Long Story Short: Cellulitis Can Be Treated in Less Than a Week - Pharmacy Times

Cellulitis develops because of pathogen entry through breaks in the skin barrier and can range from mild to severe, depending on the extent of skin layer involvement.

The condition is most common in older patients with fragile skin or patients with impaired local host defenses, such as diabetes, obesity, or venous insufficiency or lymphedema.¹ In the United States, cellulitis diagnosis leads to 2.3 million emergency department visits and accounts for 10% of infectious diseases–related hospitalizations annually.^2,3

Classic cellulitis signs and symptoms of skin inflammation include erythema, swelling, tenderness, and warmth. The skin surface often resembles an orange peel (peau d'orange) because of cutaneous edema. Systemic symptoms, including fever, hypotension, leukocytosis, and tachycardia, may also occur in some patients. Most cases involve the lower extremity and are unilateral. Most cases are also nonpurulent, with purulent cases having discharge or exudate, which may require drainage. The most common pathogen is group A streptococcus (Strep- tococcus pyogenes), with Staphylococcus aureus being less likely.^1,4 Although the majority of cases are nonculturable, results of studies have shown a steady increase in the rates of methicillin-resistant S aureus purulent cellulitis in the United States.⁴ The duration of treatment of cellulitis is not standardized, with guidelines from the Infectious Diseases Society of America (IDSA) recommending a 5-day course in uncomplicated cases and recent literature supporting shorter durations.^1,5-7

Shorter duration of treatment for a variety of infections, including cellulitis, has been a focus of recent studies aiming to reduce antibiotic consumption and decrease the emergence of antimicrobial resistance.⁸ In the recently published clinical guideline from the American College of Physicians (ACP), shorter durations are recommended for cellulitis, chronic obstructive pulmonary disease exacerbations, community-acquired pneumonia, and urinary tract infections. For uncomplicated nonpurulent cellulitis, the ACP guideline recommends 5 to 6 days with an agent active against streptococci species.⁹ Skin infection guidelines from IDSA and the National Institute for Health and Care Excellence in England recommend a duration of 5 to 7 days, highlighting an opportunity for shorter courses in some situations.^1,10

Supporting evidence for shorter durations is evident in findings from several trials. Results from a 2004 study showed no difference in clinical outcomes among mostly outpatient adults with uncomplicated cellulitis (n =87) randomized to oral levofloxacin for 5 vs 10 days.⁵ Clinical success at days 14 and 28 was demonstrated in both groups (98% success rate). Uncomplicated cellulitis was defined as the absence of bacteremia, animal or human bite–associated; deeper infection; diabetic foot infection with vascular insufficiency; immunocompromised status; sepsis; or severe renal dysfunction. A decade later, 2 randomized controlled trials evaluated tedizolid (6 days) and linezolid (10 days) in patients 12 years and older with acute bacterial skin and skin structure infections (ABSSSI), and approximately half the total study population of both ESTABLISH-1 and ESTABLISH-2 (NCT01170221, NCT01421511; n=1333 combined) had a diagnosis of cellulitis.^6,7 Exclusion criteria were similar to the previous trials and included hospitalized patients, thereby providing evidence for patients with potentially more serious infections. In the subset of patients with cellulitis, there was no statistical difference in the early clinical response end point at 48 to 72 hours, a new FDA ABSSSI clinical trial outcome requirement (79%- 85% success rate across both studies).^6,7 A posttreatment assessment at 7 to 14 days following the end of therapy demonstrated few relapses (85%-88% success rate across both studies).^6,7

Evidence continues to be scarce to inform the optimal duration of therapy in hospitalized patients with cellulitis. To address this, the controlled, multicenter, randomized DANCE trial (NCT02032654) investigated flucloxacillin intravenous (IV), with an option for oral step-down, for 6 (n=74) vs 12 (n=77) days in hospitalized patients with cellulitis or erysipelas.¹¹ The primary outcome was clinical cure by day 14 without relapse by day 28 in the intent-to-treat population. Secondary outcomes included a 90-day relapse rate. Demographics included a mean age of 62 years, a high proportion of patients with diabetes and obesity (body mass index, ≥30 kg/m2), and higher severity of disease defined by a visual scoring system used in the 2004 study above, plus C-reactive protein and erythema measurements. Patients were included and randomized if they were improving on flucloxacillin IV and were afebrile and not bacteremic. Notable exclusion criteria were having a β-lactam allergy, a diabetic foot infection, receipt of prior antimicrobials, or other concurrent infections. Primary outcomes were similar between the 6-day and 12-day groups (50% vs 49%); however, investigators observed a higher 90-day relapse in the 6-day group than in the 12-day group (8 of 34 [24%] vs 2 of 35 [6%]). The study was interrupted early because of the inability to reach the target study sample size (n =158 per group, assuming an 85% cure rate); therefore noninferiority could not be ascertained as the study was underpowered. The authors concluded that hospitalized patients with severe cellu- litis may experience a higher-than-normal rate of recurrence, prompting the need for a longer treatment course.

Shorter courses of therapy of 5 to 6 days should be considered for patients without risk factors for complications, such as those with diabetes with vascular insufficiency, renal dysfunction, or sepsis or sepsis shock, or those who are immunocompromised. Treatment for cellulitis should primarily cover group A streptococci. Larger controlled, randomized trials are needed to optimize the duration of therapy for severe cellulitis or patients with complicating risk factors.

Rania El-Lababidi, PharmD, is senior manager of pharmacy education and training at Cleveland Clinic Abu Dhabi in the United Arab Emirates.

Julie Harting, PharmD, is an associate professor at Sullivan University College of Pharmacy and Health Sciences in Louisville, Kentucky.

REFERENCES

1. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-52. doi:10.1093/cid/ciu444
2. Khachatryan A, Patel D, Stephens J, Johnson K, Patel A, Talan D. Skin and skin structure infections (SSSIs) in the emergency department (ED): who gets admitted? Society for Academic Medicine. Accessed September 12, 2021. http://content.stockpr.com/duratatherapeutics/db/ Publications/2774/file/5-6e_SAEM_Poster.pdf
3. Christensen KLY, Holman RC, Steiner CA, Sejvar JJ, Stoll BJ, Schonberger LB. Infectious disease hospitalizations in the United States. Clin Infect Dis. 2009;49(7):1025-1035. doi:10.1086/605562
4. Moran GJ, Krishnadasan A, Gorwitz RJ, et al; EMERGEncy ID Net Study Group. Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med. 2006;355(7):666-674. doi:10.1056/NEJMoa055356
5. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med. 2004;164(15):1669-1774. doi:10.1001/archinte.164.15.1669
6. Joseph WS, Culshaw D, Anuskiewicz S, De Anda C, Prokocimer P. Tedizolid and linezolid for treatment of acute bacterial skin and skin structure infections of the lower extremity versus non-lower-extremity infections: pooled analysis of two phase 3 trials. J Am Podiatr Med Assoc. 2017;107(4):264-271. doi:10.7547/15-218
7. Moran GJ, Fang E, Coey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14(8);696-705. doi:10.1016/S1473-3099(14)70737-6
8. Spellberg B, Rice LB. Duration of antibiotic therapy: shorter is better. Ann Intern Med. 2019;171(3):210-211. doi:10.7326/M19-1509
9. Lee RA, Centor RM, Humphrey LL, et al. Appropriate use of short-course antibiotics in common infections: best practice advice from the American College of Physicians. Ann Intern Med. 2021;174(6):822-827. doi:10.7326/M20-7355
10. Cellulitis and erysipelas: antimicrobial prescribing. National Institute for Health and Care Excellence. September 27, 2019. Accessed September 12, 2021. https://www.nice.org.uk/guidance/ ng141/resources/cellulitis-and-erysipelas-antimicrobial-prescribing-pdf-66141774778309
11. Cranendonk DR, Opmeer BC, van Agtmael MA, et al. Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial. Clin Microbiol Infect. 2020;26(5):606-612. doi:10.1016/j.cmi.2019.09.019

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