Skin and soft tissue infections caused by nontuberculous mycobacteria.

REVIEW URRENT C OPINION

Skin and soft tissue infections caused by nontuberculous mycobacteria Bridget L. Atkins a and Thomas Gottlieb b

Purpose of review Skin and soft tissues infections (SSTIs) caused by nontuberculous mycobacteria (NTM) are underrecognized and difficult to treat. Controversies exist for optimal medical management and the role of surgery. Defining the epidemiology in the environment, in animals and in healthcare aids disease prevention. This review focuses on recent advances in epidemiology, risk factors, diagnostics and therapy. Recent findings The increasing consumer appetite for cosmetic and body-modifying procedures (e.g. tattooing, mesotherapy, liposuction) has been associated with rises in sporadic cases and outbreaks of NTM SSTIs. In mainstream healthcare, recent epidemiological studies have helped to quantify the increased risk of NTM infection related to anti-tumour necrosis factor-a monoclonal antibody therapy. Cervicofacial lymphadenitis in children poses management dilemmas, but recent studies and resultant algorithms have simplified decision-making. Molecular studies have led to a better understanding of the epidemiology, therapy and course of Mycobacterium ulcerans infection (Buruli ulcer) that remains prevalent in many areas including sub-Saharan Africa and southeastern Australia. Apart from molecular methods, the widespread adoption of matrix-assisted laser desorption ionization-time of flight mass spectrometry by routine laboratories has potential to simplify and expedite the laboratory identification of NTMs. Summary An improved understanding of the epidemiology of NTM SSTIs indicates a need to apply effective infection control and ensure regulation of cosmetic and related procedures associated with nonsterile fluids. Broader access to newer diagnostic methods will continue to improve recognition of NTM disease. Along with a paucity of therapeutic agents, there is need for more reliable methods to assess susceptibility and selection of effective combination therapy. Keywords Buruli ulcer, fish tank granuloma, lymphadenitis, mycobacteria, nontuberculous

INTRODUCTION Nontuberculous mycobacteria (NTM) are a diverse group of environmental organisms. Recent genetic tools have facilitated taxonomy such that there are now 150 species, 25 of which have been named in the past 5 years [1 ]. They are traditionally divided into rapidly growing mycobacteria (RGM) or slowly growing mycobacteria (SGM). Cutaneous infections occur in immunosuppressed patients, after traumatic injury, and (partly due to resistance to disinfectants) after cosmetic or surgical procedures. Lesions may take weeks to months to evolve and result in rashes, papules, nodules or abscesses. SGM are more likely to involve multiple body sites than RGM infections [2 ]. The incidence of cutaneous NTM infections has increased over the past two decades [2 ]. See Table 1 for some of the medically important NTM. &&

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NTM skin and soft tissue infections are frequently underdiagnosed. This can be due to failure to do relevant cultures, hence good communication between the clinician and microbiology is essential [3 ]. As almost all NTM are ubiquitous in the environment, isolation from skin and wound specimens should always be taken in clinical context and in conjunction with histopathology results. NTM &

a Oxford University Hospitals NHS Trust, Headley Way, Oxford, OX3 9DU, UK and bDepartment of Microbiology and Infectious Diseases, Concord Hospital, Hospital Road, Concord, 2139 NSW, Australia

Correspondence to Dr Bridget L. Atkins, Department of Microbiology and Infectious Diseases, Level 6, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK. Tel: +44 1865 221226; e-mail: Bridget.Atkins @ouh.nhs.uk Curr Opin Infect Dis 2014, 27:137–145 DOI:10.1097/QCO.0000000000000041

0951-7375 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-infectiousdiseases.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Skin and soft tissue infections

KEY POINTS The increasing range and availability of bodymodifying procedures, has led to a rise in reports of cases and outbreaks of localized NTM infections. Regulation outside the hospital setting should cover the safe and and appropriate preparation and use of sterile and nonsterile fluids in such procedures. Advances in immunosuppressive agents used in SOTs and in inflammatory conditions have created new risks for NTM infections. Molecular studies are increasing the understanding of epidemiology of NTM infections, and in the routine laboratory MALDI-TOF is likely to revolutionalize the rapid identification of NTMs. In cervicofacial lymphadenitis, algorithms have a greater emphasis on complete surgical resection when disease is not too advanced. In M. marinum and M. ulcerans disease, antimicrobials are the mainstay of treatment, with surgery in M. ulcerans now reserved for removing large necrotic areas, to cover large skin defects and to correct deformities. Some of the recent advances in understanding of M. ulcerans disease (diagnostics, treatment and paradoxical reactions) may serve as a paradigm for the future management of other mycobacterial infections.

commonly associated with SSTIs include the Mycobacterium fortuitum group, M. chelonae, M. abscessus (including M. massiliense), M. haemophilum, M. ulcerans (Buruli ulcer), and M. marinum (fish-tank or swimming-pool granuloma) [4 ]. M. avium is the most frequent cause of childhood lymphadenitis but some cases are due to M. haemophilum or other species [5–7]. In contrast to data from cystic fibrosis (CF) patients, evidence of person-to-person transmissibility is lacking for SSTIs [8]. &&

RISK FACTORS FOR NONTUBERCULOUS MYCOBACTERIA SKIN AND SOFT TISSUES INFECTIONS A number of risk factors are associated with NTM infections.

Nonsurgical cosmetic and body-modification procedures In the past 3 years, outbreaks of NTM SSTIs related to tattoos have been reported [9 ,10 ,11,12 ,13–15]. A majority are due to M. chelonae, although M. abscessus and other species have also been reported [10 ]. Most cases were associated with premixed black or grey ink. In the United States, contamination of nationally distributed ink products during the manufacturing process has been demonstrated [9 ,11]. Dilution of black ink locally with tap water has also &&

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Table 1. More common nontuberculous mycobacteria causing skin and soft tissue infections in humans Mycobacterium

Common presentations

Rapid growers M. fortuitum group

Postsurgical infections, infections after cosmetic procedures, pedicure (folliculitis), implant surgery

M. abscessus group (includes M. abscessus, M. massiliense and M. bolletii)

Postsurgical infections, implant surgery, cosmetic and related procedures (e.g. liposuction, tattooing, acupuncture, mesotherapy), spa cleaning

M. chelonae

Localized lesions as per M. abscessus

Other

Cosmetic procedures, surgical procedures

Infection in organ transplantation M. mageritense M. wolinskyi M. mucogenicum Slow growers M. marinum

Localized nodules (fish tank granuloma), nodular lymphadenitis, tenosynovitis

M. avium complex

Cervicofacial lymphadenitis in children

(M. avium, M. intracellulare)

Skin lesions uncommon. Disseminated infections in HIVþ patients

M. haemophilum

Cervicofacial lymphadenitis in children

M. ulcerans

Localized and extensively destructive, necrotizing ulcers in immunocompetent hosts. (Buruli ulcer). More common in children in Africa

Skin and subcutaneous infections in SOT recipients and HIVþ patients

SOT, solid organ transplant.

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Infections caused by nontuberculous mycobacteria Atkins and Gottlieb

been implicated [11]. Patients present with localized rashes, papules, nodules or large abscesses. Infections remain localized to the tattoo area and dissemination has not been reported [10 ]. A range of antimicrobials has been used (see therapy section below) for limited infection, often oral therapy with clarithromycin alone or in combination with tetracycline or a fluoroquinolone [10 ]. Cases can be self-limiting despite no treatment [10 ]. A range of ‘high street’ cosmetic dermal procedures and spa-related treatments have been associated with NTM SSTIs. Table 2 summarizes selected case reports published since 2011 [16–25]. &

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Surgical procedures NTM infections also occur following cosmetic and implant surgery. Two major outbreaks of NTM infection following liposuction have been previously described involving 34 and 20 patients with M. chelonae and M. abscessus, respectively [26,27]. One occurred in medical tourists operated on in the Dominican Republic in 2003/2004. In this current review period only one more case has been reported, but it highlighted a lack of adequate infection control processes and procedures at an independent medical centre in the United States [28]. Twelve cases of RGM (M. fortuitum and

Table 2. Selected reports of cosmetic/spa-associated nontuberculous mycobacteria skin and soft tissues infections since 2011 Procedure

Organism

Presentation

Reference

Notes

Dermal piercing

M. fortuitum

Erythema and oedema

Patel et al. [16]

Treatment with clarithromycin and ciprofloxacin with full resolution

Dermal filler (3 cases)

M. chelonae

Rodriguez et al. [17]

Identical (by PFGE) isolate from clinic tap water

Filler injections and laser lipolysis

M. wolinskyi

Yoo et al. [18]

Treatment with incision and drainage, clarithromycin, doxycycline and ciprofloxacin for 5 months with minor dermatological sequelae

Fractionated CO2 laser resurfacing (2 cases)

M. abscessus

Culton et al. [19]

This treatment used for wrinkles, acne scars and photodamage damage

Wongkitisophon et al. [20]

Complete resolution on ciprofloxacin, doxycycline and clarithromycin for 6 months

Ebama et al. [21]

Case 1: good response to oral treatment for 8 months

Swelling, local pain and erythema

Multiple erythematous papules and pustules

M. chelonae

Painful pustules

Mesotherapy (injection into subcutaneous fat)

M. abscessus

Tender erythematous nodules

Filler injections (2 cases attending the same spa

M. marinum

Swelling and erythema Swelling and deep ulceration

Body polishers working in a hot spa (7 cases)

M. massiliense

Pedicure

Case 2: severe tissue destruction likely requiring facial reconstruction Nakanaga et al. [22]

Identified by multigenotypic analysis

M. bolletii/M. massiliense

Red nodules and papules on hands and forearms Furunculosis

Wertman et al. [23]

Identified by sequencing of 166S rRNA and hsp64 genes. Responded to different combinations of clarithromycin, doxycycline, azithromycin and moxifloaxcin

Pedicure (40 suspected or confirmed cases over 4 years)

M. chelonae/abscessus

Furunculosis

Stout et al. [24]

A range of NTMs also cultured from footbaths but no association between species distribution in the environment and implication of the salon in human infection

Acupuncture

M. fortuitum

Cellulitis and abscess

Guevara-Patin õ et al. [25]

Doxycycline and ciprofloxacin for 6 months. Recovered but left with scars

NTM, nontuberculous mycobacteria; PFGE, pulsed field gel electrophoresis.



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M. chelonae) infections were reported in one series following breast augmentation surgery [29], and a presumptive case (based on PCR but not isolated) was reported after a nasal silicone implant [30]. NTM wound infections following mesh hernia repair have been reported sporadically [31,32]. A large (>1000 suspected cases, 197 confirmed microbiologically) outbreak of M. massiliense infection related to video-assisted surgery occurred in Brazil over a 12-month period in 2006/2007. Strains were found to be tolerant to 2% glutaraldehyde [33].

Immunosuppression The understanding of NTM infections in solid organ transplant (SOT) recipients is poor as it comes from case reports and small case series. Infection occurs as a result of impairment of cell-mediated responses. With the exception of respiratory infections in lung transplantation, the most common presentations in SOTs are cutaneous lesions of the extremities, tenosynovitis and arthritis. More than half have disseminated involvement of noncontiguous areas [34 ]. Therapy is complicated by the interaction of antimicrobials with antirejection drugs. It is estimated that the rate of NTM infection is around 0.16–0.38% in renal transplant recipients, with lower rates in liver transplants and higher rates in heart and lung transplants [35 ]. M. fortuitum, M. abscessus and M. chelonae are the most frequently isolated species in SOTs [34 ]. Two recent reviews highlight epidemiological, clinical, diagnostic and therapeutic issues, with one calling for a national registry of NTM cases in SOT to allow a better understanding of epidemiology and risk factors for infection [34 ,35 ]. By contrast with SOTs, RGM skin infection is uncommon in cancer patients, in whom lung involvement and bacteraemia from a central venous catheter (CVC) site were more common presentations [36,37 ]. In these series, the most common species causing bacteraemia from a skin CVC site were M. mucogenicum and M. fortuitum. Other immunosuppressive agents also predispose to NTM infections. These include the antitumour necrosis factor (TNF)-alpha drugs. TNF-a is a proinflammatory cytokine. Monoclonal antibodies to TNF-a were developed in the 1990s and have revolutionalized the management of inflammatory conditions such as Crohn’s disease, psoriasis and rheumatoid arthritis (RA). Agents include adalimumab, etanercept, certolizumab, golimumab and infliximab. Winthrop et al. [38 ] searched pharmacy records in their centre in California and identified 8418 patients who received anti-TNF-a agents from 2000 to 2008. Sixty percent had RA. Eighteen of these patients developed infections with NTM &

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and 16 with Mycobacterium tuberculosis (MTB). Of these, four in each group had extra-pulmonary disease. These rates were 74 and 49 per 100 000 person years for NTM and MTB, respectively. They calculated comparative rates for the different agents. Infliximab had the highest odds ratio for NTM infections although there may be confounding factors. Among anti-TNF-a users, compared with uninfected individuals, NTM case patients were older and more likely have RA. Background rates in anti-TNF-a unexposed RA cases were five-fold lower and in the general population 10-fold lower. NTM cases were also most likely to be white and female, which may reflect the population with RA. MTB cases were more likely to have diabetes or chronic renal disease. The median onset time between anti-TNF start and diagnosis was 1027 days (range 77–2832 days). NTM infections do occur when anti-TNF-a drugs are used for other conditions such as Crohn’s disease; however, the increased risk is less clear [39]. A recent meta-analysis of 22 RCTs (anti-TNF-a vs. placebo) in inflammatory bowel disease showed the risk of opportunistic infections to increase from 0.3% (in 2919 patients on placebo) to 0.9% (in 4135 patients on active treatment) [40]. There were eight cases of MTB in the actively treated group; however, no cases of NTM infection were reported. There may be geographical and other factors that lead to variation in the rates of NTM infections rather than the underlying disease. Therefore, caution should be exercised in extrapolating quoted rates to other populations. Mendelian susceptibility to mycobacterial disease (MSMD) is an active topic in the field of primary immunodeficiency [41]. This is a single gene disorder with a defect in the type 1 cytokine response leading to infections with Mycobacterium or Salmonella spp. Advances have been made in identifying 10 genes that can cause MSMD when mutations occur. Current treatments include recombinant interferon-g and hematologic stem cell transplantation.

RECENT ADVANCES IN DIAGNOSTICS OF NONTUBERCULOUS MYCOBACTERIA SKIN AND SOFT TISSUES INFECTIONS The identification of mycobacteria in the laboratory has traditionally been based on growth rate, pigmentation and biochemical tests. These techniques are laborious and slow, and interpretation may be subjective. The earliest established molecular techniques included DNA probes specifically for M. tuberculosis complex, M. avium complex (MAC), M. kansasii and M. gordonae. More recently, sequence analysis of 16S rRNA, rpoB and hsp65 have been used for taxonomic studies. PCR restriction enzyme Volume 27 Number 2 April 2014



analysis or DNA gene sequencing are currently the preferred tests [42 ]. The molecular methods require expertise and reference laboratories. Recent tools such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF), DNA chip technology and Beacon probes (combined PCR probes) have shown comparable results for RGM [4 ]. MALDI-TOF has become widely adopted for bacterial identification. The turnaround time is less than 2 h. Following initial capital outlay, it is an inexpensive method that can be incorporated into the laboratory workflow for rapid and accurate identification of most strains of mycobacteria [43]. Recently, 93.8% of 178 mycobacteria were correctly identified to species level and 98.3% to genus using the manufacturer’s (Bruker) cut off [44 ]. Reducing the cut-off from 2.0 to 1.9 allowed identification to species level in 97.2% of isolates. Some clinically important closely related species such as M. abscessus subsp. abscessus and M. abscessus subsp. bolletti (formerly M. massiliense and M. bolletii) may not be easily differentiated using MALDI-TOF [42 ]. Kothavade et al. [4 ] propose an algorithm for direct identification of NTM from dermatological samples using MALDI-TOF and culture in conjunction. &&

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ANTIMICROBIAL SUSCEPTIBILITY TESTING AND THERAPY (FOR MANAGEMENT OF LYMPHADENITIS, M. MARINUM AND M. ULCERANS SEE BELOW) The American Thoracic Society and the Infectious Diseases Society of America have produced joint guidelines on the management of NTM infections [45]. More recently (2011), the Clinical and Laboratory Standards Institute has defined criteria for antimicrobial susceptibility testing of NTM with recommendations for the test method and recommended breakpoints for antimicrobials used in treatment [46]. A recent review by Brown-Elliott et al. [47 ] explores methodology and interpretation in detail and van Ingen et al. [48 ] similarly explore mechanisms of resistance as well as susceptibility testing options. The optimal therapy is not satisfactorily defined because treatment is dependent on species identification, and treatment regimens differ between RGMs and SGMs, and within slow growers (e.g. MAC vs. M. kansasii) and rapid growers (e.g. M. abscessus vs. M. fortuitum) [48 ]. Moreover, intraspecies variation in susceptibility testing is a common finding; and anatomical site of infection, extent of superficial spread and host factors influence management. Molecular studies have further

delineated the heterogeneity within species such as M. kansasii and M. abscessus that may contribute to differential outcomes. Readers are referred to more in-depth reviews [1 ,45]. Most reports and guidelines (American Thoracic Association/Infectious Diseases Society of America) focus primarily on lung infection [45]. For RGMs and when other NTMs are susceptible, clarithromycin is considered the oral agent of choice, preferably in combination with another agent to which the organism is susceptible, particularly so in the immunocompromised patient. However, antagonism between macrolides (clarithromycin and azithromycin) and the fluoroquinolones has been demonstrated in vitro and in vivo, e.g. in M. abscessus [49]. Although M. chelonae is often the most inherently resistant species, M. abscessus is increasingly recognized as a problematic species because of increased potential for acquired resistance [50 ]. For example, induction of the erm gene may need to be considered during macrolide therapy [51]. In contrast, M. fortuitum infections are susceptible to a greater variety of agents, including fluoroquinolones [1 ]. Similarly, there is greater breadth of choice for M. haemophilum infection [1 ]. Tigecycline, an intravenous agent, provides an added therapeutic option for difficult cases, providing potential synergy with clarithromycin, but experience is limited to in-vitro studies and case reports [52,53]. Management of NTM infection with multiple lesions or dissemination following cosmetic procedures can be problematic even in the immunocompetent host. At least six months of treatment is recommended [45]. However, cutaneous abscesses can persist during therapy and relapses are not uncommon despite prolonged combination therapy [53]. These may be culture negative and may in fact reflect a paradoxical response [54]. Spontaneous resolution with conservative therapy is also reported [10 ,54]. Surgery has a role but needs to be individualized. &&

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CERVICOFACIAL LYMPHADENITIS Cervicofacial lymphadenitis in young children has a wide differential diagnosis but includes mycobacterial infection. In developed countries, cervical lymphadenitis due to MTB has declined whereas that due to NTM has become more common. It is thought that infection is acquired through the oral route and may be related to tooth eruption [55]. There is no evidence of immunodeficiency in these children although a recent study suggested a weak association with a certain genotype [56]. There has been controversy about how radical any surgery should be; however, current opinion favours



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excision surgery when possible. In a randomized trial, 50 children were randomized to surgical excision or surgical curettage. Surgical excision led to more rapid resolution but four patients in this group had transient weakness of the mandibular branch of the facial nerve [57 ]. A retrospective study suggests that children not treated with primary complete excision were more likely to require further surgery later and another showed a higher chance of developing a postoperative fistula when incision and drainage was performed rather than excision [7,5]. When lymphadenitis is in an advanced stage, surgery becomes technically very difficult. Lindeboom [6] showed that in advanced disease (without surgery), the median time to resolution in a group of 25 children randomized to receive clarithromycin and rifabutin was 36 weeks, compared with 40 weeks for 25 children randomized to a ‘wait and see’ approach (no antibiotics). There were significant adverse effects in those that received antibiotics, including extrinsic tooth discolouration (64%) and gastrointestinal symptoms. Recently, algorithms for management have been produced in Germany [58] and in Spain [59]. Penn et al. [60] haved proposed a clinical staging system (I–IV) that could facilitate management decisions. &

(29 out of 30 isolates). Those that were cured had received antibiotics for longer and 10 out of the 18 cured cases had surgical debridement. Failure on doxycycline associated with in-vitro resistance has also been reported by Parrish et al. [63]. However, reporting bias may lead to failures in therapy being over reported.

MYCOBACTERIUM ULCERANS INFECTION (BURULI ULCER) M. ulcerans infection is, in some countries, the second most frequent mycobacterial disease in humans after MTB. Cases have been reported from at least 32 different countries in Africa, Australia, Southeast Asia, China, Central and South America and the West Pacific [64]. Lesions can lead to scarring, contractual deformities and amputation. In Africa most cases occur in children, and deformity leads to a significant impact on communities [64,65 ]. M. ulcerans occurs in areas associated with rivers, swamps and wetlands. It has been found in soil, water, plant biofilm, vegetation and other environmental samples [66]. Using molecular studies, M. ulcerans has been found in frogs in Ghana and in skin lesions from koalas, possums, cats, dogs, horses and alpacas in Australia [66,67 ,68–72]. The exact mode of transmission is unclear but there may be a role for zoonotic vectors such as aquatic insects, mosquitoes or other biting arthropods [64]. Comparative genomic analysis shows that M. ulcerans and all other mycolactone producing mycobacteria (MLMs) represent a single clone originally derived from M. marinum [73 ]. MLMs have acquired a plasmid but lost at least 185 genes in the process. There appear to be at least three lineages of which one is responsible for M. ulcerans disease in Africa and Australia, suggesting relatively recent transfer between these continents [73 ]. In Australia, VNTR typing can demonstrate nucleotide polymorphisms that differentiate M. ulcerans in temperate Victoria and tropical Queensland [74]. A recent questionnaire-based study of patients following a single visit to an endemic focus in Victoria, Australia has clarified the incubation period of M. ulcerans. This showed a mean incubation period of 135 days (Inter-quartile range: 109–160), corresponding to 4.5 months. The range was 32–264 days [75 ]. Diagnosis is usually made by PCR and/or culture of a lesion swab, fine needle aspirate or biopsy sample [76,77 ]. In 180 cases in southeastern Australia, 99% of lesion swabs and 95% of M. ulcerans lesion biopsies were PCR positive whereas only 19 and 47%, respectively were culture positive [77 ]. &&

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MYCOBACTERIUM MARINUM INFECTION (FISH TANK OR SWIMMING-POOL GRANULOMA) M. marinum occurs in fish, amphibians and occasionally in exposed humans. Human infections are generally cutaneous, although can become deeper in some cases resulting in tenosynovitis, arthritis and osteomyelitis. Typing of 89 M. marinum isolates from humans and fish using mycobacterial interspersed repetitive units-variable number of tandem repeats (typing) (MIRU-VNTR) typing showed that the strains are genetically structured according to the host derivation [61 ]. As expected, there was greater diversity in fish isolates, as fish are the natural host and humans only accidental hosts. A limited number of genotypes appear to infect humans, suggesting that only some strains have zoonotic potential. Antimicrobial susceptibility testing has not been recommended as M. marinum is usually susceptible to antimicrobials used for treatment, including rifampicin, ethambutol, doxycycline–minocycline, co-trimoxazole and clarithromycin [47 ]. Testing is however recommended for those that fail to respond to treatment after several months and with positive cultures. Wu et al. [62] describe eight failures in 27 patients with M. marinum infection, including a high rate of doxycycline resistance &

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The recommended treatment for M. ulcerans has moved towards a greater focus on using antimicrobials in primary therapy than was previously recognized. An eight-week course of oral rifampicin and intramuscular streptomycin has been shown to be effective and is recommended by the WHO [78,79]. A randomized trial in two centres in Ghana suggested that the number of injections could be reduced by using 4 weeks of streptomycin and rifampicin followed by 4 weeks of oral rifampicin and clarithromycin [80]. More recent evidence suggests that oral antibiotic treatment courses are effective when used in conjunction with surgical excision [81,82 ]. Oral fluoroquinolones appear to be as effective as oral clarithromycin (both in combination with rifampicin), with 100% cure in either study group (55 patients with rifampicin and ciprofloxacin and 21 patients with rifampicin and clarithromycin). All patients in the study required some degree of surgical excision [82 ]. If surgery alone is used, the relapse rate is high (around 30%) and more likely if the excision is incomplete or if the patient is immunocompromised [83 ]. It is known that antimicrobial use in mycobacterial infections such as tuberculosis or M. ulcerans may be followed by transient clinical deterioration (paradoxical response). Recognition of this is important as it avoids unnecessary surgery and/or changes in antimicrobial treatment. Nienhuis et al. [84] respectively assessed the size of 134 Buruli ulcer lesions and found the peak paradoxical response to occur at week 8 after commencing antimicrobials. Reactions occurred in 83% of nonulcerated lesions. Nine cases developed new lesions during or after treatment. All lesions subsequently healed. The southeastern Australian group describe a paradoxical reaction rate of 21% of 156 cases (42 episodes in 32 patients) [85 ]. Ten episodes occurred after treatment was completed. All episodes were culture negative for M. ulcerans. The same group describe the successful use of steroids in five patients with severe paradoxical reactions [86]. &&

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CONCLUSION Advances in molecular methods have resulted in a better understanding of NTM epidemiology and taxonomy. The increasing availability of MALDITOF will lead to improved speed and access to routine laboratory identification. Lifestyle and cosmetic surgery choices and new immunosuppressive agents and patient groups have provided expanded niches for NTM infections. Further research should be focused on improving susceptibility testing and validating single and combination drug therapeutic options in correlation with defined clinical outcomes.

Acknowledgements None. Conflicts of interest T.G. has been on advisory boards for Pfizer and AstraZeneca. He has received lecture sponsorship from MSD and Biomerieux. B.L.A. has no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Esteban J, Garcıá-Pedrazuela M, Munõz-Egea MC, Alcaide F. Current treatment of nontuberculous mycobacteriosis: an update. Expert Opin Pharmacother 2012; 13:967–986. This literature review, in conjunction with expert opinion, gives an overview of the current understanding and research on pathogenicity, susceptibility testing and treatment for individual NTM species. 2. Wentworth AB, Drage LA, Wengenack NL, et al. Increased incidence of & cutaneous nontuberculous mycobacterial infection to 2009: a populationbased study. Mayo Clin Proc 2013; 88:38–45. This study describes 40 case of NTM infection over 30 years in Minnesota. It describes risk factors and a three-fold rise in incidence over time, with the majority being RGMs in the last decade. 3. van Ingen J. Diagnosis of nontuberculous mycobacterial infections. Semin & Respir Crit Care Med 2013; 34:103–109. This review focuses on the presentation and diagnosis of NTM infection according to clinical syndrome. It includes sections on pulmonary and extra-pulmonary/ disseminated disease. 4. Kothavade RJ, Dhurat RS, Mishra SN, Kothavade UR. Clinical and laboratory && aspects of the diagnosis and management of cutaneous and subcutaneous infections caused by rapidly growing mycobacteria. Eur J Clin Microbiol Infect Dis 2013; 32:161–188. This detailed review covers many aspects of cutaneous RGM infections, including epidemiology, risk factors, therapeutic outcome tables, practices leading to RGM infections (e.g. in water supplies to hospital buildings, contaminated solutions, use of unapproved medications) and diagnostic issues. 5. Iversen RH, Illum P. Cervicofacial nontuberculous mycobacterial lymphadenitis in children. Dan Med J 2012; 59:A4349. 6. Lindeboom JA. Conservative wait-and-see therapy versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis 2011; 52:180–184. 7. Scott CA, Atkinson SH, Sodha A, et al. Management of lymphadenitis due to nontuberculous mycobacterial infection in children. Pediatr Surg Int 2012; 28:461–466. 8. Bryant JM, Grogono DM, Greaves D, et al. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet 2013; 381:1551–1560. 9. Centers for Disease Control and Prevention (CDC). Tattoo-associated non&& tuberculous mycobacterial skin infections: multiple states, 2011–2012. MMWR Morb Mortal Wkly Rep 2012; 61:653–656. This investigation of 22 cases of tattoo-associated NTM SSTIs in four states across the United States found contamination of multiple brands of ink before use, and involved multiple species of mycobacteria (e.g. chelonae, fortuitum and abscessus). They concluded that contamination could have occurred at various points in the ink-production process prior to distribution. It gives recommendations to ink manufacturers and artists that include the use of sterile ink products and sterile water with appropriate hygiene practices. 10. Conaglen PD, Laurenson IF, Sergeant A, et al. Systematic review of tattoo& associated skin infection with rapidly growing mycobacteria and public health investigation of a cluster in Scotland. Euro Surveill 2013; 18:20553. This report of a cluster of NTM infections following tattoos showed that M. chelonae grew from an unopened inkbottle. The authors include a systemic review of all reported cases in the literature and demonstrate a significant rise in reports in the past 3 years. The commonest association is with the contamination of black ink or dilution of ink with tap water. 11. Goldman J, Caron F, de Quatrebarbes J, et al. Infections from tattooing. Outbreak of Mycobacterium chelonae in France. BMJ 2010; 341:c5483. 12. Kennedy BS, Bedard B, Younge M, et al. Outbreak of Mycobacterium chelonae & infection associated with tattoo ink. N Engl J Med 2012; 367:1020–1024. This investigation of an outbreak of tattoo-associated skin lesions demonstrated that 11 M. chelonae clinical isolates were indistinguishable on pulsed field gel electrophoresis typing and the same as an isolate in unopened ink, confirming contamination during manufacture. &&



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Skin and soft tissue infections 13. Falsey RR, Kinzer MH, Hurst S, et al. Cutaneous inoculation of nontuberculous mycobacteria during professional tattooing: a case series and epidemiologic study. Clin Infect Dis 2013; 57:e143–e147. 14. Drage LA, Ecker PM, Orenstein R, et al. An outbreak of Mycobacterium chelonae infections in tattoos. J Am Acad Dermatol 2010; 62:501. 15. Sergeant A, Conaglen P, Laurenson IF, et al. Mycobacterium chelonae infection: a complication of tattooing. Clin Exp Dermatol 2013; 38:140. 16. Patel T, Scroggins-Markle L, Kelly B. A dermal piercing complicated by Mycobacterium fortuitum. Case Rep Dermatol Med 2013; 2013:49829. 17. Rodriguez JM, Xie YL, Winthrop KL, et al. Mycobacterium chelonae facial infections following injection of dermal filler. Aesthet Surg J 2013; 33:265–269. 18. Yoo SJ, Lee KH, Heo ST. Facial skin and soft tissue infection caused by Mycobacterium wolinskyi associated with cosmetic procedures. BMC Infect Dis 2013; 13:479. 19. Culton DA, Lachiewicz AM, Miller BA, et al. Nontuberculous mycobacterial infection after fractionated CO laser resurfacing. Emerg Infect Dis 2013; 19:365–370. 20. Wongkitisophon P, Rattanakaemakorn P, Tanrattanakorn S, et al. Cutaneous Mycobacterium abscessus associated with mesotherapy injection. Case Rep Dermatol 2011; 3:37–41. 21. Ebama NH, Turuvury H, Mithaiwala DO, et al. Delayed diagnosis of Mycobacterium marinum infections associated with cosmetic injections. Infect Dis Clin Pract 2012; 20:414–415. 22. Nakanaga K, Hoshino Y, Era Y, et al. Multiple cases of cutaneous Mycobacterium massiliense infection in a ‘hot spa’ in Japan. J Clin Microbiol 2011; 49:613–617. 23. Wertman R, Miller M, Groben P, et al. Mycobacterium bolletii/Mycobacterium massiliense furunculosis associated with pedicure footbaths: a report of 3 cases. Arch Dermatol 2011; 147:454–458. 24. Stout JE, Gadkowski LB, Rath S, et al. Pedicure-associated rapidly growing mycobacterial infection: an endemic disease. Clin Infect Dis 2011; 53:787– 792. 25. Guevara-Patinõ A, Sandoval de Mora M, Farreras A, et al. Soft tissue infection due to Mycobacterium fortuitum following acupuncture: a case report and review of the literature. J Infect Dev Ctries 2010; 4:521–525. 26. Meyers H, Brown-Elliott BA, Moore D, et al. An outbreak of Mycobacterium chelonae infection following liposuction. Clin Infect Dis 2002; 34:1500– 1507. 27. Furuya EY, Paez A, Srinivasan A, et al. Outbreak of Mycobacterium abscessus wound infections among ‘lipotourists’ from the United States who underwent abdominoplasty in the Dominican Republic. Clin Infect Dis 2008; 46:1181– 1188. 28. Kim MJ, Mascola L. Mycobacterium chelonae wound infection after liposuction. Emerg Infect Dis 2010; 16:1173–1175. 29. Thomas M, D’Silva JA, Borole AJ, Chilgar RM. Periprosthetic atypical mycobacterial infection in breast implants: a new kid on the block! J Plast Reconstr Aesthet Surg 2013; 66:e16–e19. 30. Rhie JW, Yeon JJ, Kim SW. Nontuberculous mycobacterial infection related to nasal implant. J Craniofac Surg 2013; 24:1257–1259. 31. Hamilton N, Roadley G. Isolation of Mycobacterium thermoresistible from a mesh used in an incisional hernia repair. N Z Med J 2013; 126:81–84. 32. Coelho JC, Claus CM, Michelotto JC, et al. Complications of laparoscopic inguinal herniorrhaphy including one case of atypical mycobacterial infection. Surg Endosc 2010; 24:2708–2712. 33. Duarte RS, Lourenço MC, Fonseca Lde S, et al. Epidemic of postsurgical infections caused by Mycobacterium massiliense. J Clin Microbiol 2009; 47:2149–2155. 34. Piersimoni C. Nontuberculous mycobacteria infection in solid organ trans& plant recipients. Eur J Clin Microbiol Infect Dis 2012; 31:397–403. This mini-review highlights the epidemiology and presentation of NTM infections in the various forms of SOT. It emphasizes the need for early recognition and aggressive treatment with a combination of antimicrobials, surgical resection and reduction of immunosuppressive agents. 35. Keating MR, Daly JS, AST Infectious Diseases Community of Practice. && Nontuberculous mycobacterial infections in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4):77–82. This review covers many practical issues, such as the timing after infection after transplantation, clinical manifestations and interactions between antimicrobials and immunosuppressive agents. It also suggests a registry of NTM infections after SOT might facilitate further research. 36. Redelman-Sidi G, Sepkowitz KA. Rapidly growing mycobacteria infection in patients with cancer. Clin Infect Dis 2010; 51:422. 37. El Helou G, Hachem R, Viola GM, et al. Management of rapidly growing & mycobacterial bacteremia in cancer patients. Clin Infect Dis 2013; 56:843– 846. This study describes 116 cancer patients with RGM bacteraemia. Ninety-six percent had a central venous catheter and there was a lower relapse rate in those who had catheter removal. M. mucogenicum was the leading cause (39%) with M. fortuitum second (21%). 38. Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour && necrosis factor therapy in USA. Ann Rheum Dis 2013; 72:37–42. This group from a centre in California determined rates and risk factors for NTM and TB infection among 8418 anti-TNF alpha users. NTM cases were more likely to have RA and MTB cases more likely to have renal failure or diabetes.

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39. Kump PK, Ho¨genauer C, Wenzl HH, Petritsch W. A case of opportunistic skin infection with Mycobacterium marinum during adalimumab treatment in a patient with Crohn’s disease. J Crohns Colitis 2013; 7:e15–e18. 40. Ford AC, Peyrin-Biroulet L. Opportunistic infections with antitumor necrosis factor-a therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol 2013; 108:1268–1276. 41. Haverkamp MH, Lindeboom JA, de Visser AW, et al. Nontuberculous mycobacterial cervicofacial lymphadenitis in children from the multicenter, randomized, controlled trial in The Netherlands: relevance of polymorphisms in candidate host immunity genes. Int J Pediatr Otorhinolaryngol 2010; 74: 752–754. 42. Brown-Elliott BA, Wallace RJ Jr. Enhancement of conventional phenotypic && methods with molecular-based methods for the more definitive identification of nontuberculous mycobacteria. Clin Microbiol Newslett 2012; 34:109– 115. This detailed review of molecular techniques and MALDI-TOF for the identification of mycobacteria in the laboratory also states that basic phenotypic characteristics retain value particularly for species that cannot be distinguished by molecular techniques. 43. Saleeb PG, Drake SK, Murray PR, Zelazny AM. Identification of mycobacteria in solid-culture media by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol 2011; 49:1790– 1794. 44. Balada-Llasat JM, Kamboj K, Pancholi P. Identification of mycobacteria from & solid and liquid media by matrix-assisted laser desorption ionization-time of flight mass spectrometry in the clinical laboratory. J Clin Microbiol 2013; 51:2875–2879. This group demonstrates that MALDI-TOF can be used for rapid mycobacterial species identification to complex or group level. Organisms are inactivated by heat, ethanol and mechanical disruption in the mycobacterial laboratory making the process well tolerated in a routine laboratory. 45. Griffith DE, Aksamit T, Brown-Elliott BA, et al., ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367–416. 46. Woods GL, Brown-Elliott BA, Conville PS, et al. Susceptibility testing of mycobacteria, nocardia and other aerobic actinomycetes; approved standard. CLSI document M24-A2. Wayne, PA: Clinical and Laboratory Standards Institute; 2011. 47. Brown-Elliott BA, Nash KA, Wallace RJ Jr. Antimicrobial susceptibility testing, && drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clin Microbiol Rev 2012; 25:545–582. This extensive review covers antimicrobial susceptibility testing, resistance mechanisms in NTM and treatment regimens by disease system, including a short section on cutaneous infections. 48. van Ingen J, Boeree MJ, van Soolingen D, Mouton JW. Resistance mechan&& isms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat 2012; 15:149–161. The authors review the literature on resistance mechanisms in NTMs, past and current phenotypic methods for determining susceptibility and newer molecular approaches. They also discuss and review the evidence in the controversial area of the relationship between clinical outcome and in-vitro susceptibility testing. 49. Choi GE, Min KN, Won CJ, Jeon, et al. Activities of moxifloxacin in combination with macrolides against clinical isolates of Mycobacterium abscessus and Mycobacterium massiliense. Antimicrob Agents Chemother 2012; 56: 3549–3555. 50. Nessar R, Cambau E, Reyrat JM, et al. Mycobacterium abscessus: a new & antibiotic nightmare. J Antimicrob Chemother 2012; 67:810–818. This detailed review article focuses on one of the most resistant NTMs, M. abscessus. It describes three new subspecies based on rpoB sequences. They highlight a need to study antibiotic susceptibilities according to this new classification, as they differ, for example with clarithromycin. 51. Choi GE, Shin SJ, Won CJ, et al. Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance. Am J Respir Crit Care Med 2012; 186:917–925. 52. Huang CW, Chen JH, Hu ST, et al. Synergistic activities of tigecycline with clarithromycin or amikacin against rapidly growing mycobacteria in Taiwan. Int J Antimicrob Agents 2013; 41:218–223. 53. Regnier S, Cambau E, Meningaud J-P, et al. Clinical management of rapidly growing mycobacterial cutaneous infections in patients after mesotherapy. Clin Infect Dis 2009; 49:1358–1364. 54. van Dissel JT, Kuijper EJ. Rapidly growing mycobacteria: emerging pathogens in cosmetic procedures of the skin. Clin Infect Dis 2009; 49:1365– 1368. 55. Haverkamp MH, Arend SM, Lindeboom JA, et al. Nontuberculous mycobacterial infection in children: a 2-year prospective surveillance study in the Netherlands. Clin Infect Dis 2004; 39:450–456. 56. Haverkamp MH, Lindeboom JA, de Visser AW, et al. Nontuberculous mycobacterial cervicofacial lymphadenitis in children from the multicenter, randomized, controlled trial in The Netherlands: relevance of polymorphisms in candidate host immunity genes. Int J Pediatr Otorhinolaryngol 2010; 74: 752–754.



Infections caused by nontuberculous mycobacteria Atkins and Gottlieb 57. Lindeboom JA. Surgical treatment for nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in children. J Oral Maxillofac Surg 2012; 70:345– 348. This trial randomized 50 children to surgical excision or curettage of involved lymph nodes. They show more rapid healing with excision, although 16% of this group had transient facial nerve weakness (marginal mandibular nerve). They conclude that where technically possible complete surgical excision should be recommended. 58. Staufner C, Sommerburg O, Holland-Cunz S. Algorithm for early diagnosis in nontuberculous mycobacterial lymphadenitis. Acta Paediatr 2012; 101: e382–e385. 59. Nuń˜ezCuadros E, BaqueroArtigao F, Grupo de trabajos obre infeccioń por micobacterias no tuberculosas de la Sociedad Espanõla de Infectologıá Pedia´trica (SEIP). [Recommendations from the Spanish Society of Paediatric Infectious Diseases on the diagnosis and treatment of nontuberculous mycobacterial cervical lymphadenitis]. An Pediatr (Barc) 2012; 77:208208. e1–208.e12. 60. Penn R, Steehler MK, Sokohl A, Harley EH. Nontuberculous mycobacterial cervicofacial lymphadenitis: a review and proposed classification system. Int J Pediatr Otorhinolaryngol 2011; 75:1599–1603. 61. Broutin V, Banuls A-L, Aubry A, et al. Genetic diversity and population & structure of Mycobacterium marinum: new insights into host and environmental specificities. J Clin Microbiol 2012; 50:3627–3634. This is a genetic study of 89 M. marinum isolates from humans and fish using MIRU-VNTR typing. They found patterns of genetic structure that were grouped according to the host, ecosystem and tissue tropism in humans. Further work to identify important genes that may determine transmission, virulence and pathogenicity is suggested by the authors. 62. Wu TS, Chiu CH, Yang CH, et al. Fish tank granuloma caused by Mycobacterium marinum. PLoS One 2012; 7:e41296. 63. Parrish N, Luethke R, Dionne K, et al. Case of Mycobacterium marinum infection with unusual patterns of susceptibility to commonly used antibiotics. J Clin Microbiol 2011; 49:2056–2058. 64. Merritt RW, Walker ED, Small PL, et al. Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis 2010; 4: e911. 65. Bratschi MW, Bolz M, Minyem JC, et al. Geographic distribution, age pattern && and sites of lesions in a cohort of Buruli ulcer patients from the Mape´ Basin of Cameroon. PLoS Negl Trop Dis 2013; 7:e2252. This house-to-house survey in the Mape´ Basin, Cameroon, was in response to a local belief that the damming of the Mape´ River has led to an increase in Buruli ulcer cases. Eighty-eight cases were confirmed by RT-PCR. The age groups affected, localization of lesions and geographical factors are described. The authors hypothesise multiple modes of transmission. 66. Fyfe JA, Lavender CJ, Handasyde KA, Legione AR, et al. A major role for mammals in the ecology of Mycobacterium ulcerans. PLoS Negl Trop Dis 2010; 4:e791. 67. Willson SJ, Kaufman MG, Merritt RW, et al. Fish and amphibians as potential & reservoirs of Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Infect Ecol Epidemiol 2013. [Epub ahead of print] PCR was used to screen 587 fish and 351 amphibians from water in Ghana. Positive specimens had VNTR typing. There was no reliable fish or amphibian host; however, M. ulcerans was found for the first time in an adult frog. 68. Mitchell PJ, Jerrett IV, Slee KJ. Skin ulcers caused by Mycobacterium ulcerans in koalas near Bairnsdale, Australia. Pathology 1984; 16:256–260. 69. Elsner L, Wayne J, O’Brien CR, et al. Localised Mycobacterium ulcerans infection in a cat in Australia. J Feline Med Surg 2008; 10:407–412. 70. O’Brien CR, McMillan E, Harris O, et al. Localised Mycobacterium ulcerans infection in four dogs. Aust Vet J 2011; 89:506–510. 71. van Zyl A, Daniel J, Wayne J, et al. Mycobacterium ulcerans infections in two horses in south-eastern Australia. Aust Vet J 2010; 88:101–106. 72. O’Brien C, Kuseff G, McMillan E, et al. Mycobacterium ulcerans infection in two alpacas. Aust Vet J 2013; 91:296–300. &

73. Doig KD, Holt KE, Fyfe JA, et al. On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer. BMC Genomics 2012; 13:258. This study reports the comparative analysis of whole genome sequences from 30 mycolactone producing mycobacteria and five M. marinum. Insights from this study may help to clarify natural reservoirs of M. ulcerans and routes of transmission. 74. Lavender CJ, Globan M, Johnson PD, et al. Buruli ulcer disease in travelers and differentiation of Mycobacterium ulcerans strains from northern Australia. J Clin Microbiol 2012; 50:3717–3721. 75. Trubiano JA, Lavender CJ, Fyfe JA, et al. The incubation period of Buruli ulcer & (Mycobacterium ulcerans infection). PLoS Negl Trop Dis 2013; 7:e2463. This was a retrospective review, in which 23 patients with a single visit exposure to Buruli ulcer endemic regions were identified from 408 notifications of Buruli ulcer in Victoria, Australia. They were able to estimate the incubation period at 4.5 months (range 1–9 months). 76. Cassisa V, Chauty A, Marion E, et al. Use of fine-needle aspiration for diagnosis of Mycobacterium ulcerans infection. J Clin Microbiol 2010; 48: 2263–2264. 77. Boyd SC, Athan E, Friedman ND, et al. Epidemiology, clinical features and && diagnosis of Mycobacterium ulcerans in an Australian population. Med J Aust 2012; 196:341–344. One hundred and eighty sequential cases of M. ulcerans infection from the Bellarine Peninsula in Victoria, Australia are described including information on demographics, geographical area, size, type and number of lesions and PCR vs. culture positivity rates. They compare and contrast the clinical presentation with African Buruli ulcer. 78. Sarfo FS, Phillips R, Asiedu K, et al. Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 2010; 54:3678–3685. 79. World Health organisation. Treatment of Mycobacterium ulcerans disease (Buruli ulcer): guidance for health workers. Geneva: WHO; 2012. 80. Nienhuis WA, Stienstra Y, Thompson WA, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010; 375:664–672. 81. Gordon CL, Buntine JA, Hayman JA, et al. All-oral antibiotic treatment for Buruli ulcer: a report of four patients. PLoS Negl Trop Dis 2010; 4:e770. 82. O’Brien DP, McDonald A, Callan P, et al. Successful outcome with oral && fluoroquinolones combined with rifampicin in the treatment of M. ulcerans: an observational cohort study. PLoS Negl Trop Dis 2012; 6:e1473. This was an analysis of prospectively collected data on all M. ulcerans infections treated in one centre in southeast Australia (133 patients with 137 lesions). Thirtyfour percent had surgery alone with a 30% failure rate. The rest had antibiotics in conjunction with surgical excision with no failures. Rifampicin/ciprofloxacin and rifampicin/clarithromycin were equivalent combinations. 83. O’Brien DP, Walton A, Hughes AJ, et al. Risk factors for recurrent Myco& bacterium ulcerans disease after exclusive surgical treatment in an Australian cohort. Med J Aust 2013; 198:436–439. This study shows that when surgery is used without antimicrobials there is a high rate of relapse. They describe factors associated with the increased risk. 84. Nienhuis WA, Stienstra Y, Abass KM, et al. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 2012; 54:519–526. 85. O’Brien DP, Robson M, Friedman ND, et al. Incidence, clinical spectrum, && diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections. BMC Infect Dis 2013; 13:416. This is an analysis of prospectively collected data on 156 patients with M. ulcerans in one centre in southeastern Australia. Thirty-two patients developed paradoxical reactions, with six having multiple episodes. These episodes are described and factors are identified which on multivariable analysis are associated with this reaction. 86. Friedman ND, McDonald AH, Robson ME, O’Brien DP. Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans. PLoS Negl Trop Dis 2012; 6:e1767. &



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Nontuberculous Mycobacteria: Skin and Soft Tissue Infections.

Pulmonary disease caused by nontuberculous mycobacteria.

Gradenigo syndrome caused by nontuberculous mycobacteria.

Diagnosis and treatment of disease caused by nontuberculous mycobacteria.

Comparison of skin and soft tissue infections caused by Vibrio and Aeromonas species.

Skin and soft-tissue infections caused by Actinobaculum schaalii: report of two cases and literature review.

Overrepresentation of Diabetes in Soft Tissue Nontuberculous Mycobacterial Infections.

Necrotizing skin and soft tissue infections.

Bacteremic skin and soft tissue infection caused by Prevotella loescheii.

Fungal skin and soft tissue infections.

Bacterial skin and soft tissue infections.

HMGB1 in severe soft tissue infections caused by Streptococcus pyogenes.

Nontuberculous mycobacteria in respiratory infections: advances in diagnosis and identification.

Nontuberculous mycobacteria.

Surveillance of Extrapulmonary Nontuberculous Mycobacteria Infections, Oregon, USA, 2007-2012.

Clinical spectrum and antimicrobial resistance pattern of skin and soft tissue infections caused by community acquired-methicillin resistant Staphylococcus aureus.

Ticarcillin-clavulanate therapy for bacterial skin and soft tissue infections.

Drugs for MRSA skin and soft-tissue infections.

Ofloxacin versus cephalexin for treating skin and soft tissue infections.

Chinese herbal medicines for treating skin and soft-tissue infections.

[Role of ceftaroline in skin and soft tissue infections].

Nontuberculous mycobacteria and associated diseases.

Endobronchial lesions caused by nontuberculous mycobacteria in apparently healthy pediatric patients.

Soft tissue abscess caused by Mycobacterium fortuitum.