Mycobacterium

Mycobacterium are acid-fast bacilli that are slow-growing opportunistic pathogens. Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. Over 190 species are recognized in this genus ¹. Mycobacterium genus includes pathogens known to cause serious diseases in humans, including tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae) in humans. If you suspect any of these infections, seek help from a clinical microbiologist or infectious diseases specialist for specific diagnosis and management.

Mycobacterium abscessus

Mycobacterium abscessus also called M. abscessus, is a bacterium distantly related to the ones that cause tuberculosis and Hansen’s Disease (Leprosy). Mycobacterium abscessus is part of a group of environmental mycobacteria and is found in water, soil, and dust. Mycobacterium abscessus has been known to contaminate medications and products, including medical devices.

Mycobacterium abscessus can cause a variety of infections. Healthcare-associated infections due to this bacterium are usually of the skin and the soft tissues under the skin. It is also a cause of serious lung infections in persons with various chronic lung diseases, such as cystic fibrosis.

People with open wounds or who receive injections without appropriate skin disinfection may be at risk for infection by mycobacterium abscessus. Rarely, individuals with underlying respiratory conditions or impaired immune systems are at risk of lung infection.

Mycobacterium abscessus is a bacterium distantly related to the ones that cause tuberculosis and leprosy. Mycobacterium abscessus is part of a group known as rapidly growing mycobacteria and is found in water, soil, and dust. It has been known to contaminate medications and products, including medical devices.

Mycobacterium abscessus transmission

Transmission of mycobacterium abscessus can occur in several ways. Infection with mycobacterium abscessus is usually caused by injections of substances contaminated with the mycobacterium abscessus bacterium or through invasive medical procedures employing contaminated equipment or material. Infection can also occur after accidental injury where the wound is contaminated by soil. There is very little risk of transmission from person to person.

Mycobacterium abscessus prevention

Anyone who touches or cares for the infected site should wash their hands carefully with soap and water. Patients should follow all instructions given by their healthcare provider following any surgery or medical procedure. Avoid receiving procedures or injections by unlicensed persons.

Mycobacterium abscessus symptoms

Skin infected with mycobacterium abscessus is usually red, warm, tender to the touch, swollen, and/or painful. Infected areas can also develop boils or pus-filled vesicles. Other signs of mycobacterium abscessus infection are fever, chills, muscle aches, and a general feeling of illness. However, for a definite diagnosis, the organism has to be cultured from the infection site or, in severe cases, from a blood culture. A medical provider should evaluate the infection to determine if it may be due to mycobacterium abscessus.

Diagnosis is made by growing this bacterium in the laboratory from a sample of the pus or biopsy of the infected area. When the infection is severe, the bacterium can be found in the blood and isolated from a blood sample. To make the diagnosis, your healthcare provider will have to take a sample from the infected area and/or blood and send it to a laboratory for identification. It is important that persons who have any evidence of infection at a site where they received procedures, such as surgery or injections, let their doctors know so the appropriate tests can be done.

Mycobacterium abscessus treatment

Treatment of infections due to mycobacterium abscessus consists of draining collections of pus or removing the infected tissue and administering the appropriate combination of antibiotics for a prolonged period of time. Infection with this bacterium usually does not improve with the usual antibiotics used to treat skin infections. Testing the bacteria against different antibiotics is helpful in guiding doctors to the most appropriate treatment for each patient.

Mycobacterium chelonae

Mycobacterium chelonae is a nonmotile, non-spore-forming, gram-positive, acid-fast bacillus. Mycobacterium chelonae is a non-tuberculous mycobacterium, which is classified as rapidly growing mycobacterium, class IV in the Runyon classification ². Mycobacterium chelonae is a large bacillus with a beaded appearance. Mycobacterium chelonae was first isolated from a turtle in 1903 by Freidmann, who referred to it as “turtle tubercle bacillus. Rapidly growing mycobacteria account for 50% of known mycobacterial species and are divided into six groups, which are as follows: Mycobacterium fortuitum group, mycobacterium chelonae/Mycobacterium abscessus complex, Mycobacterium smegmatis, Mycobacterium mucogenicum group, Mycobacterium mageritense/Mycobacterium wolinskyi and the pigmented rapidly growing mycobacterium.

Mycobacterium chelonae and mycobacterium abscessus were considered identical until 1992 when mycobacterium chelonae was elevated to species status. Both mycobacterium chelonae and mycobacterium abscessus have an identical sequence in the 54-510 region but can be differentiated by their intergenic sequence (ITS), hsp65, or gene sequences. Susceptibility profiles can be helpful, but they are not ideal in differentiating between the mycobacterium chelonae group and mycobacterium abscessus group. mycobacterium chelonae group is characterized by high MICs of cefoxitin (> 64 mg/L) and susceptibility to tobramycin (MIC ≤ 4 mg/L), whereas mycobacterium abscessus shows lower MICs of cefoxitin (≤ 64 mg/L) and resistance to tobramycin (MIC of > 8 mg/L) ³.

Currently, molecular techniques are frequently used for the diagnosis of atypical mycobacterial infection.

Mycobacterium chelonae can have unpredictable resistance pattern. However, most are sensitive to macrolide and aminoglycosides. Susceptibility testing is recommended.

Mycobacterium chelonae transmission

Mycobacterium chelonae is ubiquitous in the environment and has been found in soil, water, and aquatic animals. mycobacterium chelonae grows optimally at 86 – 89.6 °F (30-32 °C) and may have a long incubation period. Mycobacterium chelonae is commonly associated with skin and soft tissue infections, especially infections of the extremities (cellulitis, abscessus). Mycobacterium chelonae also causes catheter-related infections and post-surgical infections after implants, transplants, and injections such as sclerotherapy. The eye is second most frequent organ involved. Pulmonary infections are rare when compared to mycobacterium abscessus. Invasive infections like bacteremia, osteomyelitis, intraabdominal abscess, and disseminated cutaneous infections are common in immunosuppressed patients such as those on steroids, monoclonal antibodies, and post-transplant immunosuppression. Cancer patients and chronic kidney disease patients are also susceptible to disseminated and invasive disease due to mycobacterium chelonae. Person to person transmission has not been documented. Cervical lymphadenitis in children can occur but is rare. Mycobacterium avium intracellulare and Mycobacterium hemophilum are more frequently associated with cervical lymphadenitis in children compared to mycobacterium chelonae.

Mycobacterium chelonae signs and symptoms

Mycobacterial infections including mycobacterium chelonae infections can be categorized into several clinical patterns: pulmonary disease, skin and soft tissue infections, musculoskeletal infections, disseminated disease, catheter-associated disease. and lymphadenitis. Skin and soft tissue infections are the most common presentations of mycobacterium chelonae infections. Infections occur in both immunocompetent and in immunocompromised hosts. mycobacterium chelonae has a predilection to extremities as it has a tendency to grow at a lower temperature. Nodules, papular rash, and sporotrichoid pattern have been reported. Skin lesions due to mycobacterium chelonae in the setting of sclerotherapy, acupuncture tattoos, and other injection procedure have been reported. Skin lesions can progress to pustules, hemorrhagic crusts, and abscess formation. Disseminated cutaneous disease and advanced skin lesions are common in immunosuppressed patients. Sweet syndrome can be a presenting feature of mycobacterium chelonae infection particularly if the skin lesions are on the extremities. Skin lesions mimicking lupus vasculitis can occur due to mycobacterium chelonae infection. Disseminated disease can present with multiple lesions, complex lesions and in more proximal location. Umbilicated papules, pustules involving the face and upper trunk may be present.

• Mycobacterium chelonae involving the bone, joints, and muscles has been reported and is common in immunosuppressed patients, deep joint injections, or surgical procedures.
• Mycobacterium chelonae can be a contaminant in endoscopes. Catheter-related infections, presenting as fever, sepsis, or disseminated skin lesions due to mycobacterium chelonae have been described in immunocompromised and pregnant patients.

Mycobacterium chelonae diagnosis

Infection with mycobacterium chelonae may be asymptomatic. Colonization of the pulmonary tract in cystic fibrosis patients is likely. mycobacterium abscessus frequently cause pulmonary infections. Skin biopsy and cultures should help to evaluate skin and subcutaneous infections on the extremities, those not responding to antibiotics, or in patients who had injection procedures or are immunocompromised. The biochemical evaluation in the microbiologic lab is inadequate to identify NTM to the species level, which is important for instituting appropriate therapy. Molecular techniques such as polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) should be utilized to identify non-tuberculous mycobacterium including mycobacterium chelonae.

High-performance liquid chromatography (HPLC) alone is not enough to separate mycobacterium chelonae from mycobacterium abscessus. Acridinium ester-labeled DNA probes specific for mycobacterium chelonae have not been approved. DNA analysis of hypervariable regions A and B cannot differentiate isolates of mycobacterium chelonae and mycobacterium abscessus, although they do vary at other 16S rRNA gene sites (only by a total of 4 bp). PRA method currently has been adopted widely for identification of NTmycobacterium This system is based on the coupling of the PCR of a heat shock protein (HSP) followed by restriction fragment length identification, which is species specific. Although sufficient to differentiate mycobacterium chelonae from mycobacterium abscessus but may not be enough for newer species of non-tuberculous mycobacterium.

Mycobacterium chelonae treatment

Mycobacterium chelonae are uniformly resistant to cefoxitin, imipenem is preferred instead. Tobramycin appears to be more active than amikacin. Isolates are susceptible to tobramycin (100%), clarithromycin (100%), linezolid (90%), imipenem (60%), amikacin (50%), clofazimine, doxycycline (25%), and ciprofloxacin (20%). Clarithromycin monotherapy can be sufficient for localized skin infections. However, there are cases of development of resistance during therapy, which occurs due to a single point mutation at position 2058 of 23S rRNA. For disseminated disease and invasive disease with bone and soft tissues involvement, four to six months of therapy is recommended. Surgical debridement, removal of foreign body, and catheters are an important adjunct to successful therapy. Optimal therapy for lung infection is unknown but most likely similar to other non-tuberculous mycobacterium, which results in 12 months of sputum culture negativity. In many published cases of mycobacterium chelonae infections in immunosuppressed patients, dual therapy with macrolide and amikacin was successful. Corneal infections should be treated with topical agents as well as systemic agents. Treatment should be based on susceptibilities whenever possible. Eye drops containing macrolides, aminoglycosides, and fluoroquinolones are useful.

Mycobacterium avium complex

Mycobacterium avium complex consists of multiple non-tuberculosis mycobacterial species ⁴, which cannot be distinguished in the microbiology laboratory and requires genetic testing. Mycobacterium avium and Mycobacterium intracellular are the two original members of this complex, known for about hundred years. Mycobacterium chimaera has been included in the mycobacterium avium intracellulare complex ⁴. Some include mycobacterium subspecies paratuberculosis in the mycobacterium avium complex as well. A newcomer to the mycobacterium avium complex is the Mycobacterium paraintracellulare, identified in pulmonary infections in Southeast Asia in 2016 ⁴.

Mycobacterium avium was first isolated in chickens 1933 with a cavitary disease resembling tuberculosis. Human cases were identified decades later. Mycobacterium avium complex is the most common cause of nontuberculosis mycobacterial species infections in humans, and respiratory system is the most common site of infection ⁵.

Mycobacterium avium complex is a nonmotile, non-spore-forming, gram-positive acid-fast bacillus. Mycobacterium avium complex is a nonchromogen and slow growing and takes about 10 to 20 days to develop mature colonies ⁴. Mycobacterium avium complex belongs to class III of the Runyon classification. Mycobacterium avium grows best at 94.1 °F (34.5 °C), and Mycobacterium intracellulare grows best at 88.7 °F (31.5 °C). However, mycobacterium avium complex components can grow between 82.4 °F to 101.3 °F (28 °C to 38.5 °C). Most mycobacterium avium can survive 120.2 °F (49 °C). Whereas, only 10% of mycobacterium intracellulare survive a temperature of 120.2 °F (49 °C). Mycobacterium scrofulaceum is similar to mycobacterium avium complex in the biochemical properties and the same group. Mycobacterium avium is composed of four named subspecies; these are, mycobacterium avium subspecies avium (two strains), mycobacterium avium subspecies silvaticum, mycobacterium avium subspecies paratuberculosis, and mycobacterium avium subspecies hominissuis. It appears that the mycobacterium avium subspecies avium are responsible for pulmonary infections and the mycobacterium avium subtype hominissuis appears to be gastrointestinal in origin ⁶. mycobacterium avium subspecies paratuberculosis was identified in ruminants as a causative agent for Johne disease. Some have hypothesized and debated for decades that mycobacterium avium subspecies paratuberculosis is the etiological agent of Crohn disease in humans without strong evidence. A recent publication found, a high prevalence of mycobacterium avium subspecies paratuberculosis antibodies in inflammatory bowel diseases when compared to patients with noninflammatory bowel diseases, 64% vs. 9.7%. Live mycobacterium avium subspecies paratuberculosis was only isolated from two Chron’s disease patients. mycobacterium avium subspecies paratuberculosis has also been reported to trigger autoimmunity including multiple sclerosis and type 1 diabetes mellitus (T1DM).

In 2004 Mycobacterium chimaera were identified having a unique genetic composition of the Mycobacterium avium complex but different from both mycobacterium avium and mycobacterium intracellulare. Recently contamination of the heater-cooler system during cardiac surgery resulted in some device-related infections due to mycobacterium chimaera.

The biochemical reactions with Mycobacterium avium complex are catalase positive, negative for niacin, nitrate reduction and tween hydrolysis. The biochemical methods are inadequate for clinical use. Currently, molecular techniques have been applied and Mycobacterium avium complex polymerase chain reaction (PCR) multiplex developed, which can detect the individual components of the Mycobacterium avium complex. Restriction fragment length polymorphism (RFLP) and multilocus sequence typing (MLST) are some other ways to identify and diagnose Mycobacterium avium complex infections ⁷.

Mycobacterium avium complex is ubiquitous and has been reported from Americas, Asia, and Europe. There are pockets of high prevalence throughout the world. In the United States, the prevalence varies from 1.4 to 6.6 per 100,000 population, but no endemic area has been recognized. Recently a trend towards increasing Mycobacterium avium complex infections has been identified. A seasonal trend in mycobacterial infections around incidence cycle of 12 months, with peaks in late winter/spring and troughs in autumn, was noted. Women had higher prevalence, up to 1.6 fold relative to men. A study done in Australia has shown higher male prevalence. The differences may be due to the nature of pulmonary involvement. Women have increased predilection for the nodular/bronchiectatic disease also known as Lady Windermere syndrome. Mycobacterium avium complex has been isolated from the environment from the soil, aerosolized water, bathrooms, house dust, birds, farm animals, hot water systems, cigarette components and house dust. The ecological niche of this organism has not been identified ⁸.

Mycobacterium avium complex transmission

Mycobacterium avium complex is acquired by inhalation and can also be ingested into the gastrointestinal tract, where it adheres to the mucosal epithelial cells and infects the macrophages. From the submucosal tissues and lymph nodes, the organism is then carried by lymphatics to the rest of the body. In most people, disseminated mycobacterium avium complex infection will occur when the CD4 count is less than 50 cell per microliter. In patients who do not have HIV, the most important risk factor for mycobacterium avium complex infection is underlying lung disease. Mycobacterium avium complex has also been associated with bronchiectasis and a hypersensitivity pneumonitis-like reaction ⁹.

Mycobacterium avium complex signs and symptoms

Mycobacterial infections including mycobacterium avium complex infections can be categorized into several clinical patterns including pulmonary disease, skin and soft tissue infections, musculoskeletal infections, disseminated disease, catheter-associated disease, and lymphadenitis. Pulmonary disease is the most common presentation. Mycobacterium avium complex infections occur in both immunocompetent and in immunosuppressed patients. Mycobacterium avium is the most frequent organism in the HIV, and immunosuppressed patients, about 40% of pulmonary infections in the immunocompetent patients, can be due to mycobacterium intracellulare. With the addition of new members to the Mycobacterium avium complex, the extent of involvement of each organism within the Mycobacterium avium complex is unknown.

Risk factors for mycobacterium avium complex pulmonary disease are pneumoconiosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, other chronic lung diseases, persons with thoracic and skeletal abnormalities such as severe scoliosis, straight back syndrome, patients with mitral valve prolapse, CD4 less than 50 in AIDS patients, low CD4 in lymphoreticular malignancies, elderly women who suppress cough, immunosuppression post transplant and in patients with deficiency in IFN-gamma production as well as IFN-gamma receptor deficiency. Siblings of an index patient have a much higher prevalence of Mycobacterium avium complex infection compared to the general population. There are no known risk factors for cutaneous mycobacterium avium complex infection and cervical lymphadenitis due to Mycobacterium avium complex.

The mycobacterium avium complex pulmonary disease can be radiologically classified into fibro-cavitary and nodular bronchiectatic types. Case reports for atypical presentation such as pulmonary nodules, pleurisy, multiple cavitary nodules and pleural effusion with hydropneumothorax have been published. Pleural involvement may be seen in 5% to 15% of patients.

Symptoms in immunocompetent patients are nonspecific, with a chronic cough as the most frequent symptom. Fever and hemoptysis are not as frequent as in tuberculosis and uncommon in HIV patients. Fibro-cavitary disease is more common in Caucasian men, occurs in the setting of underlying structural lung disease, presents with worsening cough, hemoptysis and constitutional symptoms.

The bronchiectasis with centrilobular nodules has a predilection for middle lobe and the lingula. In the fibro-cavitary forms, the cavities are thin-walled with a predilection to the upper lobes. Elsewhere there may be tree-in-bud opacities, suggesting endobronchial spread.

A chest x-ray may not show bronchiectasis very well. A high-resolution CT (HRCT) is more sensitive to changes such as bronchiectasis, small nodules, tree-in-bud appearance, ground glass opacities and pleural thickening. When compared to pulmonary tuberculosis, upper lobe cavitation is less common and middle lobe bronchiectasis more frequent in Mycobacterium avium complex pulmonary infections. High-resolution CT may show a feeding bronchus sign, which suggests that peribronchial nodules due to Mycobacterium avium complex infection evolve into focal cystic bronchiectasis and manifest as cavitary lesions; in this regard, the cavities are different from tuberculosis, where cavities are due to caseous necrosis of lung parenchyma. In the nodular-bronchiectatic form, the nodules are smaller than 5 mm to 10 mm and closely associated with areas of bronchiectasis. Both radiologic forms of Mycobacterium avium complex pulmonary infections are prevalent equally, but the nodular bronchiectatic form is more common in elderly Caucasian women, who suppress a cough while the fibro-cavitary disease is more common in white men with underlying chronic lung disease.

Mycobacterium avium complex is also most frequent nontuberculosis mycobacterial species cause of cervical lymphadenitis commonly seen in children.

Hypersensitivity pneumonitis-like presentation can occur. Initially thought to be an allergic reaction only, the current opinion may be shifting towards both infection and inflammation.

Disseminated infections with mycobacterium avium complex occur in the setting of AIDS and immunosuppression.

Mycobacterium avium complex in HIV patients

Mycobacterium avium complex infections occur when the CD4 counts are less than 50. Mycobacterium avium complex infections frequently present as disseminated infections. Disseminated Mycobacterium avium complex infections are uncommon outside of HIV patients. Most infections are due to M. avium. For unknown reasons, mycobacterium intracellulare does not cause disseminated disease in HIV patients. The clinical presentation of the disseminated disease is non-specific. Common clinical findings are fever (more than 80%), night sweats (more than 35%), weight loss (more than 25%), abdomen pain, diarrhea, mesenteric lymphadenopathy, anemia, elevated alkaline phosphatase and elevated lactate dehydrogenase.

Antiretroviral therapy can begin simultaneously. Rifabutin can be used instead of rifampin to avoid drug-drug interactions with antiretroviral agents. Preferred regimens must contain clarithromycin and ethambutol.

Mycobacterium avium complex in Cystic fibrosis patients

The principles of the therapy are the same as in an immunocompetent patient. There may be some patients who may tolerate medications but never become sputum negative, in which case prolonged treatment may be required. Azithromycin is preferred over clarithromycin due to better tolerance profile.

Mycobacterium avium complex in transplant patients

Nontuberculosis Mycobacterial species infections are more common in hematopoietic stem cell transplant patients than in solid organ transplant patients. The most common site of infection has been the lungs, and there is an increasing trend. Most infections have been in the setting of chronic rejection.

Mycobacterium avium complex diagnosis

Infection with Mycobacterium avium complex may be asymptomatic. Colonization of the pulmonary tract without infection is unproven in the nontuberculosis mycobacterial species diseases. Contamination of sputum sample is possible therefore more than one sputum sample is required. Symptoms are non-specific, and the differential diagnosis is wide, microbiologic isolation is required to make the diagnosis. As per recommendations of Infectious Disease Society of America (IDSA), a minimum evaluation of a patient suspected of nontuberculous mycobacterial infection should include radiologic, microbiologic and clinical evaluation. Clinically exclusion of pulmonary tuberculosis is important. Clinical evaluation of underlying diseases, risk factors for mycobacterial diseases, and ability to tolerate prolonged multidrug therapy should be undertaken.

While Mycobacterium avium complex is not a part of the microbiome of the lung, there is no need to treat all patients with sputum positive for Mycobacterium avium complex. Selecting patients for therapy is a clinical calculus combining, microbiologic, radiologic and clinical criteria. The therapy is long, and there is significant potential for adverse drug reactions ¹⁰.

Mycobacterium avium complex treatment

The macrolide antibiotic is the backbone of therapy for Mycobacterium avium complex infections. The Infectious Disease Society of America recommended triple antibiotic therapy for fibro cavitary and severe nodular bronchiectatic disease. For moderate to mild disease, dual antibiotic therapy is sufficient. Observation is reasonable but in general Mycobacterium avium complex pulmonary infections are progressive, and eventually, a patient will have indications for therapy. In this situation, expert opinion suggests, that sputum should be checked once in three months and radiological evaluation once in six months. A chest x-ray may be sufficient for the fibro-cavitary disease, but high-resolution CT is needed to assess nodular bronchiectatic disease. Risk factors for progressive disease are cavitary disease, low body mass index, older age, and co-morbidities. The risk of progression must be weighed against the potential risk of treatment ¹¹.

The medications used in the treatment of Mycobacterium avium complex infections are a macrolide, clofazimine, rifampin, rifabutin, ethambutol, fluoroquinolone, linezolid, and aminoglycosides. There is no proven correlation between in-vitro susceptibility and clinical response. The only susceptibility to macrolide and amikacin may be useful clinically. If the patient is intolerant to first-line drugs than susceptibility testing to secondary medications may be of some value. The goal of therapy is to have culture negativity for 12 months. Sputum conversion takes three to six months. Close monitoring for drug intolerance is required. At the initiation of therapy, baseline audiogram, electrocardiogram, eye exam for visual acuity and color discrimination complete blood count and the comprehensive metabolic panel must be obtained.

For severe and fibrocavitary disease, a typical three-drug regimen consists of daily oral azithromycin, rifampin, and ethambutol; intermittent dosing is inadequate in this situation. For severe fibrocavitary disease, parenteral aminoglycoside can be used in the initial phase (first eight to 16 weeks of therapy) as a fourth agent, but there is no proven benefit. In patients who cannot tolerate parenteral aminoglycoside, inhaled amikacin can be used. For severe localized cavitary disease, surgical resection, after the sputum becomes negative, can be considered. Surgery is not without risk of formation of a bronchopleural fistula. For mild to moderate nodular bronchiectatic disease intermittent dosing of the three-drug regimen can be used.

No prospective studies evaluate the efficacy of the macrolide-containing three-drug or two-drug regimens. However long term sputum conversion rates of 86% have been documented. Small randomized controlled trials comparing three-drug and two-drug regimens showed higher treatment failure with two drug therapy. Macrolide containing regime was not evaluated in this trial.

The key to successful therapy is close monitoring for disease worsening and drug-related toxicity. Patients should be followed once every two months while on therapy. Introduce one drug at a time and a lower dose and increase to a therapeutic dose over two to five days. Therapeutic drug monitoring is of no proven value. Azithromycin peak levels can be measured in the setting of malabsorption or treatment failure or if the dose is considered to be low. A peak level of greater than 0.4 mcg/mL was independently associated with the favorable microbiologic response. Rifampin can decrease macrolide levels. A study by Koh WJ et al. ¹² in 101 patients showed no correlation between clarithromycin level and favorable microbiologic response.

Mycobacterium fortuitum

Mycobacterium fortuitum is a non-tuberculous mycobacterium, is a member of Runyon group 4 of non-pigmented Rapidly Growing Mycobacteria ¹³. Mycobacterium fortuitum has been found in natural and processed water sources, as well as in sewage and dirt. Distribution is probably worldwide. Infections with non-tuberculous mycobacterium have been described increasingly, especially in immunocompromised patients and as iatrogenic infections in immunocompetent patients, causing a variety of local and disseminated disease. Mycobacterium fortuitum infection is a rare cause of isolated lymphadenitis. Disseminated disease, usually with disseminated skin lesions and soft tissue lesions, occurs almost exclusively in the setting of severe immunosuppression, especially AIDS. Endocarditis has been documented.

Surgical-site infections due to Mycobacterium fortuitum infection are well-documented, especially in association with cardiothoracic surgery. The source is frequently contamination of the wound, directly or indirectly, with colonized tap water. Other nosocomial infections with this organism include infections of implanted devices (eg, catheters) and injection-site abscesses. Pseudo-outbreaks have been associated with contaminated endoscopes. Recent outbreaks have also been described in immunocompetent hosts after use of contaminated whirlpool footbaths in nail salons ¹⁴.

Mortality due to localized Mycobacterium fortuitum infection is rare. Death may result from extensive pulmonary or disseminated disease in patients who are immunocompromised. Morbidity depends largely on the site of the infection. Localized skin lesions may eventually heal without therapy or surgical intervention. At other sites, chronic infection is the rule ¹⁵.

With debridement and antibiotic therapy, prognosis is very good for most sites of infection ¹⁵.

Lung disease may be difficult or impossible to eradicate. Chronic suppression of the infection and slowing of the progression of lung disease may be the only achievable goal in this setting.

Cure of infected implants that cannot be removed may be impossible ¹⁵.

Mycobacterium gordonae

Mycobacterium gordonae is a type of slow-growing non-tuberculous mycobacterium, that is generally regarded as a weak pathogen, although it has caused some disease in humans ¹⁶. Mycobacterium gordonae is an acid-and alcohol-fast bacillus belonging to Runyon group 2 as a scotochromogens mycobacteria. Mycobacterium gordonae is found widely throughout the environment and commonly isolated from water (in fact, it was previously known as the “tap water bacillus” or Mycobacterium aquae), soil and non-pasteurized fresh milk ¹⁷. Infections caused by mycobacterium gordonae usually occur in the lungs (and only occasionally in other organs) of immunocompromised patients ¹⁶. Most cases of presumed infection have occurred in patients with trauma, underlying immunosuppression, or a prosthetic device ¹⁸. Nosocomial pseudo-infections due to antimicrobial and laboratory solutions, medical instrumentation, aerosol devices and continuous ambulatory peritoneal dialysis fluid have been reported ¹⁹. The contamination of instrumentation is related to the high resistance of mycobacteria, and especially of mycobacterium gordonae, to common chemical disinfection ²⁰, and to the practice of rinsing medical instruments with tap water after immersion in disinfectant ²¹. Although mycobacterium gordonae is considered one of the least pathogenic among environmental mycobacteria, some cases of infections have occasionally been reported in immunocompromised and in HIV positive patients ¹⁷. The skin and soft tissues, cornea, synovial tissue, meninges, prosthetic heart value, liver and peritoneum, and lower respiratory tract are most commonly involved ²². The infection may also be disseminated ²³. A cutaneous infection with mycobacterium gordonae is unusual and a paranasal sinus infection even rarer. Seven cases of cutaneous infection with mycobacterium gordonae have been reported; all were in women 38–80 years of age. The infection can affect persons who have not experienced trauma or been exposed to immunosuppressants. The most common lesions caused by mycobacterium gordonae are nodules that slowly enlarge and become ulcerated over several months. Lesions usually are located on the face, at distal extremities, or at sites of previous trauma ²⁴.

Common laboratory methods for diagnosis of nontuberculous mycobacterial infection include histopathologic stainings, tissue culture, PCR, and gene sequencing. Tissue culture and sequencing usually provide the most reliable evidence for diagnosis; however, tissue culture has a low sensitivity and is time-consuming, making early diagnosis difficult ²⁵. Although it is generally believed that a positive T-SPOT.TB result means the patient has an M. tuberculosis infection, positive results have been reported for infections caused by nontuberculous mycobacteria (2,9). The T-SPOT.TB assay uses the M. tuberculosis antigens ESAT-6 and CFP-10. The ESAT-6 and CFP-10 genes are located within the mycobacterium tuberculosis region of difference 1 (RD1), a DNA sequence that is also present in mycobacterium marinum, mycobacterium kansasii, mycobacterium szulgai, and mycobacterium gordonae ²⁶. Because these genes are present in other mycobacterial genomes, the T-SPOT.TB assay might be useful for diagnosing infections with multiple RD1-possessing mycobacteria. However, further studies are needed to confirm its diagnostic value.

Mycobacterium kansasii

Mycobacterium kansasii is a non-tuberculosis mycobacterium that is readily recognized based on its characteristic photochromogenicity; it produces a yellow pigment when exposed to light ²⁷.

Buhler and Pollack first described this slow-growing mycobacterium in 1953 ²⁸. Under light microscopy, mycobacterium kansasii appears as thick rectangular, beaded, gram-positive rods which are longer than those of mycobacterium tuberculosis. Clinically, mycobacterium kansasii causes a chronic, upper-lobe cavitary disease, resembling that from mycobacterium tuberculosis. The prevalence of non-tuberculosis mycobacterium infections has steadily increased when compared to tuberculosis whose prevalence has decreased in the last few decades ²⁹. There is no clear data regarding the prevalence of mycobacterium kansasii, although some studies have in fact shown decreasing prevalence ²⁹.

Mycobacterium Kansasii is a slow-growing acid-fast bacillus. It grows best at 89.6 °F (32 °C), but can be cultured at 98.6 ° F (37 °C). Its in-vitro and chemical characteristics are similar to those of mycobacterium marinum and mycobacterium szulgai. Mycobacterium Kansasii produces mature colonies in greater then 7 days. Like other mycobacteria in the family, mycobacterium kansasii is strictly a gram-positive, non-motile and non-spore-forming organism. Colony morphology ranges from flat to raised and smooth to rough. When grown in the dark mycobacterium kansasii colonies are at first non-pigmented but turn yellow after exposure to light due to deposition of beta-carotene crystals ³⁰. Microscopic examinations show that when compared to mycobacterium tuberculosis, mycobacterium kansasii appears longer and broader and are often beaded or cross-barred in appearance when stained with Ziehl Neelsen or Kinyoun stain ³¹. In Runyon classification, mycobacterium kansasii belongs to the group photochromogens. Biochemical characteristics include Catalase positive, nitrate reduction, tween hydrolysis, and urea hydrolysis. Identification using traditional methods could take as long as two months.

Although mycobacterium Kansasii was long thought to be homogenous species, genetic studies have shown that there are at least seven subtypes, with subtype one being most frequently isolated in human infections ²⁹. Pulsed-field gel electrophoresis techniques demonstrate that the clinical isolates are very closely related and may be clonal worldwide. Clinical isolates from Japan are similar those from Europe and USA. Pathogenic strains are highly Catalase positive.

Mycobacterium kansasii is widely prevalent in the environment but has seldom been isolated from soil. Some documented sources include city tap water, swimming pools, fish tanks, fish bites, brackish water, and seawater ³². Tap water appears to be the major reservoir. Infection is mostly acquired through the aerosol route. Infectivity is low in regions of endemicity. Transmission from humans to humans is not thought to occur, except in two cases where familial clustering was noted ³³. Clustering was thought to be due to a shared environment, susceptibility or genetic predisposition rather than true human to human transmission ³⁴.

Mycobacterium kansasii transmission

Mycobacterium kansasii infection mostly occurs in males, at an average patient age of 45–62 years ³⁵. Lung infections caused by mycobacterium kansasii occur in geographic clusters ³⁶. In the United States, mycobacterium kansasii infections are more common in southern and central states with the highest incidence seen in the southern states of Texas, Louisiana and Florida, as well as the central states of Illinois, Kansas, and Nebraska. mycobacterium kansasii infections are more likely to occur in urban areas than rural areas, and several studies have reported an association with mining practices ³⁷. In the United Kingdom, mycobacterium kansasii infections are most frequent in Wales. Of all countries in Europe, Poland has the highest mycobacterium kansasii isolation rate (35% of all NTM compared to 5% in Europe) ³⁸.

Mycobacterium kansasii infections are also prevalent in areas where HIV infection is common due to the susceptibility of the hosts.

mycobacterium kansasii infections were the most common non-tuberculosis mycobacterial infections during the 1960s and 70s, before being surpassed by mycobacterium avium-intracellulare. In the 80s with the rise of HIV infections, there was a resurgence of mycobacterium kansasii, which has now decreased in the antiretroviral therapy era. mycobacterium kansasii infections can occur in both immunocompetent and immunosuppressed patients ³⁹. In the 1980s the overall prevalence of mycobacterium kansasii infections was estimated to be 0.5 cases per 100,000 persons. Since mycobacterial infections are not reported, there is no reliable data for mycobacterium kansasii infections in transplant patients. Generally in transplant patients mycobacterial infections present as disseminated infections ⁴⁰. Fifty percent of patients with pulmonary disease also have dissemination. Renal transplant patients have been the most frequently reported to have disseminated disease. mycobacterium abscesses, mycobacterium chelonae, and mycobacteriumkansasii are the mycobacteria most commonly present with dissemination. Even in HIV and late-stage AIDS patients, mycobacterium kansasii presents with pulmonary disease. In one study from California, the prevalence of mycobacterial infections was 0.75 /100 000 in HIV-negative patients, 115/100000 in HIV-positive patients, and 647/100000 persons in AIDS patients ⁴¹.

Mycobacterium kansasii signs and symptoms

Mycobacterial infections, including mycobacterium kansasii infections, can be categorized into six clinical patterns: pulmonary disease, skin, and soft tissues, musculoskeletal infections (monoarticular septic arthritis and tenosynovitis), disseminated disease, catheter-associated disease, and lymphadenitis ⁴². Chronic pulmonary cavitary disease in the upper lobe is the most common presentation of mycobacterium kansasii infections. Not surprisingly these patients may be initially diagnosed with pulmonary tuberculosis. In one study, the mean age of patients with mycobacterium kansasii infection was 58 years, and 64% were men. However, mycobacterium kansasii can infect adults of any age, sex, or race. Infection results in symptoms in 85% of cases.

The most common symptoms of pulmonary mycobacterium kansasii infection include a cough (91%), sputum production (85%), weight loss (53%), breathlessness (51%), chest pain (34%), hemoptysis (32%), and fever or sweats (17%). Of all the NTM infections, mycobacterium kansasii infections most often resemble Mycobacterial tuberculosis infections ⁴³. Risk factors for mycobacterium kansasii infections are the same as those for other mycobacteria, namely, smoking, pneumoconiosis, silicosis, chronic obstructive pulmonary disease, malignancy, immunosuppressed state, chronic kidney disease, alcoholism and concurrent or prior mycobacterium tuberculosis infection ⁴⁴.

While cavitary disease occurs in 90% mycobacterium kansasiiI infections, nodular and brochiectatic disease can also occur. If left untreated pulmonary infections (both cavitary and nodular) are characterized by the persistence of AFB in the sputum and progressive destruction of the lung architecture. Pulmonary disease may be present in AIDS patients but there is less likelihood of cavitations; hilar lymphadenopathy and interstitial infiltrates are more common. However, if the CD4 count is high there is an increased chance of cavitary disease.

The second most frequent organ involved in mycobacterium kansasii infection is the skin ⁴⁵. Cutaneous infection resembles secondary to local lymphatic spread. Cutaneous lesions may include nodules, pustules, verrucous lesions, erythematous plaques, abscesses, and ulcers. In HIV and immunocompromised patients, the presentation can be atypical and include bacteremia, osteomyelitis, abscesses, and cellulitis. Pericarditis with cardiac tamponade has been reported in HIV patients ⁴⁶.

In disseminated disease, the symptoms are vague and nonspecific. In a series of 49 patients, fever was present in 60%, hepatosplenomegaly in 40%; pulmonary infiltrates in 25% and lymphadenopathy in 10%. Bone involvement, such as vertebral osteomyelitis and sacroiliitis, is common with mycobacterium kansasii disseminated diseases. Psoas abscess, bone marrow granuloma, liver granuloma, and possible spleen abscesses have been described.

In patients with an advanced immunocompromised state, HIV and mycobacterium kansasii co-infection can occur and reported average CD count in these patients has been less than <50/mm³ ⁴⁷.

Mycobacterium kansasii complications

Complications can include disseminated disease. Bone involvement, such as vertebral osteomyelitis and sacroiliitis are common with disseminated diseases ⁴⁸. Pneumothorax, Psoas abscess, bone marrow granuloma, liver granuloma, and possible spleen abscesses have also been described in the literature ⁴⁹. CNS complications like meningoencephalitis are very rare and are usually fatal.

Mycobacterium kansasii diagnosis

Since the symptoms are not specific and the differential diagnosis is broad, microbiologic isolation is required to make the diagnosis. mycobacterium kansasii rarely represents colonization or environmental contamination. Therefore any isolation of the organism needs to be evaluated for therapy ⁵⁰. Highly sensitive and specific PCR tests are available for mycobacterium kansasii ⁵¹.

Culture results along with clinical and radiological diagnosis are recommended for accurate diagnosis of mycobacterium kansasii. As per the guidelines from American Thoracic Society and Infectious Disease Society of America diagnosis of non-tuberculosis mycobacterium should include a minimal radiological evaluation which includes a chest X-ray (or computed tomography of the chest if there is an absence of cavitation), combined with positive sputum cultures and exclusion of other diagnoses clinically. Cultures are considered positive when two consecutive positive sputum cultures, one positive culture from bronchoscopy specimens, or one positive sputum culture with compatible pathology is present ⁵⁰. Cultures are considered to be positive when a) 2 sputum cultures are consecutively positive, b) bronchoscopy specimens with one positive culture or c) one sputum culture is positive and a compatible pathology is present ⁵⁰.

Mycobacterium kansasii treatment

Rifampin is the cornerstone of mycobacterium kansasii therapy. The first line therapy recommended by Infectious Disease Society of America-American Thoracic Society guidelines for mycobacterium kansasii is rifampin, ethambutol, and isoniazid plus pyridoxine ⁵². The recommended duration of therapy is at least 12 months or more with the goal to have culture negative results for 12 months on therapy. mycobacterium kansasii are predictably resistant to pyrazinamide. Isoniazid resistance should be interpreted with caution as a higher concentration is needed for mycobacterium kansasii when compared to mycobacterium tuberculosis. mycobacterium kansasii organisms show resistance to isoniazid at one mcg/mL but are susceptible at five mcg/mL. In a treatment naïve patient, isoniazid is effective regardless of concentration achieved in the serum. Rifampin-containing regimens have low failure rates (1.1%) and low long-term relapse rates (< 1%). Based on mycobacterium kansasii susceptibilities in vitro, patients with rifampin-resistant mycobacterium kansasii disease should be treated with a 3-drug regimen, which should include clarithromycin or azithromycin. The other two drugs should be chosen from moxifloxacin, ethambutol, sulfamethoxazole, or streptomycin ⁴⁴. The Clinical and Laboratory Standards Institute recommends that all initial isolates of mycobacterium kansasii be tested only for clarithromycin and rifampin susceptibility. Isoniazid and streptomycin susceptibility should be tested as secondary agents.

Mycobacterium kansasii in HIV patients:

One strategy to treat mycobacterium kansasii infection in HIV-positive patients is to use an NRTI-based regimen, allowing for a full dose of rifampin, which is the cornerstone of therapy for mycobacterium kansasii. If a protease inhibitor such as darunavir or atazanavir or non-nucleoside reverse transcriptase inhibitor [NNRTI] such as efavirenz or nevirapine is included in HIV treatment regimens, rifabutin can be used instead of rifampin. Clarithromycin can be added to improve efficacy, but rifabutin-related toxicity can increase when combined with clarithromycin.

Monitoring therapy:

Serial sputum samples for AFB should be obtained regularly so patients failing therapy are recognized early and susceptibility testing for additional drugs can be done. Serial CXR can be administered, although lung disease is likely to evolve at a slow pace. Routine monitoring for adverse effects of medications and drug-drug interactions is recommended.

Mycobacterium kansasii prognosis

With appropriate treatment, the prognosis is usually good ⁵³. Mortality is higher and can go up to 50% in patients with HIV who have mycobacterium kansasii infection ⁴⁷. In HIV patients who have a pulmonary infection with mycobacterium kansasii, survival predictors include higher CD4 cell count, negative smear microscopy, antiretroviral therapy and adequate treatment for mycobacterium kansasii ⁴⁷.

Mycobacterium marinum

Mycobacterium marinum is a non-motile, non-spore forming, gram-positive, acid-fast bacillus. Mycobacterium marinum is slow growing mycobacteria, belonging to group 1 of the Runyon classification. Mycobacterium marinum is a photochromogen and produces a yellow pigment when exposed to light. Mycobacterium marinum is a non-tuberculous mycobacterium first isolated from tubercles obtained at necropsy of dead saltwater fish in an aquarium in Philadelphia in 1926 ⁵⁴. Mycobacterium marinum causes a tuberculosis-like illness in fish. In humans, when injured skin is exposed to an aqueous environment contaminated with mycobacterium marinum, infection occurs. Mycobacterium marinum infection presents as a nodular granulomatous disease, which can spread along lymphatics similar to a sporothrix infection ⁵⁵. Mycobacterium marinum is found in plants, soil, and fish. Mycobacterium marinum infections are usually limited to skin and soft tissues and occur in immunocompetent patients. Disseminated mycobacterium marinum infection in HIV/AIDS patients have infrequently been reported ⁵⁶.

Mycobacterium marinum grows best on Lowenstein-Jensen medium at 89.6 °F (32 °C). Unlike mycobacterium tuberculosis, the growth of mycobacterium marinum is inhibited at 98.6 °F (37 degrees C). Phylogenetically, mycobacterium marinum is very closely related to mycobacterium ulcerans, and both are closely related to mycobacterium tuberculosis based on their 99.3%, 16SrRNA sequence homology. In fact, mycobacterium marinum causes tuberculosis-like disease in fish and frogs. Like mycobacterium tuberculosis, mycobacterium marinum can survive inside host cells and is proposed as a model to study mycobacterium tuberculosis. Like in mycobacterium tuberculosis infection, mycobacterium marinum may cause a positive tuberculin test ⁵⁷. Mycobacterium marinum has one rRNA operon per genome, which dictates the pace of mRNA-protein synthesis. Genomic analysis suggests that the rRNA operon is similar in both Mtuberculosis and Mycobacterium marinum. Unlike Mtuberculosis, Mycobacterium marinum is a rapid grower, so the reason for this difference is unknown. At the infection site, mycobacterium marinum has a generation time of 24 hours, similar to Mtuberculosis, but in the laboratory, at 89.6 °F (32 °C) the generation time is 4 hours. Mycobacterium tuberculosis generation time in the lab is 24 hours when grown at 98.6 °F (37 degrees C). There is no one good antibiotic regimen for Mycobacterium marinum ⁵⁸.

Mycobacterium marinum signs and symptoms

Patient evaluation should identify the likely exposure of the injured skin to aqueous material contaminated with Mycobacterium marinum. Skin injury may be in the form of minor abrasions, cuts, or major trauma. Besides the aqueous environment, Mycobacterium marinum is also found in plants and soil ⁵⁹. The most common clinical infections due to Mycobacterium marinum are skin and soft tissue infections most likely due to its propensity to flourish in the cooler environment ⁶⁰. A skin infection may present as a solitary, violaceous or red, and plaque or nodule. The nodular surface can be crusted or verrucous. The nodule may appear inflammatory and may have pus. There can be lymphangitic spread in the sporotrichoid presentation ⁶¹. Mycobacterium marinum should be in the differential diagnosis of poorly healing nodular lesions not responding to antibiotics in the upper extremities ⁶⁰. Based upon the exposure to Mycobacterium marinum, skin lesions can also be present in the lower extremities. Mycobacterium marinum infections in HIV patients have been reported in the pre-anti-retroviral therapy (ART) era but are uncommon in the post-ART era. Disseminated infection occurs in non-HIV immunocompromised hosts as well.

Mycobacterium marinum diagnosis

The laboratory should be notified that Mycobacterium marinum is suspected, so Lowenstein-Jensen agar cultures can be incubated at 82.4 to 89.6 °F (28 to 32 degrees C), in addition to incubating at 98.6 °F (37 degrees C). Cultures should be left for six weeks. The positivity rate of cultures ranges from 70% to 80%. Lesions have very low concentration of microorganisms, hence cultures should be obtained even in the absence of microscopic evidence of bacilli. Typical tuberculoid granulomas are seen only in two-thirds of the cases, and the histopathology of nodules can be confused with rheumatoid nodules. One in five nodules may not appear to be of infectious origin in histology. Samples from the deeper parts of the nodule or skin or synovial biopsy may provide information at times, and repeating biopsy can be helpful. Mycobacterium marinum infections can mimic other histopathological patterns such as a sarcoid-like granuloma or granuloma annulare ⁶².

Polymerase chain reaction (PCR) amplification techniques using Mycobacterium genus-specific primers can be used to diagnose Mycobacterium marinum infection directly in the biopsy sample. Ziehl-Neelson stain of biopsy specimens or yellowish discharge is only rarely positive since the number of mycobacteria in clinical specimens is low.

Mycobacterium marinum infection can also be an opportunistic infection in patients treated with anti-tumor necrosis factor (TNF)-alpha and other biological drugs ⁶³. Therefore underlying immunosuppressed state must be excluded upon the diagnosis of Mycobacterium marinum infection. Tuberculin skin test using purified protein derivative is positive in 67%-100% of cases. Quantiferon-TB Gold and enzyme-linked immunospot assay may also be positive in Mycobacterium marinum infections but are unhelpful for diagnosis. Positive blood culture findings have also been reported in disseminated infections. Recently in vivo imaging to monitor long-term anti-mycobacterial therapy has been proposed and such diagnostic tools are being developed ⁶⁴.

Mycobacterium marinum treatment

Routine susceptibility testing is not recommended when treating Mycobacterium marinum infections. There is not much correlation between in vitro susceptibilities and clinical response. The therapy is not standardized. Rifampin is the most active drug against Mycobacterium marinum with MIC90 of < 0.5mg/mL ⁶⁵. In one study, the MIC for ethambutol was 2 to 4.0 mg/mL, for doxycycline was 16.0mg/mL, for imipenem was 8.0mg/mL, and for INH was 8.0mg/mL. Mycobacterium marinum is intrinsically resistant to pyrazinamide. Mycobacterium marinum has moderately high MIC90 for ciprofloxacin and levofloxacin but is susceptible to moxifloxacin (MIC90 of 1-2 mg/ml). Linezolid has activity against Mycobacterium marinum ⁶⁶. Clinically clarithromycin-based regimens have had a good success rate irrespective of the in vitro MIC values ⁶⁷.

There is no consensus on the regimen or the duration of therapy in Mycobacterium marinum infections. A spectrum of antibiotic regimens has been used in published cases or case series. There are no randomized controlled trials. Minocycline monotherapy in immunocompetent patients has been used. Combination therapy for immunosuppressed patients has been used. Consider treatment with a chosen regimen for three months prior to changing the antibiotic therapy as the response to therapy is slow. Surgical debridement is often needed. Effective antibiotic therapy is usually associated with healing of all skin lesions within one month of commencing therapy. After that, immunocompetent patients should continue the medications for two more months. Patients who are immunocompromised will need to be treated with two agents for at least six months. In one report, an AIDS patient was successfully treated with rifampin and ethambutol for six months. The lesion recurred after stopping therapy, so therapy was restarted with clarithromycin regimen. Sometimes chronic lifelong suppressive therapy may be needed ⁶⁵.

Therefore, it seems prudent to treat immunocompromised hosts with Mycobacterium marinum infection with two agents, including clarithromycin. The optimal duration of therapy in the setting of the immunocompromised host is unknown. Most experts would treat for six months and possibly lifelong in cases of the persistent immunocompromised state. The disseminated disease was treated for the duration of one year in published case reports. Rifampin and ethambutol were frequently used in invasive Mycobacterium marinum infections. In a study of 61 clinical isolates, rifamycins and clarithromycin were the most potent against Mycobacterium marinum ⁶⁸.

Surgical debridement is frequently necessary and should be included in the management plan. Antibiotic therapy is needed as well, after surgical debridement ⁶⁹.

Mycobacterium leprae

Mycobacterium leprae also known as Hansen’s bacillus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy or Hansen’s disease. It can affect the nerves, skin, eyes, and lining of the nose (nasal mucosa). With early diagnosis and treatment, the disease can be cured. People with Hansen’s disease can continue to work and lead an active life during and after treatment.

Leprosy was once feared as a highly contagious and devastating disease, but now scientists know it doesn’t spread easily and treatment is very effective. However, if left untreated, the nerve damage can result in crippling of hands and feet, paralysis, and blindness.

Mycobacterium leprae is an intracellular, pleomorphic, acid-fast, pathogenic bacterium ⁷⁰. Mycobacterium leprae is an aerobic bacillus (rod-shaped bacterium) surrounded by the characteristic waxy coating unique to mycobacteria. In size and shape, it closely resembles Mycobacterium tuberculosis. Due to its thick waxy coating, mycobacterium leprae stains with a carbol fuchsin rather than with the traditional Gram stain. The culture takes several weeks to mature.

Mycobacterium leprae transmission

It is not known exactly how leprosy (Hansen’s disease) spreads between people. Scientists currently think it may happen when a person with Hansen’s disease coughs or sneezes, and a healthy person breathes in the droplets containing the Mycobacterium leprae bacteria. Prolonged, close contact with someone with untreated leprosy over many months is needed to catch the disease.

You cannot get leprosy from a casual contact with a person who has Hansen’s disease like:

• Shaking hands or hugging
• Sitting next to each other on the bus
• Sitting together at a meal

Hansen’s disease is also not passed on from a mother to her unborn baby during pregnancy and it is also not spread through sexual contact.

Due to the slow-growing nature of the bacteria and the long time it takes to develop signs of the disease, it is often very difficult to find the source of infection.

In the southern United States, some armadillos are naturally infected with the bacteria that cause Hansen’s disease in people and it may be possible that they can spread it to people. However, the risk is very low and most people who come into contact with armadillos are unlikely to get Hansen’s disease.

For general health reasons, avoid contact with armadillos whenever possible. If you had a contact with an armadillo and are worried about getting Hansen’s disease, talk to your healthcare provider. Your doctor will follow up with you over time and perform periodic skin examinations to see if you develop the disease. In the unlikely event that you have Hansen’s disease, your doctor can help you get treatment.

In the U.S., Hansen’s disease is rare. Around the world, as many as 2 million people are permanently disabled as a result of Hansen’s disease.

Overall, the risk of getting Hansen’s disease for any adult around the world is very low. That’s because more than 95% of all people have natural immunity to the disease.

You may be at risk for the disease if you live in a country where the disease is widespread. Countries that reported more than 1,000 new cases of Hansen’s disease to WHO between 2011 and 2015 are:

• Africa: Democratic Republic of Congo, Ethiopia, Madagascar, Mozambique, Nigeria, United Republic of Tanzania
• Asia: Bangladesh, India, Indonesia, Myanmar, Nepal, Philippines, Sri Lanka
• Americas: Brazil

You may also be at risk if you are in prolonged close contact with people who have untreated Hansen’s disease. If they have not been treated, you could get the bacteria that cause Hansen’s disease. However, as soon as patients start treatment, they are no longer able to spread the disease.

Mycobacterium leprae signs and symptoms

Mycobacterium leprae infection symptoms mainly affect the skin, nerves, and mucous membranes (the soft, moist areas just inside the body’s openings).

Mycobacterium leprae infection can cause skin symptoms such as:

• Discolored patches of skin, usually flat, that may be numb and look faded (lighter than the skin around)
• Growths (nodules) on the skin
• Thick, stiff or dry skin
• Painless ulcers on the soles of feet
• Painless swelling or lumps on the face or earlobes
• Loss of eyebrows or eyelashes

Symptoms caused by damage to the nerves are:

• Numbness of affected areas of the skin
• Muscle weakness or paralysis (especially in the hands and feet)
• Enlarged nerves (especially those around the elbow and knee and in the sides of the neck)
• Eye problems that may lead to blindness (when facial nerves are affected)

Symptoms caused by the disease in the mucous membranes are:

• A stuffy nose
• Nosebleeds

Since Hansen’s disease affects the nerves, loss of feeling or sensation can occur. When loss of sensation occurs, injuries such as burns may go unnoticed. Because you may not feel the pain that can warn you of harm to your body, take extra caution to ensure the affected parts of your body are not injured.

If left untreated, the signs of advanced leprosy can include:

• Paralysis and crippling of hands and feet
• Shortening of toes and fingers due to reabsorption
• Chronic non-healing ulcers on the bottoms of the feet
• Blindness
• Loss of eyebrows
• Nose disfigurement

Other complications that may sometimes occur are:

• Painful or tender nerves
• Redness and pain around the affected area
• Burning sensation in the skin

Mycobacterium leprae diagnosis

Hansen’s disease can be recognized by appearance of patches of skin that may look lighter or darker than the normal skin. Sometimes the affected skin areas may be reddish. Loss of feeling in these skin patches is common. You may not feel a light touch or a prick with a needle.

To confirm the diagnosis, your doctor will take a sample of your skin or nerve (through a skin or nerve biopsy) to look for the bacteria under the microscope and may also do tests to rule out other skin diseases.

Mycobacterium leprae treatment

Hansen’s disease is treated with a combination of antibiotics. Typically, 2 or 3 antibiotics are used at the same time. These are dapsone with rifampicin, and clofazimine is added for some types of the disease. This is called multidrug therapy. This strategy helps prevent the development of antibiotic resistance by the bacteria, which may otherwise occur due to length of the treatment.

Treatment usually lasts between one to two years. The illness can be cured if treatment is completed as prescribed.

If you are treated for Hansen’s disease, it’s important to:

• Tell your doctor if you experience numbness or a loss of feeling in certain parts of the body or in patches on the skin. This may be caused by nerve damage from the infection. If you have numbness and loss of feeling, take extra care to prevent injuries that may occur, like burns and cuts.
• Take the antibiotics until your doctor says your treatment is complete. If you stop earlier, the bacteria may start growing again and you may get sick again.
• Tell your doctor if the affected skin patches become red and painful, nerves become painful or swollen, or you develop a fever as these may be complications of Hansen’s disease that may require more intensive treatment with medicines that can reduce inflammation.

If left untreated, the nerve damage can result in paralysis and crippling of hands and feet. In very advanced cases, the person may have multiple injuries due to lack of sensation, and eventually the body may reabsorb the affected digits over time, resulting in the apparent loss of toes and fingers. Corneal ulcers or blindness can also occur if facial nerves are affected, due to loss of sensation of the cornea (outside) of the eye. Other signs of advanced leprosy may include loss of eyebrows and saddle-nose deformity resulting from damage to the nasal septum.

Antibiotics used during the treatment will kill the bacteria that cause leprosy. But while the treatment can cure the disease and prevent it from getting worse, it does not reverse nerve damage or physical disfiguration that may have occurred before the diagnosis. Thus, it is very important that the disease be diagnosed as early as possible, before any permanent nerve damage occurs.

In the U.S., people with Hansen’s disease may be treated at special clinics run by the National Hansen’s Disease Program. There are several federally supported outpatient clinics throughout the U.S. and Puerto Rico.

Mycobacterium tuberculosis

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). Mycobacterium tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, mycobacterium tuberculosis can appear either Gram-negative or Gram-positive ⁷¹. Acid-fast stains such as Ziehl-Neelsen, or fluorescent stains such as auramine are used instead to identify mycobacterium tuberculosis with a microscope. The physiology of mycobacterium tuberculosis is highly aerobic and requires high levels of oxygen. Mycobacterium tuberculosis bacteria usually attack the lungs, but mycobacterium tuberculosis bacteria can attack any part of the body such as the kidney, spine, and brain. Not everyone infected with mycobacterium tuberculosis bacteria becomes sick. As a result, two mycobacterium tuberculosis-related conditions exist: latent tuberculosis infection and tuberculosis disease. If not treated properly, tuberculosis disease can be fatal.

Latent tuberculosis infection

Mycobacterium tuberculosis bacteria can live in the body without making you sick. This is called latent tuberculosis infection. In most people who breathe in mycobacterium tuberculosis bacteria and become infected, the body is able to fight the bacteria to stop them from growing.

People with latent tuberculosis infection:

• Have no symptoms
• Don’t feel sick
• Can’t spread mycobacterium tuberculosis bacteria to others
• Usually have a positive tuberculosis skin test reaction or positive tuberculosis blood test
• May develop tuberculosis disease if they do not receive treatment for latent tuberculosis infection

Many people who have latent tuberculosis infection never develop tuberculosis disease. In these people, the Mycobacterium tuberculosis bacteria remain inactive for a lifetime without causing disease. But in other people, especially people who have a weak immune system, the bacteria become active, multiply, and cause tuberculosis disease.

Tuberculosis Disease

Mycobacterium tuberculosis bacteria become active if the immune system can’t stop them from growing. When mycobacterium tuberculosis bacteria are active (multiplying in your body), this is called tuberculosis disease. People with tuberculosis disease are sick. They may also be able to spread the bacteria to people they spend time with every day.

Many people who have latent tuberculosis infection never develop tuberculosis disease. Some people develop tuberculosis disease soon after becoming infected (within weeks) before their immune system can fight the mycobacterium tuberculosis bacteria. Other people may get sick years later when their immune system becomes weak for another reason.

For people whose immune systems are weak, especially those with HIV infection, the risk of developing tuberculosis disease is much higher than for people with normal immune systems.

Table 1. The difference between latent tuberculosis Infection (LTBI) and tuberculosis disease

A Person with Latent Tuberculosis Infection (LTBI)	A Person with Tuberculosis Disease
Has no symptoms	Has symptoms that may include a bad cough that lasts 3 weeks or longer pain in the chest coughing up blood or sputum weakness or fatigue weight loss no appetite chills fever sweating at night
Does not feel sick	Usually feels sick
Cannot spread TB bacteria to others	May spread TB bacteria to others
Usually has a skin test or blood test result indicating TB infection	Usually has a skin test or blood test result indicating TB infection
Has a normal chest x-ray and a negative sputum smear	May have an abnormal chest x-ray, or positive sputum smear or culture
Needs treatment for latent TB infection to prevent TB disease	Needs treatment to treat TB disease

There are two kinds of tests that are used to detect mycobacterium tuberculosis bacteria in the body: the tuberculosis skin test (TST) and tuberculosis blood tests. A positive tuberculosis skin test or tuberculosis blood test only tells that a person has been infected with tuberculosis bacteria. It does not tell whether the person has latent tuberculosis infection (LTBI) or has progressed to tuberculosis disease. Other tests, such as a chest x-ray and a sample of sputum, are needed to see whether the person has tuberculosis disease.

Mycobacterium tuberculosis transmission

Mycobacterium tuberculosis bacteria are spread through the air from one person to another. The mycobacterium tuberculosis bacteria are put into the air when a person with tuberculosis disease of the lungs or throat coughs, speaks, or sings. People nearby may breathe in these bacteria and become infected.

Mycobacterium tuberculosis is NOT spread by:

• shaking someone’s hand
• sharing food or drink
• touching bed linens or toilet seats
• sharing toothbrushes
• kissing

When a person breathes in mycobacterium tuberculosis bacteria, the bacteria can settle in the lungs and begin to grow. From there, they can move through the blood to other parts of the body, such as the kidney, spine, and brain.

Tuberculosis disease in the lungs or throat can be infectious. This means that the bacteria can be spread to other people. TB in other parts of the body, such as the kidney or spine, is usually not infectious.

People with tuberculosis disease are most likely to spread it to people they spend time with every day. This includes family members, friends, and coworkers or schoolmates.

Risk factors for tuberculosis

Some people develop tuberculosis disease soon after becoming infected (within weeks) before their immune system can fight the mycobacterium tuberculosis bacteria. Other people may get sick years later, when their immune system becomes weak for another reason.

Overall, about 5 to 10% of infected persons who do not receive treatment for latent tuberculosis infection will develop tuberculosis disease at some time in their lives. For persons whose immune systems are weak, especially those with HIV infection, the risk of developing tuberculosis disease is much higher than for persons with normal immune systems.

Generally, persons at high risk for developing tuberculosis disease fall into two categories:

1. Persons who have been recently infected with tuberculosis bacteria
2. Persons with medical conditions that weaken the immune system

Persons who have been Recently Infected with mycobacterium tuberculosis bacteria

This includes:

• Close contacts of a person with infectious tuberculosis disease
• Persons who have immigrated from areas of the world with high rates of tuberculosis
• Children less than 5 years of age who have a positive tuberculosis test
• Groups with high rates of tuberculosis transmission, such as homeless persons, injection drug users, and persons with HIV infection
• Persons who work or reside with people who are at high risk for tuberculosis in facilities or institutions such as hospitals, homeless shelters, correctional facilities, nursing homes, and residential homes for those with HIV

Persons with Medical Conditions that Weaken the Immune System

Babies and young children often have weak immune systems. Other people can have weak immune systems, too, especially people with any of these conditions:

• HIV infection (the virus that causes AIDS)
• Substance abuse
• Silicosis
• Diabetes mellitus
• Severe kidney disease
• Low body weight
• Organ transplants
• Head and neck cancer
• Medical treatments such as corticosteroids or organ transplant
• Specialized treatment for rheumatoid arthritis or Crohn’s disease

Tuberculosis prevention

Preventing latent tuberculosis infection (LTBI) from progressing to tuberculosis disease

Many people who have latent tuberculosis infection never develop tuberculosis disease. But some people who have latent tuberculosis infection are more likely to develop tuberculosis disease than others. Those at high risk for developing tuberculosis disease include:

• People with HIV infection
• People who became infected with tuberculosis bacteria in the last 2 years
• Babies and young children
• People who inject illegal drugs
• People who are sick with other diseases that weaken the immune system
• Elderly people
• People who were not treated correctly for tuberculosis in the past

If you have latent tuberculosis infection and you are in one of these high-risk groups, you should take medicine to keep from developing tuberculosis disease. There are several treatment options for latent tuberculosis infection. You and your health care provider must decide which treatment is best for you. If you take your medicine as instructed, it can keep you from developing tuberculosis disease. Because there are less bacteria, treatment for latent tuberculosis infection is much easier than treatment for tuberculosis disease. A person with tuberculosis disease has a large amount of tuberculosis bacteria in the body. Several drugs are needed to treat tuberculosis disease.

Preventing exposure to tuberculosis disease while traveling abroad

In many countries, tuberculosis is much more common than in the United States. Travelers should avoid close contact or prolonged time with known tuberculosis patients in crowded, enclosed environments (for example, clinics, hospitals, prisons, or homeless shelters).

Although multidrug-resistant (MDR) and extensively drug-resistant (XDR) mycobacterium tuberculosis bacteria are occurring globally, they are still rare. HIV-infected travelers are at greatest risk if they come in contact with a person with multidrug-resistant or extensively drug-resistant mycobacterium tuberculosis bacteria.

Air travel itself carries a relatively low risk of infection with tuberculosis of any kind. Travelers who will be working in clinics, hospitals, or other health care settings where tuberculosis patients are likely to be encountered should consult infection control or occupational health experts. They should ask about administrative and environmental procedures for preventing exposure to tuberculosis. Once those procedures are implemented, additional measures could include using personal respiratory protective devices.

Travelers who anticipate possible prolonged exposure to people with mycobacterium tuberculosis bacteria (for example, those who expect to come in contact routinely with clinic, hospital, prison, or homeless shelter populations) should have a tuberculosis skin test or a tuberculosis blood test before leaving the United States. If the test reaction is negative, they should have a repeat test 8 to 10 weeks after returning to the United States. Additionally, annual testing may be recommended for those who anticipate repeated or prolonged exposure or an extended stay over a period of years. Because people with HIV infection are more likely to have an impaired response to tuberculosis tests, travelers who are HIV positive should tell their physicians about their HIV infection status.

Tuberculosis Vaccine (BCG)

Bacille Calmette-Guérin (BCG) is a vaccine for tuberculosis disease. This vaccine is not widely used in the United States, but it is often given to infants and small children in other countries where tuberculosis is common. BCG does not always protect people from getting tuberculosis.

BCG Recommendations

In the United States, BCG should be considered for only very select people who meet specific criteria and in consultation with a tuberculosis expert. Health care providers who are considering BCG vaccination for their patients are encouraged to discuss this intervention with the tuberculosis control program in their area.

Children

BCG vaccination should only be considered for children who have a negative tuberculosis test and who are continually exposed, and cannot be separated from adults who

• Are untreated or ineffectively treated for tuberculosis disease, and the child cannot be given long-term primary preventive treatment for tuberculosis infection; or
• Have tuberculosis disease caused by strains resistant to isoniazid and rifampin.

Health Care Workers

BCG vaccination of health care workers should be considered on an individual basis in settings in which

• A high percentage of tuberculosis patients are infected with tuberculosis strains resistant to both isoniazid and rifampin;
• There is ongoing transmission of drug-resistant tuberculosis strains to health care workers and subsequent infection is likely; or
• Comprehensive tuberculosis infection-control precautions have been implemented, but have not been successful.

Health care workers considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and treatment of latent tuberculosis infection.

Testing for tuberculosis in BCG-Vaccinated People

Many people born outside of the United States have been BCG-vaccinated.

People who were previously vaccinated with BCG may receive a tuberculosis skin test to test for tuberculosis infection. Vaccination with BCG may cause a positive reaction to a tuberculosis skin test. A positive reaction to a tuberculosis skin test may be due to the BCG vaccine itself or due to infection with tuberculosis bacteria.

Tuberculosis blood tests (IGRAs), unlike the tuberculosis skin test, are not affected by prior BCG vaccination and are not expected to give a false-positive result in people who have received BCG.

For children under the age of five, the tuberculosis skin test is preferred over tuberculosis blood tests.

A positive tuberculosis skin test or tuberculosis blood test only tells that a person has been infected with tuberculosis bacteria. It does not tell whether the person has latent tuberculosis infection or has progressed to tuberculosis disease. Other tests, such as a chest x-ray and a sample of sputum, are needed to see whether the person has tuberculosis disease.

Mycobacterium tuberculosis signs and symptoms

Symptoms of tuberculosis disease depend on where in the body the mycobacterium tuberculosis bacteria are growing. Mycobacterium tuberculosis bacteria usually grow in the lungs (pulmonary tuberculosis). Tuberculosis disease in the lungs may cause symptoms such as:

• a bad cough that lasts 3 weeks or longer
• pain in the chest
• coughing up blood or sputum (phlegm from deep inside the lungs)

Other symptoms of tuberculosis disease are:

• weakness or fatigue
• weight loss
• no appetite
• chills
• fever
• sweating at night

Symptoms of tuberculosis disease in other parts of the body depend on the area affected.

People who have latent tuberculosis infection (LTBI) do not feel sick, do not have any symptoms, and cannot spread tuberculosis to others.

Mycobacterium tuberculosis diagnosis

There are two kinds of tests that are used to detect mycobacterium tuberculosis bacteria in the body: the tuberculosis skin test (TST) and tuberculosis blood tests. A positive tuberculosis skin test or tuberculosis blood test only tells that a person has been infected with tuberculosis bacteria. It does not tell whether the person has latent tuberculosis infection (LTBI) or has progressed to tuberculosis disease. Other tests, such as a chest x-ray and a sample of sputum, are needed to see whether the person has tuberculosis disease.

Mycobacterium tuberculosis treatment

Not everyone infected with mycobacterium tuberculosis bacteria becomes sick. As a result, two tuberculosis-related conditions exist: latent tuberculosis infection and tuberculosis disease. Both latent tuberculosis infection and tuberculosis disease can be treated.

Without treatment latent tuberculosis infection can progress to tuberculosis disease. If not treated properly, tuberculosis disease can be fatal.

Treatment of latent tuberculosis infection should start after excluding the possibility of tuberculosis disease.

Groups who should be given high priority for Latent tuberculosis Infection Treatment include:

• People with a positive tuberculosis blood test (interferon-gamma release assay or IGRA).
• People with a tuberculin skin test (TST) reaction of 5 or more millimeters who are:
  • HIV-infected persons.
  • Recent contacts to a patient with active tuberculosis disease.
  • Persons with fibrotic changes on chest radiograph consistent with old tuberculosis.
  • Organ transplant recipients.
  • Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-α antagonists).
• People with a tuberculin skin test (TST) reaction of 10 or more millimeters who are:
  • From countries where tuberculosis is common, including Mexico, the Philippines, Vietnam, India, China, Haiti, and Guatemala, or other countries with high rates of tuberculosis. (Of note, people born in Canada, Australia, New Zealand, or Western and Northern European countries are not considered at high risk for tuberculosis infection, unless they spent time in a country with a high rate of tuberculosis.)
  • Injection drug users.
  • Residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes, homeless shelters, hospitals, and other health care facilities).
  • Mycobacteriology laboratory personnel.
  • Children under 4 years of age, or children and adolescents exposed to adults in high-risk categories.

Persons with no known risk factors for tuberculosis may be considered for treatment of latent tuberculosis infection if they have either a positive IGRA result or if their reaction to the tuberculin skin test (TST) is 15 mm or larger. However, targeted tuberculosis testing programs should only be conducted among high-risk groups. All testing activities should be accompanied by a plan for follow-up care for persons with latent tuberculosis infection or disease.

As of 2018, there are four CDC-recommended treatment regimens for latent tuberculosis infection that use isoniazid (INH), rifapentine (RPT), and/or rifampin (RIF). All the regimens are effective. Healthcare providers should prescribe the more convenient shorter regimens, when possible. Patients are more likely to complete shorter treatment regimens. Treatment must be modified if the patient is a contact of an individual with drug-resistant tuberculosis disease. Consultation with a tuberculosis expert is advised if the known source of tuberculosis infection has drug-resistant tuberculosis.

Treatment for tuberculosis disease

When mycobacterium tuberculosis bacteria become active (multiplying in the body) and the immune system can’t stop the bacteria from growing, this is called tuberculosis disease. Tuberculosis disease will make a person sick. People with tuberculosis disease may spread the mycobacterium tuberculosis bacteria to people with whom they spend many hours.

It is very important that people who have tuberculosis disease are treated, finish the medicine, and take the drugs exactly as prescribed. If they stop taking the drugs too soon, they can become sick again; if they do not take the drugs correctly, the mycobacterium tuberculosis bacteria that are still alive may become resistant to those drugs. Tuberculosis that is resistant to drugs is harder and more expensive to treat.

Tuberculosis disease can be treated by taking several drugs for 6 to 9 months. There are 10 drugs currently approved by the U.S. Food and Drug Administration (FDA) for treating tuberculosis. Of the approved drugs, the first-line anti-tuberculosis agents that form the core of treatment regimens are:

• isoniazid (INH)
• rifampin (RIF)
• ethambutol (EMB)
• pyrazinamide (PZA)

Regimens for treating tuberculosis disease have an intensive phase of 2 months, followed by a continuation phase of either 4 or 7 months (total of 6 to 9 months for treatment).

Table 2. Drug susceptible tuberculosis disease treatment regimens

	INTENSIVE PHASE		CONTINUATION PHASE
Regimen	Drugsa	Interval and Doseb (minimum duration)	Drugs	Interval and Doseb,c (minimum duration)	Range of Total Doses	Commentsc, d	Regimen Effectiveness
1	INH RIF PZA EMB	7 days/week for 56 doses (8 weeks) or 5 days/week for 40 doses (8 weeks)	INH RIF	7 days/week for 126 doses (18 weeks) or 5 days/week for 90 doses (18 weeks)	182 to 130	This is the preferred regimen for patients with newly diagnosed pulmonary TB.
2	INH RIF PZA EMB	7 days/week for 56 doses (8 weeks) or 5 days/week for 40 doses (8 weeks)	INH RIF	3 times weekly for 54 doses (18 weeks)	110 to 94	Preferred alternative regimen in situations in which more frequent DOT during continuation phase is difficult to achieve.
3	INH RIF PZA EMB	3 times weekly for 24 doses (8 weeks)	INH RIF	3 times weekly for 54 doses (18 weeks)	78	Use regimen with caution in patients with HIV and/or cavitary disease. Missed doses can lead to treatment failure, relapse, and acquired drug resistance.
4	INH RIF PZA EMB	7 days/week for 14 doses then twice weekly for 12 dosese	INH RIF	Twice weekly for 36 doses (18 weeks)	62	Do not use twice-weekly regimens in HIV-infected patients or patients with smear positive and/or cavitary disease. If doses are missed then therapy is equivalent to once weekly, which is inferior.

Abbreviations: DOT = directly observed therapy; EMB = ethambutol; HIV = human immunodeficiency virus; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin.

Footnotes:

• (a) Other combinations may be appropriate in certain circumstances; additional details are provided in the Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible TuberculosisExternal.
• (b) When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. DOT should be used when drugs are administered less than 7 days per week.
• (c) Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase.
• (d) Pyridoxine (vitamin B6), 25–50 mg/day, is given with INH to all persons at risk of neuropathy (e.g., pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
• (e) Alternatively, some U.S. TB control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses.

Use of once-weekly therapy with INH 900 mg and rifapentine 600 mg in the continuation phase is not generally recommended. In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus rifapentine 600 mg may be considered for use only in HIV uninfected persons without cavitation on chest radiography.

Continuation Phase of Treatment

The continuation phase of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in most patients. The 7-month continuation phase is recommended only for the following groups:

• Patients with cavitary pulmonary TB caused by drug-susceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive;
• Patients whose intensive phase of treatment did not include PZA;
• Patients with HIV who are not receiving antiretroviral treatment (ART) during TB treatment; and
• Patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the intensive phase is positive.
• (Note: Use of once-weekly therapy with INH 900 mg and rifapentine 600 mg in the continuation phase is not generally recommended. In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus rifapentine 600 mg may be considered for use only in HIV uninfected persons without cavitation on chest radiography.)

Treatment Completion

Treatment completion is determined by the number of doses ingested over a given period of time.

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