Extrapulmonary Infections Associated with Nontuberculous

Over the past several years, the prevalence of human

disease caused by nontuberculous mycobacteria (NTM)

has increased. Whether the increase in cases is real or

whether more cases are being recognized remains unclear.

Despite a considerable increase in knowledge about NTM

infections, they still represent a diagnostic and therapeutic

challenge for several reasons: 1) pathogenic isolates may

be indistinguishable from contaminant or saprophytic iso-

lates; 2) timely and reliable identication of isolates may

depend on proper communication between clinicians and

laboratory staff; 3) lack of standardized susceptibility test-

ing makes adoption of tailored therapies unrealistic; and 4)

lack of treatment guidelines exposes patients to toxic drugs

and disappointing outcomes. Laboratory research and mul-

ticenter controlled trials are needed to improve diagnosis

and treatment of these infections.

he >120 recognized species of nontuberculous myco-

bacteria (NTM) share common features: 1) they are

facultative pathogens; 2) evidence of human-to-human

transmission is lacking; 3) some NTM species are ubiqui-

tous and others have more restricted distribution; 4) treat-

ment may be difcult and vary according to the involved

organism and disease site; and 5) pathogenesis is still un-

dened, depending on the interaction between the micro-

organism and the host’s immune system (1). About 90%

of cases involve the pulmonary system; the rest involve

lymph nodes, skin, soft tissues, and bones. Less frequently

Extrapulmonary Infections

Associated with Nontuberculous

Mycobacteria in Immunocompetent

Persons

Claudio Piersimoni and Claudio Scarparo

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009 1351

Author afliations: United Hospitals, Ancona, Italy (C. Piersimoni);

and Santa Maria della Misericordia University Hospital, Udine, Italy

(C. Scarparo)

DOI: 10.3201/eid1509.081259

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Learning Objectives

Upon completion of this activity, participants will be able to:

Diagnose and treat nontuberculous mycobacterial (NTM) lymphadenitis effectively•

Identify elements of NTM osteoarticular infections•

Treat NTM skin infections according to standards of care•

Describe infections with rapidly growing mycobacteria•

Editor

P. Lynne Stockton, VMD, MS, Copyeditor, Emerging Infectious Diseases. Disclosure: P. Lynne Stockton, VMD, MS, has disclosed no relevant

nancial relationships.

CME Author

Charles P. Vega, MD, FAAFP, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine,

California, USA. Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant nancial relationships.

Authors

Disclosures: Claudio Piersimoni, MD; and Claudio Scarparo, MD, have disclosed no relevant nancial relationships.

SYNOPSIS

reported are central nervous system disease, keratitis, and

otitis media (1,2). We reviewed the epidemiology, clini-

cal features, diagnosis, and treatment of the most common

extrapulmonary diseases associated with NTM in immuno-

competent persons (2–5).

Lymphadenitis

Localized lymphadenitis most commonly affects chil-

dren; peak incidence occurs at 1–5 years of age (6). The

route of infection is hypothesized to be by way of the lym-

phatic vessels that drain the mouth and pharynx. The most

frequently isolated species is Mycobacterium avium com-

plex (MAC), followed by M. scrofulaceum, M. malmoense,

and M. hemophilum (7). However, a growing number of

previously unrecognized slow-growing mycobacteria have

been implicated with increasing frequency in reports of iso-

lated or microclustered cases (Table 1) (8).

Generally, NTM adenitis is an indolent disease; most

patients are otherwise healthy and have as their sole clini-

cal sign a chronic neck mass that does not respond to an-

timicrobial drug therapy. The disease is usually unilateral

and occurs in the cervical, submandibular, or preauricular

lymph nodes, although parotid and postauricular node in-

volvement has been reported. The nodes enlarge and may

rapidly soften and rupture, forming a draining sinus. Al-

though spontaneous regression has occasionally been de-

scribed, healing usually occurs by brosis and calcication.

Pyogenic and tuberculous adenitis are the most important

differential diagnoses.

Although a presumptive diagnosis of nontuberculous

mycobacterial adenitis can be made on the basis of clini-

cal history and physical examination, denitive diagnosis

depends upon the recovery of mycobacteria. Every effort

should be made to obtain material for culture and further

identication. Cultures of draining and ulcerated lesions, es-

pecially when swabs are used for specimen sampling, have

been shown to give a lower diagnostic yield than do needle

aspirates (9) or tissue biopsy samples. For recovery of NTM,

use of a liquid medium or radiometric growth detection are

regarded as the standard. Moreover, in children who have

not been vaccinated with M. bovis BCG, puried protein

derivative skin testing may be used as a surrogate test to di-

agnose chronic cervicofacial lymphadenitis (10). Histologic

appearance of necrotizing granulomatous inammation with

various degrees of caseation is also diagnostic.

Treatment of uncomplicated NTM lymphadenitis is

complete surgical excision. Incision and drainage are dis-

couraged because they usually lead to sinus tract formation

with chronic discharge. In a recent well-designed trial in-

cluding 100 children with culture- or PCR-conrmed diag-

noses, surgery was more effective than chemotherapy; cure

rates were 96% and 66%, respectively (11). Total excision

should be performed as early as possible to maximize re-

covery of the causative agent, to prevent further cosmetic

damage, to prevent extensive spread and subsequently

more difcult excision, and to cure disease. For some pa-

tients, however, surgery is associated with substantial risk

either because of a discharging sinus or proximity of facial

nerve branches. For these patients, chemotherapy preceded

by a diagnostic biopsy sample is recommended. Chemo-

therapy should also be considered for patients in whom

lymphadenitis recurs after surgery or for whom all abnor-

mal tissue could not be excised. Recent data indicate ne-

needle aspiration as the preferred diagnostic technique for

patients with nontuberculous mycobacterial adenitis who

do not undergo surgical excision. The optimal chemothera-

peutic regimen and its duration are still undetermined, but

combination therapy including clarithromycin and a rifa-

mycin, either rifampin or rifabutin and/or ethambutol, may

be benecial.

Osteoarticular Infections

NTM infections involving the musculoskeletal system

are uncommon. However, when they do occur, both rapid-

and slow-growing species have been implicated in chronic

granulomatous infections involving tendon sheaths, bursae,

bones, and joints. These are usually acquired by direct in-

oculation of the pathogen from an environmental source or

a contiguous infection focus as a consequence of surgical

procedures, penetrating trauma, injuries, or needle injec-

tions. Most affected patients are immunocompetent, but

some mycobacterial species, such as M. chelonae and M.

hemophilum, are almost entirely recovered from patients

with serious underlying diseases (HIV infection, immu-

nosuppressive therapy, or blood disorders) (4). In a recent

study of vertebral osteomyelitis caused by NTM (12),

various degrees of immunosuppression were found in 17

(51.5%) of 33 patients. From the 31 patients with spinal

infection studied, the following NTM species were recov-

ered: MAC (n = 13), M. xenopi (n = 7), M. fortuitum (n =

1352 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009

Table 1. Less frequently encountered mycobacterial species

recovered from immunocompetent persons with lymphadenitis*

Mycobacterium sp.

No. cases

reported

Identification method

M. bohemicum

3 GS

M. celatum

1 RH, HPLC, GS

M. genavense

1 RH, GS

M. heckeshornense

1 GS

M. heidelbergense

1 GS

M. interjectum

4 GS

M. lentiflavum

5 HPLC, GS

M. palustre

1 GS

M. parmense

1 HPLC, GS

M. simiae

4 RH, HPLC, GS

M. triplex

4 GS

M. tusciae

1 HPLC, GS

*Most persons were children. GS, gene sequencing; RH, reverse

hybridization; HPLC, high-performance liquid chromatography.

Extrapulmonary Infections and NTM

5), M. abscessus (n = 3), M. kansasii (n = 1), M. simiae (n =

1), and unidentied NTM species (n = 1). M. hemophilum

also causes NTM osteomyelitis infections in bone marrow

and solid organ transplants (13). The hand and wrist are the

most frequently reported sites of NTM tenosynovitis be-

cause of their abundance of synovial uid and tissue com-

bined with a higher probability of penetrating injury. Most

frequently, M. marinum and M. kansasii are involved; less

frequently, M. avium complex, M. szulgai, M. terrae, M.

fortuitum, M. chelonae, M. abscessus, M. malmoense, and

M. xenopi are found (14).

Clinically, osteoarticular infections caused by NTM are

indistinguishable from tuberculosis-associated infections.

Signs and symptoms such as localized pain (with or without

neurologic impairment), joint stiffness and swelling, low-

grade fever, sweating, chills, anorexia, malaise, and weight

loss have been reported (Table 2). On rare occasions, sup-

puration followed by extensive necrosis of the synovial tis-

sue may occur (3), although in more severe cases infection

may extend to the periosteum and lead to osteomyelitis (3).

The clinical course of the disease is typically protracted;

average time from onset of symptoms to diagnosis may be

as long as 10 months. To prevent severe tissue destruction

and neurologic disorders, prompt and accurate diagnosis is

essential. Diagnosis relies on clinical suspicion and must

be considered for patients with increasing musculoskeletal

system signs, those with inammation after penetrating or

blunt trauma, and those with underlying risk factors who

undergo a medical procedure. Culture of synovial uid and

tissue biopsy are mandatory for denitive diagnosis and

identication of the causative agent. Computed tomogra-

phy and sonography may help guide percutaneous tissue

biopsy sampling of infected areas or diagnostic aspiration

of intraarticular uid (15). Histopathologic examination

has shown a spectrum of inammatory changes, including

granulomatous lesions with or without caseation (3).

Lack of the following have greatly limited develop-

ment of consensus guidelines for the treatment of mus-

culoskeletal infections caused by NTM: correlation be-

tween in vitro susceptibility testing and clinical outcome,

standardized antimicrobial-drug susceptibility testing for

most NTM species, and clinical trials comparing differ-

ent therapeutic regimens among an adequate number of

patients. Prolonged chemotherapy with an isolate-tailored

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009 1353

Table 2. Clinical signs associated with osteoarticular infections caused by nontuberculous mycobacteria

Disease Affected site Mycobacterium spp.

Underlying diseases and risk factors

(no. cases reported)

Arthritis,

osteomyelitis

Thumb (interphalangeal

joint)

M. malmoense

Rheumatoid arthritis (1)

Arthritis Knee, ankle

M. xenopi

None* (6), invasive medical procedure (1)

Arthritis Multiple joints: wrist, knee,

finger, ankle, elbow,

vertebrae, shoulder

M. kansasii

AIDS (13), rheumatoid arthritis (3), systemic lupus

erythematous (2), renal transplant (2), polymyositis (1),

progressive systemic sclerosis (1), myelodysplasia (1),

none (26), localized trauma (10), steroid therapy (10)

Arthritis Knee

M. kansasii

Prosthetic joint (1)

Synovitis (carpal

tunnel syndrome)

Wrist

M. szulgai

No underlying disease, fish-tank cleaning (2)

Tenosynovitis Hand

M. intracellulare

None* (1)

Tenosynovitis Hand

M. chelonae

Penetrating injury (2), fracture (1),

Immunosuppression (3)

Tenosynovitis Hand, wrist M. avium complex Steroid injection (1), trauma (8), surgery (4)

Osteomyelitis Sternum, foot, elbow

M. wolinsky

Cardiac surgery (1), stepped on nail (1), open fracture (1)

Osteomyelitis Femur, tibia, calcaneus,

toe, elbow, sternum

M. goodii

Open fracture (4), stepped on nail (1), surgery (2),

penetrating trauma (2), puncture wound (1)

Osteomyelitis Wrist

M. scrofulaceum

Diabetes (1)

Osteomyelitis Hand, ankle, wrist

M. marinum

Fisherman exposed to aquarium (25), trauma (1), local

or systemic steroids (20)

Osteomyelitis

M. ulcerans

Traumatic injury (213)

Osteomyelitis Vertebrae

M. avium complex,

M. xenopi, M. fortuitum,

M. abscessus, M. kansasii,

M. simiae

Systemic lupus erythematous and treatment with

steroids (7), AIDS (4), interferon receptor defect (3),

carcinoma (1), renal failure (1), chronic granulomatous

disease (1), none* (16)

Osteomyelitis Vertebrae

M. xenopi

Vertebral disk surgery (58)

Osteomyelitis Tibia

M. conceptionense

Fracture (1)

Osteomyelitis Vertebrae

M. abscessus

Trauma to the back (1)

Osteomyelitis Vertebrae

M. avium complex

Trauma to the back (1)

Osteomyelitis Lower extremity, upper

extremity, vertebrae,

disseminated disease

M. hemophilum

AIDS (21), bone marrow or solid organ transplant (7);

AIDS plus solid organ transplant (1),

lymphoma (2), polycythemia vera (1)

*Otherwise healthy with no underlying disease or risk factor.

SYNOPSIS

drug combination associated with surgical debridement is

currently recommended for all musculoskeletal infections,

especially in patients with abscesses (12).

Skin and Soft Tissue Infections

Skin and soft tissue infections usually occur after trau-

matic injury, surgery, or cosmetic procedures, which may

expose a wound to soil, water, or medical devices occa-

sionally contaminated with environmental mycobacteria.

Although the epidemiology and clinical presentations of

NTM responsible for skin and soft tissue infections differ,

some species (MAC, M. kansasii, M. xenopi, and M. mari-

num) have been reported worldwide, whereas others (M.

ulcerans) have limited geographic distribution.

M. marinum causes diseases in many sh species and

is distributed worldwide. It is an opportunistic pathogen of

humans, in whom infection is infrequent and occurs by di-

rect injury from sh ns or bites or after cutaneous trauma

and subsequent exposure to contaminated water or other

sources of infection (shrimp, shellsh, frogs, turtles, dol-

phin, eels, and oysters). An increasing number of cases have

been reported from most countries with temperate climates

(1). Predisposing occupations and activities include sh-

ery worker, seafood handler, sh-tank owner, sherman,

pet shop worker, and water-related recreational exposure

(4). Consistent with the organism’s growth at low tempera-

tures, M. marinum infections are usually limited to the skin

and conned, with few exceptions, to 1 extremity. For sh-

tank owners, disease is often located in the hand or ngers;

for those who swim in pools, the elbow is affected for 85%,

followed by knee and foot (16). The incubation period is

usually <4 weeks but can be as long as 9 months. Signs and

symptoms of early infection are nonspecic, e.g., swelling

and pain followed by >1 skin lesions (17). At the inocula-

tion site, an erythematous or bluish papulonodular lesion

(≈0.5–3 cm) develops and slowly enlarges, becoming more

tender until it suppurates (18) (Figure). In ≈33% of patients,

M. marinum infection may spread to deeper structures (soft

tissues, tendons, and bone) (19), leading to extensive scar-

ring and varying degrees of functional impairment. Less

frequently, the disease extends from the inoculation site to

regional lymph nodes along the lymphatic vessels, mim-

icking the clinical appearance of cutaneous sporotrichosis

(20). Key elements for diagnosis of M. marinum infection

are a history of exposure to potential sources of infection;

a histopathologic appearance of granulomatous inamma-

tion but no caseation; and culture growth of M. marinum,

which strongly depends on incubation temperature. For lo-

calized skin lesions without a history of exposure to sh

tanks, swimming pools, or tropical sh, other NTM must

be considered (21).

Although presumptive identication can rely on a

few biochemical and phenotypic tests such as production

of photochromogenic pigment, negative nitrate reduction,

and positive tests for urease and Tween 80 hydrolysis, de-

nitive identication involves reverse hybridization tech-

niques, or, alternatively, high-performance liquid chroma-

tography analysis of mycolic acids and DNA sequencing

assays (22,23). In vitro susceptibility test results of M.

marinum clinical isolates have been reported extensively in

the literature. Only clarithromycin, minocycline, and ami-

kacin provide complete coverage (100% susceptibility);

doxycycline, rifampin, and trimethoprim/sulfamethoxazole

encounter different degrees of resistance (24). Drug-sus-

ceptibility testing of M. marinum isolates is recommended

only for patients who remain culture positive after several

months of therapy (25). Although a standardized regimen

for M. marinum disease is still undened, monotherapy with

doxycycline, minocycline, trimethoprim/sulfamethoxazole,

or clarithromycin should be limited to patients with mild

disease only. Clarithromycin combined with ethambutol or

rifampin is likely the best combination therapy. Treatment

with 2 agents should be continued for at least 1–2 months

after resolution of skin lesions. In addition, surgical treat-

ment (from mild debridement to amputation) may be re-

quired, especially when deep structures are involved (2).

M. ulcerans is the causative agent of Buruli ulcer, a

disease reported in >30 countries, mainly in tropical and

subtropical regions of Western and Central Africa but also

in Central and South America, Southeast Asia, and the

Western Pacic region (26). Currently limited knowledge

is mainly the result of a low number of reported cases and

inadequate surveillance. Recently, however, studies con-

ducted in some areas in which M. ulcerans is highly en-

demic have reported infection rates higher than those for

either tuberculosis or leprosy (27). Epidemiologic data on

detection of M. ulcerans DNA in aquatic insects (e.g., or-

1354 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009

Figure. Mycobacterium marinum infection of the arm of a sh-tank

worker.

Extrapulmonary Infections and NTM

ders Odonata and Coleoptera) and snails, as well as in the

biolm of aquatic plants, strongly suggest that the organism

is associated with exposure to surface water involved in

environmental changes such as mining, deforestation, ag-

riculture, and hydraulic installations and that it is likely to

occupy a specic niche within aquatic environments from

which it is transmitted to humans by an unknown mecha-

nism (28). It is hypothesized that M. ulcerans reaches the

human dermis through a cut or wound contaminated with

water, soil, or vegetation. M. ulcerans is a unique species

able to produce a potent, virulence-associated toxin called

mycolactone, which prevents phagocytosis of live organ-

isms and induces tissue destruction by its cytotoxic and im-

munosuppressive properties. Although all age groups can

be affected, Buruli ulcer is more frequent among children

<15 years of age; the lower limbs (which are involved 3.2×

more often than the upper limbs) are the most frequently

affected sites (29). The incubation period varies but is gen-

erally <3 months (4). Buruli ulcer usually starts as a single

painless subcutaneous nodule or papule, which later moves

to form an ulcer with undermined edges (30). Spontaneous

healing usually takes 4–6 months and involves extensive

scar formation, resulting in severe deformity with joint

contracture, subluxation, atrophy, or distal lymph edema

(4). Sometimes tissue destruction may be so extensive that

amputation is unavoidable. In addition, dissemination to

distant sites can occur, especially in younger patients (<15

years). Multiple lesions represent the most severe form of

the disease; a high percentage of cases are osteomyelitis,

often leading to amputation or even death (29). Disabilities

are frequent, estimated for 25% to 58% of cases (31). Al-

though in M. ulcerans–endemic areas, diagnosis and treat-

ment are determined essentially by clinical appearances,

laboratory methods are available. These methods consist

of direct smear examination of specimens taken from the

ulcer edge or from tissue (≈40% sensitivity); culture incu-

bated at 29°C–33°C for 6–8 weeks (≈20%–60% sensitiv-

ity); histopathologic necrosis of subcutaneous tissues and

dermal collagen accompanied by a scant nongranuloma-

tous inammatory reaction embedding acid-fast bacilli

(≈90% sensitivity) (30); and PCR, a highly sensitive test

that can produce results within 2 days but is still conned

to reference and research laboratories (32). Case conrma-

tion requires at least 2 positive results from the above diag-

nostic tests (33). A standardized method for susceptibility

testing of M. ulcerans is not currently available (25). The

main treatment for Buruli ulcer is surgery. To ensure com-

plete removal of visibly affected tissue and to prevent re-

currence, excision should include a wide margin, including

healthy tissue. Although in early disease simple excision is

usually curative, in advanced disease wide and traumatiz-

ing excision is needed, followed by skin grafting and long

hospital stays. Although many antimicrobial agents have

demonstrated excellent in vitro and in vivo activity against

M. ulcerans clinical isolates, further studies are needed to

assess whether experimental susceptibility data will corre-

late with clinical outcome (33). A recent report stated that

rifampin plus streptomycin (1×/day for 4 weeks) and surgi-

cal excision inhibited the spread of infection and converted

early lesions (nodules and plaques) from culture positive

to culture negative (34). In edematous M. ulcerans disease,

the most rapidly progressive form, rifampin and strepto-

mycin have demonstrated a dramatically benecial effect.

Other treatments (e.g., topical phenytoin powder, topical

nitrogen oxides, and dressing plus triple-drug therapy [ri-

fampin, amikacin, and heparin]) are still being evaluated.

M. bovis BCG vaccination appears to offer some short-term

protection, especially against the most severe form of the

disease (33).

Cutaneous MAC disease occurs by direct inoculation

(trauma, surgery, injection) and is characterized by skin le-

sions such as ulceration, abscess with sinus formation, or

erythematous plaque with a yellow crusted base. The le-

sions are indolent, with little or no lymph node reaction or

systemic symptoms; some MAC skin infections resemble

Lupus vulgaris infections. Diagnosis requires a high index

of suspicion; a history of exposure to a potential source of

infection may be suggestive. For an accurate diagnosis,

histopathology, proper acid-fast bacilli identication, and

susceptibility testing are needed. A combination of exci-

sion (or surgical debridement) and chemotherapy is usually

required. Therapy is continued for 6–12 months and con-

sists of at least 3 drugs, usually clarithromycin, rifampin,

and ethambutol. Additional therapy with amikacin is some-

times included for 6 weeks (2).

Rapidly growing mycobacteria (RGM) are a complex

group of environmental pigmented and nonpigmented my-

cobacteria. Their optimal incubation temperatures range

from 25°C to 40°C, and they are characterized by a rapid

(within 7 days) growth rate on subculture. Organisms re-

sponsible for disease in humans belong to the M. fortuitum

group, the M. chelonae/abscessus group, and the M. smeg-

matis group; M. abscessus, M. fortuitum, and M. chelonae

are the most common species involved in cutaneous and

soft tissue infections. Able to survive in harsh conditions,

these organisms produce biolm in aquatic environments,

mostly in piped water systems from which large clumps

of mycobacteria are released into water and can be subse-

quently transmitted to humans (35,36). In addition, RGM

are resistant to sterilizing agents (2% formaldehyde and

glutaraldehyde), antiseptics (organomercurial compounds),

and other common disinfectants (37). Clinical manifesta-

tions of RGM disease largely depend on the immunocom-

petence of the infected person. Cutaneous and soft tissue

infections may appear as a single lesion in an immunocom-

petent person, usually after penetrating trauma or invasive

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009 1355

SYNOPSIS

surgical procedure at the site of infection (M. fortuitum is

the predominant causative agent), or they may appear as

multiple or disseminated lesions, usually associated with

immunosuppressive treatments (especially long-term treat-

ment with steroids) or other immunosuppressive conditions

or concurrent illnesses (38). For the latter, M. chelonae and

M. abscessus are the predominant causative agents. Several

reported infections that occurred after traumatic, cosmetic,

or other medical procedures are summarized in Table 3.

In a large outbreak of RGM infection related to pedicures,

the median onset of signs and symptoms was 3 weeks, but

for some, signs and symptoms were delayed as long as 4

months after exposure (39). Histopathologic examination

of lesions showed suppurative granulomata and abscesses.

Areas of necrosis were typically seen, but caseation was

uncommon (21). Denitive diagnosis of clinically sus-

pected RGM soft tissue disease can be made by culture of

organisms from drainage material, aspiration uid, or tis-

sue biopsy sample. When NTM disease is suspected on the

basis of clinical signs, with any patient history, laboratory

staff should be alerted so they can use appropriate isola-

tion protocols (M. chelonae and some strains of M. absces-

sus are relatively heat intolerant and can be recovered by

primary isolation at 30°C). Identication of RGM at the

species level is of utmost importance because treatment

regimens and consequently clinical outcome are strongly

species related. Proper identication involves molecular

techniques (22) coupled with a few traditional biochemical

and phenotypic tests (use of the carbohydrates citrate, man-

nitol, inositol, and sorbitol; tolerance to 5% NaCl; nitrate

reduction; iron uptake; and 3-day arylsulfatase activity)

(35). Susceptibility testing performed by the broth microdi-

lution technique (25) is essential for choosing the most ef-

fective drug therapy and monitoring for the development

of mutational drug resistance (2). Most experts recommend

the use of specic antimicrobial drugs, given in combina-

tion to avoid the emergence of drug resistance. Treatment

for the M. fortuitum group may include amikacin, cefoxi-

tin, ciprooxacin, the newer quinolones gatioxacin and

moxioxacin, sulfonamides, and imipenem. Some degree

of susceptibility to doxycycline and clarithromycin has

been reported. M. abscessus strains are usually suscepti-

ble to amikacin, cefoxitin, imipenem, clarithromycin, and

azithromycin; M. chelonae are usually susceptible to amika-

cin, imipenem, tobramycin, clarithromycin, and sometimes

linezolid. Clarithromycin is generally the drug of choice

for localized disease caused by M. chelonae and M. absces-

sus (5,35). The duration of therapy is usually 4 months for

mild disease and 6 months for severe disease. Surgery is an

important complementary tool for treating these infections,

depending on disease severity and location.

Laboratory Diagnosis

Of all the currently described mycobacterial species,

≈60% have caused human diseases. For this reason, mod-

ern techniques for faster culture, identication, and drug

susceptibility testing are urgently needed in mycobacteri-

ology laboratories (22,25). In addition to the collection of

high-quality specimens, timely diagnosis of NTM disease

requires regular communication of clinical suspicion to the

laboratory staff because optimal recover of some fastidi-

ous species requires additional tasks. Routine techniques

include microscopy and culture; the latter should be per-

formed by using both liquid and solid media incubated at

1356 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009

Table 3. Skin and soft tissue infections caused by rapidly growing mycobacteria

Type of infection or procedure Mycobacterium spp. Clinical findings

Posttraumatic wound infections

M. fortuitum, M. chelonae, M. abscessus,

M. wolinskyi, M. goodii, M. porcinum

Subcutaneous abscesses, cellulitis

Pedicures

M. fortuitum, M. chelonae, M. mageritense

Furunculosis

Subcutaneous, intraarticular, or

periarticular Injections

M. chelonae, M. abscessus

Subcutaneous abscesses, painful nodules,

multiple sinus tracts, joint infections, fever,

chills after injection

Acupuncture

M. abscessus, M. chelonae, M.

nonchromogenicum

Erythematous papules, nodules, ulcerative

lesions, abscesses, confluent plaques, draining

sinus tracts with discharge, wrist tenosynovitis

Cardiac surgery

M. peregrinum, M. fortuitum, M. fortuitum

(third biovariant) complex, M. wolinskyi, M.

goodii, M. abscessus

Sternal wound infection, endocarditis

Cosmetic surgery or other surgical

procedures: liposuction, liposculpture,

face lift, breast lift (reduction

augmentation), silicon injection

M. fortuitum, M. chelonae, M. chelonae, M.

porcinum, M. wolinskyi, M. goodii

Erythema, tenderness, nodules, skin

induration, subcutaneous or deep-tissue

abscesses, fever, malaise, multiple abscesses

along original suction tracts, draining sinus

tracts, local pain, swelling

Nipple piercing

M. fortuitum, M. abscessus

Asymptomatic nodules, tender nodules

Implanted with prosthetic material

M. abscessus, M. goodii

Abscesses

Pacemaker placement

M. fortuitum, M. abscessus, M. wolinskyi

Abscesses

Peritoneal dialysis catheter

M. abscessus

Abscesses

Extrapulmonary Infections and NTM

different temperatures (22). Although optimal recovery

for most clinically relevant mycobacteria is obtained at

35C°–37C°, some species (M. hemophilum, M. marinum,

M. ulcerans and some species of RGM) require a lower

incubation temperature to grow. For this reason, all clinical

specimens that may harbor the above species (skin, syn-

ovial uid, and bone) should be cultured at 28C°–30C° and

at 35C°–37C°. Use of conventional biochemical and phe-

notypic tests for the identication of NTM is currently dis-

couraged; more rapid and specic methods are favored, in-

cluding high-performance liquid chromatography analysis

of mycolic acids and commercial molecular assays. These

may use either in-solution hybridization (Accuprobe, Gen-

Probe Inc., San Diego, CA, USA) or solid-format reverse-

hybridization assays (line probe assays) (22).Both tech-

niques are specic, but the latter (in which amplication

precedes hybridization) is more sensitive, enabling iden-

tication in the early stage of bacterial growth. Finally,

gene (16S rDNA) sequencing is required for those species

that cannot be identied by the above systems (22). Care-

ful strategies should be recommended for using 16S rDNA

sequence analysis databases because public databases may

have wrong sequences and commercial ones tend to be un-

derdeveloped and outdated (23,40).

Conclusion

Although NTM cause a broad spectrum of human dis-

ease, data on incidence of NTM infections are still lacking,

mainly because of the absence of systematic epidemiologic

studies, standard case denitions, and accurate mycobacte-

rial identication. Furthermore, nonspecic clinical mani-

festations, lack of familiarity with these infections, and

inadequate laboratory services make denitive diagnosis

of NTM diseases often delayed or even impossible. Cor-

relation of in vitro susceptibility testing with the clinical

outcome, composition and duration of treatment regimens,

and use of surgery or other therapeutic approaches are still

undened for most NTM species involved in human dis-

eases. Laboratory research and multicenter controlled trials

are needed to improve diagnosis and treatment of extrapul-

monary NTM infections.

Dr Piersimoni is a clinical microbiology consultant at the

United Hospitals, Ancona, Italy. His primary research interest

focuses on diagnostic and clinical aspects of mycobacterial infec-

tions.

Dr Scarparo is a medical microbiologist and head of the

Clinical Microbiology Laboratory at the Santa Maria della Mise-

ricordia University Hospital, Udine, Italy. His primary interests

include the epidemiology, diagnosis, and treatment of mycobacte-

rial infections.

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Address for correspondence: Claudio Piersimoni, Department of Clinical

Microbiology, United Hospitals, via Conca 71, I-60020 Ancona, Italy;

email: [email protected]

1358 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 9, September 2009