The Use of Hyaluronidase in Aesthetic Practice: A Comparative Study of Practitioner Usage in Elective and Emergency Situations.

BACKGROUND: Hyaluronic acids (HAs) continue to be the fillers of choice worldwide and their popularity is growing. Adverse events (AEs) are able to be resolved through the use of hyaluronidase (HYAL). However, routine HYAL use has been at issue due to perceived safety issues. OBJECTIVES: There are currently no guidelines on the use of HYAL in aesthetic practice, leading to variability in storage, preparation, skin testing, and beliefs concerning AEs. This manuscript interrogated the use of this agent in daily practice. METHODS: A 39-question survey concerning HYAL practice was completed by 264 healthcare practitioners: 244 from interrogated databases and 20 from the consensus panel. Answers from those in the database were compared to those of the consensus panel. RESULTS: Compared to the database group, the consensus group was more confident in the preparation of HYAL, kept reconstituted HYAL for longer, and was less likely to skin test for HYAL sensitivity and more likely to treat with HYAL in an emergency, even in those with a wasp or bee sting anaphylactic history. Ninety-two percent of all respondents had never observed an acute reaction to HYAL. Just over 1% of respondents had ever observed anaphylaxis. Five percent of practitioners reported longer-term adverse effects, including 3 respondents who reported loss of deep tissues. Consent before injecting HA for the possible requirement of HYAL was always obtained by 74% of practitioners. CONCLUSIONS: Hyaluronidase would appear to be an essential agent for anyone injecting hyaluronic acid filler. However, there is an absence of evidence-based recommendations with respect to the concentration, dosing, and treatment intervals of HYAL, and these should ideally be available.

Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections.

BACKGROUND: The pathogenesis of delayed-onset tissue nodules (DTNs) due to hyaluronic acid (HA) injections is uncertain. OBJECTIVES: To formulate a rational theory for DTN development and their avoidance and treatment. METHODS: A multidisciplinary and multicountry DTN consensus panel was established, with 20 questions posed and consensus sought. Consensus was set at 75% agreement. RESULTS: Consensus was reached in 16 of 20 questions regarding the pathogenesis of DTNs, forming the basis for a classification and treatment guide. CONCLUSIONS: The group believes that filler, pathogens, and inflammation are all involved in DTNs and that DTNs most likely are infection initiated with a variable immune response. Injected filler may incorporate surface bacteria, either a commensal or a true pathogen, if the skin barrier is altered. The initially high molecular weight HA filler is degraded to low molecular weight HA (LMWHA) at the edge of the filler. Commensals positioned within the filler bolus may be well tolerated until the filler is degraded and the commensal becomes visible to the immune system. LMWHA is particularly inflammatory in the presence of any local bacteria. Commensals may still be tolerated unless the immune system is generally heightened by viremia or vaccination. Systemic pathogenic bacteremia may also interact with the filler peripheral LMWHA, activating Toll-like receptors that induce DTN formation. Given this scenario, attention to practitioner and patient hygiene and early systemic infection treatment deserve attention. Classification and treatment systems were devised by considering each of the 3 factors-filler, inflammation, and infection-separately.

Inverted-V Deformity: An Anatomic Study.

BACKGROUND: The inverted-V deformity is an unwanted aesthetic consequence of dorsal hump resection. Despite their attachment to the nasal bones, the upper lateral cartilages (ULCs) can separate from the nasal bones, creating a step-off after cartilaginous dorsal hump removal. OBJECTIVES: The mechanism of how the ULCs can separate from the nasal bones despite their attachment was studied to improve understanding of the inverted-V complication and its prevention. METHODS: A dorsal hump resection (bony and cartilaginous) was performed on 12 fresh cadavers to observe the effect on the ULCs. As a secondary study, the effect of different preventative maneuvers was investigated. RESULTS: Cartilaginous dorsal resection destroys the spreader mechanism of the T-frame and impacts the stabilization of the ULCs, resulting in them becoming free-floating. This causes them to migrate in a posterior, medial, and cranial direction relative to the nasal bones. The dynamic attachment of the ULCs to the nasal bones is key in this mechanism and allows actual separation of the ULCs from the nasal bones to result in the inverted-V deformity. Caudal traction to the ULCs re-tensions these attachments, pulling the ULCs against the nasal bones again. CONCLUSIONS: This anatomic dissection study has established that the connection between the nasal dorsum and ULCs is not a static fusion but is dynamic. This attachment can be used in primary rhinoplasty to prevent inverted-V deformity by applying caudal traction to the ULCs when reconstructing the dorsum which will tension the ULCs toward the nasal bones.

Movement of the Syringe During Filler Aspiration: An Ultrasound Study.

BACKGROUND: Aspiration prior to hyaluronic acid filler injection is often taught as a safety maneuver to minimize the risk of intravascular injection; however, the validity of this technique in aesthetic practice is being increasingly challenged. One key assumption underpinning the validity of the aspiration test is that the needle tip does not move during the aspiration and subsequent injection of filler. OBJECTIVES: The aim of this study was to visualize and measure needle tip movement in real time during aspiration and injection of filler. Secondary objectives were to assess the impact of injector experience and double-handed versus single-handed aspiration technique in maintaining stability of the syringe. METHODS: Under real-time ultrasound visualization, 3 injectors with different levels of experience injected hyaluronic acid filler into pork belly tissue utilizing both double-handed and single-handed aspiration techniques. Needle tip movements were recorded and measured by means of ultrasound and video. RESULTS: The aspiration maneuver is in all cases associated with retrograde movement of the needle tip, ranging from 1.1 to 5.3 mm (mean, 2.9 mm), whereas injection leads to anterograde movement ranging from 0.6 to 4.1 mm (mean, 1.9 mm). Double-handed aspiration is associated with less needle tip movement than single-handed aspiration (P = 0.037). Greater experience is also associated less movement of the needle tip (P < 0.0001). CONCLUSIONS: In all cases, the aspiration and injecting maneuver is associated with micromovements of the needle tip, of a magnitude consistently significant relative to the typical size of facial vessels. Although needle tip movement is only a single factor limiting the usefulness of the aspiration test, the results of this study suggest that it is not advisable to rely only on aspiration as a method to prevent intravascular injection.

Aspiration Before Tissue Filler-An Exercise in Futility and Unsafe Practice.

BACKGROUND: Aesthetic physicians rely on certain anecdotal beliefs regarding the safe practice of filler injections. These include a presumed safety advantage of bolus injection after a negative aspiration. OBJECTIVES: The authors sought to review and summarize the published literature on inadvertent intravascular injection of hyaluronic acid and to investigate whether the technique of aspiration confers any safety to the practitioner and the patient. METHODS: Pertinent literature was analyzed and the current understanding of the safety of negative and positive aspiration outlined. RESULTS: The available studies demonstrate that aspiration cannot be relied on and should not be employed as a safety measure. It is safer to adopt injection techniques that avoid injecting an intravascular volume with embolic potential than utilize an unreliable test to permit a risky injection. CONCLUSIONS: To prevent intravascular injection, understanding "injection anatomy" and injection plane and techniques such as slow, low-pressure injection are important safety measures. Assurance of safety when delivering a bolus after negative aspiration does not appear to be borne out by the available literature. If there is any doubt about the sensitivity or reliability of a negative aspiration, there is no role for its utilization. Achieving a positive aspiration would just defer the risk to the next injection location where a negative aspiration would then be relied on.

Re Facial aesthetic injections in clinical practice: Pretreatment and post-treatment consensus recommendations to minimise adverse outcome Region-specific changes in line with the Covid-19 pandemic.

Despite the recent publication in March 2020 of guidelines for facial injectable treatments, the speed of the COVID-19 pandemic and its safety implications necessitate changes to these guidelines The authors described what would constitute safest practice in the provision of facial injectable treatments and summarised these in table form. Adherence to a high standard of asepsis and infectious disease precautions remain a key patient safety requirement when performing facial aesthetic injections. A revision and update of these guideline summary tables follows. Changes made should enhance both patient and staff safety regarding COVID-19/SARS-CoV-2, a highly infective respiratory pathogen transmitted by respiratory droplets, respiratory/mucosal secretions and contaminated fomites. Some of the additions are COVID-19 specific and are likely to evolve and change, particularly should serological tests determining acquired immunity become available. Other additions represent further tightening of our infection control precautions.

Facial aesthetic injections in clinical practice: Pretreatment and posttreatment consensus recommendations to minimise adverse outcomes.

Facial aesthetic treatment with injectable neuromodulators and hyaluronic acid fillers is well established, with favourable safety profiles and consistent outcomes. As with any medical treatment, adverse events and complications may occur. Adverse events associated with these products are typically transient and mild to moderate in severity. Serious adverse events, such as infection and intravascular occlusion, are rare. Proper patient selection, consent and counselling, preparation and impeccable injection technique are important risk reduction strategies. Both clinicians and patients must be alert to the signs and symptoms of complications so that appropriate treatment can be started promptly. In this article, the authors review the current literature and provide their consensus recommendations for minimising adverse outcomes when treating patients with botulinum toxin or hyaluronic acid fillers.

Paediatric Buruli ulcer in Australia.

AIM: This study describes an Australian cohort of paediatric Buruli ulcer (BU) patients and compares them with adult BU patients. METHODS: Analysis of a prospective cohort of all BU cases managed at Barwon Health, Victoria, from 1 January 1998 to 31 May 2018 was performed. Children were defined as ≤15 years of age. RESULTS: A total of 565 patients were included: 52 (9.2%) children, 289 (51.2%) adults aged 16-64 years and 224 (39.6%) adults aged ≥65 years. Among children, half were female and the median age was 8.0 years (interquartile range 4.8-12.3 years). Six (11.5%) cases were diagnosed from 2001 to 2006, 14 (26.9%) from 2007 to 2012 and 32 (61.5%) from 2013 to 2018. Compared to adults, children had a significantly higher proportion of non-ulcerative lesions (32.7%, P < 0.001) and a higher proportion of severe lesions (26.9%, P < 0.01). The median duration of symptoms prior to diagnosis was shorter for children compared with adults aged 16-64 years (42 vs. 56 days, P = 0.04). Children were significantly less likely to experience antibiotic complications (6.1%) compared with adults (20.6%, P < 0.001), but had a significantly higher rate of paradoxical reactions (38.8%) compared with adults aged 16-64 (19.2%) (P < 0.001). Paradoxical reactions in children occurred significantly earlier than in adults (median 17 vs. 56 days, P < 0.01). Cure rates were similarly high for children compared to adults treated with antibiotics alone or with antibiotics and surgery. CONCLUSIONS: Paediatric BU cases in Australia are increasing and represent an important but stable proportion of Australian BU cohorts. Compared with adults, there are significant differences in clinical presentation and treatment outcomes.

A Consensus on Minimizing the Risk of Hyaluronic Acid Embolic Visual Loss and Suggestions for Immediate Bedside Management.

BACKGROUND: Hyaluronic acid fillers have a satisfactory safety profile. However, adverse reactions do occur, and rarely intravascular injection may lead to blindness. Currently there is no internationally recognized consensus on the prevention or management of blindness from hyaluronic acid filler. OBJECTIVES: The authors sought to give guidance on how to minimize the risk and optimize the management of this rare but catastrophic adverse reaction. METHODS: A multinational group of experts in cosmetic injectables from multiple disciplines convened to review current best practice and develop updated consensus recommendations for prevention and bedside intervention if visual loss occurs after cosmetic injection of hyaluronic acid filler. RESULTS: The consensus group provided specific recommendations focusing on the consenting process, prevention, and early management of visual impairment related to intravascular hyaluronic acid filler injection. CONCLUSIONS: Although visual loss due to filler injections is rare, it is important that both patient and physician be aware of this risk. In this paper the authors describe methods and techniques available to reduce the risk and also document suggested initial management should a clinician find themselves in this situation.

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

With the demonstration of the effectiveness of antibiotic treatment, the management of Mycobacterium ulcerans disease has changed from a predominantly surgically to a predominantly medically treated disease. However, research among Australian patients has revealed that antibiotic treatment alone is associated with prolonged wound healing times, high rates of treatment toxicity, and the potential for significant tissue destruction associated with severe paradoxical reactions. We present the current state of M. ulcerans management in Barwon Health, Australia, where a close working relationship exists between the Plastic Surgical and Infectious Diseases units. Here treatment has evolved based on nearly 20 years of experience gained from managing more around 600 patients from a M. ulcerans epidemic on the nearby Bellarine and Mornington Peninsulas. In our experience, surgery has re-emerged to play an important role in the treatment of M. ulcerans in improving the rate of wound healing, minimizing antibiotic associated toxicity and preventing further tissue loss associated with severe paradoxical reactions. For selected small lesions surgery without antibiotics may also be an effective treatment option, however aggressive surgical resection of lesions with wide margins through uninvolved tissue should no longer be performed. Furthermore, extensive excisional surgery that will require the use of split skin grafts and vascularized tissue flaps to repair skin defects should be avoided if possible.

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

BACKGROUND: Healing times following treatment with antibiotics, and factors that influence healing, have not been reported in Australian patients with Mycobacterium ulcerans. METHODOLOGY/PRINCIPAL FINDINGS: Healing 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]. CONCLUSIONS: In 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.

The Role of Bacterial Biofilm in Adverse Soft-Tissue Filler Reactions: A Combined Laboratory and Clinical Study.

BACKGROUND: The development of chronic nodules and granulomatous inflammation after filler injections has been attributed to bacterial biofilm infection. The authors aimed to investigate the relationship between filler and bacterial biofilm using a combined in vitro and in vivo study. METHODS: In vitro assays to investigate the ability of filler materials to support the growth of Staphylococcus epidermidis biofilm and the effect of multiple needle passes through a biofilm-contaminated surface were designed. Analysis of clinical biopsy specimens from patients presenting with chronic granulomas following filler administration using a number of laboratory tests for biofilm was performed. RESULTS: All fillers (i.e., hyaluronic acid, polyacrylamide gel, and poly-L-lactic acid) supported the growth of S. epidermidis biofilm in vitro. Multiple needle passes through a biofilm-contaminated surface resulted in significantly increased contamination of filler material by a factor of 10,000 (p < 0.001). Six clinical samples from five patients all demonstrated bacterial biofilm. The mean number of bacteria was found to be 2.2 × 10 bacteria/mg tissue (range, 5.6 × 10 to 3.7 × 10 bacteria/mg tissue). Microbiome analysis detected a predominance of Pseudomonas, Staphylococcus, and Propionibacterium as present in these samples. CONCLUSIONS: Filler material can support the growth of bacterial biofilm in vitro. Multiple needle passes can significantly increase the risk of filler contamination. Biofilm appears to be associated with high numbers in clinical samples of patients presenting with chronic granulomatous inflammation. Strategies to reduce the risk of bacterial contamination need to be further studied and translated into clinical practice. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Experience and Management of Intravascular Injection with Facial Fillers: Results of a Multinational Survey of Experienced Injectors.

BACKGROUND: Intravascular injection leading to skin necrosis or blindness is the most serious complication of facial injection with fillers. It may be underreported and the outcome of cases are unclear. Early recognitions of the symptoms and signs may facilitate prompt treatment if it does occur avoiding the potential sequelae of intravascular injection. OBJECTIVES: To determine the frequency of intravascular injection among experienced injectors, the outcomes of these intravascular events, and the management strategies. METHODS: An internet-based survey was sent to 127 injectors worldwide who act as trainers for dermal fillers globally. RESULTS: Of the 52 respondents from 16 countries, 71 % had ≥11 years of injection experience, and 62 % reported one or more intravascular injections. The most frequent initial signs were minor livedo (63 % of cases), pallor (41 %), and symptoms of pain (37 %). Mildness/absence of pain was a feature of 47 % of events. Hyaluronidase (5 to >500 U) was used immediately on diagnosis to treat 86 % of cases. The most commonly affected areas were the nasolabial fold and nose (39 % each). Of all the cases, only 7 % suffered moderate scarring requiring surface treatments. Uneventful healing was the usual outcome, with 86 % being resolved within 14 days. CONCLUSION: Intravascular injection with fillers can occur even at the hands of experienced injectors. It may not be always associated with immediate pain or other classical symptoms and signs. Prompt effective management leads to favorable outcomes, and will prevent catastrophic consequences such as skin necrosis. Intravascular injection leading to blindness may not be salvageable and needs further study. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Mycobacterium ulcerans in the Elderly: More Severe Disease and Suboptimal Outcomes.

BACKGROUND: The clinical presentation of M. ulcerans disease and the safety and effectiveness of treatment may differ in elderly compared with younger populations related to relative immune defficiencies, co-morbidities and drug interactions. However, elderly populations with M. ulcerans disease have not been comprehensively studied. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective analysis was performed on an observational cohort of all confirmed M. ulcerans cases managed at Barwon Health from 1/1/1998-31/12/2014. The cohort included 327 patients; 131(40.0%) ≥65 years and 196(60.0%) <65 years of age. Patients ≥65 years had a shorter median duration of symptoms prior to diagnosis (p<0.01), a higher proportion with diabetes (p<0.001) and immune suppression (p<0.001), and were more likely to have lesions that were multiple (OR 4.67, 95% CI 1.78-12.31, p<0.001) and WHO category 3 (OR 4.59, 95% CI 1.98-10.59, p<0.001). Antibiotic complications occurred in 69(24.3%) treatment episodes at an increased incidence in those aged ≥65 years (OR 5.29, 95% CI 2.81-9.98, p<0.001). There were 4(1.2%) deaths, with significantly more in the age-group ≥65 years (4 compared with 0 deaths, p = 0.01). The overall treatment success rate was 92.2%. For the age-group ≥65 years there was a reduced rate of treatment success overall (OR 0.34, 95% CI 0.14-0.80, p = <0.01) and when surgery was used alone (OR 0.21, 95% CI 0.06-0.76, p<0.01). Patients ≥65 years were more likely to have a paradoxical reaction (OR 2.06, 95% CI 1.17-3.62, p = 0.01). CONCLUSIONS/SIGNIFICANCE: Elderly patients comprise a significant proportion of M. ulcerans disease patients in Australian populations and present with more severe and advanced disease forms. Currently recommended treatments are associated with increased toxicity and reduced effectiveness in elderly populations. Increased efforts are required to diagnose M. ulcerans earlier in elderly populations, and research is urgently required to develop more effective and less toxic treatments for this age-group.

Mycobacterium ulcerans treatment--can antibiotic duration be reduced in selected patients?

INTRODUCTION: Mycobacterium ulcerans (M. ulcerans) is a necrotizing skin infection endemic to the Bellarine Peninsula, Australia. Current treatment recommendations include 8 weeks of combination antibiotics, with adjuvant surgery if necessary. However, antibiotic toxicity often results in early treatment cessation and local experience suggests that shorter antibiotic courses may be effective with concurrent surgery. We report the outcomes of patients in the Barwon Health M. ulcerans cohort who received shorter courses of antibiotic therapy than 8 weeks. METHODOLOGY / PRINCIPAL FINDINGS: A retrospective analysis was performed of all M. ulcerans infections treated at Barwon Health from March 1, 1998 to July 31, 2013. Sixty-two patients, with a median age of 65 years, received < 56 days of antibiotics and 51 (82%) of these patients underwent concurrent surgical excision. Most received a two-drug regimen of rifampicin combined with either ciprofloxacin or clarithromycin for a median 29 days (IQR 21-41 days). Cessation rates were 55% for adverse events and 36% based on clinician decision. The overall success rate was 95% (98% with concurrent surgery; 82% with antibiotics alone) with a 50% success rate for those who received < 14 days of antibiotics increasing to 94% if they received 14-27 days and 100% for 28-55 days (p<0.01). A 100% success rate was seen for concurrent surgery and 14-27 days of antibiotics versus 67% for concurrent surgery and < 14 days of antibiotics (p = 0.12). No previously identified risk factors for treatment failure with surgery alone were associated with reduced treatment success rates with < 56 days of antibiotics. CONCLUSION: In selected patients, antibiotic treatment durations for M. ulcerans shorter than the current WHO recommended 8 weeks duration may be associated with successful outcomes.

Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update.

• Guidelines reflecting contemporary clinical practice in the management of Buruli ulcer (Mycobacterium ulcerans infection) in Australia were published in 2007. • Management has continued to evolve, as new evidence has become available from randomised trials, case series and increasing clinical experience with oral antibiotic therapy. • Therefore, guidelines on the diagnosis, treatment and prevention of Buruli ulcer in Australia have been updated. They include guidance on the new role of antibiotics as first-line therapy; the shortened duration of antibiotic treatment and the use of all-oral antibiotic regimens; the continued importance, timing and role of surgery; the recognition and management of paradoxical reactions during antibiotic treatment; and updates on the prevention of disease.

Clinical features and risk factors of oedematous Mycobacterium ulcerans lesions in an Australian population: beware cellulitis in an endemic area.

INTRODUCTION: Oedematous lesions are a less common but more severe form of Mycobacterium ulcerans disease. Misdiagnosis as bacterial cellulitis can lead to delays in treatment. We report the first comprehensive descriptions of the clinical features and risk factors of patients with oedematous disease from the Bellarine Peninsula of south-eastern Victoria, Australia. METHODS: Data on all confirmed Mycobacterium ulcerans cases managed at Barwon Health, Victoria, were collected from 1/1/1998-31/12/2012. A multivariate logistic regression model was used to assess associations with oedematous forms of Mycobacterium ulcerans disease. RESULTS: Seventeen of 238 (7%) patients had oedematous Mycobacterium ulcerans lesions. Their median age was 70 years (IQR 17-82 years) and 71% were male. Twenty-one percent of lesions were WHO category one, 35% category two and 41% category three. 16 (94%) patients were initially diagnosed with cellulitis and received a median 14 days (IQR 9-17 days) of antibiotics and 65% required hospitalization prior to Mycobacterium ulcerans diagnosis. Fever was present in 50% and pain in 87% of patients. The WCC, neutrophil count and CRP were elevated in 54%, 62% and 75% of cases respectively. The median duration of antibiotic treatment was 84 days (IQR 67-96) and 94% of cases required surgical intervention. On multivariable analysis, there was an increased likelihood of a lesion being oedematous if on the hand (OR 85.62, 95% CI 13.69-535.70; P<0.001), elbow (OR 7.83, 95% CI 1.39-43.96; p<0.001) or ankle (OR 7.92, 95% CI 1.28-49.16; p<0.001), or if the patient had diabetes mellitus (OR 9.42, 95% CI 1.62-54.74; p = 0.02). CONCLUSIONS: In an Australian population, oedematous Mycobacterium ulcerans lesions present with similar symptoms, signs and investigation results to, and are commonly mistakenly diagnosed for, bacterial limb cellulitis. There is an increased likelihood of oedematous lesions affecting the hand, elbow or ankle, and in patients with diabetes.

Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections.

BACKGROUND: Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population. METHODS: Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions. RESULTS: Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions. CONCLUSIONS: Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.