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

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.

Mycobacterium ulcerans disease management in Australian patients: the re‐emergence of surgery as an important treatment modality

“…The aims of surgical treatment in our experience include: (i) to improve the rate of wound healing. This is achieved by removing necrotic tissue and the mycolactone toxin which inhibit healing, or by the use of reconstructive surgery to cover large wounds, (ii) to allow a reduction in the duration of the antibiotic treatment by reducing the burden of organisms, (iii) to prevent deformity or scarring from lesions with significant skin and soft‐tissue necrosis, (iv) to remove dead tissue and organisms to prevent or treat paradoxical immune reactions that impair wound healing, and (v) to sterilize lesions when antibiotics are not used for selected small lesions (Table ).…”

“…An 8‐week course of combination rifampicin‐based antimicrobial therapy is now the recommended treatment, and curative outcomes are excellent . In selected cases, surgery can be combined with a shortened duration of antibiotic treatment without compromising outcomes, presumably through the reduction of M. ulcerans organism burden …”

“…Overall, 22% of patients suffer an antibiotic‐associated complication severe enough to warrant cessation of that antibiotic; this figure increasing to 39% in those 65 and older . Secondly, wound healing times with antibiotic treatment alone are long, with a median time to heal of 4.5 months from the start of antibiotic treatment . This is further prolonged in larger wounds (more than 4 cm in diameter), with some wounds taking longer than 12 months to heal .…”

“…Secondly, wound healing times with antibiotic treatment alone are long, with a median time to heal of 4.5 months from the start of antibiotic treatment . This is further prolonged in larger wounds (more than 4 cm in diameter), with some wounds taking longer than 12 months to heal . Long healing times result in significant inconvenience and the cost of prolonged wound dressings and medical care.…”

“…This leads to a paradoxical worsening of the clinical appearance of lesions on treatment, after an initial improvement, and if severe can result in significant additional tissue loss, often requiring further surgery . Additionally, paradoxical reactions delay wound healing by an average 1–2 months, depending on the size of the lesion . Fourthly, there are a number of patients who cannot take antibiotics due to previous drug allergy or drug–drug interactions and a proportion who do not wish to take them at all.…”