Breadth and Length - Antibiotics in Uncomplicated Cellulitis

The Gist:  Many cases of uncomplicated, non-purulent* cellulitis can be treated with a five day course of oral antibiotics, such as cephalexin or dicloxacillin, without covering for MRSA.  The Infectious Disease Society of America (IDSA) and core emergency medicine texts support this recommendation, with provisions for extended coverage (duration and/or MRSA antibiotics) in high-risk or sicker patients [1-3]. Despite these recommendations, providers often prescribe lengthier courses with broader spectrum coverage, which may have lead to adverse effects, increased cost, or resistant microbes [4-6,8].

The Case:  A 38 year old female presents to the emergency department (ED) with right lower extremity erythema and warmth, progressing over the past four days.  She has no known trauma, no prior history of cellulitis or abscesses, and her history was remarkable for "borderline" diabetes, hypertension, and depression.  Vital signs are within normal limits and examination reveal a diffusely erythematous area of approximately 7 x 4 cm, warm to touch, with some edema but no induration or drainage.  This patient seems to be an ideal candidate for outpatient therapy.  Should the provider write for cephalexin for 5 days? 7 days? Does the patient also need TMP-SMX or clindamycin?

Despite revolutionizing medical care, antibiotics prescribed for skin and soft tissue infections are not benign as patients incur costs and may develop allergic reactions, yeast infections, antibiotic associated diarrhea, or provoke resistant pathogens.  In national survey data, antibiotics have been associated with nearly 1 in 5 ED visits for adverse drug events and more than 1 in 4 similar events in the pediatric population [5,6].  Antibiotics prescribed for skin and soft tissue infections have been associated with a large proportion of these events, at least in children [7].  As a result, there's an increasing emphasis on using appropriate antibiotics for the minimum duration needed to treat the infection.

Duration of therapy: In 2005, the IDSA issued a recommendation a 5 day course of treatment for uncomplicated cellulitis and this is offered up as an option in core EM texts [1,3,6].  However, many practitioners prescribe an initial 7-10 day course of treatment. Interestingly, the most recent iterations of both Tintinalli and Rosen's do not hazard a suggestion for antibiotic duration for any skin and soft tissue infections [2,3].

The five day recommendation** is based on study by Hepburn et al.  Outpatients presenting to the clinic or ED (n=121) with uncomplicated cellulitis were treated with levofloxacin for 5 days and then randomized (n=87), at a 5 day visit, to receive either 5 additional days of antibiotics or placebo. Patients were reevaluated at an appointment between days 10-14 and then at 28 days by telephone.  Treatment success was not different between groups, with 98% resolution in both arms [8].

• Diabetes was not an exclusion criteria and was present in 5% (n=12) and 7% (n=16) in the treatment and placebo groups, respectively.
• At the time of randomization (day 5), patients were allowed to have persistent erythema and warmth, as long as it had not worsened and seemed marginally improved.  This was somewhat subjective.  
• Patients were enrolled within 24 hours of diagnosis and treatment so some patients received different antibiotics during the first 24 hours.  
• Levofloxacin isn't routinely used for cellulitis in most populations. 

Choice of antibiotics:  Most non-purulent cellulitis is caused by streptococcus (strep), even in areas with a high prevalence of MRSA.  As such, the IDSA and core texts recommend targeting strep only for most uncomplicated, non-purulent cellulitis [1].  Literature suggests these low risk patients do no better on coverage for both strep and staph [9].  In higher risk patients or those with purulence that do require staph coverage, it is recommended that providers use anti-MRSA antibiotics in areas with high prevalence of MRSA [1-4].  Use of anti-MRSA antibiotics in high risk groups including those with history of MRSA, diabetic ulcers, systemic illness, IVDU, and other higher risk patients is less controversial and more broadly supported [1-4].

A study comparing monotherapy with cephalexin versus TMP-SMX have demonstrated that in systemically well, uncomplicated patients, cephalexin monotherapy suffices [9]. Review of the study. A trial comparing TMP-SMX, placebo, cephalexin, or combination was completed in July 2013, with no posted results at this time [11].

Of note, studies examining the microbiology of cellulitis may be skewed by selection bias, as staph and MRSA tend to cause more purulent infections which may be more likely to be cultured [12]. Furthermore, cultures are only indicated and, theoretically obtained, in the sicker patients and in those with comorbidities which may further also skew the results.

Do we prescribe antibiotics appropriately? Not commonly.
Hurley et al conducted a retrospective cohort study in Denver of ED patients and outpatients in 2010-2011 that measured the frequency of "avoidable antibiotic exposure." The authors defined "avoidable" antibiotics with a broad spectrum of gram-negative activity (beta-lactam/beta-lactamase inhibitor combinations, second, third, or fourth-generation cephalosporins, fluoroquinolones, carbapenems, or aminoglycosides); combination therapy (2 antibiotics or more); or treatment for more than 10 days.

• n=364 of whom 155 had cellulitis
• Only 7% (n=8) of patients with cellulitis received 5 days of antibiotics and 47% (n=54) received 10 or more days of antibiotics
• 61% of patients with cellulitis received MRSA coverage [9]

Also, there's no benefit to a single dose of IV antibiotics in the ED and blood cultures aren't helpful in these patients.  On a more controversial note, a recent retrospective chart review by Paolo et al found that blood cultures may not significantly alter management in cases of complicated cellulitis as the contaminant rate (3%) was roughly equivalent to our true positive rate (4%).

*Complicated - varies by reference, but typically includes immunocompromised, those with signs of systemic illness, extremes of age, or diabetes.
Purulent - drainage or signs of abscess. History of abscess and eschar are also associated with staphylococcus (staph).  
**It's difficult to determine what, precisely, the 7 and 10 day historical attachments are based on other than history and familiarity.

References:

1.  Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373–406. 

2.  Kelly EW, Magilner D.  "Soft Tissue Infections."  Tintinalli's Emergency Medicine: A Comprehensive Study Guide.  7th ed. p 1017-1018.
3 .Marx JA, Hockberger RS, Walls RM.  Rosen's Emergency Medicine , Eighth Edition. Chapter 137, 1851-1863.e1
4. Meislin HW, Giusto G.  Rosen's Emergency Medicine , Seventh Edition. Chapter 135, 1836-1838. 
5.  Shehab N1, Patel PR, Srinivasan A, Budnitz DS. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008 Sep 15;47(6):735-43. 
6.  Bourgois FT, Mandl KD, Valim C et al.  Pediatric Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis. Pediatrics. Oct 2009; 124(4): e744–e750.
7. Goldman JL, Jackson MA, Herigon JC et al.  Trends in Adverse Reactions to Trimethoprim-Sulfamethoxazole.  Pediatrics. Jan 2013; 131(1): e103–e108.

8. Hepburn MJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis.  Arch Intern med 2004; 164, 1669-1674
9. Hurley HJ, Knepper BC, Price CS, et al. Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting. Am J Med. 2013;126(12):1099–106. 
10. Pallin DJ, Binder WD, Allen MB et al.  Clinical Trial: Comparative Effectiveness of Cephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone for Treatment of Uncomplicated Cellulitis: A Randomized Controlled Trial.  Clin Infect Dis. (2013) 56 (12): 1754-1762.
11.  ClinicalTrials.gov: A Service of the U.S. National Institutes of Health (NCT00729937). 
12.  Ray GT1, Suaya JA, Baxter R. Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis. 2013 May;76(1):24-30.