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    Recurrent cellulitis treatment can be complex

    A Cochrane Database literature review finds strong evidence for the effectiveness of antibiotics as preventative treatment for recurrent cellulitis of the lower limbs for patients under prophylactic treatment.

    But once antibiotic treatment is discontinued, the data seems to suggest that the preventive effects of antibiotics wears off, wrote researchers who were led by Adam Dalal, M.D., of Rabin Medical Center in Israel.

    The study applies to patients who have had at least two episodes of leg cellulitis within three years. This analysis did not include studies of other interventions such as lymphoedema reduction methods or skin care.

    "Recurrent cellulitis is a common problem causing severe pain, and inconvenience related to the need for hospitalization," says co-author Mical Paul, M.D., director, Infectious Diseases, Rambam Healthcare Campus in Israel. Up to 50% of patients with cellulitis experience repeated episodes, she said. Yet to date, no clear guidelines spell out effective prophylactic treatments.


    Investigators searched six medical databases, five trial-registry databases and two sets of dermatology conference proceedings up to June 2016. They also checked reference lists of included studies for further references to relevant randomized controlled trials. The study's primary outcome was recurrence of cellulitis when on prophylactic treatment and after treatment. While erysipelas affects the upper skin layers and cellulitis affects deeper layers, the difficulty of telling them apart clinically led investigators to consider both entities for the purposes of their review.

    Out of 5,995 records, only six trials with a total of 573 participants (average age: 50-70 years; 373 female) met investigators' inclusion criteria. Combining results of 5 trials that used antibiotics, Dalal et al. found moderate-certainty evidence that, compared with no treatment or placebo, antibiotic treatment in general, and penicillin in particular, is probably safe and effective prophylactic treatment.

    Four studies evaluated penicillin, and one evaluated erythromycin. Meta-analysis revealed that versus placebo or no treatment, taking antibiotics following one or two episodes of cellulitis decreased patients' risk of any future episode by 69% and the overall number of recurrences by 56%. Three studies including 437 participants showed that patients receiving antibiotic prophylaxis experienced half the rate of recurrent cellulitis as the control group (P = 0.002); one study showed that antibiotic prophylaxis lengthened the interval between episodes by 3 months.2 However, investigators note that when prophylaxis stopped, its protective effects disappeared (low-certainty evidence).

    "The total evidence to date shows that taking a simple antibiotic (penicillin) regularly will prevent recurrent cellulitis quite efficiently, while the antibiotic is taken. Fortunately, the common bacteria that cause skin infections — Streptococcus group A (Streptococcus pyogenes) — have not changed and remain susceptible to penicillin. Thus, the evidence from all studies remains relevant.

    "The paucity of data available for such an important clinical question was surprising. Two important recent clinical studies, PATCH I and II, contributed most of the data," Dr. Paul said.

    These trials used low-dose oral penicillin, gathering nearly 400 patients with leg cellulitis into carefully designed and scrupulously analyzed RCTs, Dalal et al. say. But overall, they write, "We noted a clinically important heterogeneity in the type of antibiotic, dosage and route of administration." Additional included studies explored higher oral penicillin doses (2-4 g daily) or penicillin injections, but the studies' size and less stringent designs limited the utility of their results. In a separate review of 42 cellulitis RCTs, authors led by Emma Smith, Ph.D., of Nottingham Trent University, found that only 28 stated their primary outcome; clinical responses to treatment were characterized in 25 different ways.

    Strengths of Dalal et al.'s review include the fact that the vast majority of patients included were diagnosed by either dermatologists or infectious disease specialists; the PATCH studies used "consistent and rigorous criteria to diagnose cellulitis, enabling extrapolation of data to the general population affected," namely, Western populations over age 50 who are overweight and suffer local predisposing conditions such as leg edema or fungal foot infections.

    But with only two rigorously designed research clinical trials, "The quality of the evidence was graded as moderate to low, mainly due to the imprecision of the overall results deriving from the small number of patients evaluated overall."

    Regarding secondary outcomes, meta-analysis of three studies showed no difference in the number of hospitalizations between patients on antibiotic prophylaxis and those who were not (P = 0.47, low-certainty evidence). Existing data did not allow investigators to explore the impact of antibiotic prophylaxis on length of hospital stay. Nor was there sufficient information to examine the impact of antibiotic prophylaxis after a single episode of leg cellulitis. In three studies, patients had had two previous cellulitis episodes, versus four episodes in one study and one episode in another.

    The characteristics of participants in the included studies, along with the magnitude of the preventive effect, favor antibiotic prophylaxis in people with at least two past episodes of lower-limb cellulitis within a timeframe of up to three years, the authors conclude.

    "The paucity of evidence leaves many open questions. The most important probably is, ‘When should antibiotic prophylaxis be started? Immediately after the first episode? After two or more episodes? And, does that apply to all people with cellulitis or only for those with risk factors such as leg edema?" Dr. Paul said.

    Additional unanswered questions include what antibiotics physicians should use, how they should be administered and for how long, she said.

    Ultimately, says Dr. Paul, the review exemplifies how little evidence exists for very important healthcare questions when the answers do not involve new drugs or devices. In such instances, "There is very little incentive and support for researchers to study these topics."



    Adam Dalal, Marina Eskin-Schwartz, Daniel Mimouni, et al. "Interventions for the prevention of recurrent erysipelas and cellulitis," Cochrane Database of Systemic Reviews. June 20, 2017. DOI: 10.1002/14651858.CD009758.pub2


    John Jesitus
    John Jesitus is a medical writer based in Westminster, CO.


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