Resident Short Reviews
Localized Cutaneous Infections in Immunocompetent
Individuals Due to Rapidly Growing Mycobacteria
John Fowler, MD; Steven D. Mahlen, PhD, D(ABMM)
Rapidly growing mycobacteria (RGM) cause skin infections that are refractory to standard antibiotic regimens.
Although typically associated with disseminated cutaneous
or other systemic infections in immunocompromised
patients, RGM sometimes cause localized cutaneous
infections in immunocompetent hosts. These infections
are almost always associated with precedent skin trauma
and inoculation, and therefore have been implicated in
outbreaks involving contaminated tattoo ink and inadequately sterilized acupuncture needles. Histologic features
often include suppurative granulomatous inflammation,
and microorganisms are rarely visualized with stains for
acid-fast bacilli. The differential diagnosis includes granulomatous fungal and non-RGM bacterial infections as well
as noninfectious suppurative or sarcoidlike conditions.
Because no pathognomonic histologic features exist for
cutaneous RGM infections, clinical suspicion and appropriate workup are essential to reach an accurate and timely
diagnosis. Most localized cutaneous RGM infections in
immunocompetent individuals respond well to either
clarithromycin or amikacin, in combination with surgical
debridement.
(Arch Pathol Lab Med. 2014;138:1106–1109; doi:
10.5858/arpa.2012-0203-RS)
terium smegmatis group and other rarely pathogenic groups1
(Table).
Bacilli of the M smegmatis group, first discovered by
Sigmund Lustgarten in the smegma of a man with a penile
ulcer, were described in 1885.2 Fifty-three years later, a
report of a strain of RGM now known to be M fortuitum
isolated from a human postinjection abscess was published
by da Costa Cruz.3 In 1953, Moore and Frerichs4 recovered a
novel acid-fast bacillus from a knee abscess and subsequently named it M abscessus; and in 1972, Stanford et al5
published their findings regarding an RGM isolate from
postinjection abscess outbreaks. This isolate, named M
chelonae, was thought by some to be the same organism as
M abscessus, but modern classification techniques have
demonstrated these to be separate species.
Accepted for publication July 16, 2013.
From Pathology and Area Laboratory Services, Madigan Army
Medical Center, Tacoma, Washington (Dr Fowler); and the Bacterial
Diseases Branch, Walter Reed Army Institute of Research, Silver
Spring, Maryland (Dr Mahlen).
The authors have no relevant financial interest in the products or
companies described in this article.
The views expressed in this paper are those of the authors and do
not reflect the official policy or position of the Department of the
Army, the Department of Defense, or the US government.
Reprints: Steven D. Mahlen, PhD, D(ABMM), 503 Robert Grant
Ave, Bacterial Diseases Branch, Walter Reed Army Institute of
Research, Silver Spring, MD 20910-7500 (e-mail: steven.mahlen@
us.army.mil).
CLINICAL FEATURES
The RGM typically cause disseminated cutaneous infections in immunocompromised hosts, but have also been
implicated in lung, bone, joint, ocular, and prosthetic heart
valve infections.6–8 In most cases, patients with disseminated
cutaneous nontuberculous mycobacterial (NTM) infections
are taking low-dose systemic corticosteroids. The most
commonly implicated RGM in these instances are M
chelonae or M abscessus.1,9 On rare occasion, RGM cause
cutaneous infections in immunocompetent hosts. In contrast to cutaneous RGM infections in the immunocompromised, these infections are associated with precedent skin
trauma, such as puncture wounds or injuries sustained in
motor vehicle accidents. Patients with localized cutaneous
infections caused by RGM and other NTM typically present
with tender violaceous papules, plaques, nodules, or
cellulitis at sites of skin penetration or trauma that, despite
treatment with standard antibiotic regimens, have not
regressed. Gram stain and routine cultures may be negative,
and it is not until after a protracted course that NTM
infection is considered. The majority of solitary lesions occur
on the lower extremities, but the upper extremities, trunk,
and rarely head and neck may also be involved.9,10
Additionally, there are a number of reports of cutaneous
M chelonae infections in immunocompetent hosts due to
subcutaneous inoculation with contaminated tattoo
ink,8,11,12 after acupuncture,13,14 and after mesotherapy.15
Mycobacterium abscessus, M chelonae, Mycobacterium conceptionense, and M fortuitum have all been isolated in
postoperative infections after plastic surgery procedures.16,17
Myalgia, fatigue, and night sweats were observed in one
immunocompetent patient with tattoo-associated M chelo-
1106 Arch Pathol Lab Med—Vol 138, August 2014
Cutaneous Rapidly Growing Mycobacteria Infection—Fowler & Mahlen
R
apidly growing mycobacteria (RGM) are defined as
nontuberculous species that grow on laboratory media
within 7 days.1 There are currently 70 recognized species of
RGM that are classified into 6 groups based on genetic
relatedness, pigmentation, and biochemical properties.
Approximately 80% of disease in humans due to RGM is
caused by the nonpigmented Mycobacterium chelonae,
Mycobacterium abscessus, and Mycobacterium fortuitum, with
the remainder caused by RGM of the pigmented Mycobac-
Clinical Manifestations of Rapidly Growing Mycobacteria (RGM) Infections by Group
Clinical Manifestationsa
Mycobacterium fortuitum group
Mycobacterium chelonae/Mycobacterium
abscessus group
Mycobacterium mucogenicum group
Mycobacterium smegmatis group
Early-pigmented RGM
Mycobacterium mageritense/Mycobacterium
wolinskyi group
a
Localized skin and soft tissue infections, disseminated cutaneous disease (rare),
bone and joint infections, lung infections (rare), central nervous system disease
(rare, M fortuitum), keratitis, iatrogenic infections
Localized skin and soft tissue infections, disseminated cutaneous disease, lung
infections (M abscessus in particular), keratitis (M chelonae, M abscessus, otitis
media (M abscessus), iatrogenic infections
Iatrogenic infections
Localized skin and soft tissue infections, bone infections, lung infections (M
smegmatis)
Iatrogenic infections
Localized skin and soft tissue infections, bone infections
Data derived from Brown-Elliot BA, Wallace RJ. Mycobacterium: clinical and laboratory characteristics of rapidly growing mycobacteria. In:
Versalovic J, Carroll KC, Jorgensen JH, Funke G, Landry ML, Warnock DW, eds. Manual of Clinical Microbiology. 10th ed. Washington, DC: ASM
Press; 2011:525–538.1
nae infection,11 but constitutional symptoms often are not
present during localized cutaneous infections with these
organisms.9
HISTOPATHOLOGY
Biopsy of cutaneous RGM infections can show a variety of
patterns, depending on the stage at which the biopsy is
performed and the immune status of the patient. Suppurative mixed granulomatous inflammation is typically present
in immunocompetent patients (Figure 1). In a report of an
iatrogenic M abscessus outbreak, Rodrı́guez et al18 separated
the histopathologic findings into 3 categories: nodular or
diffuse inflammation with mixed granulomas containing
abscesses surrounded by epithelioid and Langhans giant
cells, neutrophilic abscesses with a subtle granulomatous
response, and deep dermal and subcutaneous granulomatous inflammation without neutrophils. Of these patterns,
the most commonly observed was the mixed pattern with a
robust granulomatous response. The authors observed that
broad abscesses with a weak-to-absent granulomatous
response were more characteristic of biopsies from immunocompromised patients, and that acid-fast bacilli were
more likely to be seen in these instances. In 82% of the
biopsies, clear vacuoles surrounded by neutrophils or
epithelioid cells were present, and of these nearly one-third
contained clumps of acid-fast bacilli (Figure 2). These
findings are corroborated by Gable et al,19 who describe a
pattern of suppurative infection with a variable degree of
granulomatous inflammation in 6 immunocompromised
patients with cutaneous RGM infections. Of these cases, 2
had pseudocysts containing microorganisms. This pattern
has been suggested to be unique to the RGM.20
Other studies characterizing the histopathologic features
of NTM in immunocompetent patients show mixed results:
Dodiuk-Gad et al21 reported granulomas in 36% of biopsies
from immunocompetent hosts, whereas Bartralot et al22
reported granulomas in 83%. Acid-fast bacilli were observed
in even fewer cases. Other patterns observed include robust
tuberculoid, palisading, or sarcoidlike granulomas, as well as
nongranulomatous patterns, such as necrotizing folliculitis,
panniculitis, and nonspecific chronic inflammation.22
Because biopsy does not necessarily demonstrate microorganisms or granulomatous inflammatory reaction, and
because RGM infections may not always be detected on
standard wound cultures, a clinical suspicion for RGM or
other NTM is essential for accurate and timely diagnosis. In
such cases, a clinical history of skin infection that follows
Arch Pathol Lab Med—Vol 138, August 2014
penetrating skin trauma, lacks response to standard
antibiotics, or has negative standard wound cultures should
prompt further investigation to include acid-fast bacilli
stains and cultures. In cases where mycobacterial infection is
suspected but the Ziehl-Neelsen stain is negative, it may be
useful to perform a Fite stain, which differs in that tissue
sections are deparaffinized using a mixture of mineral oil
and xylene rather than xylene alone. This method is
considered to be less harsh, preventing loss of the
organism’s acid-fast properties, and typically is used to
detect Mycobacterium leprae. However, no recent studies
have been published that evaluate the sensitivity of modified
versus standard acid-fast stains for diagnosis of cutaneous
RGM infections.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for each of the granulomatous
patterns encountered in cutaneous RGM infections is broad.
Suppurative versus nonsuppurative granulomatous inflammations raise divergent differential diagnoses, and in both
cases, the cause of the granulomas may be either infectious
or noninfectious. As with any suppurative cutaneous skin
infection—particularly following trauma to the skin—
bacterial infection due to more commonly encountered
organisms such as Staphylococcus aureus and Streptococcus
pyogenes must be considered in the differential diagnosis.
These cases are usually excluded by culture and successful
empirical treatment. If standard wound cultures are negative
and empirical treatment is unsuccessful, then RGM infection
should be considered.
Suppurative granulomas are associated with a myriad of
infectious conditions, including blastomycosis, coccidiomycosis, paracoccidiomycosis, phaeohyphomycosis, cryptococcosis, cat-scratch disease, nocardiosis, actinomycosis, and
other atypical mycobacterial infections.23,24 Additional stains
for microorganisms should be considered if there is a
possibility that these infectious agents are present. Periodic
acid–Schiff and Gomori methenamine silver will facilitate
visualization of the causative microorganisms in blastomycosis, coccidiomycosis, and paracoccidiomycosis, whereas
specific histochemical stains are typically not needed for
visualizing the diverse pigmented fungal organisms that
cause phaeohyphomycosis, but periodic acid–Schiff and
Gomori methenamine silver may still be useful. Cryptococcal microorganisms are highlighted by mucicarmine and
Fontana-Masson, and Warthin-Starry highlights rare bacilli
in the necrotic granulomas of cat-scratch disease.23 Nocardia
Cutaneous Rapidly Growing Mycobacteria Infection—Fowler & Mahlen 1107
histochemical stains and cultures will be negative in these
cases, and other findings, such as a history of sarcoidosis or
the presence of polarizable material or keratin debris within
granulomas, would favor a diagnosis other than RGM
infection.
Tuberculoid granulomas are seen in tuberculosis, leprosy,
leishmaniasis, and other conditions.24 A Ziehl-Neelsen
histochemical stain will highlight microorganisms within
granulomas in M tuberculosis cutaneous infections, and
wound cultures for mycobacteria should not show growth
by 7 days. Mycobacterium leprae is best visualized using a Fite
stain, though microorganisms often are not readily visualized in tuberculoid leprosy, and a wound culture will fail to
grow microorganisms. Cutaneous leishmaniasis may show
amastigotes within macrophages using hematoxylin-eosin,
but these organisms are not always readily visualized in
biopsies of later lesions. If the clinical history suggests
cutaneous leishmaniasis or leprosy, polymerase chain
reaction may be useful for their detection.
Figure 1. Mycobacterium chelonae infection of the hand following
accidental incision on the lid of a metal can. There is diffuse
granulomatous inflammation with focal suppuration surrounding
vacuoles within the dermis, and the epidermis shows irregular
acanthosis and parakeratosis (hematoxylin-eosin, original magnification
310).
Figure 2. Vacuole containing numerous Mycobacterium chelonae
bacteria (Fite acid-fast bacilli, original magnification 3100).
stains gram positive in a beaded pattern and is also partially
acid fast. This can be confounding, as the RGM—when
detected on Gram stain—will stain with a beaded pattern
that may be mistaken for gram-positive bacilli.1 Definitive
diagnosis often requires culture of the wound, particularly
when other atypical mycobacterial infections such as
Mycobacterium marinum are in the differential diagnosis.
Noninfectious causes of suppurative granulomas include
superficial granulomatous pyoderma and ruptured cysts and
follicles.24 Lesions of superficial granulomatous pyoderma
tend to occur on the trunk but may also occur at surgical
sites.25 A recent case report of facial superficial granulomatous pyoderma following surgical scar revision demonstrates
the potential similarity of superficial granulomatous pyoderma and RGM infection with regard to clinical presentation and histologic appearance.26 In this case, appropriate
histochemical stains and negative cultures aided in establishing the correct diagnosis.
Sarcoidlike granulomas raise the differential diagnosis of
sarcoid and foreign body giant cell reaction. However,
1108 Arch Pathol Lab Med—Vol 138, August 2014
LABORATORY IDENTIFICATION
Isolation of the RGM is best accomplished by culture at
288C to 308C.1 Once colonies are isolated, additional testing
for definitive speciation is performed. Before the widespread
use of molecular testing, biochemical and antimicrobial
susceptibility tests were used to classify the RGM. For
example, the M fortuitum and M chelonae/M abscessus groups
are strongly positive for the arylsulfatase reaction at 3 days,
in contrast to Mycobacterium wolinskyi and the M smegmatis
group. Other tests, such as nitrate reduction, carbohydrate
utilization, and growth in 5% NaCl, can help distinguish
among species. Though historically these tests have been
useful in a clinical context, molecular methods are now
preferred for clinical identification.1 Therefore, biochemical
testing is reserved as an adjunct to new species characterization and not used routinely for diagnosis.
Molecular identification methods have shown their
usefulness for differentiating among RGM. These methods
have the advantage of producing accurate results that are
rapidly available. In one method, 2 main hypervariable
domains on the 5 0 end of the 16S rRNA gene (region A and
region B) are analyzed for signature sequences that
differentiate among species.1,27 Two of the major RGM, M
chelonae and M abscessus, are identical in these regions, but
differ in the 3 0 end of the 16S rRNA gene. Sequence
differences within the heat shock protein gene (hsp65) are
very useful in differentiating among species that have a high
degree of similarity in the 16S rRNA gene, including M
chelonae and M abscessus. Additionally, the hsp65 gene is
amenable to polymerase chain reaction restriction enzyme
analysis, which does not rely on growth rates or nutritional
requirements for initial identification and is relatively
inexpensive. However, it is a relatively complex test that,
as of 2011, has not been approved by the Food and Drug
Administration and therefore requires extensive in-house
validation. The utility of sequencing the rpoB gene has more
recently been demonstrated in instances where neither the
16S rRNA nor the hsp65 gene differentiated among the
RGM species.1
TREATMENT AND PROGNOSIS
Several factors must be considered when treating NTM
skin infections, such as immune status and number of
cutaneous lesions. If multiple lesions are present, or if
Cutaneous Rapidly Growing Mycobacteria Infection—Fowler & Mahlen
surgical debridement would result in cosmetically or
functionally unacceptable results, medical therapy alone
may suffice. Although M chelonae and M abscessus historically have been considered to be particularly resistant to
antibiotics as compared with M fortuitum,2 more recent
evidence suggests that clarithromycin is reliably active
against M chelonae and M abscessus but not M fortuitum.9
In cases of M fortuitum infection, amikacin is the antibiotic
of choice.2,9 The results of one small clinical trial published
in 1993 by Wallace et al28 showed that monotherapy with
clarithromycin was effective in treating disseminated infection from M chelonae in immunocompromised patients;
however, it is questionable whether these results could be
extrapolated to immunocompetent patients, as both the
mechanism of infection and the hypothetical virulence of
the infectious agents are likely different between the 2
groups. Regardless, monotherapy should be undertaken
with caution, as development of resistance to individual
agents has been reported.9 Moreover, Uslan et al9 have
noted higher levels of resistance to previously favored
antibiotics of multiple different classes. Development of
resistance to the cell wall synthesis inhibitors in particular is
conjectured to be due to asymmetric and time-regulated cell
elongation and division that leads to variable sensitivity of
the RGM to these antibiotics,29 which may partially explain
the protracted course of RGM infections. With localized
cutaneous NTM infections, it may be reasonable to delay
treatment until susceptibility test results are available,
whereas delay of treatment may not be feasible in cases of
disseminated disease. In immunocompetent hosts, complete
surgical excision, if possible, may be curative,17 though cure
is most reliably achieved with a combination of medical and
surgical therapy.9,10,16 This is in contrast to disseminated
cutaneous infection in immunocompromised hosts, for
whom prognosis can be quite poor even with adequate
treatment.30
References
1. Brown-Elliot BA, Wallace RJ. Mycobacterium: clinical and laboratory
characteristics of rapidly growing mycobacteria. In: Versalovic J, Carroll KC,
Jorgensen JH, Funke G, Landry ML, Warnock DW, eds. Manual of Clinical
Microbiology. 10th ed. Washington, DC: ASM Press; 2011:525–538.
2. Brown-Elliot BA, Wallace RJ. Clinical and taxonomic status of pathogenic
nonpigmented or late-pigmenting rapidly growing mycobacteria. Clin Microbiol
Rev. 2002;15(4):716–746.
3. da Costa Cruz JC. Mycobacterium fortuitum: um novo bacilo acidoresistente patogenico para o homen [Mycobacterium fortuitum: new acid fast
bacillus pathogenic for man]. Acta Med (Rio de Janeiro). 1938;1:298–301.
4. Moore M, Frerichs JB. An unusual acid fast infection of the knee with
subcutaneous, abscess-like lesions of the gluteal region: report of a case study
with a study of the organism, Mycobacterium abscessus. J Investig Dermatol.
1953;20(2):133–169.
5. Stanford JL, Pattyn SR, Portaels F, Gunthorpe WJ. Studies of Mycobacterium
chelonae. J Med Microbiol. 1972;5(2):177–182.
Arch Pathol Lab Med—Vol 138, August 2014
6. Freitas D, Alvarenga L, Sampaio J, et al. An outbreak of Mycobacterium
chelonae infection after LASIK. Ophthalmology. 2003;110(2):276–285.
7. Grange JM. Mycobacterial infections following heart valve replacement. J
Heart Valve Dis. 1992;1(1):102–109.
8. Preda VA, Maley M, Sullivan JR. Mycobacterium chelonae infection in a
tattoo site. Med J Aust. 2009;190(5):278–279.
9. Uslan DZ, Kowalski TJ, Wengenack NL, Virk A, Wilson JW. Skin and soft
tissue infections due to rapidly growing mycobacteria: comparison of clinical
features, treatment, and susceptibility. Arch Dermatol. 2006;142(10):1287–1292.
10. Escalonilla P, Esteban J, Soriano ML, et al. Cutaneous manifestations of
infection by nontuberculous mycobacteria. Clin Exp Dermatol. 1998;23(5):214–
221.
11. Goldman J, Caron F, de Quatrebarbes J, et al. Infections from tattooing:
outbreak of Mycobacterium chelonae in France. BMJ. 2010;341:c5483.
12. Kappel S, Cotlair J. Inoculation of mycobacterium chelonae from a tattoo. J
Am Acad Dermatol. 2011;64(5):998–999.
13. Lee WJ, Kang SM, Sung H, et al. Non-tuberculous mycobacterial infections
of the skin: a retrospective study of 29 cases. J Dermatol. 2010;37(11):965–972.
14. Woo PC, Li JH, Tang W, Yuen K. Acupuncture mycobacteriosis. N Engl J
Med. 2001;345(11):842–843.
15. Regnier S, Cambau E, Meningaud JP, et al. Clinical management of rapidly
growing mycobacterial cutaneous infections in patients after mesotherapy. Clin
Infect Dis. 2009;49(9):1358–1364.
16. Lim JM, Kim JH, Yang HJ. Management of infections with rapidly growing
mycobacteria after unexpected complications of skin and subcutaneous surgical
procedures. Arch Plast Surg 2012;39:18–24.
17. Panossian A, Cohen MJ, Posalski I. Upper extremity Mycobacterium
chelonae cutaneous infection. Plast Reconstr Surg. 2011;127(6):163e–165e.
18. Rodrı́guez G, Ortegón M, Camargo D, Orozco LC. Iatrogenic Mycobacterium abscessus infection: histopathology of 71 patients. Br J Dermatol. 1997;
137(2):214–218.
19. Gable AD, Marsee DK, Milner DA, Granter SR. Suppurative inflammation
with microabscess and pseudocyst formation is a characteristic histologic
manifestation of cutaneous infections with rapid-growing mycobacterium
species. Am J Clin Pathol. 2008;130:514–517.
20. Meyers WM. Mycobacterial infections of the skin. In: Ashworth TG, ed.
Tropical Pathology. Vol 8. 2nd ed. Berlin, Germany: Springer; 1995:291–378.
21. Dodiuk-Gad R, Dyachenko P, Ziv M, et al. Nontuberculous mycobacterial
infections of the skin: a retrospective study of 25 cases. J Am Acad Dermatol.
2007;57(3):413–420.
22. Bartralot R, Pujol RM, Garcı́a-Patos V, et al. Cutaneous infections due to
nontuberculous mycobacteria: histopathological review of 28 cases: comparative
study between lesions observed in immunosuppressed patients and normal hosts.
J Cutan Pathol. 2000;27(3):124–129.
23. Hirsh BC, Johnson WC. Pathology of granulomatous diseases: mixed
inflammatory granulomas. Int J Dermatol. 1984;23(9):585–597.
24. Weedon D. The granulomatous reaction pattern. In: Weedon D, Strutton G,
Rubin AI, Houston M, Davie B. Weedon’s Skin Pathology. 3rd ed. London, United
Kingdom: Churchill Livingstone; 2010:169–194.
25. Quimby SR, Gibson LE, Winkelmann RK. Superficial granulomatous
pyoderma: a clinicopathologic spectrum. Mayo Clin Proc. 1989;64(1):37–43.
26. Persing SM, Laub D. Superficial granulomatous pyoderma of the face: a
case report and review of the literature. Eplasty. 2012;12:e56.
27. Patel JB, Leonard DG, Pan X, Musser JM, Berman RE, Nachamkin I.
Sequence-based identification of mycobacterium species using the MicroSeq 500
16S rDNA bacterial identification system. J Clin Microbiol. 2000;38(1):246–251.
28. Wallace RJ, Tanner D, Brennan PJ, Brown BA. Clinical trial of
clarithromycin for cutaneous (disseminated) infection due to Mycobacterium
chelonae. Ann Intern Med. 1993;119:482–486.
29. Aldridge BB, Fernandez-Suarez M, Heller D, et al. Asymmetry and aging of
mycobacterial cells lead to variable growth and antibiotic susceptibility. Science.
2012;335(6064):100–104.
30. Bartralot R, Garcı́a-Patos V, Sitjas D, et al. Clinical patterns of cutaneous
nontuberculous mycobacterial infections. Br J Dermatol. 2005;152:727–734.
Cutaneous Rapidly Growing Mycobacteria Infection—Fowler & Mahlen 1109