CHAPTER 10 Case Series and Review of the Literature of chelonae Infections of the Lower Extremities

Edmund Yu, DPM Patricia Forg, DPM Nancy F. Crum-Cianflone, MD, MPH

INTRODUCTION outbreaks of rapid growing NTM infections (M chelonae, M abscessus) linked to water exposure in the context of pedicures Mycobacterial infections include Mycobacterium or recent surgery/trauma (10-13). complex (e.g., M tuberculosis, , Mycobacterium The clinical manifestations of M chelonae infections include leprae), Mycobacterium avium complex (MAC), and other skin/soft tissue or skeletal (tendon, joint, bone) infections non-tuberculosis mycobacteria (NTM), the latter of which after local inoculation of the organism. Examination findings includes over 150 diverse species. NTM are differentiated can resemble cellulitis, subcutaneous abscesses, or multiple from mycobacteria that cause tuberculosis because they are vesicular lesions (1), however there are no pathognomonic not spread by human-to-human transmission, rather are signs to differentiate it from other microbiologic causes ubiquitous in the environment including water, soil, and (6,14). Their proliferation can be masked within a chronic plant material, with tap water being considered the major non-healing wound or a prior non-healing surgical site. The reservoir for human infections (1). Routes of infection include non-pathognomonic and often indolent findings associated cutaneous inoculation including in the setting of open wounds. with M chelonae infections signify the need for a thorough Organisms are identified as acid-fast bacilli (AFB) positive on clinical and diagnostic work-up for their identification. This staining and subsequent growth on specialized mycobacterium includes early clinical suspicion and collection of mycobacterial culture media (2,3). NTM were classically categorized by cultures and acid fast stains to achieve early diagnosis and to growth rate (rapid, immediate, or slow-growing species) help prevent progressive disease including bone and joint and colony characteristics including pigmentation (e.g., involvement (8). Runyon System); however, today isolates are increasingly This article consists of a case series illustrating the identified using molecular systems (3-5). Rapidly growing importance of considering M chelonae infections in the mycobacteria (defined as mature growth on plates by <7 days) diagnosis of non-healing infections of the feet that develop include 6 specific complexes and include pigmented and non- in the setting of prior trauma/surgery and environmental pigmented pathogenic species. is a non- exposures. Multiple AFB tissue cultures and antimicrobial pigmented, rapid-grower closely related to the Mycobacterium susceptibility testing should be obtained for making the abscessus group (6). diagnosis and directing optimal antimicrobial therapy. We The incidence of NTM infections, including rapid also conducted a comprehensive review of the literature of growers, have significantly increased since they were M chelonae infections occurring in the feet/lower extremities identified as human pathogens in 1950 (3). For example, published since 1946 to summarize the predisposing since 1981, the rates of NTM infections have risen to an conditions, clinical manifestations, treatment approaches, estimated 1.8 cases/100,000 person-years, however, the and outcomes of this rare but emerging clinical entity. exact number of annual cases in the US is unknown since While the number of atypical mycobacterium infections are NTM infections are not reportable conditions (7). The increasing, there is a paucity of detailed and systemically rising incidence may be related to an increasing number summarized data on M chelonae infections in the current of immunosuppressed persons as well as environmental published literature. exposures (3,8). NTM produce a protective biofilm in aquatic environments that allows them to withstand harsh CASE 1 conditions and persist in water collection and piping systems. Additionally, their resistance to sterilizing agents An 86-year-old man with a medical history of hypothyroidism such as and household disinfectants makes and dementia presented with pain and erythema of his left them formidable pathogens (9). Studies have shown foot. He had received 2 courses of oral cephalexin (14 increasing incidences of NTM released from piped water days) with no notable improvement in May 2017. Four systems in both public and household water supplies leading weeks after the initial development of his foot pain and to an increased risk of exposure (1,9). This is exemplified by erythema, he presented to the emergency department and 44 CHAPTER 10 was admitted in June 2017. Examination revealed normal aspiration of a lesion on the left foot and blood cultures vital signs with a temperature of 36.5C. An examination of were both negative. A magnetic resonance image (MRI) of the left foot revealed pain on range of motion of the second the left foot demonstrated mild tenosynovitis of the anterior digit and multiple vesicular lesions and erythema localized tibialis tendon near the navicular bone. He was empirically to the midfoot (Figure 1). Standard left foot radiographs treated with intravenous cefazolin and vancomycin for 5 showed no evidence of soft tissue or osseous abnormalities days, followed by 14 days of intravenous vancomycin and (Figure 2). Initial white blood cell (WBC) count was 11.4 ciprofloxacin with only mild improvement. x 103/μl (93% neutrophils), the C-reactive protein (CRP) The patient returned to the emergency department 4 level was 11.9 mg/liter, and the erythrocyte sedimentation times after the initial hospitalization for similar symptoms. rate (ESR) was 42 mm/hour. Bacterial wound cultures from He was again prescribed a variety of antibiotics including amoxicillin/clavulanic acid and doxycycline, which provided

Figure 2A. Nonweightbearing lateral radiograph of left foot, and B, Non- weightbearing medial oblique radiograph of left foot demonstrating no soft tissue gas or osseous abnormality. Figure 1A. View of patient’s left foot demonstrating multiple vesicular lesions; B, Extent of erythema marked with a pen up to level of the distal leg.

Figure 3A. Coronal T2-weighted view of the left foot demonstrating a Figure 4A. Multiple firm vesicular lesions on dorsal left foot 8.1 mm-sized fluid collection bewteen the first and second metatarsals. refractory to prior multiple courses of standard antibiotic therapies. B, Saggital T2-weighted view of the left foot demonstrating trace B, 2ml sanguineous bedside aspiration from the lesion at base of peripheral enhancement and edema of the extensor hallucis longus second digit. tendon. CHAPTER 10 45 only minimal improvement. Ultimately, numerous vesicular after 8 weeks of therapy due to thrombocytopenia, a known lesions with increased erythematous changes to the left side effect associated with its prolonged use. The patient lower extremity warranted a second hospital admission 6 responded well to the treatment plan with near resolution of months later. All laboratory markers including WBC, CRP, the wounds at 12 weeks postoperatively without evidence of ESR, and uric acid were within normal limits. A repeat MRI recurrence (Figure 7). He has finished his course of antibiotics of the left lower extremity was obtained revealing additional (imipenem and azithromycin) in June of 2018 and continues findings including tenosynovitis of the extensor hallucis to have monthly follow-up visits with no new symptoms. longus tendon and trace fluid collection between bases of the first and second metatarsals (Figure 3). A bedside aspiration of the largest vesicular lesion at the base of the second digit (Figure 4) was negative for bacterial organisms and crystals. Upon further history, the patient recalled that his foot condition began as a small pruritic lesion that started in between his hallux and second digit of the left foot with subsequent water exposure of this area. The patient consented to surgical debridement with cultures for bacterial, fungal, Nocardia, and AFB, as well as pathology. Intraoperative findings included a small pocket of necrotic tissue in the first interspace. The postoperative appearance is shown in Figure 5. The histological findings from the samples showed neutrophil aggregation and poorly formed granulomas with central microabscesses (Figure 6). AFB cultures grew M chelonae with susceptibilities to tobramycin, imipenem, clarithromycin, and linezolid. The patient was started on intravenous imipenem 500 mg every 6 hours, azithromycin 250 mg oral daily, and linezolid 600 mg oral daily due to the extent of infection and the fact that complete resection was not possible. Linezolid was stopped Figure 5. Postoperative day 1 following surgical debridement of left foot for obtaining intra-operative soft tissue cultures.

Figure 6. Hematoxylin and eosin stain. A, High resolution, 10x magnification of a soft tissue pathology sample from the left foot first interspace> Arrow indicates a poorly formed granuloma and Figure 7. Left foot 3 months after surrounding neutrophils. B, Low resolution, 4x surgical debridement while receiving magnification of the above same finding. anti-mycobacterial therapy. 46 CHAPTER 10

CASE 2 be nearly or fully resected and he had no other cutaneous findings, therapy with azithromycin 500 mg oral daily alone A 72-year-old man with a medical history of well-controlled was commenced with a planned duration of 6 months. HIV infection developed erythematous vesicles around Subsequent examinations showed only postoperative the incision site after a neurectomy procedure over the changes without evidence of residual or recurrent infection. left fourth metatarsal. The patient had initially noted mild In summary, the M chelonae infections in our case series discoloration near the surgical incision site, which developed were successfully treated with surgical debridement and approximately 1 month after surgery, but it was felt that anti-mycobacterial therapy without evidence of recurrence this may be an allergic reaction to the sutures and hence at this time. Case 1 completed a 6-month course of no work-up was performed. Around the time of surgery, azithromycin 250 mg oral daily and imipenem 500 mg the patient noted exposure to public pool water as well as intravenously every 6 hours. Local wound care was effective exposure to tap water during showering. in closing the wound without recurring complications. Case Over the course of 1 year, the foot condition did 2 will finish a planned 6-month course of azithromycin 500 not improve and there was slow progression with vesicle mg oral daily after surgical debridement. Both patients are formation (Figure 8). Examination revealed normal vital ambulating well without clinical evidence of recurrence at signs and there was no significant pain or drainage at the the prior inoculation sites or disseminated disease. site. The lesions were confined to this area and there was no lymphangitic spread or other cutaneous involvement. DISCUSSION The WBC was 5.9 x 103/μl and CD4 count was 389 cells/mm3 with an undetectable HIV viral load while A comprehensive review of the published English literature receiving antiretroviral therapy (abacavir, lamivudine, and utilizing PubMed, Ovid Medline, UpToDate, Embase, dolutegravir). and the Cochrane Library was conducted for articles Radiographs and MRI of the left foot were unremarkable. from 1946-2018. Search terms included “Mycobacterium A biopsy of the skin lesions and mycobacterial cultures were chelonae” or “Non-tuberculous mycobacterium” and positive for M chelonae, but antimicrobial susceptibilities “foot, feet, ankle, ankles, leg, legs, or lower extremity.” were not performed. He was empirically begun on a multi- Our review included only those articles focused on lower drug regimen of clarithromycin and moxifloxacin, but extremity infections involving M chelonae with adequate discontinued both medications due to nausea. He elected individualized patient information. Cases involving co- to have complete surgical debridement of the infected area infections with other organisms along with M chelonae (Figure 9). Intra-operative soft tissue cultures were negative were excluded. Additionally, we excluded articles without for new growth on AFB cultures. There was also no growth individualized patient data or ones that contained very on bacterial and fungal cultures. Since the area was felt to

Figure 8. Left foot showing erythematous vesicular Figure 9. Left foot post-surgical debridement with lesions around the incision site of prior neuroma no new areas of infection. removal over the fourth metatarsal. CHAPTER 10 47 limited information such as missing diagnosis, patient of clinical findings such as vesicular-like lesions that are firm information, and treatment plans (1,2,6,11,15-18,39- to palpation as well as indolent changes in skin texture and 41). In addition to our search terms, we also utilized the color. Prompt consideration for this diagnosis is important references of articles to identify additional cases. Overall, as our review of the literature found a median time between we identified 22 cases in the literature including our 2 cases onset of symptoms to diagnosis was notably delayed with a representing the most comprehensive literature review on mean time of 7.9 months (10,12,13,20-22,24-35). this topic to date (Table 1). M chelonae is an important, albeit Diagnosis relies on a thorough history of prior water often under recognized, cause of lower extremity infections. or environmental exposures as well as preceding cutaneous Our 2 cases and review of the literature exemplify the delay trauma and/or surgery (2,6,9,33). Lesions may not appear in the diagnosis of this condition and the importance of until 2-3 weeks after exposure, further delaying prompt obtaining AFB cultures, especially in the setting of chronic diagnosis (2,6,12). When the diagnosis of an NTM soft wounds, and prior water/environmental exposures. Since tissue infection is considered, multiple AFB smears and non-tuberculosis mycobacteria are emerging infections with cultures of tissue samples should be obtained. Additionally, an increasing number of cases over the past decade, early notification to the laboratory of the concern for rapid- recognition and diagnostic testing are important. growing mycobacterium should be conveyed to ensure NTM infections, including those involving the lower proper culturing techniques are conducted as M chelonae extremities, have significantly increased over time to an grows best at low temperatures between 28o to 30oC., estimated 1.8 cases per 100,000 person-years (7). An hence cultures should be plated at this lower temperature as increasing number of cases have been noted in the southern well as at 35oC. Routine Gram stains and bacterial cultures United States including Florida, Georgia, Louisiana, and are not sensitive, and also may be misleading as other Texas, possibly due to environmental conditions (e.g., colonizing organisms (such as Enterobacter, Morganella, temperature and rainfall) in these areas (14). Exact numbers and Proteus) may be noted (26,29). More recent techniques of NTM and M chelonae infections are unknown since they including fluorochrome staining can improve sensitivity are not reportable conditions, however an increasing case of detection with a lower risk of contamination (5, 36). number is suggested in the current literature. In addition Regarding culture media, Middlebrook 7H10 or 7H11 to environmental factors such as increasing quantities or Lowenstein-Jensen media are commonly used, and the of NTM in the water supply, host factors including non-pigmented colonies of M chelonae may begin to appear immunosuppression, iatrogenic factors (e.g., surgery, at 7 or more days. The majority of M chelonae infections injury), and outdoor activities may predispose to infection. are identified via AFB culture, rendering this the current Regarding underlying host factors, the literature gold standard (6,11,26). In addition to mycobacterial reports that most M chelonae infections occur in those who cultures, rapid diagnostic systems and polymerase chain are immunosuppressed, especially those with autoimmune reaction (PCR) are increasingly being utilized for their diseases (e.g., rheumatoid arthritis) or those taking long- identification (36). Biopsies from the infection site should term steroids steroids (12,20-23). Our study highlights also be referred to pathology; both cases in our series had that this infection, when involving the lower extremities, evidence of superficial and deep perivascular infiltrates with often occurs in normal hosts as 11 (50%) of the cases in aggregations of neutrophils and granulomas. Prior literature our review were not immunosuppressed. Steroid use was documented a mean of 86% samples containing chronic noted in 5 cases (22.7%), 2 had diabetes (9.1%), 3 had inflammatory granulomas, but only 30% were positive on a autoimmune conditions (13.6%) and 2 had cancer (9.1%) single AFB smear – further emphasizing that pathology may (10,12,13,20-22,24-35). Case 2 in our series is novel as aid in earlier diagnosis (12). it is the sole reported case of M chelonae causing a lower To date, there are no controlled clinical trials evaluating extremity infection in an HIV-infected person found in our the optimal antibiotic treatment for M chelonae infections review of the English literature. This exemplifies that M of the lower extremities. Despite documented successful chelonae infections may not be associated with HIV infection resolution of infections in case studies, there is no definitive per se (compared with MAC and Mycobacterium kansasii, which treatment algorithm. As documented in our study and have an association with HIV), but that our case may rather the prior literature, surgical debridement is important in have been a result of surgical trauma and water exposure. improving outcome. This allows for removal of infected Clinical manifestations of M chelonae infections are tissues as well as intra-operative specimens for stains, cultures, variable, hence the clinician must remain astute to consider and pathology. Species-level determination of the involved this diagnosis. M chelonae can mimic other causative mycobacterium as well as susceptibility testing is paramount pathogens involved in chronic, non-healing wounds of the in determining the best antimycobacterial treatments. The lower extremities since there are no known pathognomonic American Thoracic Society (ATS) currently recommends signs (6,13). However, our review highlights the importance testing a minimum of 7 antibiotics for susceptibilities in 48 CHAPTER 10

Table 1. Comprehensive review of literature involving lower extremity Mycobacterium chelonae infections*

Reference Year Age Sex Past Medical Predisposing Site(s) of Presenting Examination Time from symptoms Diagnostic studies Treatment Outcome a Abbreviations: + = positive; History condition(s) infection symptoms findings to diagnosis AFB = acid fast bacilli; BID Cooper et 1989 50 F ESRD, renal Injection Left shin/ankle n/a n/a ~1 month n/a 1 time surgical Lesions still al. (#5) transplant debridement progressing, = twice a day; BKA = below Cefoxitin, , still on tobramycin and antibiotics knee amputation; BPH = erythromycin

Cooper et 1989 63 M ESRD, renal Injection Right leg n/a n/a 12 months n/a 1 time surgical Unknown, still benign prostatic hyperplasia; al. (#7) transplant debridement on antibiotics CHF = congestive heart Bactrim Cooper et 1989 77 F Gout Steroid injection for Left foot and leg Ulceration over Ulceration over 2 months Culture + for M. 2 time surgical Fluctuating failure; CRP = C-reactive al. (#8) Achilles tendinitis 4 Achilles tendon, Achilles tendon, chelonae debridement, lesions, still on months prior multiple 5mm multiple 5mm Cefoxitin, amikacin, antibiotics protein; DM = diabetes nodules on left nodules on left shin erythromycin, shin doxycycline, mellitus; ESR = erythrocyte tobramycin, clofazimine sedimentation rate; ESRD = Johnson et 1993 70 F Asthma Puncture wound on Left and right 1st ulcer on right Multiple ulcerations 3 years n/a n/a n/a al. right ankle ankle/leg ankle was on both left and right end stage renal disease; HIV chronic, non- leg/ankle progressed healing = human immunodeficiency Saluja et 1997 65 F Basal cell Mohs surgery Left lower leg 10 weeks after 2 papulo-pustules ~18 weeks AFB +, culture on Clarithromycin 500mg 18 month al. carcinoma of surgery, small inferior to Mohs Lowenstein-Jensen BID for 10 weeks follow-up virus; IBS = inflammatory left lower leg erythematous surgical scar medium + for M. period, resolved lesions chelonae bowel syndrome; I&D = appeared Toussirot 1998 82 M Lower back 6 months of steroids Right lateral Peroneal tendon n/a n/a AFB culture + for M. Amikacin, Death due to incision and drainage; IV = et al. pain ankle tenosynovitis chelonae ciprofloxacin, infectious ESR of 94 and normal clarithromycin and pneumonitis intravenous; MIC = minimum WBC with histological clofazamine findings of non- caseating granulomas inhibitory concentration;

Brown- 2001 57 M 30 year history None Right lower thigh Ulcerating Worsening ulcerated Over 1 year Histology found Failed clarithromycin, Treated with IV PCR = polymerase chain Elliott et al. of steroid to dorsal foot nodules that nodules necrotizing tobramycin, linezolid 600mg dependent failed granulomatous azithromycin, and BID with reaction; PO = by mouth; myasthenia amoxicillin/clavul inflammation with imipenem after 12 complete gravis anic acid, microabscesses months even with resolution and WBC = white blood cell. b ciprofloxacin; Wound culture and surgical I&D no relapse after cachectic/wheelc PCR with microbroth 12 months hair bound dilution to determine The remaining 19 published MIC studies with Mycobacterium Terry et al. 2001 80 F DM, right scratch Right Cellulitis shortly Two 2.0x2.0cm Unknown AFB culture + for M. Clarithromycin Resolved sided paresis anterior/medial after scratch, abscesses chelonae chelonae diagnosis did lower leg failed IV cefazolin and not have adequate patient amoxicillin/clavul anic acid demographics and information Sniezek et 2003 25 F None Pedicure – shaved Left and right 6 week earlier, Firm tender 3 months Punch biopsy, AFB +, Ciprofloxacin and After 10 weeks, al. legs prior lower leg right leg 0.4cm erythematous and culture + for M. clarithromycin for 8 resolved and left leg ulcerated nodules chelonae with weeks to be included in this table. 1.5cm sensitivity data -Right leg worsened at week 10 and required I&D, added trimethropim- sulfamethaxazole

Sniezek et 2003 32 F 13 week Pedicure – shaved Left and right 9 month history Right leg – 5.0mm ~15 months Punch biopsy, AFB +, trimethropim- After 3 months, al. pregnant legs prior lower leg of papules and non-tender, and negative cultures sulfamethaxazole for resolved nodules on both erythematous papule initially. Repeat 3 months lower legs examined culture 6 months later + for M. chelonae

Pasapula 2005 33 F None Gunshot wound to Left foot Worsening ulcer WBC, CRP, ESR Over 18 months Prior standard wound Initially – rifampin, After 9 months, et al. left foot 6 years ago, on left forefoot normal cultures grew out clarithromycin, complete not same site as measuring Left foot radiographs variety of ethambutol and resolution ulceration 3.0x4.0cm with shows changes of polymicrobial flora switched to only Lives on a several adjacent possible after surgical I&D but clarithromycin and boathouse and verrucas osteomyelitis, M. chelonae ciprofloxacin for 9 wading in stagnant confirmed on confirmed on AFB months water for several histology weeks

Chung et 2009 52 M None None Left and right 6 weeks earlier, 4cm erythematous 13 weeks Blood tests normal 1 gram clarithromycin No recurrence, al. medial shins first 0.5cm flaccid plaques Negative AFB PO daily for 13 weeks resolved papule on right, Culture + for M. followed by the chelonae left 2 weeks later Lee et al. 2010 49 M Lung cancer On Right 2nd digit Solitary abscess, n/a n/a AFB culture + for M. Clarithromycin and Resolved immunosuppressive tender with chelonae amikacin for 4 months drugs (carboplatin, associated ifosfamide, tenosynovitis etoposide) Drage et 2010 43 F None Tattoo Left lower leg 1 week after 1 week after tattoo, ~20.5 weeks AFB and culture neg., Azithromycin 250mg Resolved al. tattoo, lichenoid/hyperkerat diagnosis based on daily lichenoid/hyperk otic like papules histology finding of eratotic like dermal papules granulomatous inflammation

Bamias et 2011 60 F 12 year history Immunocompromise Right lower leg 4 month history Right leg – multiple Unknown AFB +, cultures on Clarithromycin 500mg Resolved al. of ulcerative d and foot of multiple purulent lesions, 2- blood agar and PO BID for 6 months colitis, 16 mg nodules on right 5cm in size Lowenstein Jensen of steroid lower leg medium + for M. chelonae Yu et al. 2013 78 F Adrenal Used public baths Left foot Worsening Worsening multiple Over 10 days AFB stain was Amikacin 250mg Deceased insufficiency multiple ulcerations with positive and PCR daily, cefoxitin 3g on 7.5mg ulcerations with exposed muscle for confirmed M. daily, clarithromycin prednisolone, exposed muscle 10 days chelonae 375mg daily, however CHF, for 10 days wounds did not hypothyroidis improve and required m left BKA, and patient eventually deceased Lui et al. 2014 20 M None None Right heel Wound n/a n/a AFB culture with Amikacin 400mg Healed Achilles dehiscence of tissue sample from q12h for 4 weeks, oral tendon with no surgical incision Achilles tendon + for clarithromycin 500mg infection, to repair Achilles M. chelonae BID for 6 months, and resolved tendon imipenem 500mg q6h for 2 weeks

Schmidt et 2014 60 M Non-ischemic Pedicure Right foot 1 week after Numerous punched ~1.5 months Biopsy with culture + Azathioprine, Passed away al. cardiomyopath pedicure, out ulcerations and for M. chelonae doxycycline, and due to cardiac y, CHF, DM multiple papules ciprofloxacin complications ulcerations Tanagho 2015 57 F None None Left foot, 1st Sudden onset No lesions, only ~10 days Intra-operative bone Clarithromycin and 1st ray et al. metatarsal cellulitis and cellulitic region over and soft tissue culture ciprofloxacin amputation as pain 1st metatarsal + for M. chelonae bone destruction progressed despite antibiotics

Lickiss et 2016 49 F Inclusion body Flatfoot Left foot Worsening Bone samples Over 3 months 2/4 AFB cultures Ertapenem 1gram IV After 1 year, al. myositis (rare reconstruction on left wound showed positive for M. daily for 6 weeks, complete inflammatory foot 3 years ago dehiscence of osteomyelitis, but no chelonae azithromycin 500mg resolution with myopathy) surgical incisions pathological oral daily for 5 months full weight- on medial and comment on bearing and no lateral side, mycobacterium pain surgical I&D 3 infection times before growing out positive M. chelonae on AFB Yu et al. 2017 86 M IBS, Small, pruritic lesion Left foot Transient lesions Multiple firm and 6 months - 2 surgical Linezolid 600mg daily Wound from hypothyroidis 1st interspace left and cellulitis to painful vesicular debridements (stopped after 8 surgical m, BPH, foot the left foot and lesions and weeks due to debridement dementia ankle, pain worsening cellulitic Multiple intra- thrombocytopenia), and vesicular changes operative AFB imipenem 500mg IV lesions have cultures and q6hours, azithromycin healed, no pathology specimen + 250mg oral daily for 6 evidence of for M. chelonae months total recurrence at this time Yu et al. 2017 72 M HIV+ (CD4 Neuroma excision Left foot Pain, itching Discoloration and ~1 year 1 time surgical Azithromycin 500mg Wound from count of 389) surgery, public pool small vesicular debridement oral daily for 6 months surgical water exposure lesions around total debridement shortly after surgery incision site around Biopsy + for M. and vesicular 4th metatarsal area chelonae lesions have healed, no evidence of recurrence and repeat AFB cultures are negative

a Abbreviations: + = positive; AFB = acid fast bacilli; BID = twice a day; BKA = below knee amputation; BPH = benign prostatic hyperplasia; CHF = congestive heart failure; CRP = C-reactive protein; DM = diabetes mellitus; ESR = erythrocyte sedimentation rate; ESRD = end stage renal disease; HIV = human immunodeficiency virus; IBS = inflammatory bowel syndrome; I&D = incision and drainage; IV = intravenous; MIC = minimum inhibitory concentration; PCR = polymerase chain reaction; PO = by mouth; WBC = white blood cell. b The remaining 19 published studies with Mycobacterium chelonae diagnosis did not have adequate patient demographics and information to be included in this table.

Table 1. Comprehensive review of literature involving lower extremity Mycobacterium chelonae infections (N=22)a,b CHAPTER 10 49

M chelonae infections: amikacin, cefoxitin, ciprofloxacin, as mentioned above. However, the vesicular lesions and clarithromycin, doxycycline, imipenem, and sulfonamides; chronic courses described in our cases may point toward linezolid and tobramycin are also typically evaluated (37). an atypical infection such as M chelonae. As illustrated in this Broth microdilution is the standard technique utilized, and review, maintaining NTM on the differential is important as the Clinical & Laboratory Standards Institute (CLSI) has well as obtaining deep tissue specimens for AFB cultures and published guidance on interpretation (38). pathology. A combination of thorough surgical debridement Since susceptibility testing may take up to 4-6 weeks, of the involved soft tissues and/or osseous structures as well initial antibiotics are often selected based on the literature. as anti-mycobacterial therapy based on susceptibility data Drugs that often have activity against M chelonae include are the cornerstones of treatment for M chelonae infections. clarithromycin, azithromycin, amikacin, tobramycin, Overall, health providers should maintain a high suspicion cefoxitin, imipenem, moxifloxacin, and sometimes linezolid for possible NTM infections in the differential when (21,37). Clarithromycin is generally the drug of choice for challenged with a lower extremity wound refractory to localized disease in the setting of thorough debridement, standard antibiotics and treatment modalities. whereas multi-drug regimens are often utilized for disseminated or severe skin/soft tissue infections especially REFERENCES without aggressive and/or complete debridement (21,22). 1. Wagner D, Young LS. Nontuberculous mycobacterial infections: a Traditionally, clarithromycin was included in initial clinical review. Infection 2003;32:257-70. regimens given its high oral bioavailability, good tissue 2. Escalonilla P, Ebsteban J, Soriano ML, Farina MC, Pique E, Grilli penetration, and gastrointestinal stability (16,17,27). Given R, et al. Cutaneous manifestations of infection by nontuberculous mycobacteria. Clin Exp Dermatol 1998;23:214-21. concerns of emerging resistance to macrolides (due to an 3. Hypolite T, Grant-Kels JM, Chirch LM. Nontuberculous inducible erythromycin resistance methylase gene), careful mycobacterial infections: a potential complication of cosmetic consideration of the treatment options is important and procedures. Int J Womens Dermtol 2015;1:51-4. infectious disease consultation considered (3). While there 4. Timpe A, Runyon EH. The relationship of “atypical” acid-fast to human disease, a preliminary report. J Lab Clin Med is no clear standard for antibiotic duration, the current case 1954;44:202-9. series demonstrated a duration of 24 weeks with a mean 5. Yakrus MA, Hernandez SM, Floyd MM, Sikes D, Butler WR, time of 21.2 weeks in other studies (6,12,33). The current Metchock B. Comparison of methods for identification of and M chelonae isolates. J Clin Microbiol ATS guidelines recommend 4-6 months for skin/soft tissue 2001;39:4103-10. disease assuming good clinical response (37). Regular visits 6. Dodiuk-Gad R, Dyachenko P, Ziv M, Shani-Adir A, Oren Y, are recommended to ensure improving clinical response Mendelovici S, et al. Nontuberculosis mycobacterial infections of the skin: a retrospective study of 25 cases. J Am Acad Dermatol and for monitoring adverse drug reactions in the setting of 2007;57:413-20. prolonged antimicrobial therapy. 7. O’Brien RJ, Geiter LJ, Snider DE. The epidemiology of Strengths of this paper include it being the most nontuberculous mycobacterial diseases in the United States, results comprehensive review in the English literature of the from a national survey. Am Rev Respir Dis 1987;135:1007-14. 8. Uslan DZ, Kowalski TJ, Wengnack NL, Virk A, Wilson JW. Skin clinical findings, diagnosis and treatment, and outcomes and soft tissue infections due to rapidly growing mycobacteria. Arch of M chelonae infections of the lower extremities. Another Dermatol 2006;142:1287-92. important strength includes the detailed, long-term care of 9. Piersimoni C, Scarparo C. Extrapulmonary infections associated with nontuberculous mycobacteria in immunocompetent persons. both cases in our series. This length of time allowed us to Emerg Infect Dis 2009;15:1351-8. document the initial diagnosis through treatment efficacy 10. Schmidt AN, Zic JA, Boyd AS. Pedicure associated Mycobacterium including the favorable outcomes of our cases. Limitations chelonae infection in a hospitalized patient. J Am Acad Dermatol 2014;71:248-50. of our review include the small sample size given the paucity 11. Winthrop, KL, Abrams M, Yakrus M, Schwartz I, Ely J, Gillies D, of cases in the literature and that some previously published et al. An outbreak of mycobacterial furunculosis associated with cases lacked individualized clinical data. footbaths at a nail salon. N Engl J Med 2002;346:1366-71. In summary, M chelonae infections should be considered 12. Lee WJ, Kang SM, Sung H, Won CH, Chang SE, Lee MW, et al. Non- tuberculous mycobacterial infections of the skin: a retrospective in cases of a non-healing wound of the lower extremity study of 29 cases. J Dermatol 2010;37:965-72. especially in the setting of prior environmental exposure. 13. Lickiss J, Olsen A, Ryan JD. Mycobacterium chelonae-abscessus In our series, a thorough history revealed that both patients complex infection after flatfoot reconstruction. J Foot Ankle Surg 2016;55:1327-32. had preceding skin trauma followed by water exposure 14. Han XY. Seasonality of clinical isolation of rapidly growing and our literature review found that 15 cases (68%) also mycobacteria. Epidemiol Infect 2008;136:1188-91. reported similar relevant exposures. Since the infection 15. Wallace RJ, Brown-Elliot BA, Ward SC, Crist CJ, Mann LB, Wilson RW. Activities of linezolid against rapidly growing mycobacteria. has no pathognomonic signs and the initial presentation Antimicrob Agents Chemother 2001;45:764-7. of generalized cellulitic and peri-wound erythema is 16. Wallace RJ, Tanner D, Brennan PJ, Brown BA. Clinical trial of non-specific, delays in accurate diagnosis are common clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993;119:482-6. 50 CHAPTER 10

17. Wallace RJ, Meier A, Brown BA, Zhang Y, Sander P, Onyi GO, 29. Pasapula C, Fitzmaurice K, Sharp B, Cooke P. Mycobacterium et al. Genetic basis for clarithromycin resistance among isolates chelonae as a cause of forefoot infections. Foot 2005;15:104-6. of Mycobacterium chelonae and Mycobacterium abscessus. 30. Chung WK, Kim MS, Kim CH, Lee MW, Choi JH, Moon KC, et Antimicrob Agents Chemother 1996;40:1676-81. al. Cutaneous Mycobacterium chelonae infection presenting as 18. Wilson S, Cascio B, Neitzschman HR. Nail puncture wound to the symmetrical plaques on both shins in an immunocompetent patient. foot. J La State Med Soc 1999;151:251-2. Acta Derm Venereol 2009;89:663-4. 19. Spaulding AB, Lai YL, Zelazny AM, Olivier KN, Kadri SS, Prevots 31. Drage LA, Ecker PM, Orenstein R, Phillips K, Edson RS. An DR, et al. Geographic distribution of nontuberculous mycobacterial outbreak of Mycobacterium chelonae infections in tattoo. J Am species identified among clinical isolates in the United States, 2009- Acad Dermatol 2010;62:501-6. 2013. Ann Am Thorac Soc 2017;14:1655-61. 32. Bamias G, Daikos GL, Siakavellas SI, Kaltsa G, Smilakou S, 20. Toussirot E, Chevrolet A, Wendling D. Tenosynovitis due to Katsogridakis I, et al. Atypical mycobacterial infection presenting Mycobacterium avium intracellulare and Mycobacterium chelonei: as persistent skin lesion in a patient with ulcerative colitis. Case Rep report of two cases with review of the literature. Clin Rheumatol Med 2011;2011:480987. 1998;17:152-6. 33. Yu JR, Heo ST, Lee KH, Jim J, Sung JK, Kim YR, et al. Skin and soft 21. Brown-Elliott BA, Nash KA, Wallace RJ. Antimicrobial susceptibility tissue infection due to rapidly growing mycobacteria: case series and testing, drug resistance mechanisms, and therapy of infections with literature review. Infect Chemother 2013;45:85-93. nontuberculous mycobacteria. Clin Microbio Rev 2012;25:545-82. 34. Lui TH, Chan KB. Achilles infection due to Mycobacterium 22. Brown-Elliott BA, Wallace RJ, Blinkhorn R, Crist CJ, Mann LB. chelonae. J Foot Ankle Surg 2014;53:350-2. Successful treatment of disseminated Mycobacterium chelonae 35. Tanagho A, Hatab S, Hawkins A. Atypical osteomyelitis caused by infection with linezolid. Clin Infect 2001;33:1433-4. Mycobacterium chelonae in a nonimmunocompromised patient. 23. Oelberg DA, Mendelson J, Miller MA, Dascal A. JBJS Case Connect 2015;5:e1-4. disseminated Mycobacterium chelonae infection presenting as 36. Somoskovi A, Mester J, Hale YM, Parsons LM, Salfinger M. progressive multifocal osteomyelitis: report of two cases and a Laboratory diagnosis of nontuberculous mycobacteria. Clin Chest review of the literature. Can J Infect Dis 1994;5:28-32. Med 2002;23:585-97. 24. Cooper JF, Lichtenstein MJ, Graham BS, Schaffner W. Mycobacterium 37. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley chelonae: a cause of nodular skin lesions with a proclivity for renal C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, transplant patients. Am J Med 1989;86:173-7. treatment and prevention of nontuberculous mycobacterial 25. Johnson S, Weir TW. Multiple cutaneous ulcers of the legs, diseases. Am J Respir Crit Care Med 2007;175:367-416. Mycobacterium chelonae infection. Arch Dermatol 1993;129:1190-3. 38. Lee SM, Kim JM, Jeong J, Park YK, Bai GH, Lee MK, et al. 26. Saluja A, Peters NT, Lowe L, Johnson TM. A surgical wound Evaluation of the broth microdilution method using 2,3-diphenyl- infection due to Mycobacterium chelonae successfully treated with 5-thienyl-(2)-tetrazolium chloride for rapidly growing mycobacteria clarithromycin. Dermatol Surg 1997;23: 539-43. susceptibility testing. J Korean Med Sci 2007;22:784-90. 27. Terry S, Timothy NH, Zurlo JJ, Manders EK. Mycobacterium 39. Dhillon MS, Singh P, Sharma S, Gill SS, Nagi ON. Tuberculous chelonae: nonhealing leg ulcers treated successfully with an oral osteomyelitis of the cuboid: a report of four cases. J Foot Ankle antibiotic. J Am Board Fam Pract 2001;14:457-61. Surg 2000;39:329-35. 28. Sniezek PJ, Graham BS, Busch HB, Lederman ER, Lim ML, 40. Ferguson KB, Jones CE, Thomson AG, Moir JS. A rare case of Poggemyer K, et al. Rapidly growing mycobacterial infections after tuberculosis of the midfoot. Foot Ankle Spec 2012;5:327-9. pedicures. Arch Dermatol 2003;139:629-34. 41. Kennedy BS, Bedard B, Younge M, Tuttle D, Ammerman E, Ricci J, et al. Outbreak of mycobacterium chelonae infection associated with tattoo ink. N Engl J Med 2012;367:1020-4.