Research Article: Wound healing: Natural history and risk factors for delay in Australian patients treated with antibiotics for Mycobacterium ulcerans disease

Date Published: March 19, 2018

Publisher: Public Library of Science

Author(s): Daniel P. O’Brien, N. Deborah Friedman, Anthony McDonald, Peter Callan, Andrew Hughes, Aaron Walton, Eugene Athan, Gerd Pluschke.

Abstract: BackgroundHealing times following treatment with antibiotics, and factors that influence healing, have not been reported in Australian patients with Mycobacterium ulcerans.Methodology/Principal findingsHealing times were determined for all M. ulcerans cases treated by a single physician with antibiotics at Barwon Health, Victoria, from 1/1/13-31/12/16. Lesions were categorised by induration size: category A ≤ 400mm2, Category B 401-1600mm2 and Category C ≥1601mm2. A logistic regression analysis was performed to determine risk factors for prolonged wound healing (>150 days from antibiotic commencement).163 patients were included; 92 (56.4%) were male and median age was 58 years (IQR 39–73 years). Baseline lesion size [available in 145 (89.0%) patients] was categorised as A in 46 (31.7%), B in 67 (46.2%) and C in 32 (22.1%) patients. Fifty (30.7%) patients had surgery. In those treated with antibiotics alone, 83.0% experienced a reduction in induration size after 2 weeks, then 70.9% experienced an increase in induration size from the lowest point, and 71.7% experienced an increase in ulceration size. A linear relationship existed between the time induration resolved and wound healing began.Median time to heal was 91 days (IQR 70–148 days) for category A lesions; significantly shorter than for category B lesions (128 days, IQR 91–181 days, p = 0.05) and category C lesions (169 days, IQR 159–214 days, p<0.001). Fifty-seven (35.0%) patients experienced a paradoxical reaction. Of those treated with antibiotics alone, lesions experiencing a paradoxical reaction had longer healing times [median time to heal 177 days (IQR 154–224 days) compared to 107 days (IQR 79–153 days), p<0.001]. On multivariable logistic regression, lesion size at baseline (p<0.001) and paradoxical reactions (p<0.001) were independently associated with prolonged healing times.For category A and B lesions, healing time was significantly shorter with antibiotics plus excision and direct closure compared with antibiotics alone [Category A lesions median 55 days (IQR 21–63 days) compared with 91 days (IQR 70–148 days), p<0.001; Category B lesions median 74 days (IQR 21–121 days) compared to 128 days (IQR 97–181 days), p<0.001].ConclusionsIn Australian patients treated with antibiotics M. ulcerans lesions usually initially improve, then clinically deteriorate with increased induration and ulceration, before healing after the inflammation associated with lesions resolves. The time to complete healing of lesions is generally long, and is further prolonged in those with larger initial lesion size or who develop paradoxical reactions. For small lesions (<4cm2), excisional surgery may reduce healing times.

Partial Text: Mycobacterium ulcerans (M. ulcerans) causes necrotising lesions of skin, soft-tissue and occasionally bone that, if left untreated, usually progress and can lead to significant tissue loss, morbidity and long-term deformity.[1, 2] It has been demonstrated that antibiotics are highly effective at curing M. ulcerans lesions and preventing disease recurrence,[3–7] and oral antibiotics have reduced hospitalisations and the cost of treatment.[8] Despite antibiotics, healing times can be prolonged, lasting up to 12 months after completion of the recommended 8-week antibiotic regimen if skin defects are large.[6] Prolonged wound healing can lead to significant expense and inconvenience as a result of the need for regular dressings and medical reviews, can be disabling, and can lead to time off work or school resulting in both patient and healthcare provider dissatisfaction.

All M. ulcerans cases treated with antibiotics at Barwon Health, Victoria, from 1/1/13-31/12/16 by a single physician (DOB) were assessed for inclusion in the study. A M. ulcerans case was defined as the presence of a lesion clinically suggestive of M. ulcerans plus any of [1] a culture of M. ulcerans from the lesion, [2] a positive PCR from a swab or biopsy of the lesion, or [3] histopathology of an excised lesion showing a necrotic ulcer with the presence of acid-fast bacilli (AFB) consistent with acute M. ulcerans infection. The initial size of the lesion was determined by measuring with a ruler the diameter of induration of lesions in millimetres and calculating the surface area in millimetres squared. Lesions were catagorised by the size of induration as follows: category A ≤ 400mm2, Category B 401-1600mm2 and Category C ≥1601mm2. These categories were chosen to allow specific study of small lesions (<2cm diameter and 2–4 cm diameter), common in the Australian context, which would not have been possible using World Health Organization categories. Lesion type and WHO category was assigned according to published definitions.[10] We have described the natural history of M. ulcerans lesions following treatment with antibiotics in Australian patients. We have shown that for the majority of lesions the following changes occur: in the first weeks of treatment a significant reduction occurs in the size of induration surrounding a lesion. Following this, the size of induration once again increases, and can often become larger than at the start. Additionally, despite ongoing antibiotic treatment, the size of the ulceration increases for most patients. Over time, the induration around the ulceration resolves and at that time, but usually not before, the wound begins to heal. Total healing time is long, with the majority of lesions taking more than 4 months to heal, and is longer in patients with larger lesions or in those who experience paradoxical reactions. Source: