Prophylactic Antibiotics for Recurrent Cellulitis

I meant to write about HTLV-1 tropical spastic paraparesis, however halfway through reading the papers I realized I bit more than I could chew. This is likely due to the fact I am awful with neurology (despite being a neuro major in college) and my lack of familiarity with tropical medicine. Needless to say, that post will take a while so I figured I would appease the people who stumble upon this blog with a simple topic.

Cellulitis is something that is reasonably simple and most people are familiar with. When looking at lower extremity cellulitis, these tend to be unilateral and most likely due to group A streptococcus. In short, you can do either a first gen cephalosporin such as cefazolin or cephalexin and elevate the leg and most of the time, you’ll be ok. The issue comes with recurrent cellulitis, which not surprisingly is a quite common occurrence. One review (1) noted that roughly 22-49% of patients who report an episode of cellulitis have a prior episode, with recurrences occurring anywhere from 14% at one year and 45% at 3 years from the initial episode. Recurrence also has an impact on subsequent hospitalizations. A retrospective review of nearly 500,000 cases of cellulitis reported a 30-day all cause readmission rate of approximately 9.8% (2), with the rate being higher in females and those aged >65yo. The causes of readmission included cellulitis (obviously), but also heart diseases and other types of bacterial infections:

I will not delve into details with regards to the risk factors for cellulitis, but I think it is reasonable to get a gist as we go forward. A retrospective study (3) evaluated 313 patients of which 126 had recurrent erysipelas (not quite cellulitis, but there is significant overlap). Patients with recurrent cellulitis were more likely to have T2DM, obesity, tonsillectomy, and history of malignancy:

Moreover, local risk factors such as peripheral vascular diseaes, prior ulcer, history of lymphedema, fungal infections, and prior orthopedic surgical intervention were more common in the recurrent group:

Another retrospective cohort from the Mayo Clinic (4) use multivariate model and bootstrapping resampling to generate a score-based predictive model for recurrent cellulitis. History of cancer, tibial location of the initial episode of cellulitis and ispilateral dermatitis were associated with increased risk of recurrence:

At one point a piece, a score 1 increased the risk of recurrence by 4.5% by 3 months and up to 12.4% by one year:

Early studies in the 90s explored the possibility of prophylactic antibiotics for recurrent cellulitis. In one retrospective cohort of 40 patients (5) who have had 2 prior episodes of erysipelas found that PO penicillin (and erythromycin if penicillin allergic) reduced the incidene of recurrence, but this result was not statistically significant. Another study of 36 patients used erythromycin for 18 months and found that none of the antibiotic group had recurrence compared to 8 in the no antibiotic group (6). A small double-blind, placebo controlled trial compared clindamycin with placebo in patients with more that 3 Staph aureus abscesses in the previous 6 months (7). 26 patients were randomized, and found that a higher proportion of patients in the clindamycin group who completed the trial at 3 months had lower recurrences compared to the placebo group:

The above studies seem to suggest that antibiotics may be beneficial, but these are small and for the most part, not randomized. The most robust data comes in from the PATCH (Adams) I and II studies. The PATCH II (8) study was a double-blind, randonmized controlled trial evaluating 6 months of PO Penicillin V with placebo (250mg twice per day) in patients who had completed therapy for cellulitis. Patients randomized in a 1:1 fashion with primary end point being time to next episode of cellulitis. 123 patients were randomized (much smaller than their calculated 400), of which around 80% having recurrent episode at enrollement. There was a non-statistical significant reduction in recurrence with PO penicillin (HR 0.53, 95% CI 0.26-1.07), which was similar after adustment for stratification factors (HR 0.51, 95% CI 0.25-1.05). The results seem to hold up during the follow up phase (beyond the 6 months of prophylaxis):

The similarly designed PATCH I study (9) evaluated 12 months of penicillin with follow up of 3 years being evaluated. 274 patients were randomized, with 22% of patients in the PCN group having recurrence during the prophylaxis phase compared to 37% in the placebo group, corresponding to a 45% reduction in recurrence during the phrophylaxis phase (HR 0.55, 95% CI 0.35 to 0.86):

As you can see above, the protective effects seem to go away once prophylaxis is removed at year 3:

Multivariate analysis performed during the prophylactic phase found that BMI >33, >3 episodes of cellulitis, and presence of edema were associated with prophylaxis failure:

Notably, these trials excluded those who had leg ulceration, surgery, or prior penetrating trauma due to the high likelihood of staph being the etiology. As such, this may not apply to the entire internal medicine population, but one study suggests there is a possiblity this could be a cost-saving measure (10), however this was not statistical significant. A single-center, retrospective cohort of patients with >2 occurrences of erysipelas found that 1.2 million units of penicillin IM every 3 weeks resulted in an incidence of 8 per 100 patient years during the prophylaxis period compared to 28 per 100 person years during the follow up period (11). This resulted in an IR of 0.20 (95% CI 0.05-0.34), however I would think the use of a pill would be better than intramuscular injection, though perphaps adherence could be better with IM shots if the infrastructure was in place. 

A meta-analysis of 5 studies (most of which are included above, 12) found that prophylactic antibiotics were overal benefitcial for the recurrence of cellulits (RR 0.46, 95% CI 0.26-0.79), though this was not seen in those who had more than 2 prior episodes of cellulitis (RR 0.35, 95% CI 0.12-1.02):

Notably, while most of the studies in the meta-analysis used penicillin, the authors also found benefit with erythromycin.

I think there is some utility of prophylactic antibiotics in recurrent cellulitis, though the utility in purulent cellulitis is something that remains to be explored. Further, those with significant risk factors such as prior surgical intervention, significant obesity, and >3 prior episodes may not benefit much and it begs the question if the possible adverse events would preculde the use of penicillin in this population. I would be interested to see if something like cephalexin could be used, or if an alternative for staph could be found. 

References:

1. Raff AB, Kroshinsky D. Cellulitis: A Review. JAMA. 2016 Jul 19;316(3):325-37. doi: 10.1001/jama.2016.8825. PMID: 27434444.
2. Fisher JM, Feng JY, Tan SY, Mostaghimi A. Analysis of Readmissions Following Hospitalization for Cellulitis in the United States. JAMA Dermatol. 2019 Jun 1;155(6):720-723. doi: 10.1001/jamadermatol.2018.4650. PMID: 30810708; PMCID: PMC6563554.
3. Brishkoska-Boshkovski V, Kondova-Topuzovska I, Damevska K, Petrov A. Comorbidities as Risk Factors for Acute and Recurrent Erysipelas. Open Access Maced J Med Sci. 2019 Mar 15;7(6):937-942. doi: 10.3889/oamjms.2019.214. PMID: 30976336; PMCID: PMC6454161.
4. McNamara DR, Tleyjeh IM, Berbari EF, Lahr BD, Martinez J, Mirzoyev SA, Baddour LM. A predictive model of recurrent lower extremity cellulitis in a population-based cohort. Arch Intern Med. 2007 Apr 9;167(7):709-15. doi: 10.1001/archinte.167.7.709. PMID: 17420430.
5. Sjöblom AC, Eriksson B, Jorup-Rönström C, Karkkonen K, Lindqvist M. Antibiotic prophylaxis in recurrent erysipelas. Infection. 1993 Nov-Dec;21(6):390-3. doi: 10.1007/BF01728920. PMID: 8132369.
6. Kremer M, Zuckerman R, Avraham Z, Raz R. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J Infect. 1991 Jan;22(1):37-40. doi: 10.1016/0163-4453(91)90898-3. PMID: 2002231.
7. Klempner MS, Styrt B. Prevention of recurrent staphylococcal skin infections with low-dose oral clindamycin therapy. JAMA. 1988 Nov 11;260(18):2682-5. PMID: 3184334.
8. UK Dermatology Clinical Trials Network’s PATCH Trial Team, Thomas K, Crook A, Foster K, Mason J, Chalmers J, Bourke J, Ferguson A, Level N, Nunn A, Williams H. Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg: results of the UK Dermatology Clinical Trials Network’s PATCH II trial. Br J Dermatol. 2012 Jan;166(1):169-78. doi: 10.1111/j.1365-2133.2011.10586.x. Epub 2011 Dec 6. PMID: 21910701; PMCID: PMC3494300.
9. Durand M, Wistaff R, Lelorier J. Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013 Aug 29;369(9):880. doi: 10.1056/NEJMc1307321. PMID: 23984745.
10. Mason JM, Thomas KS, Crook AM, Foster KA, Chalmers JR, Nunn AJ, Williams HC. Prophylactic antibiotics to prevent cellulitis of the leg: economic analysis of the PATCH I & II trials. PLoS One. 2014 Feb 14;9(2):e82694. doi: 10.1371/journal.pone.0082694. PMID: 24551029; PMCID: PMC3925077.
11. Rob F, Hercogová J. Benzathine penicillin G once-every-3-week prophylaxis for recurrent erysipelas a retrospective study of 132 patients. J Dermatolog Treat. 2018 Feb;29(1):39-43. doi: 10.1080/09546634.2017.1329507. Epub 2017 May 30. PMID: 28489486.
12. Oh CC, Ko HC, Lee HY, Safdar N, Maki DG, Chlebicki MP. Antibiotic prophylaxis for preventing recurrent cellulitis: a systematic review and meta-analysis. J Infect. 2014 Jul;69(1):26-34. doi: 10.1016/j.jinf.2014.02.011. Epub 2014 Feb 24. PMID: 24576824.