Mycobacterium Chelonae

Background

Mycobacterium chelonae belongs to the family of nontuberculous mycobacteria (NTM) classified in the rapidly growing mycobacteria (RGM), Runyon group IV that are nonpigmented. RGM typically show visible colonies on solid growth media within 1 week.^[1] M chelonae is further grouped in the M chelonae-abscessus group that encompasses Mycobacterium immunogenum, Mycobacterium massiliense, and Mycobacterium bolletii, in addition to M chelonae and M abscessus.

In 1992, M chelonae became its own species based on previous genomic studies.^{[2, 3]} Hence, when researching and reviewing the literature prior to 1992, M abscessus and M chelonae were considered the same organism or subspecies within the M chelonae-abscessus group, which complicated its taxonomy. In addition, further identification of the newer species M massiliense and M bolletii and the proper taxonomy surrounding these 2 species and others cause the taxonomy of this group to be a dynamic process.^{[4, 5]}

M chelonae, along with M abscessus, are considered the most drug resistant of the NTM group, which leads to difficulty when treating infections these organisms. It is important to establish that M chelonae is the pathogen causing a particular infection . The severity of disease and the patient’s underlying medical condition also influence therapy. M chelonae tends to respond better to treatment regimens since is lacks the erm gene that confers macrolide resistance in M abscessus strains.^[6] Most information about treatment recommendations are based upon in vitro laboratory observations, clinical anecdotes, retrospective observational series, and expert opinion. Optimal therapeutic interventions and their duration, as well as outcomes data, are not firmly established based upon large, controlled, evidence-based experimental studies.

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Pathophysiology

M chelonae, like many NTM, are ubiquitous in the environment and have been isolated from both natural and potable freshwater sources, soil, contaminated solutions, and reptiles.^[7] The organism can grow in distilled and unsupplemented water. It is hydrophobic and adheres to surfaces, owing to the structure and make up of its mycolic acids resulting in biofilm formation.^{[8, 9]} Like most RGM, it is resistant to chlorine and some industrial grade detergents (ie, glutaraldehyde) commonly used in hospital settings.^[10] Household water heaters are favorable growth environments owing to the stagnant water and its elevated temperature.^[11]

M chelonae causes disease sporadically, as well as in patients with identifiable risk factors, owing to its hardiness, resistance to chemical and antimicrobial degradation, and ubiquitous environmental presence.

M chelonae most commonly causes infection of the skin and skin structures where infections can be classified as a localized cellulitis, as a subcutaneous abscess, or as disseminated disease.^[12] According to some series, as many as 75% of patients with disseminated disease are initially colonized with M chelonae, and skin trauma is thought to be the etiology for cutaneous invasion.^{[13, 14]}

Accidental penetrating trauma, particularly when associated with pedicure salons and footbaths are well-known risk factors for disease. Initial reports of NTM cutaneous infection associated with tattoos occurred in 2003. M chelonae has caused outbreaks of skin infections associated with tattoo parlors and has been found in contaminated tattoo ink.^[15] Disseminated infection is associated with organ transplants, diabetes mellitus, malignancy, long-term corticosteroid administration, immunosuppressant therapy, and tumor necrosis factor-alpha (TNF-α) inhibitors.^{[15, 16]}

Healthcare-associated M chelonae infections have been associated with surgical infections of all types, complicating eye, otolaryngologic, chest, abdominal, cardiovascular, reconstructive, cosmetic, and orthopedic procedures. Any intervention involving injectable foreign materials, artificial prostheses, and implantable devices (eg, pacemakers, prosthetic valves) are at risk.^[17] Surgical site infections have ranged from sternal wound infections associated with the bone wax to plastic and reconstructive surgical infections linked to contaminated water or marking solution.^{[18, 19]} These infections have been associated with acupuncture and mesotherapy in South America.^[20] M chelonae has caused peritonitis and dialysis catheter infections in peritoneal dialysis patients.^[21] It causes intravascular catheter infections of all types and is particularly common in the immunocompromised patient.

The eye is the second most common site of M chelonae infection. The organism is known to cause dacryocystitis, canaliculitis, conjunctivitis, scleritis, endophthalmitis, and keratitis.^[22] Risk factors for infection include both accidental and surgical trauma, laser in situ keratomileusis (LASIK), penetrating keratoplasty (PK), and all procedures involving retained biomaterial.^[23] Additional risk factors include the presence of contact lens, corticosteroid use, and human immunodeficiency virus (HIV) infection.

Pulmonary disease with M chelonae is uncommon, and other atypical mycobacteria such as M avium complex (MAC), M kansasii, and M abscessus are the more likely lung pathogens.^[24] When M chelonae has been described as the causative pathogen, it usually occurs in patients with severe underlying lung disease such as cystic fibrosis or bronchiectasis, patients with significant gastroesophageal disorders, or in patients with signs of connective-tissue disorders such as mitral valve prolapse (MVP), scoliosis, and pectus excavatum.^[25]

Musculoskeletal involvement with M chelonae is also uncommon, but is associated with penetrating trauma. Both osteomyelitis and granulomatous tenosynovitis have been reported without any known preceding trauma.^{[12, 26]} Prosthetic joint infections with M chelonae have been described.^[27]

Sinusitis and otitis media secondary to M chelonae has been reported.^[28] Cases associated with prior surgery, topical corticosteroid usage, and pressure equalization (PE) tube insertion have been described.^{[18, 29]} M abscessus is the more likely atypical organism to cause otitis media.

Bacteremia is usually associated with fever, with or without chills and sweats. Shock and multisystem organ failure is unusual. Patients typically possess intravascular catheters, dialysis catheters, biliary stents, or prosthetic heart valves and are usually immunocompromised.

Immune defects such as autoantibodies to specific interleukins (ILs), interferon-gamma (INF-γ), and IL or INF receptor deficiencies have been reported and are risk factors for disseminated NTM, in addition to known risk factors such as HIV infection, long-term steroid use, immunosuppressives, and TNF-α inhibitors.^{[25, 29, 30]}

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Epidemiology

Frequency

United States

M chelonae and the other RGM are not reportable infections in the United States, and the true prevalence is unknown. Most of the NTM have been shown to have geographic variation in the United States. M chelonae can occour anywhere in the United States, but the prevalence of M chelonae/abcessus cases is increased cases in the southern and coastal states of Florida, Georgia, Louisiana, and Texas.^{[1, 25]}

The first national survey evaluating the prevalence of NTM in the United States was done between 1981 and 1983, and it showed an annual disease prevalence of 1.78 NTM cases per 100,000 persons, with M chelonae/abcessus reported as 0.08 case per 100,000 persons.^[31] NTM lung disease in hospitalized patients was studied from 1998 to 2005 in 11 states and showed increasing prevalence with age in men and women, with some variation between states.^[32] In Oregon from 2005 to 2006, individuals meeting a strict case definition for NTM disease were studied, with a reported annualized prevalence of 7.2 cases per 100,000 persons. In that study, M chelonae prevalence was 0.2 case per 100,000 persons, with the majority of cases isolated from skin and soft tissue infections.^[33]

Overall, it appears that NTM prevalence is increasing in certain populations and geographic areas throughout the country, but the degree to which M chelonae specifically contributes is uncertain. It represents a smaller percentage of these infections than other NTM species.

International

The global epidemiology of pulmonary NTM infections has been reviewed, with limited reported information about M chelonae.^[34] The incidence and prevalence of NTM varies considerably, and M chelonae has been reported in South America, Australia, Taiwan, China, Japan, Canada, Korea, Germany, Italy, France, Switzerland, the United Kingdom, and The Netherlands.^[1]

A 2-year review of NTM isolates in a South Korean medical center was evaluated for clinical relevance. Approximately one fourth of 1548 isolates from 794 patients were found to be clinical significant, with M chelonae representing 29 isolates from 25 patients. Of those, only 6 patients (3%) were determined to be definite or probable NTM infection based on American Thoracic Society (ATS) and British Thoracic Society (BTS) guidelines.^[35]

A national Australian survey in 2000 reported that all 22 M chelonae pulmonary isolates were not considered pathogens, while the organism was considered pathogenic in 17 of 131 soft-tissue isolates.^[36]

Mortality/Morbidity

Mortality from localized or systemic infection with M chelonae is rare but may result from disseminated disease or surgical complications.

Race

M chelonae infection has no clear racial predilection.

Sex

M chelonae infection has no clear sexual predominance.

Age

M chelonae has no clear age predilection, although increased age is frequently identifiable based on associated risk factors and associated events (ie, cardiac surgery, TNF-α inhibitor administration).

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Prognosis

With debridement and antibiotic therapy guided by susceptibility data, the prognosis is very good for most infections. Prognosis is worse if the patient is immunocompromised or noncompliant with therapy, which can be prolonged and poorly tolerated.

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

Cure of infected implants that cannot be removed may be impossible and require antimicrobial suppressive therapy. Infection of cosmetic implants and procedures can be disfiguring.

Unacceptable toxicities with prolonged antibiotic use may develop, particularly with linezolid (lactic acidosis, neuropathy, myelosuppression), aminoglycosides (renal failure, hearing loss, tinnitus), and fluoroquinolones (tendon rupture).

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Patient Education

Educate patients on the importance of adherence with multiple drug regimens to avoid the development of antibiotic resistance.

Patients may confuse this disease with tuberculosis. Reassure patients that they are not contagious to others.

Discuss possible medication adverse effects with patients to increase the chances of early detection. Advise patients to avoid prevent pregnancy if possible. If pregnancy is present, expert consultation is recommended.

For excellent patient education resources, see eMedicineHealth's patient education article Bronchoscopy.

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History

Patients with Mycobacterium chelonae skin involvement may have a chronic, nonhealing cellulitis or skin ulcer that is slow to spread. Areas of cellulitis associated with the infection are frequently hyperpigmented. Skin nodules, sinus tract, and abscess formation may be present. Sinus tracts and abscesses may drain and appear to resolve, only to recur days to weeks later during the first months of treatment.

Patients with M chelonae lung disease may have a chronic cough, sputum production, or progressive dyspnea.

Easy fatigability, fever, night sweats, and weight loss occur with pulmonary or disseminated disease, although less commonly than with tuberculosis.

Infections associated with surgical procedures may present as wound infections, draining fistulae/sinus tracts, or inflamed and/or dysfunctional prosthetic devices.^{[17, 18]}

Bacteremia is associated fever, with or without chills, in immunocompromised patients with intravascular catheters, hemodialysis catheters, peritoneal dialysis catheters, biliary stents, and prosthetic heart valves.^[18]

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Physical

No physical examination findings are pathognomonic for M chelonae infection. Findings, as follows, depend on infection site and the cause:

• Skin: Ulcerative lesions and/or subcutaneous nodules may be present. Deep infection may lead to abscess formation and draining sinus tracts. In contrast to Mycobacterium fortuitum infection, the skin lesions caused by M chelonae infection tend to be multiple and tend to occur in older patients or individuals receiving immunosuppressive drugs.^[12] The sinus tracts may drain thick purulence, which may appear and disappear over time. Skin involvement is often associated with hyperpigmentation. Lesions are indolent and not particularly warm to the touch. See the image below.
• Eye: Conjunctivitis, episcleritis, canniculitis, corneal ulcers, dacryocystitis, or keratitis may be present.
• Lungs: Rales or rhonchi may be present.
• Heart: Valvular murmur with endocarditis may be present.
• Abdomen: Diffuse tenderness with peritonitis may be associated with peritoneal dialysis.

Overlying cellulitis, cold abscess formation, late-onset incisional drainage, and/or joint pain/dysfunction suggests prosthetic infection of all types.

Fever, with or without chills, in the presence of intravascular catheters, dialysis catheters, or prosthetic heart valves raises the possibility of bacteremia, particularly in an immunocompromised patient.

View Image

Cutaneous lesions from Mycobacterium abscessus. Courtesy of K. Galil, US Centers for Disease Control and Prevention.

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Causes

Causes of M chelonae infection are as follows:

• Trauma or injection - Accidental or surgical trauma, particularly puncture wounds (eg, tattoos, acupuncture, injection sites)
• Disseminated disease - Immunosuppression, immune defects, and cytotoxic chemotherapy^{[25, 30]}
• Lung disease -Bronchiectasis, cystic fibrosis
• Tattoo ink and contaminated skin marking solutions^{[15, 19]}
• Indwelling catheters, dialysis catheters, prosthetic valves, orthopedic prostheses, biliary stents, scleral buckles, and breast implants^[1]
• Associated surgical procedures include bronchoscopy, laparoscopy, liposuction, and mammoplasty, as well as all types of cardiac, otolaryngologic, orthopaedic, plastic/reconstructive, and ophthalmologic surgery^[1]

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Complications

Complications of M chelonae infections may include the following:

• Severe lung disease or disseminated disease may cause death.
• Skin lesions and subsequent debridement may be disfiguring.
• Loss of surgically implanted prosthetic devices may occur.
• Antimycobacterial monotherapy may lead to drug resistance.
• Antimycobacterial chemotherapy of all types may be associated with adverse drug reactions, organ failure, and death.

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Laboratory Studies

According to American Thoracic Society (ATS) criteria, diagnosis of Mycobacterium chelonae lung disease requires the following 3 elements^[25] :

• Pulmonary symptoms with consistent radiographic features (see Imaging Studies)
• Exclusion of other diagnoses (especially tuberculosis and other nontuberculous mycobacteria [NTM])
• Appropriate microbiological findings (which are listed immediately below)

Primary testing methodology

Primary testing methodology is sputum smear for acid-fast bacilli (AFB) and culture for mycobacteria.

Microbiological findings to satisfy ATS diagnostic criteria include the following (at least one needed for accurate diagnosis):

• Positive culture from 2 separate sputum samples
• One positive culture from bronchial wash or lavage
• A biopsy specimen with appropriate histopathologic features and a positive culture from an associated bronchial wash or biopsy culture

Induced sputum samples may be substituted for expectorated sputum samples, but data establishing the effectiveness of this technique are lacking.

A single positive isolate may represent a contaminant or a persistent or transient colonizer without pathogenicity.^{[35, 36]}

Swab culture for acid-fast bacillus

Swab specimens are less optimal than cultures obtained via aspiration. Notifying microbiology laboratory personnel to communicate clinical suspicion and concerns results in the proper procedures regarding adequate specimen processing to increase the yield and significance of cultures.

Interpret microbiological results with caution because a single positive culture, especially of a superficial lesion or sputum, may represent a contaminant or colonization. In one study from Spain, 13 of 24 isolates of M chelonae were deemed of questionable clinical significance.^[17]

Species identification of the NTM as well as susceptibility studies performed by a competent reference laboratory are important steps when evaluating all forms of NTM, since their clinical presentation and manifestations, as well as their response to therapy, can be quite different.

Additional testing

If M chelonae,Mycobacterium abscessus or any rapidly growing mycobacteria (RGM)infection is discovered, additional testing for underlying disease may be needed. Speciation points to the clinical sequelae that can be anticipated.

An HIV test may be warranted, especially if disseminated disease with any NTM is diagnosed without an obvious underlying condition.

Sweat chloride and/or genetic screening for cystic fibrosis may be warranted if lung infection is found not only in a relatively young patient, but also in older patients with evidence of bronchiectasis.

A purified protein derivative (PPD) of tuberculin test should be considered to assist in ruling out tuberculosis. Similarly, interferon-gamma release assays (IGRA) may help identify a true Mycobacterium tuberculosis infection.

Susceptibility testing

Susceptibility testing should be performed on all isolates to guide treatment. General susceptibility results reported in the ATS guidelines are as follows^[25] :

• Tobramycin - 100%
• Clarithromycin - 100%
• Linezolid - 50-90%
• Imipenem - 60%
• Amikacin - 50%
• Doxycycline - 25%
• Ciprofloxacin - 20%

In vitro susceptibility testing may not correlate with in vivo results and vice versa.

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Imaging Studies

Chest radiography

Perform chest radiography if pulmonary symptoms are present. Typical findings are bilateral patchy nodular or cavitary opacities (15% are cavitary) with an upper lobe predominance.

Normal chest radiographic findings with a single positive culture suggest that the organism is a contaminant or a transient colonizer and is not clinically significant. However, in the presence of chronic persistent pulmonary symptoms or repeatedly positive culture results, additional testing may be necessary.

Chest CT scanning

If the patient has significant respiratory symptoms or repeatedly positive cultures for the M chelonae with a lack of cavitary disease on chest radiography, high-resolution CT scanning is likely indicated.

Typical CT scan findings include bronchiectasis, “tree-in-bud” appearance, or diffuse small nodules, which may not be apparent on routine chest radiography.

If the chest radiographic findings are abnormal, chest CT scanning may be performed to obtain better definition of the abnormalities present. Small cavities, nodules, and lymphadenopathy may be detected.

CT scanning of the abdomen and pelvis

CT scanning of the abdomen and pelvis may be indicated to detect intra-abdominal or retroperitoneal abscesses. It may also be used to evaluate localizing signs or symptoms of soft-tissue infection, especially in patients with a recent history of abdominal wall injections.

Bone imaging, MRI, and nuclear imaging

These studies may be helpful in detecting suspected osteomyelitis or joint disease, especially in patients with a history of penetrating trauma.

MRI can be helpful in evaluating the anatomy sinus tracts and fistulae and whether underlying abscess formation, foreign material, or marrow edema (osteomyelitis) is present.

Gallium scanning may be useful to screen for supradiaphragmatic lymphadenopathy (intrathoracic or axillary).

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Other Tests

Erythrocyte sedimentation rate or C-reactive protein assessments may be useful to differentiate colonizer and pathogen, but these are nonspecific tests and the results must be carefully evaluated within the clinical context of the patient.

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Procedures

Pulmonary procedures

Bronchoscopy is frequently indicated. Tests to be sent include bronchial washes for AFB culture and transbronchial biopsy samples sent for culture and histopathology. Bronchoalveolar lavage (BAL) may also be useful. Fungal cultures are typically sent as well, given an uncertain differential diagnosis.

Open or Video-assisted thorascopic (VATS) lung biopsy may be considered if suspicion is high but diagnostic criteria have not been met. Specimens for fungal and AFB cultures should be sent along with histopathology.

A positive culture from a sterile surgical biopsy is considered diagnostic for M chelonae.

Lung biopsy histology documenting the presence of AFB or granulomas along with positive sputum or BAL culture is considered diagnostic.

Skin tests

Skin testing with nontuberculous mycobacterial specific antigens is nonspecific and generally not indicated. These tests are not commercially available.

A positive standard PPD test result may raise suspicion for an unsuspected M tuberculosis infection.

A biopsy for localized or disseminated skin lesions should be performed. Specimens for AFB and fungal cultures should be sent, as well as histopathology. The microbiology laboratory needs to be alerted of the concern for atypical organisms since the organism can be overlooked as a pathogen.

Abscess drainage

Fluid from a localized abscess should be obtained for culture; this method is preferred over swab culture of a draining abscess, sinus tract, or fistula.

Fine-needle aspiration and biopsy should be attempted on lymphadenitis for histopathology, cytology, and culture.

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Histologic Findings

Histologic findings may reveal acute inflammation, microabscesses, granulomas (with or without caseation), and/or diffuse granulomatous inflammation. Special tissue stains for AFB may or may not reveal organisms.

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Staging

There is no formal staging classification for M chelonae. Isolates represent either contamination, colonization, or true infection. When present, infections are either localized or disseminated.

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Medical Care

Localized cutaneous infection usually resolves with appropriate antibiotics with combined indicated excision or debridement. An optimal drug regimen for Mycobacterium chelonae infection has not been established.

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Surgical Care

Aggressive debridement of infected soft tissue has always been advocated as a modality of therapy. Uncomplicated infections may not require surgical intervention, and it is not unusual for practitioners to try antimicrobial chemotherapy alone before undertaking a surgical procedure. Excision and debridement is currently recommended when infection is extensive, recurrent, or drug resistant. Abscess formation with or without sinus tract formation and bone involvement usually requires formal debridement.^{[25, 29]} In addition, infections in patients intolerant of drug therapy may need surgical excision.

Any infected foreign body or implanted device usually must be removed in combination with antibiotic therapy to optimize the therapeutic outcome.^{[18, 20, 21, 27, 29]}

Ocular infections usually require surgical intervention.^[23]

Pulmonary infection only requires surgical intervention when it is extensive, cavitary, or nonresponsive to drug therapy. Surgery usually involves lobectomy or segmentectomy and has been reported to have acceptable morbidity and mortality in most cases with reasonable preserved lung function.^[37]

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Consultations

Consultation with the following specialists may be indicated:

• An infectious diseases specialist for diagnostic and therapeutic guidance
• A pulmonologist for lung lesions, possible bronchoscopy, and therapeutic guidance
• A dermatologist for possible biopsy of cutaneous lesions
• A surgeon for debridement, biopsy or surgical guidance

Consider obtaining expert advice from the following institutions:

• National Institutes of Health in Bethesda, Maryland
• National Jewish Medical and Research Center in Denver, Colorado
• The University of Texas Health Science Center in Tyler, Texas

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Diet

No specific dietary restrictions are indicated.

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Activity

Patients with M chelonae infections are not contagious and should not be isolated.

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Prevention

No specific deterrence methods are available. Mycobacterium chelonae and Mycobacterium abscessus are ubiquitous organisms.

Isolation is not indicated.

Patients with disease due to nontuberculous mycobacteria (NTM) should be considered for treatment prior to starting anti–tumor necrosis factor-alpha (TNF α) agents, basiliximab, therapeutic corticosteroids, immunosuppressive therapy, and cytotoxic chemotherapy.

If an M chelonae or an M abscessus infection is believed to be nosocomial, notify hospital infection control. Finding even a single case of nosocomial NTM may warrant an investigation.

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Long-Term Monitoring

Further Outpatient Care

The frequency of outpatient visits is determined by the extent of the disease, its sequelae, and whether the patient is receiving oral or intravenous therapy. Initially, patients on oral antibiotics should be evaluated at least monthly for signs of adverse events. More frequent visits may be necessary for patients with parenteral therapy and intravascular catheters to evaluate for complications and line infections.

Outpatients taking aminoglycoside therapy should undergo periodic (at least weekly) assessment of renal function, hearing, and antibiotic levels to avoid toxicity.

Monthly sputum cultures are recommended in patients with pulmonary disease to determine the efficacy and duration of therapy.

Further Inpatient Care

Most patients do not require inpatient care. The duration of inpatient care is dictated by the time needed to recover from any procedures performed.

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Inpatient & Outpatient Medications

Antibiotics are typically administered daily (see Medication). Infrequent dosing schedules (eg, 2-3 times per week) have not been extensively evaluated and are not generally recommended without expert opinion.

One exception is the administration of aminoglycosides, which have been shown to have efficacy when given 3 times a week in combination with other agents given daily.^[38]

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Transfer

Patients who require intravenous antibiotic therapy but who are unable to receive home intravenous therapy need to be placed in a facility capable of administering antibiotics.

Patients with refractory disease may require a referral to a specialty center (usually as an outpatient rather than as an inpatient transfer).

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British Thoracic Society Guidelines for the Workup and Treatment of Nontuberculous Mycobacterial Pulmonary Disease

Workup

Sputum, induced sputum, bronchial washings, bronchoalveolar lavage, or transbronchial biopsy samples can be used to evaluate individuals suspected of having nontuberculous mycobacterial (NTM) pulmonary disease.

Whenever possible, less invasive sampling should be attempted first to minimize procedural risks.

Respiratory samples should be processed within 24 hours of collection (or refrigerated at 4°C if delays are anticipated).

Oropharyngeal swab culture or serology testing should not be used to diagnose NTM pulmonary infection.

If sputum cultures are negative but clinical suspicion of NTM infection is high, consider performing CT-directed bronchial washings to obtain targeted samples.

If individuals undergoing diagnostic evaluation for NTM infection are taking antibiotics that may impair NTM growth (eg, aminoglycosides, macrolides, tetracyclines, cotrimoxazole, linezolid), consider discontinuing these antibiotics 2 weeks before collecting samples.

A validated rapid method should be used to detect NTM in respiratory samples.

All respiratory samples should be stained using auramine-phenol after liquefaction and concentration and then examined by microscopy.

Respiratory tract samples should be cultured (following decontamination) on solid and liquid media in a ISO15189-accredited clinical laboratory for 8 weeks, extending to 12 weeks if necessary.

Routine use of non–culture-based detection methods is not recommended at the present time.

All NTM isolates from respiratory samples should be identified to at least species level using validated molecular or mass spectrometry techniques.

Isolates of M abscessus should be subspeciated using appropriate molecular techniques.

If person-to-person transmission of M abscessus is suspected, isolates should be typed, preferably using whole genome sequencing.

Drug susceptibility testing and reporting

Drug susceptibility testing and reporting should follow the Clinical Laboratory Standards Institute (CLSI) guidelines.

For M avium complex (MAC), clarithromycin and amikacin susceptibility testing should be performed on an isolate taken before initiation of treatment and on subsequent isolates if the patient fails to respond to treatment or recultures MAC after culture conversion.

Macrolide-resistant MAC isolates should be tested against a wider panel of antibiotics to guide, but not dictate, treatment regimens.

For M kansasii, rifampicin susceptibility testing should be performed on an isolate prior to initiation of treatment and on subsequent isolates if the patient fails to respond to treatment or recultures M kansasii after culture conversion.

Rifampicin-resistant M kansasii isolates should be tested against a wider panel of antibiotics to guide, but not dictate, treatment regimens.

Susceptibility testing for M abscessus should include at least clarithromycin, cefoxitin, and amikacin (and preferably also tigecycline, imipenem, minocycline, doxycycline, moxifloxacin, linezolid, co-trimoxazole, and clofazimine if a validated method is available) to guide, but not dictate, treatment regimens.

A minimum of 2 sputum samples collected on separate days should be sent for mycobacterial culture when investigating an individual suspected of having NTM pulmonary disease.

Individuals suspected of having NTM pulmonary disease whose sputum samples are consistently culture-negative for mycobacteria should have CT-directed bronchial washings sent for mycobacterial culture.

Individuals suspected of having NTM pulmonary disease who are unable to expectorate sputum should have CT-directed bronchial washings sent for mycobacterial culture.

Transbronchial biopsies should not be performed routinely in individuals suspected of having NTM pulmonary disease.

Treatment

Clarithromycin-sensitive MAC pulmonary disease should be treated with rifampicin, ethambutol, and clarithromycin or azithromycin using an intermittent (3 times per week) or daily oral regimen. The choice of regimen should be based on the severity of disease and treatment tolerance.

An intermittent (3 times per week) oral antibiotic regimen should not be used in individuals with severe MAC pulmonary disease or in individuals with a history of treatment failure.

An injectable aminoglycoside (amikacin or streptomycin) should be considered in individuals with severe MAC pulmonary disease.

Clarithromycin-resistant MAC pulmonary disease should be treated with rifampicin, ethambutol, and isoniazid or a quinolone, and consider an injectable aminoglycoside (amikacin or streptomycin).

Nebulized amikacin may be considered in place of an injectable aminoglycoside when intravenous/intramuscular administration is impractical or contraindicated or when longer-term treatment with an aminoglycoside is required for the treatment of MAC pulmonary disease.

Macrolide monotherapy or macrolide/quinolone dual therapy regimens should not be used for the treatment of MAC pulmonary disease.

Antibiotic treatment for MAC pulmonary disease should continue for a minimum of 12 months after culture conversion.^[39]

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Medication Summary

Antibiotic therapy for Mycobacterium chelonae infection is generally less intense compared with Mycobacterium abscessus infections since the organism does not possess the erm gene that is responsible for inducible macrolide resistance.^[6] Like many of the nontuberculous mycobacteria (NTM), the in vitro susceptibilities of M chelonae do not always correspond to the clinical response and success seen in vivo. Therefore, it is recommended that susceptibility testing be obtained to guide treatment decisions, after careful consideration of the susceptibility test limitations.^[25]

Susceptibility testing for M chelonae and related mycobacteria lacks standardization and is hampered by previous studies that considered the more resistant organism, M abscessus, to be the same as M chelonae. Microbiological studies published after 2000 are more likely to be reliable than those of the 1990s, especially if published before 1992.

Most M chelonae infections are uncomplicated, localized, and may resolve before treatment is rendered. Chronic, nonresolving infection requires antimicrobial therapy guided by appropriate identification and susceptibility testing. Empiric therapy should be avoided except in unusual circumstances. One should seek consultation from experts in the field if empiric therapy is required or when difficult, life-threatening clinical scenarios arise. The authors routinely seek outside opinions when encountering unusual and difficult cases.

Macrolide antibiotics are the cornerstone of treatment for M chelonae, and either clarithromycin or azithromycin is the agent of choice.^[25] Macrolide monotherapy for localized disease may be sufficient, particularly when used with surgical debridement. The development of resistance during prolonged therapy has been described with macrolide monotherapy and is less common with aminoglycoside monotherapy.^{[25, 29, 40]}

Disseminated infection is usually treated with at least 2 drugs that include a macrolide, and a parental agent, usually an aminoglycoside.^{[1, 29]} Treatment duration for disseminated disease is recommended to be at least 6 months or until all symptoms and signs resolve.^{[29, 40]}

Lung disease with M chelonae is treated with at least 2 drugs that are based on in vitro susceptibility testing. Tobramycin is the preferred aminoglycoside based on in vitro minimum inhibitory concentrations (MICs).^{[25, 29]} Treatment duration should include 12 months of negative sputum cultures.^[25]

Ocular disease is usually treated with a combination of topical antimicrobial agents that usually include aminoglycosides, macrolides, and quinolones for many weeks.^[23] In vitro susceptibility testing for ocular infections uses the same MIC breakpoints as with systemic agents and may not be applicable to usage of topical agents. In a recent review of ocular NTM infections, M chelonae were greater than 90% susceptible in vitro to tobramycin, amikacin, clarithromycin, and azithromycin. With regards to the fluoroquinolones, gatifloxacin and ciprofloxacin were the most susceptible, at 93% and 73%, respectively, compared with levofloxacin and , at 39% and 64%, respectively.^[41]

Bone and prosthetic joint infections require at least 6 months of appropriate therapy with a combination of antimicrobials agents based on in vitro susceptibilities.^{[27, 42]}

Various antimicrobials, parenteral and oral, are summarized below that can be used in treatment of M chelonae infection if susceptible. In contrast to other NTM, tobramycin remains the aminoglycoside of choice compared with amikacin for M chelonae.^{[25, 29]} Imipenem is the carbapenem of choice for treatment. M chelonae is universally resistant to cefoxitin in vitro. Approximately 20% of M chelonae isolates have a susceptible MIC to doxycycline.^[29] Tigecycline has been shown to have good in vitro activity against M chelonae, but it does not have an established breakpoint and is usually considered when other alternatives are exhausted.^{[43, 44]}

Linezolid has good in vitro activity against M chelonae, and greater than 50% of isolates have susceptible MICs.^{[25, 29, 45]} It has been shown to be successful in treatment, and, similar to tigecycline, it is usually considered when other options have been exhausted owing to the expense and risk of toxicity with long-term therapy.^{[46, 47]} The authors do not recommend linezolid therapy for treatment durations of more than 4 weeks if it can be avoided, owing to unacceptable toxicities.

Other than ocular disease, the fluoroquinolones have limited use for M chelonae infection. Overall, M chelonae isolates have susceptible MICs to moxifloxacin and ciprofloxacin of 25% and 20%, respectively.^[29]

Clofazimine also has good in vitro activity against M chelonae and has been shown to have in vitro synergy with amikacin.^[48]

Empiric antimicrobial therapy is rarely necessary, and waiting for species identification prior to treatment is prudent. Antibiotics can be tailored or changed based on in vitro susceptibility.

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Clarithromycin (Biaxin)

• Dosing, Interactions, etc.

Clinical Context:  Clarithromycin inhibits bacterial growth by binding to the 50S ribosomal subunit and inhibiting protein synthesis. It is recommended to treat in combination with other antibiotics. Clarithromycin is frequently used as a component of oral therapy.

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Azithromycin (Zithromax)

• Dosing, Interactions, etc.

Clinical Context:  Azithromycin inhibits bacterial growth by binding to the 50S ribosomal subunit and inhibiting protein synthesis. It is recommended to treat in combination with other antibiotics. Azithromycin is frequently used as a component of oral therapy.

• References

Tobramycin (AKTob, Tobrex)

• Dosing, Interactions, etc.

Clinical Context:  Tobramycin inhibits bacterial growth by binding to the 30S subunit of bacterial ribosomes and inhibiting protein synthesis. Use the patient's ideal body weight for dosage calculation. Tobramycin is used in combination with other antibiotics.

• References

Amikacin

• Dosing, Interactions, etc.

Clinical Context:  Amikacin inhibits bacterial growth by binding to the 30S subunit of bacterial ribosomes and inhibiting protein synthesis. Use the patient's ideal body weight for dosage calculation. Amikacin is used in combination with other antibiotics.

• References

Imipenem/cilastatin (Primaxin)

• Dosing, Interactions, etc.

Clinical Context:  Imipenem/cilastatin combination inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs). Cilastatin prevents renal metabolism of imipenem by competitive inhibition of dehydropeptidase along the brush border of the renal tubules. This combination is used in combination with other antimicrobials.

• References

Linezolid (Zyvox)

• Dosing, Interactions, etc.

Clinical Context:  Linezolid inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit.

• References

Tigecycline (Tygacil)

• Dosing, Interactions, etc.

Clinical Context:  Tigecycline inhibits bacterial protein by binding to the 30S ribosomal subunit. Tigecycline is used in combination with other antibiotics.

• References

Doxycycline (Adoxa, Alodox, Doryx, Vibramycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline inhibits protein synthesis by binding with the 30S subunit.

• References

Moxifloxacin (Avelox)

• Dosing, Interactions, etc.

Clinical Context:  Moxifloxacin inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. It is used in combination with other antibiotics. Ensure the organism is susceptible.

• References

Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin inhibits bacterial DNA synthesis by binding to gyrase.

• References

Ciprofloxacin ophthalmic (Ciloxan)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin ophthalmic is used with or without systemic antibiotics (either oral or parenteral). It inhibits bacterial growth by inhibiting DNA gyrase. It is indicated for superficial ocular infections of the conjunctiva or cornea caused by strains susceptible to ciprofloxacin.

• References