ACP medicine, 3rd Edition

Infectious Disease

Infections Due to Mycobacterium Leprae and Nontuberculous Mycobacteria

Michael K. Leonard Jr MD¹

Henry M. Blumberg MD, FACP²

¹Assistant Professor of Medicine, Division of Infectious Diseases, Emory University School of Medicine

²Associate Professor, Emory University School of Medicine

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

November 2005

Mycobacterium leprae infection (i.e., leprosy) is a disease that has been recognized—and has often been misunderstood—since ancient times. Nontuberculous mycobacteria (NTM) (i.e., mycobacteria other than M. tuberculosis complex [M. tuberculosis, M. bovis, M. africanum, and M. microti] and M. leprae) have been recognized to cause human disease since at least the 1950s. The emergence of the AIDS pandemic and the development of newer culture methodologies and molecular diagnostic tools have brought about increased interest in the epidemiology, diagnosis, and treatment of human infections from NTM.

More than 100 species of NTM have been identified; approximately 50 of these may be pathogenic for humans, causing a broad spectrum of disease.¹ Most NTM organisms are readily recovered from the environment, including environmental and drinking water, soil, and aerosols.^1,2 NTM organisms are important environmental pathogens that can cause a broad spectrum of diseases. NTM disease usually develops in immunocompromised hosts, such as development of M. avium complex [MAC] infection and other NTM infections in persons with HIV infection; but occasionally, NTM disease does occur in immunocompetent persons, such as those with underlying lung disease. Other types of NTM infection are skin and soft tissue infections from rapidly growing mycobacteria in postoperative patients and M. marinuminfection after aquatic exposure. NTM infections also occasionally develop in otherwise healthy patients. This chapter covers both M. lepraeand selected NTM organisms, including MAC; M. kansasii; M. marinum; and rapidly growing mycobacteria such as M. chelonae, M. fortuitum, and M. abscessus. Discussion of other NTM pathogens is beyond the scope of this chapter, but these other organisms are discussed in several reviews.^1,2,3,4,5 M. ulcerans, the causative agent of Buruli ulcer, which is common only in children in rural tropical areas, primarily in West Africa (i.e., Ghana, Côte d'Ivoire, and Benein), is also discussed elsewhere.^6,7

Leprosy (M. leprae Infection)

A classic scourge described in ancient medical texts and the Bible, leprosy (Hansen disease) is a mycobacterial disease caused by M. lepraethat affects the skin and peripheral nerves and can lead to severe disfigurement. Worldwide, about one to two million people are affected, with 763,917 new cases reported in 2002.⁸ In the United States, however, fewer than 100 new cases are diagnosed each year, almost all of them in immigrants from endemic areas.⁹ Secondary transmission from imported cases has not been recognized. Prompt recognition is imperative to limit morbidity from irreversible nerve damage. The disease is curable with multidrug therapy.

1. lepraehas two unique properties: it is thermolabile, growing best at 27° to 30° C, and it divides extremely slowly—the generation time is 12 to 14 days (in the mouse footpad model; the organism cannot be cultured in artificial media). Because of this slow growth, the incubation period in humans is long: a minimum of 2 to 3 years, with the average incubation time thought to be 5 to 7 years and the maximum time as long as 40 years. Because of the long and variable incubation period of the disease, its epidemiology and pathophysiology remain incompletely understood. Humans are the principal reservoir for M. leprae, but leprosy has also been found in armadillos and primates.⁹The main modes of disease transmission are by aerosolized droplets from lepromatous persons and, much less commonly, by direct skin contact.⁹ Transmission is thought to occur by the respiratory route because large numbers of bacilli are often found in the nasal discharge of untreated patients with multibacillary disease [see Diagnosis, Laboratory Studies, below]. Although these are believed to be the main modes of transmission, many patients have no identifiable contacts.¹⁰

Host genetics are thought to play an important role in both development of disease in exposed persons and the pattern of disease that develops. The vast majority of the world's population is not susceptible to leprosy; however, familial clustering of leprosy has been demonstrated, and twin studies have revealed high concordance rates.¹⁰ Susceptibility appears to be governed at least partly by the nramp1gene, which controls susceptibility to mycobacteria in mice. A human leukocyte antigen (HLA) association appears to play a role in the clinical spectrum of disease, with the HLA-DR3 genotype overrepresented in tuberculoid leprosy and the HLA genotype DQ1 or MT1 more often seen in lepromatous disease.¹⁰

DIAGNOSIS

Clinical Manifestations and Classification

Because M. leprae grows at cooler temperatures, leprosy primarily affects skin and nerves in the peripheral tissues. The clinical features are a result of interaction of the organism with the host's immune system. Infection of sensory neurons results in the loss of the sensation of pain; this leads to the mutilation that is characteristic of advanced leprosy. Infection of motor neurons causes paralysis. The manifestations of leprosy depend on the infected person's immune response to the causative agent, M. leprae.¹⁰ Clinically, leprosy may resemble many dermatologic and neurologic conditions; thus, a high index of suspicion is necessary for accurate diagnosis.

Early leprosy and indeterminate leprosy, which are characterized by hypopigmented, ill-defined skin lesions, often heal on their own and may even be ignored by some patients. Nevertheless, all such patients should receive chemotherapy. If healing does not occur, the disease progresses along a clinical spectrum [see Figure 1]. Leprosy typically presents as anesthetic skin lesions associated with thickened peripheral nerves.¹⁰ The appearance of the skin lesions varies according to the spectrum of disease.

Figure 1. Natural History of Leprosy The natural history and clinical spectrum of leprosy. (BL—borderline leprosy; BLL—borderline lepromatous leprosy; BTL—borderline tuberculoid leprosy; LL—lepromatous leprosy; TL—tuberculoid leprosy)

Advanced infection can be divided into two polar forms: tuberculoid leprosy and lepromatous leprosy. The stages of the spectrum of disease, in order of decreasing cell-mediated immune response to M. leprae, are tuberculoid leprosy, which is characterized by few skin lesions and low bacterial loads; borderline tuberculoid leprosy; borderline leprosy; borderline lepromatous leprosy; and lepromatous leprosy, which is characterized by diffuse skin lesions and high bacterial loads. The cell-mediated immunity of patients with tuberculoid leprosy is intact. Patients who have lepromatous leprosy are anergic and show severely impaired cell-mediated immunity to M. leprae and thus have a high burden of disease.

Tuberculoid leprosy

Patients at the tuberculoid pole of the disease spectrum typically present with a limited number (i.e., less than six) of large, asymmetrical, well-defined skin lesions. The skin is rough, anhidrotic, and usually anesthetic; central healing of lesions may occur. Neurologic involvement is limited to a few peripheral nerves. Enlargement of a single nerve is common, and marked nerve damage can occur early in the course of tuberculoid disease, often resulting in wristdrop, clawing of the hand, and footdrop.¹⁰ Tuberculoid leprosy often involves the greater auricular, radial cutaneous, ulnar, common peroneal, and posterior tibial nerves. Early treatment is key to minimizing nerve damage. Skin lesions of patients with tuberculoid leprosy contain predominantly helper T cells, well-formed granulomas, and few organisms.

Lepromatous leprosy

Patients at the lepromatous pole of the spectrum of disease present with skin lesions that are widely and symmetrically disseminated, often demonstrating only slight hypopigmentation or erythema. The major defect in lepromatous leprosy appears to be a specific inability of T cells to respond to M. leprae; as a result, these patients are unable to generate the chemokines and lymphokines that normally activate macrophages and thereby enhance killing of the organisms. Because of the poor cell-mediated immune response to M. leprae, the bacterial burden becomes quite large in patients with lepromatous leprosy. Typically, skin lesions are numerous. At times, the entire skin surface can be involved, yielding a diffuse, waxy appearance. Loss of eyebrows and hypertrophy of earlobes produce the characteristic leonine facies. Neurologic involvement is widespread. A symmetrical peripheral neuropathy progresses proximally; sensory loss precedes paralysis. Other cool tissues are often involved, including the anterior chamber of the eye, the upper airway, and the testes. Sustained bacillemia with multisystem infection can occur.

On biopsy, skin lesions of patients with lepromatous leprosy are practically devoid of granulomas and helper T cells; instead, they contain suppressor T cells and numerous bacilli. A biopsy specimen showing many organisms and foam cells but no granulomas confirms the diagnosis, as does the finding of numerous acid-fast bacilli (AFB) in smears of skin-slit preparations. If left untreated, lepromatous leprosy is relentlessly progressive.

Borderline leprosy

Many patients with leprosy have disease that falls between the tuberculoid and lepromatous forms. These patients are classified as having borderline tuberculoid or borderline lepromatous disease [see Figure 1].

Laboratory Studies

According to the World Health Organization (WHO) classification of leprosy, patients have paucibacillary disease when no bacilli are demonstrated on skin smears, and have multibacillary disease when bacilli are seen on skin smears.¹¹ The diagnosis of leprosy is usually suspected on clinical grounds. However, demonstration of acid-fast bacilli in slit-skin smears provides laboratory confirmation of the diagnosis in cases of multibacillary disease. Samples for skin smears are obtained by using a scalpel blade to scrape the openings of small slits made in pinched skin. The tissue fluid obtained is smeared on a slide and stained for AFB by the Fite method.^10,11

Skin biopsy is another method of diagnosing leprosy, especially in patients with paucibacillary disease, and it can be used to classify the disease according to the clinical spectrum. Bacilli are frequently not seen in specimens from patients with disease in the tuberculoid end of the spectrum. In such cases, a biopsy that shows well-formed granulomas but few or no organisms can help establish the diagnosis of tuberculoid leprosy; the finding of inflamed nerves usually confirms the diagnosis.¹⁰

Serologic testing has little clinical utility in diagnosing leprosy.

TREATMENT

Patients with leprosy should be treated by physicians who are experienced in the management of this disease. Antimicrobial agents that are used include rifampin, dapsone, clofazimine, ofloxacin, and minocycline. The WHO has recommended treatment regimens for leprosy [seeTable 1].

Table 1 World Health Organization Recommendations for Treatment of Leprosy12

Disease Classification (Leprosy Type) Drugs Dosages Duration Paucibacillary (indeterminate, tuberculoid, or borderline tuberculoid) Rifampin 600 mg once monthly, supervised 6 mo Dapsone 100 mg daily, self-administered Single-lesion, paucibacillary Rifampin 600 mg Single dose Ofloxacin 400 mg Minocycline 100 mg Multibacillary (borderline, borderline lepromatous, or lepromatous) Rifampin 600 mg once monthly, supervised 12 mo Dapsone 100 mg daily, self-administered Clofazimine 300 mg once monthly, supervised       or 50 mg daily, self-administered

Rifampin is the most effective agent against M. leprae and can render lepromatous patients noninfectious within days. Patients with paucibacillary disease that is indeterminate, tuberculoid, or borderline tuberculoid receive monthly rifampin (under supervision) and daily dapsone (self-administered) therapy for 6 months. In the past, dapsone was used alone, but this is no longer recommended, because monotherapy led to the emergence of drug resistance. Patients with a single-lesion paucibacillary disease can be treated with triple-drug therapy consisting of a single dose of rifampin, of lexicon, and minocycline. Multibacillary disease requires a minimum of 12 months of therapy with a three-drug regimen that includes daily dapsone and monthly rifampin therapy plus clofazimine therapy either monthly or daily; monthly medication is given under supervision, whereas daily medication is self-administered.¹² Long-term follow-up is often suggested because late relapses may occur.

Leprosy Reactions

After initiation of therapy for M. leprae, patients may experience episodic immunologically mediated acute inflammatory responses called reactions, which are important mechanisms for causing nerve damage [see Table 2]. These immune reconstitution reactions can be characterized by swelling and edema in preexisting skin lesions or by peripheral neuropathy and neuritis, which can cause pain, tenderness, and loss of function. If not recognized and treated aggressively, these reactions can lead to irreversible nerve damage and permanent limb deformity.

Table 2 Characteristics and Treatment of Leprosy Reactions13

Type Clinical Features Risk Factors Pathogenesis Management Type I: reversal reactions Occurs in BT and BB, but most common in BL; skin lesions are new, or there is increased inflammation in preexisting lesions; acute inflammation of nerve trunks may or may not occur Recent pregnancy, facial plaques, extensive skin involvement, and preexisting neuritis Increase in cell-mediated immunity to bacilli in dermis and Schwann cells, leading to inflammation of skin and nerve trunks Prolonged anti-inflammatory therapy, analgesia, and physical support of active neuritis; high-dose steroids (1 mg/kg) for 4–6 mo; azathioprine and cyclosporine are also effective; surgical decompression of swollen nerves if medical therapy is unsuccessful Type II: erythema nodosum leprosum Occurs in BL and LL; skin lesions are new, small, tender, erythematous subcutaneous nodules; fever, arthralgia, neuritis, vasculitis, adenopathy, iridocyclitis, orchitis, and dactylitis are present Pregnancy, age < 40 yr Systemic inflammatory response to deposition of extravascular immune complexes formed fromMycobacterium leprae antigen Thalidomide is the drug of choice; systemic symptoms and pain are alleviated in 24–48 hr, and nodules involute in 3 days; starting dose, 200 mg, may be decreased with control of symptoms; pentoxifylline and colchicine may be effective in mild cases; neuritis requires systemic steroids BB—borderline leprosy   BL—borderline lepromatous leprosy   BT—borderline tuberculoid leprosy   LL—lepromatous leprosy

There are two types of leprosy reactions. Type I reactions, or reversal reactions, are characterized by cellular hypersensitivity. Type II reactions, or erythema nodosum leprosum (ENL), are characterized by a systemic inflammatory response to immune complex distribution. Reversal reactions typically occur after initiation of leprosy treatment but can occur spontaneously before or after multidrug therapy. Treatment of type I reactions includes the use of anti-inflammatory agents; thalidomide is indicated for treatment of type II reactions.¹³ A decline in ENL has been observed since the introduction of multidrug therapy, perhaps in part because of the anti-inflammatory effects of clofazimine.

CHALLENGES

The enormous progress in chemotherapy, which has helped to reduce the number of leprosy cases by nearly 90% over the past 10 years, makes the worldwide elimination of leprosy a realistic goal. However, there are challenges to eradicating this disease: many patients present late in the course; multidrug therapy is still not used in some endemic areas, so relapses may occur; and unfortunately, the disease still carries a stigma, which can interfere with effective disease management.

Nontuberculous Mycobacteria Infections

NTM infections are associated with several major clinical syndromes [see Table 3]. Selected NTM infections are associated with pulmonary disease, lymphadenitis, skin and soft tissue disease, skeletal infection, and infections related to catheters and other foreign bodies. In addition, disseminated disease (e.g., caused by MAC) is common in persons with advanced HIV infection.

Table 3 Major Clinical Syndromes Associated with Nontuberculous Mycobacterial Infections1

Clinical Disease Selected Etiologic Species Common Less Common Unusual More Unusual   Chronic bronchopulmonary disease M. aviumcomplex M. kansasii M. abscessus M. malmoense M. xenopi M. simiae M. szulgai M. fortuitum M. celatum M. gordonae M. asiaticum M. shimodii M. smegmatis M. haemophilum Lymphadenitis M. aviumcomplex M. scrofulaceum M. malmoense — M. fortuitum M. chelonae M. kansasii M. abscessus M. haemophilum M. lentiflavum M. interjectum M. heidelbergense M. bohemicum Skin and soft tissue infection M. ulcerans M. marinum M. abscessus M. chelonae M. fortuitum M. kansasii M. haemophilum M. malmoense M. smegmatis Otitis media M. abscessus M. chelonae — — Tenosynovitis M. marinum M. aviumcomplex — M. fortuitum M. abscessus M. chelonae M. kansasii M. haemophilum M. scrofulaceum M. smegmatis M. nonchromogenicum M. malmoense M. xenopi M. szulgai Osteomyelitis M. fortuitum M. abscessus M. xenopi M. marinum M. kansasii Catheter-related infections M. fortuitum M. abscessus M. chelonae — M. mucogenium M. neoaurum M. aurum M. avium complex M. smegmatis Prosthetic valve infections M. fortuitum M. chelonae M. gordonae — Surgical site infections M. fortuitum M. chelonae M. abscessus M. simiae

Traditionally, NTM infections have been categorized on the basis of characteristic colony morphology, growth rate, and pigmentation (i.e., the Runyon system of classification). The availability of rapid molecular diagnostics has reduced the usefulness and importance of this system. However, growth rates and colony pigmentation continue to provide a practical way for grouping mycobacteria specimens in the clinical microbiology laboratory. Rapidly growing mycobacteria include nonpigmented and pigmented species that produce mature growth on agar plates within 7 days. So-called slowly growing mycobacteria include species that require more than 7 days to reach mature growth on solid media; this group includes MAC and M. kansasii, which are pigmented and require 7 to 10 days to mature on solid media. M. marinumgrows optimally at 28° to 30° C (which in large part explains its proclivity to cause skin and soft tissue infections), whereas M. gordonae (a common laboratory contaminant that rarely causes human disease) grows best at 35° to 37°C.

Although growth characteristics on solid media may be used to help categorize NTM infections, molecular diagnostic tests provide a definitive diagnosis for many NTM infections. Current guidelines recommend that for culture of NTM, as with culture for M. tuberculosis, both solid and liquid media be used to optimize recovery of mycobacterial species.^14,15 Mycobacteria grow more quickly in broth or liquid media than on solid media, which can decrease time to detection of a positive culture; in addition, liquid media may be more sensitive than solid media for some mycobacteria. Commercially available genetic probes for identification of selected NTM are available, including an acridinium ester-labeled nonradioactive DNA probe based on the detection of ribosomal RNA (rRNA). These probes are approved by the Food and Drug Administration for identification of M. tuberculosis and some common species of NTM, including M. kansasii, MAC, and M. gordonae.¹⁴ No commercial probes are available for identification of other NTM species, but polymerase chain reaction (PCR) has proved useful for identification of rapidly growing mycobacteria. High-performance liquid chromatography, which is generally available at large reference laboratories (e.g., state public health laboratories, the Centers for Disease Control and Prevention) is useful in identifying Mycobacteriumspecies.

MYCOBACTERIUM AVIUM COMPLEX

MAC comprises two closely related species, M. avium and M. intracellulare. MAC is encountered most often as an opportunistic pathogen in immunosuppressed patients, especially those with advanced HIV infection or AIDS. However, MAC infection can occur in immunocompetent hosts; it is especially likely to cause pulmonary infections in persons with underlying chronic lung disease. The environmental reservoirs for MAC include both water and soil. The portal of entry is the respiratory tract or the gastrointestinal tract. When isolated from immunocompetent patients, MAC may be a simple contaminant or a true pathogen.¹⁶ Because MAC is an organism of relatively low virulence, especially compared with M. tuberculosis, its presence does not always represent disease; colonization by MAC must be excluded through consideration of the clinical, radiographic, and pathologic features of the disease.

MAC Infection in the Immunocompetent Host

Chronic pulmonary disease is the clinical condition that is most often associated with MAC infection in the immunocompetent host; lymphadenitis and, rarely, disseminated disease are also seen. MAC pulmonary disease was initially described predominantly in men with underlying lung disease; often, such patients had a history of tobacco or alcohol consumption, and some had a prior history of tuberculosis.¹⁷ The radiographic presentation is similar to that of tuberculosis, with upper lobe fibronodular or cavitary disease.¹⁸ Patients with these radiographic abnormalities may present with pulmonary and systemic symptoms. CT findings may include multiple nodular infiltrates and bronchiectasis.¹⁷

Since the late 1980s, pulmonary MAC has been described in other immunocompetent patients, such as nonsmoking elderly women with fibronodular bronchiectasis and those with limited radiographic changes.^19,20 In addition, carriage of a cystic fibrosis or an abnormal α1-antiproteinase gene appears to predispose to the development of MAC lung disease.¹⁸ Older women without previous lung disease may present with fewer systemic symptoms and less pronounced radiographic findings. Pulmonary MAC infection in women, typically elderly women, with a radiographic pattern of nodules initially in the middle or lingual lobes has been termed the Lady Windermere syndrome and has been attributed to habitual voluntary suppression of cough.²¹ Pulmonary MAC infection may develop in patients with cystic fibrosis. A hypersensitivity pneumonitis has been reported in persons exposed to MAC aerosolized from contaminated hot tubs or pools.²² The radiographic picture is similar to that of other hypersensitivity pneumonitides.

Criteria for the diagnosis of NTM infection include repeated isolation of a potentially pathogenic species, the absence of other pathogens, and a compatible clinical, radiologic, or pathologic picture. The American Thoracic Society has developed criteria for the diagnosis of NTM infection, including pulmonary infection by MAC [see Table 4].²³

Table 4 American Thoracic Society Criteria for Diagnosis of Nontuberculous Mycobacterial Lung Disease21*

Radiographic Criteria Laboratory Criteria Infiltrate, reticulonodular infiltrate, or cavitary disease on chest x-ray      or Multifocal bronchiectasis or multiple small nodules on high-resolution chest CT Two positive respiratory (sputum and/or bronchial wash) cultures within 12 mo, if one or both specimens are AFB smear positive    or Three positive sputum/bronchial wash cultures within 12 mo, if none of the specimens are AFB smear positive    or In patients unable to produce sputum, one positive bronchial wash culture with a 2+, 3+, or 4+ AFB smear and/or growth on solid media    or A transbronchial biopsy yielding NTM    or Biopsy showing mycobacterial histopathologic features (granulomatous infiltration and/or AFB) and one or more sputa/bronchial washings are positive for NTM *For symptomatic patients who are HIV seropositive or HIV seronegative. AFB—acid-fast bacilli   CT—computed tomography   NTM—nontuberculous mycobacteria

Lymphadenitis from MAC typically affects previously healthy children who are 1 to 5 years of age.²⁴ Submandibular lymph nodes are most often involved. The patient usually does not have evidence of pulmonary or systemic illness. The lymph node may become tender and erythematous, and it may eventually drain. Diagnosis is made by pathologic examination of the excised node, which in most cases reveals caseating granulomas and positive AFB smears. Without culture data or nucleic acid testing, it is impossible to distinguish NTM lymphadenitis from tuberculous lymphadenitis. Excision of the infected node is the treatment of choice, because incision and drainage may lead to the formation of a draining fistulous tract.²⁵ Treatment with antimicrobials is rarely indicated except for serious disease or recurrences.

MAC Infection in AIDS

Disseminated MAC infection is an opportunistic disease that typically occurs late in the course of AIDS—in patients with CD4⁺ T cell counts lower than 50/mm³—when other opportunistic infections and neoplasia have already occurred. The mode of acquisition of MAC in patients with AIDS is not clear. The genetic diversity of MAC isolates from patients with AIDS implies that the organisms may be acquired from multiple environmental sources.

MAC produces widely disseminated infection in patients with AIDS.²⁶ Systemic symptoms predominate, including fever, chills, night sweats, and profound weight loss. Fever and night sweats are the most common manifestations, occurring in more than 75% of patients.²⁷Gastrointestinal symptoms, notably diarrhea, are present in at least a third of patients. Pulmonary symptoms are often present, but their significance is difficult to interpret because other opportunistic pathogens (e.g., cytomegalovirus and Pneumocystis) are often present, as well. Anemia and an elevated alkaline phosphatase level are frequently observed laboratory abnormalities.

Disseminated MAC infection can be readily documented by recovery of the organism from AFB and mycobacterial blood cultures. Blood is the preferred source of diagnostic specimens, but organisms may also be seen (and recovered by AFB culture) in biopsy specimens of the lung, liver, spleen, bone marrow, and lymph nodes. Despite the presence of many mycobacteria in macrophages, well-formed granulomas are typically absent; this so-called lepromatous histology reflects the profound impairment of cell-mediated immunity and explains the inability to contain the MAC infection. Intestinal or pulmonary infection may precede MAC bacteremia, but smears and cultures of these sites are not sensitive enough to be used as screening tests for early infection. Positive intestinal and pulmonary smear and culture results may represent colonization; however, positive cultures of stool and sputum are strongly predictive of subsequent dissemination in patients with low CD4⁺ T cell counts.²⁸

Treatment

Immunocompetent patients

Treatment of pulmonary MAC is lengthy (longer than 1 year), but success rates have increased with the availability of newer macrolide drugs. Multidrug therapy is indicated to prevent the development of resistance. The cornerstone of therapy is the administration of a macrolide; clarithromycin is the preferred agent, with azithromycin an alternative. Ethambutol and rifabutin are used in conjunction with a macrolide. In severe cases, an aminoglycoside (e.g,. amikacin) may be needed. Treatment should be continued for at least 12 months after sputum cultures have converted to negative. Surgical resection may be indicated in patients with severe, refractory disease or in those who develop severe complications (e.g., life-threatening hemoptysis).

HIV-infected patients

The treatment and survival of AIDS patients with MAC infection have improved greatly, especially since the advent of highly active antiretroviral therapy (HAART). More effective agents for MAC prophylaxis and treatment are now available, and the use of HAART can reduce the burden of disseminated MAC.²⁷ Patients with CD4⁺ T cell counts of 50/mm³ or lower should receive MAC prophylaxis with azithromycin (1,200 mg weekly) or clarithromycin (500 mg twice daily).²⁹ The drugs are equally effective, but azithromycin is often preferred for MAC prophylaxis because of its greater convenience. Rifabutin is an alternative prophylactic agent for patients who cannot tolerate a macrolide.³⁰ An AFB blood culture should be obtained before the initiation of MAC prophylaxis to rule out disseminated disease.

Macrolides are the cornerstone of treatment of MAC disease. In HIV-infected patients with disseminated MAC, treatment should consist of clarithromycin or azithromycin plus ethambutol [see Table 5]. The addition of rifampin or rifabutin may be indicated in patients with advanced AIDS who are not receiving antiretroviral treatment and who have a high mycobacterial load.³¹ Clarithromycin is the preferred macrolide for initial therapy. Clarithromycin may be slightly more active than azithromycin, but it is associated with more gastrointestinal side effects.²³ The debate continues as to which rifamycin is best. Rifabutin has lower minimum inhibitory concentrations than rifampin, but rifampin achieves higher serum levels.³² Rifampin is also associated with many more drug interactions than rifabutin and cannot be given with protease inhibitors; this is an important consideration in patients receiving treatment for HIV infection. In some patients who do not respond to therapy, the addition of a third and even a fourth drug may be indicated. Amikacin or a fluoroquinolone such as levofloxacin is used for this purpose.^31,33

Table 5 Treatment Regimens for Selected Nontuberculous Mycobacterial Infections1

Species Clinical Syndrome Treatment Duration M. aviumcomplex Pulmonary disease (e.g., HIV seronegative patients) Clarithromycin, 500 mg b.i.d. (preferred)       or Azithromycin, 600 mg q.d.*      plus Ethambutol, 15–25 mg/kg/day      plus Rifabutin, 300 mg q.d.       or Rifampin, 600 mg q.d.       with or without Streptomycin, 1 g q. 3–5 days/wk for 6–12 wk Amikacin, 7.5–15 mg/kg I.V. q.d.† (may add initially for cavitary disease) Until 12 mo after sputum cultures become negative (usually at least 18 mo of therapy) Disseminated disease (e.g., HIV-infected patients Clarithromycin, 500 mg b.i.d. (preferred) or Azithromycin, 600 mg q.d.*      plus Ethambutol, 15 mg/kg/day       with or without Rifabutin, 300 mg q.d.‡      or Rifampin, 600 mg q.d.§ For HIV-infected patients, duration depends on CD4+ T cell count M. kansasii Infiltrate/invasive pulmonary disease  Disseminated disease Rifampin, 600 mg q.d.      plus Ethambutol, 15 mg/kg/day      plus Isoniazid, 300 mg q.d. For severe disease, consider streptomycin, 0.5–1 g I.M. three times/wk or clarithromycin, 500 mg b.i.d., p.o., for first 2–4 mo 18 mo total therapy, with 12 mo of therapy after patient becomes culture negative Disease in HIV-infected patients As for pulmonary disease, but replace rifampin with rifabutin, 150 µg q.d. for patients on a protease inhibitor; clarithromycin, 500 mg b.i.d., can be substituted for rifampin/rifabutin in patients unable to take either drug M. abscessus Pulmonary, disseminated, or extensive cutaneous disease Amikacin, 15 mg/kg/day I.V. in one or two doses, with peaks at 20 µg/ml if given in two divided doses      plus Clarithromycin, 500 mg b.i.d.      plus Cefoxitin, 200 mg/kg, usually 3 g q. 6 hr I.V.   or Imipenem, 500–750 mg t.i.d. I.V. Unknown; surgical resection is the only curative therapy for pulmonary disease, but intermittent treatment with clarithromycin or azithromycin alone for weeks to months may be an alternative in selected patients Cutaneous localized disease Clarithromycin, 500 mg b.i.d. 4–6 mo M. fortuitum Pulmonary or cutaneous disease Clarithromycin, 500 mg b.i.d. plus Doxycycline, 100 mg b.i.d. or Trimethoprim-sulfamethoxazole, 800/160 mg b.i.d. or Levofloxacin, 500–750 mg q.d. or Gatifloxacin, 400 mg q.d. For pulmonary disease, 6–12 mo; for cutaneous disease, 4–6 mo M. marinum Cutaneous disease Ethambutol, 15 mg/kg/day      plus Rifampin, 600 mg q.d. or Clarithromycin, 500 mg b.i.d. or Minocycline, 100 mg b.i.d. or Doxycycline, 100 mg b.i.d. Minimum, 3 mo (see text) M. ulcerans Cutaneous disease Rifampin, 600 mg q.d. or Amikacin, 15 mg/kg b.i.d. I.M. or Streptomycin, 15 mg/kg/day I.M.    with or without Surgical resection, if possible 4–6 wk *Maximum dosage used in clinical study; adjust on individual basis depending on drug toxicity; dosages of 250 mg/day, 500 mg/day, or 500 mg three times/wk have been discussed. †A possible alternative is to give amikacin two or three times a week in doses of 15 to 20 mg/kg. ‡Rifabutin dose may need to be adjusted in HIV-infected patients on antiretroviral therapy. §Rifampin cannot be given with certain antiretroviral agents, including protease.

HIV-infected patients who start antiretroviral therapy can discontinue primary prophylaxis for MAC infection when their CD4⁺ T cell counts exceed 100/mm³ for more than 6 months.³⁴ Maintenance therapy (i.e., secondary prophylaxis) for MAC infection may be discontinued after 12 months if the patient remains asymptomatic and the CD4⁺ T cell count has been above 100/mm³ for at least 3 months.^29,31

Immune reconstitution syndromes can be an adverse event in the treatment of patients with HIV infection who have disseminated MAC. These syndromes sometimes occur in HIV-infected patients with unrecognized MAC who are started on antiretroviral agents. Pathogen-specific immune responses to MAC can occur in the first few months after the initiation of highly active antiretroviral therapy.³⁵ Immune reconstitution reactions to MAC usually manifest themselves as fever and lymphadenopathy (peripheral, intrathoracic, or intra-abdominal). Bacteremia does not occur. In severe cases, treatment with corticosteroids or nonsteroidal anti-inflammatory drugs may be necessary to ameliorate the symptoms associated with the immune response.

MYCOBACTERIUM KANSASII

1. kansasiiis found in the United States, Europe, and Japan; but in the United States, most cases are clustered in the Midwest—hence the name M. kansasii. Cases are also clustered in the South. Water is the only known reservoir; this organism has not been found in soil. M. kansasiiis the second most common organism responsible for NTM pulmonary disease. Risk factors include cigarette smoking, pneumoconiosis, and HIV infection. M. kansasii is also the second most common NTM infection causing disseminated disease in patients with AIDS.³⁶ Infection probably occurs through the respiratory route. Clinical symptoms of M. kansasii infection can be identical to those of pulmonary tuberculosis (i.e., fever, cough, weight loss, and hemoptysis). The radiographic presentation usually involves fibronodular or fibrocavitary upper lobe disease resembling pulmonary tuberculosis, except that the cavities may be thin walled and look like bullae.³⁷ In patients with HIV infection who have CD4⁺ T cell counts above 200/mm³, M. kansasii pulmonary disease can be cavitary. Patients with lower CD4⁺ T cell counts are more likely to have noncavitary pulmonary disease, sometimes in association with disseminated disease.

Treatment

Treatment for M. kansasii includes isoniazid, rifampin, and ethambutol given for a total of 18 months, with continuation of therapy for at least 12 months after the patient is culture negative [see Table 5].²³ M. kansasii is resistant to pyrazinamide; hence, this drug is not used. Treatment failures may result from rifampin resistance. Fluoroquinolones and aminoglycosides are alternative agents in selected cases. HIV-infected patients may benefit from the addition of clarithromycin as a fourth agent.¹

RAPIDLY GROWING MYCOBACTERIA

Rapidly growing mycobacteria constitute a group of nonpigmented and pigmented NTM species that produce growth on agar plates within 7 days. Of the rapidly growing mycobacteria, three groups account for most disease in humans: the M. fortuitum group, the M. chelonae-abscessus group, and the M. smegmatis group [see Table 6].^3,38 The use of molecular tools, including 16S ribosomal gene (rDNA) sequencing, has led to a recategorization of rapidly growing mycobacteria and recognition of new taxa. This is particularly the case with theM. chelonae-abscessus group, which consists of M. chelonae (formerly M. chelonae chelonae) and M. abscessus (formerly M. chelonae abscessus), along with M. immunogenum. Rapidly growing mycobacteria are associated with a variety of clinical syndromes, but they most commonly cause skin and soft tissue infections, both in the community and in hospitalized postoperative patients; other infections include skeletal infections (e.g., bone, joint, tendon), pulmonary disease (M. abscessus), and, on occasion, catheter-related infections [see Table 3].

Table 6 Principal Species of Rapidly Growing Mycobacteria That Are Human Pathogens

Group Species M. fortuitum M. fortuitum (formerly M. fortuitum biovar fortuitum) M. peregrinum (formerly M. fortuitum biovar peregrinum) M. mucogenicum (formerly M. chelonae-like organism) M. senegalense M. septicum M. magertiense M. porcinum M. houstonense M. bonickei M. neworleansense M. chelonae-abscessus M. chelonae (formerly M. chelonae subsp. chelonae) M. immunogenum M. smegmatis M. smegmatis sensu stricto M. goodie M. wolinskyi

Skin, Soft Tissue, and Skeletal Infections

The skin and soft tissues are the most common sites of infection from rapidly growing mycobacteria; indeed, of all NTM species, rapidly growing mycobacteria are the most common cause of skin and soft tissue infections. The M. fortuitum group and the M. chelonae-abscessusgroup cause localized infections, usually after local trauma or surgery.^1,38 Unlike infections with the M. chelonae-abscessus group, however, most M. fortuitum infections occur in patients who have no underlying chronic disease or immunosuppression. Furunculosis from M. fortuitum and M. fortuitum-group organisms have been reported in association with whirlpool footbaths in customers of nail salons.^39,40Shaving the legs with a razor before a pedicure was a risk factor for infection. In these cases, molecular typing techniques were used to match rapidly growing mycobacteria recovered from the footbaths with isolates recovered from patients.

Like other NTM species, rapidly growing mycobacteria can cause infections of tendon sheaths, bursae, bones, and joints after direct inoculation through accidental trauma, surgery, puncture, or injection.¹ Surgical debridement is often necessary for the diagnosis and treatment of such infections, along with chemotherapy (see below).

Health Care-Related Infections

There have been a number of reports of nosocomial or health care-associated infections caused by rapidly growing mycobacteria.^41,42,43These include infections from colonization of long-term venous access devices or peritoneal dialysis catheters, postinjection abscesses, and surgical wound infections (e.g., after cardiac bypass surgery, as well as augmentation mammoplasty, facelifts, and other plastic surgery; postoperative keratitis has been reported after ophthalmic surgery). Clusters of infections and outbreaks of true infection and pseudoinfections have occurred from contaminated fluids, irrigation with or exposure to tap water, injectable medicines, and topical skin solutions and markers. Most have involved M. fortuitum or M. abscessus, but M. chelonae has also been reported as a pathogen.⁴¹

Pulmonary Infections

1. abscessusis the third most common cause of pulmonary infection from NTM, after MAC and M. kansasii. M. abscessuscauses 80% of the pulmonary disease from rapidly growing mycobacteria; M. fortuitum accounts for about 15%.⁴⁴ M. chelonae and other rapidly growing mycobacteria cause pulmonary disease less commonly. Adolescents with cystic fibrosis are at increased risk for NTM-related pulmonary disease; MAC is the most common pathogen in these cases, but other mycobacteria, especially M. abscessus, have been reported with increasing frequency.

Signs and symptoms of pulmonary disease caused by rapidly growing mycobacteria are variable and nonspecific. Most patients have a cough that becomes productive as the disease progresses. Fatigue and weight loss may also occur as the disease progresses. In many patients, symptoms have been present for months to years and have been attributed to chronic bronchitis or bronchiectasis.

The chest radiograph usually demonstrates patchy, reticular, nodular opacities—usually in the upper lobes, although any portion of the lung can be involved. Cavitation occurs in less than 20% of cases.⁴⁴ CT scan may show findings similar to those noted in patients with pulmonary MAC infection.

The diagnostic approach to lung disease that is suspected to be caused by rapidly growing mycobacteria is the same as that followed with infections from MAC and other NTM infections [see Table 4]. All patients with suspected mycobacterial infection should have three sputum specimens examined microscopically for AFB and cultured for mycobacteria.

Disseminated Cutaneous Infections

Disseminated cutaneous disease from rapidly growing mycobacteria is unusual. When it does occur, the pathogen is usually from the M. abscessus-chelonae group. More than 90% of patients with disseminated cutaneous disease from rapidly growing mycobacteria are immunocompromised. They generally have risk factors such as chronic renal failure, renal transplantation, or, especially, long-term use of corticosteroid therapy; few have HIV infection, however.³⁸

Treatment

Selection of antimicrobial agents for infections from rapidly growing mycobacteria depends on the site of infection and the presumed pathogen. Empirical therapy is usually required initially, because final species identification and susceptibility testing are often performed at reference laboratories, and it may take weeks to obtain the results. Susceptibility testing should be performed on all clinically significant initial isolates, as well as on isolates recovered from patients who experience therapeutic failure or relapse.²¹ Standardization guidelines for susceptibility testing of all Mycobacterium species, including rapidly growing mycobacteria and other NTM species, have been recommended by the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards).¹⁵ To meet these standards, rapidly growing mycobacteria should be tested against clarithromycin, amikacin, cefoxitin, imipenem, tobramycin, doxycycline, ciprofloxacin, and trimethoprim-sulfamethoxazole; other drugs that may be included are linezolid and the newer fluoroquinolones (e.g., levofloxacin, gatifloxacin, and moxifloxacin).

Treatment regimens for infections from rapidly growing mycobacteria have been developed [see Table 5]. Recommendations are based on in vitro and case series reports, because data from controlled trials are lacking. For pulmonary disease from M. abscessus, antimicrobial therapy alone is usually unsuccessful.⁴⁵ Surgical resection of the involved lung is recommended, preferably after an initial period of antimicrobial therapy.¹ Unfortunately, some patients with M. abscessus lung disease have bilateral disease and thus are not surgical candidates.

Treatment of M. fortuitum pulmonary disease with antimicrobial therapy alone has been much more successful. A 6- to 12-month regimen is recommended, starting with clarithromycin plus a second drug (e.g., doxycyline, trimethoprim-sulfamethoxazole, or a newer fluoroquinolone such as levofloxacin, gatifloxacin, or moxifloxacin) [see Table 5]. Therapy should be adjusted on the basis of susceptibility-testing results.

Generally, the length of treatment with any of the current antimicrobials for most skin and soft tissue infections from rapidly growing mycobacteria has been 4 months for mild disease and 6 months for serious disease.³⁸ For more serious disease, treatment may include the use of injectable agents; however, these are usually limited to the first 2 to 6 weeks of therapy, to minimize cost and drug toxicity. Surgical excision or debridement of the wound site combined with appropriate antimicrobial therapy is recommended because of better outcomes (e.g., healing without relapse).³⁸ Treatment of cutaneous infection from rapidly growing mycobacteria generally includes the use of a newer macrolide such as clarithromycin [see Table 5]. Treatment of skeletal infections such as osteomyelitis from rapidly growing mycobacteria has been accomplished by surgical wound debridement plus a minimum of 6 months of drug therapy with agents selected on the basis of the in vitro susceptibilities of the isolate. Treatment of disseminated cutaneous disease involves drainage of abscesses plus appropriate antimicrobial therapy (usually including clarithromycin) for at least 6 months. Because of the risk of the development of clarithromycin resistance with monotherapy for disseminated disease (estimated to be about 10% to 20% in this setting), therapy for the first 3 to 6 weeks should include other drugs, selected on the basis of in vitro susceptibilities whenever possible.³⁸

MYCOBACTERIUM MARINUM

1. marinumis an NTM organism (group I of the Runyon classification) that causes skin infections in humans. M. marinumcauses disease in many fish species from cold water, warm water, freshwater, or saltwater; and human infection follows contact with diseased fish or contaminated water.⁴⁶ M. marinum is distributed widely in aquatic environments, especially in relatively still or stagnant water, such as in fish tanks and in naturally occurring bodies of water; swimming pools are rarely reported as a source at present, likely because of chlorination. First described as so-called swimming-pool granulomas, M. marinum skin infections have also been termed fish-tank granulomas, because infection is most often acquired from aquarium maintenance.⁴⁶ Additional investigations are needed to further develop preventive strategies; some investigators have suggested that gloves be worn when cleaning fish tanks.

Infection is acquired by direct inoculation of the bacterium through broken skin in an aquatic environment; typically, this is seen after lacerations or abrasions are exposed to freshwater or saltwater or in injuries from fish spines. Human skin and soft tissue infections are manifested by cutaneous ulcers, nodules, or nodular lymphangitis; such infections can result in significant morbidity.⁴⁷ Although infection is most commonly limited to skin, it can spread to deeper structures, resulting in tenosynovitis, arthritis, and osteomyelitis. Disseminated infections are rare. Delays in diagnosis have been noted and can lead to adverse outcomes. In a number of cases, delayed or missed diagnoses led to the use of corticosteroids, which may have facilitated the spread of infection.⁴⁶ Clues in the clinical history, such as exposure to fish, natural bodies of water, or swimming pools, can expedite diagnosis and therapy in patients presenting with cutaneous infections.⁴⁷ The median incubation period after exposure to M. marinum is about 3 weeks, but the incubation period was longer than 30 days for more than a third of the patients in one series, and the incubation period can be up to months after exposure.⁴⁷

A definitive diagnosis of M. marinum infection is made by biopsy and AFB culture results. The optimal therapy for M. marinum infection is unknown; there are no controlled trials on which to base treatment decisions, and data on M. marinum susceptibility are scarce.⁴⁶ Data from case series suggest that most skin infections can be adequately treated with antibiotics alone, with surgical intervention considered for those who do not respond to initial antimicrobial therapy. Adjunctive surgical debridement has been suggested for patients with deeper infections.⁴⁶ The length of treatment is also not standardized and has ranged from 3.5 months to 8 months in different series.⁴⁸ Treatment includes clarithromycin or minocycline (as monotherapy or in combination with other agents) or rifampin plus ethambutol [see Table 5]. Some authors recommend using at least two drugs.⁴⁸ A minimum of 3 months of therapy is recommended, with longer courses of therapy advocated for patients with more invasive infection (beyond skin and soft tissue) and those requiring surgical debridement. Some authors have suggested that treatment of M. marinum should include two drugs for 1 to 2 months after resolution of lesions, typically 3 to 4 months in total.⁴⁸ Although routine susceptibility testing has not been recommended for M. marinum,¹ it may be considered in special situations, such as for patients who do not respond clinically after several months of therapy and for those who continue to have positive cultures.

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Editors: Dale, David C.; Federman, Daniel D.