and if there were any predictive models for them, since those who have abscesses are much more likely to have MRSA and should be treated differently. For one thing, those who are basically healthy (no immunocompromise, lots of comorbidities) who have no systemic symptoms and especially with small abscesses (eg <2cm) do just as well with incision and drainage and without antibiotics at all. And if antibiotics are indicated, they should cover MRSA.
so, this article, though not obviously generalizable to all settings (eg no ultrasound in many settings, perhaps higher medication adherence in primary care setting), does suggest reasonably strongly that TMP/SMX does not add much to the treatment of clinical cellulitis. Though imperfect, the per-protocol analysis does support this conclusion. Therefore, I think it is very reasonable to treat patients with cellulitis but without systemic symptoms/immunocompromise/etc just with a cephalosporin, thereby avoiding the unusual but occasionally severe adverse reactions of TMP/SMX, but with the caveat that there be close followup. Other studies have found that 90% of patients with cellulitis have significant clinical improvement within 3 days, so that might be a reasonable target for a return visit. On the other hand, it seems reasonable to me to use the combo therapy in a patient who has a low probability for coming for follow-up, especially if one cannot rule-out a small abscess for lack of an ultrasound, where I would imagine that MRSA is more likely…