Mycobacterium Fortuitum 

Updated: Nov 18, 2019
Author: Sami M Akram, MD, MHA, RDMS; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 

Overview

Background

Mycobacterium fortuitum is a rapidly growing nontuberculous mycobacterium (NTM), classified in the Runyon group IV.[1] Other mycobacteria in this group include Mycobacterium abscessus, Mycobacteria chelonae, and Mycobacteria peregrinum. M fortuitum was first isolated from frogs, explaining why it was formerly called Mycobacterium ranae. It is distributed worldwide and is found in soil and water.[2]

M fortuitum is isolated with increasing frequency from clinical samples.[2] At least 50 strains of M fortuitum exist.[3] The taxonomy of mycobacteria, including rapidly growing mycobacteria (RGM), is constantly evolving. Distribution is probably worldwide.

Pathophysiology

M fortuitum infection can cause a wide spectrum of clinical syndromes, often based on the initial exposure. M fortuitum infection occurs in both immunocompetent and immunocompromised individuals.

Surgical or nonsurgical trauma and contaminated water introduce the organisms into the body; thereafter, M fortuitum establishes infection at these sites. Therefore, infections after cardiac, ophthalmologic, neurologic,[3] orthopedic, endoscopic, plastic, and reconstructive surgeries have been reported. For this reason, infections of implanted devices (eg, defibrillators, catheters, dialysis catheters) and injection-site abscesses can occur.

Pseudo-outbreaks after exposure to contaminated whirlpools in nail salons[4] and contaminated tattoo ink[5] have been reported.

M fortuitum can cause transient or chronic pulmonary infections, particularly in individuals with underlying structural defects and/or gastroesophageal abnormalities such as achalasia.[6]

Epidemiology

Geographic Distribution

The epidemiological study of NTM infections is still in its infancy. NTM infections, including M fortuitum infections, occur globally.

Recently, epidemiological reports from Europe, North America, China, India, Africa, the Middle East, and Australia have been published.

To date, M fortuitum has no identifiable endemic areas.

Age-, Sex-, and Race-Based Incidence

Patients who develop M fortuitum infection related to plastic and reconstructive surgery tend to be younger (in the mid-fourth decade of life[7] ), while patients with pulmonary M fortuitum infection tend to be older (>50 years[8] ). Lung disease in a younger patient (< 50 years) strongly suggests a primary underlying lung disorder. Isolated lymphadenitis primarily occurs in children. M fortuitum infections do not appear to have a sexual or racial predilection.

Frequency

NTM infections are not required to be reported; therefore, exact estimates of disease prevalence and incidence are difficult to determine. Sputum is most frequently examined for acid-fast bacilli (AFB) so is easiest to track. In one study, of the 6,800 patients tested for AFB, 40 had M fortuitum lung disease.[8] In a study of Kaiser Permanente patients in Hawaii, 109 of 2,197 (4.9%) respiratory specimen cultures were positive for M fortuitum.[9] Rapidly growing NTM were more frequently isolated in medical tourists, who developed postoperative wound infections. M abscesses is the most prevalent isolate, followed by M fortuitum.[10]

Mortality/Morbidity

Mortality due to localized M fortuitum infection is rare. Death may result from extensive pulmonary or disseminated disease in immunocompromised patients.

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.

Prognosis

The prognosis of M fortuitum infection is very good for most sites of infection if debridement is performed and appropriate antibiotic therapy administered, particularly if more than one antibiotic is used, including a quinolone.

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.

Patient Education

Medical tourists have developed chronic NTM infections (particularly rapidly growing mycobacteria) of surgical sites, breast prostheses, and injection sites. Tap water may be contaminated with mycobacteria, which are resistant to disinfecting procedures, so may be present even in treated water.

Multidrug therapy is necessary to successfully treat mycobacterial infections. Frequently, two or three antibiotics are needed. The success rate of antibiotic monotherapy is dismal, so it is important that patients adhere to the prescribed antibiotic regimen.

Patients may confuse the disease with tuberculosis and need to be reassured that they are not contagious to others.

 

Presentation

History

Patients who developed M fortuitum infection related to breast implants presented with breast pain or tenderness after an average incubation period of 9 months.[7]

In a cohort of 40 patients with pulmonary M fortuitum infection, common presenting symptoms included sputum (68.6%), hemoptysis (51.4%), cough (45.7%), and gastroesophageal disease (22.9%). Underlying lung disease and smoking were common predisposing factors.[8] Fever, weight loss, and night sweats are less frequent in pulmonary M fortuitum infection than in M tuberculosis infection.

In tattoo-associated M fortuitum infections, a nonpruritic papular eruption occurred 1-2 weeks after the tattoo procedure.[11] Clustering of cases may occur.[5] Patients with cutaneous disease may develop a nonhealing skin ulcer.

Physical

No findings are pathognomonic of M fortuitum infection. Physical findings depend on the infection site, as follows:

  • Eye: Keratitis or corneal ulcers 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 present (eg, a patient undergoing peritoneal dialysis). [12]
  • Skin: Ulcerative skin lesions and/or subcutaneous nodules may be present. Deeper infections may lead to draining fistulas. [13, 11] Various other skin lesions may be present, including cellulitis, nonhealing ulcers, nodular lesions, chronic nodular lesions, verrucous lesions, and/or lymphadenitis. [7]

Causes

Risk factors for M fortuitum infection include the following:

  • Trauma or injection - Skin lesions, subcutaneous lesions, ocular lesions, and osteomyelitis.
  • Immunosuppression - Development of infection is driven by the environmental exposure and not by an immunocompromised state. However, infections may be deeper and more extensive in persons who are immunocompromised.
  • Disseminated disease, especially in patients with AIDS or in those who use corticosteroids
  • Lung disease - M fortuitum is a common colonizer that can cause transient infection. [6] Chronic infections may occur in individuals with underlying achalasia or gastroesophageal disorders. [8]

Complications

Lung involvement in individuals with underlying structural lung disease is frequently debilitating.

Skin lesions and subsequent debridement may be disfiguring.

Antibiotic monotherapy is ineffective and leads to drug resistance.

 

DDx

Diagnostic Considerations

Specimens from suspected infection sites (eg, sputum, bronchial wash, skin biopsy) should be sent to the laboratory for histopathology or cytopathology, AFB staining, and mycobacterial culture. Species-specific diagnosis is necessary, as antibiotic therapy must be guided by sensitivity and minimum inhibitory concentration (MIC).

Clinically, the differential diagnoses include other organisms that can cause chronic cutaneous, pulmonary, and deep-seated infections. The history of trauma is important in the pathogenesis of M fortuitum infections. Often, cervical adenitis is treated empirically with antituberculous medications in endemic areas, although M fortuitum infection rarely causes cervical lymphadenitis.[14]

Endemic fungal infection such as histoplasmosis, blastomycosis, and coccidioidomycosis can manifest as cutaneous lesions. However, such fungal cutaneous lesions frequently occur in immunocompromised individuals as a component of disseminated disease and without a history of trauma.[15]

Nocardia infections can cause cutaneous and chronic pulmonary manifestations in both immunocompromised and immunocompetent individuals.[16] Pulmonary infections in immunocompetent patients with structural lung disease have been reported.[17]

Microbiologically, M fortuitum infection must be differentiated from other members of its group, such as M abscessus, M chelonae, and M peregrinum. This is important, as antibiotic sensitivities may vary.

Deeper infections may lead to development of fistulae, in which case Actinomyces infections may also be included in the differential diagnoses.

Nodular skin lesions in the upper extremity that progressively worsen may resemble sporotrichosis.

Furunculosis may result from multiple bacterial and mycobacterial agents. Inquire about a history of exposure to a hot tub, nail salon procedure, or tattoo procedure.

Differential Diagnoses

 

Workup

Laboratory Studies

According to American Thoracic Society criteria,[18] diagnosis of NTM lung disease requires (1) pulmonary symptoms with consistent radiographic features, (2) exclusion of other diagnoses, especially tuberculosis, and (3) appropriate microbiological findings.[18]

Microbiological findings to satisfy ATS diagnostic criteria include the following (at least one must apply):

  • Positive culture from at least 2 separate sputum samples
  • Positive culture from bronchial wash or lavage
  • 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 persistent or transient colonizer without pathogenicity. In one study, M fortuitum was present in 24% of specimens positive for pathogenic NTM, but, at 2 years, was present in only 6% of the cohort. [9]

Swab culture for acid-fast bacilli

Notifying the microbiology laboratory personnel that a NTM infection is suspected may help ensure appropriate processing of specimens. Most laboratories use liquid media (eg, BACTEC) for mycobacterial cultures.

Swab specimens are less optimal than cultures obtained via aspiration. Consider contacting laboratory personnel for proper procedures regarding adequate specimen collection to increase the yield and significance of cultures.

Interpret the result with caution because a single positive culture, especially of a superficial lesion, may represent a contaminant. M fortuitum may be a colonizer in pulmonary specimens.

Initial tests frequently include sputum smear for acid-fast bacilli (AFB) and culture for mycobacteria. Culture is the criterion standard, which can take up to 8-12 weeks for final results Smear cannot differentiate between M tuberculosis and NTM, so the diagnosis will be delayed.

Susceptibility testing

Susceptibility testing for M fortuitum should be performed for amikacin, imipenem, cefoxitin, doxycycline, fluoroquinolones, trimethoprim-sulfamethoxazole, clarithromycin, linezolid, and tobramycin.[7]  

Polymerase chain reaction

Rapid detection using polymerase chain reaction (PCR) techniques are being used with increasing frequency.

A new multiplex polymerase chain reaction (PCR) test performed on the BD MAX System was shown to be sensitive and specific for M fortuitum complex.[19] Similarly, other PCR-based assays are used to detect mycobacteria directly on respiratory samples or mycobacterial cultures.

A biochip immunoassay kit based on the 16S rRNA gene sequence is commercially available. It can identify 17 mycobacteria directly in AFB smear–positive respiratory specimens within 6 hours.[20] The concordance between biochip and mycobacterial culture was 95.4%. PCR identification of 16SrRNA gene sequence is superior to culture when multiple isolates are involved, since organisms may be growing at different speeds.

Imaging Studies

Chest radiography

Perform chest radiography if pulmonary symptoms are present.

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 same organism with a lack of cavitary disease on chest radiography, high-resolution CT scanning is indicated.

Typical CT scan findings include bronchiectasis or diffuse small nodules; these are often not revealed by routine chest radiography.

If the chest radiographic findings are abnormal, chest CT scanning may be performed to obtain better definition of the abnormalities present. Lymphadenopathy may also be detected. This study is not necessary in every case but should be strongly considered.

CT scanning of the abdomen and pelvis

This study may be indicated to detect local abscesses or lymphadenopathy, including retroperitoneal abscesses or lymph nodes, in patients with disseminated disease, localizing signs or symptoms, or a history of injections in those locations.

Bone imaging, MRI, and nuclear imaging

These studies may be helpful in detecting osteomyelitis or joint disease if suspected, especially in patients with a history of penetrating trauma.[21]

Other Tests

Erythrocyte sedimentation rate (ESR), C-reactive protein, and other inflammatory markers may be useful if mycobacterial disease is suspected. However, these tests are nonspecific, and their precise role in aiding diagnosis and follow-up care is not well-defined.

Procedures

Lung procedures

Perform bronchoscopy with bronchial washes and/or bronchoalveolar lavage, ideally in conjunction with transbronchial biopsy, for AFB smear, culture, and histology. Because the diagnosis is usually uncertain at this stage, bacterial and fungal cultures are often also sent.

Open or thoracoscopic lung biopsy may be considered if suspicion is high but diagnostic criteria have not been met. Send specimens for fungal and AFB cultures, as well as histology.

A biopsy specimen culture positive for M fortuitum is considered diagnostic. A positive AFB smear result correlates with an increased number of organisms and further supports the diagnosis.

The presence of either AFB or granulomas in a lung biopsy specimen or a transbronchial biopsy specimen, along with even a single positive culture result of sputum or bronchial wash (even in low numbers), is considered diagnostic.

Skin tests

Perform a biopsy for localized or disseminated skin lesions. Send specimens for mycobacterial and fungal cultures, as well as histology.

Purified protein derivative (PPD) testing with NTM-specific antigens is nonspecific and generally not indicated. These tests are not commercially available.

Aspiration biopsy

Perform an aspiration biopsy of a localized abscess for culture.

Perform a fine-needle aspiration biopsy or a surgical excision of lymph nodes for histology and culture.

Histologic Findings

Histologic findings may reveal acute inflammation, microabscesses, granulomatous inflammation, or granulomas (with or without caseation). These findings may be mixed. Special stains for AFB may reveal organisms.

Staging

The disease may be limited or disseminated (two noncontiguous organs) or in the blood (mycobacteremia).

 

Treatment

Medical Care

Tissue samples from biopsy, respiratory samples, or other appropriate specimens should be sent for culture and species identification. Antibiotic pattern of susceptibilities may not be sufficient to differentiate between rapidly growing mycobacterial isolates.[22] DNA sequencing (PCR) restriction endonuclease assay (PRA) may be required. In vitro susceptibility tests with MIC determination should be performed to select appropriate antibiotics.[23] Dual antibiotic therapy is recommended for treating M fortuitum infections to prevent development of resistance. No specific combination of antibiotics has been determined to be optimal.[22] M fortuitum isolates are usually susceptible to multiple oral antimicrobial agents, including the newer macrolides and quinolones, doxycycline and minocycline, and sulfonamides. Isolates are susceptible to amikacin (100%), ciprofloxacin and ofloxacin (100%), sulfonamides (100%), cefoxitin (50%), imipenem (100%), clarithromycin (80%), and doxycycline (50%).[24]

All M fortuitum isolates have been demonstrated to contain erm gene, which can be induced, causing methylation of 23sRNA and conferring macrolide resistance.[24] A 2018 study showed that the least resistance occurred with tigecycline.[25] M fortuitum is resistant to antituberculous medications.[25]

Pulmonary infections should be treated until sputum results are negative for 12 months. Treatment should be based on susceptibility results. An initial combination of amikacin and cefoxitin with or without levofloxacin is usually used for first 2-6 weeks, based on response, followed by trimethoprim-sulfamethoxazole plus doxycycline or levofloxacin to complete 6-12 months. Disseminated infections are also treated with similar parenteral followed by oral combination regimens for 4-6 months.[19]

Skin infections should be treated for at least 4-6 months with minocycline or doxycycline and either trimethoprim-sulfamethoxazole or a fluoroquinolone, based on susceptibility results. For bone infections, 6 months of therapy is recommended.[22] How much additional therapy is needed to prevent relapse is unclear.

Local wound care for cutaneous lesions is always appropriate. Small lesions may improve with local care and antibiotics without surgical intervention.

In vitro susceptibilities may not correlate with in vivo activities. Before considering major surgery, a course of at least 2 drugs may be useful, even with resistant organisms.

Surgical Care

Consider antibiotic therapy for 2 months prior to surgery, even with resistant species. Surgery is generally indicated in cases of extensive disease, abscess formation, or unsuccessful drug therapy. Removal of foreign bodies, such as breast implants and percutaneous catheters, is important and essential to achieving cure, as M fortuitum forms biofilm.

Surgical debridement of cutaneous or subcutaneous lesions is often required to achieve cure. Surgical debridement of ocular and bone lesions is almost always required.

Surgical excision of pulmonary lesions may be considered if response to therapy is lacking or if the organism is relatively resistant to antibiotics.

Surgical excision of lymphadenitis is the therapy of choice and is usually curative.

Consultations

Obtain consultation with an infectious disease specialist for diagnostic and therapeutic guidance.

Obtain consultation with a pulmonologist for lung lesions, for possible bronchoscopy, and for therapeutic guidance.

Obtain consultation with a surgeon for debridement and/or biopsy. Indwelling intravenous catheter placement may also be necessary if long-term antibiotics are to be administered.

Obtain consultation with a dermatologist for possible biopsy of cutaneous lesions.

Prevention

No specific deterrence methods are available. M fortuitum is a ubiquitous organism. Avoiding exposure to tap water in the operating room and during cosmetic skin procedures helps to prevent infection. M fortuitum is resistant to chlorine disinfection. A combination of silver and copper has been shown to be more effective and holds promise as secondary disinfectants.[26]

Long-Term Monitoring

The frequency of outpatient visits is determined by the extent of the disease and whether the patient is receiving oral or intravenous therapy. Initially, at least monthly follow-up care for adverse effects is reasonable. More frequent visits may be necessary for patients with central catheters to evaluate for line infections.

Outpatients taking aminoglycoside therapy should undergo periodic (at least weekly) assessment of renal function and antibiotic levels. Patients on aminoglycosides also need periodic audiology assessments to detect any hearing loss.

Monthly sputum cultures may be useful in patients with pulmonary disease to demonstrate the efficacy of the treatment plan.

Further Inpatient Care

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

Inpatient & Outpatient Medications

Administer antibiotics daily (see Medication).

Intermittent dosing (eg, 2-3 times/wk) has not been evaluated for M fortuitum infection and is not recommended.

Transfer

Patients who require intravenous antibiotic therapy but who are unable to receive home intravenous therapy may need to be placed in an extended-care 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).

 

Medication

Medication Summary

Prolonged antibiotic therapy is generally required for M fortuitum infection. Intravenous therapy is preferred for serious illness or disseminated disease, at least initially.

Although numerous reports have documented cases of successful therapy with one drug (eg, clarithromycin), reports also describe resistance to treatment. Therefore, antibiotic therapy with 2 drugs is preferable in most patients. Test initial isolates for antibiotic sensitivity to guide therapy because the sensitivity of individual isolates can vary considerably.[23] Susceptibility testing does not guarantee clinical success as correlations of susceptibility testing and clinical response have not been assessed.

In many patients, the disease has been long-standing, and no urgency in initiating therapy is indicated. In this setting, waiting for the results of sensitivity testing before beginning treatment provides much greater certainty in the choice of an antibiotic regimen. First-line antituberculous drugs (eg, isoniazid, rifampin, pyrazinamide) have no role in the treatment of M fortuitum infection.[25]

Amikacin is the aminoglycoside preferred for treatment of M fortuitum infection, and almost all isolates are susceptible. Both cefoxitin and imipenem have been used successfully, but susceptibility is variable. Some fluoroquinolones have very good activity. Ciprofloxacin and levofloxacin have both been used successfully. Moxifloxacin is largely untested clinically but has good in vitro activity and would be expected to work.[27] Doxycycline has activity against roughly one half of isolates. This organism may possess an inducible erythromycin methylase erm gene. Thus, the use of erythromycin should be avoided. This gene may also confer resistance to other macrolides despite minimum inhibitory concentration (MIC) levels that are considered susceptible. These agents may be active against M fortuitum, but they should be used with caution.

Sulfamethoxazole has activity against M fortuitum. Conflicting data exist regarding whether trimethoprim, which has no activity alone, adds activity to sulfamethoxazole. The trimethoprim-sulfamethoxazole fixed-dose combination is a readily available form of the sulfa drug, and the combination has been used successfully, even as monotherapy. In vitro, more than 90% of isolates of M fortuitum were susceptible to linezolid; however, little clinical experience exists with its use specifically for this organism. Linezolid has been used successfully for other rapidly growing mycobacteria, so it is a reasonable consideration in patients whose organism is resistant to other antimicrobials. Tigecycline has also shown good in vitro results.[25]

Amikacin is recommended for severe disease, as it enables intra-macrophage killing of M fortuitum. Resistance can be detected during therapy by testing for aminoglycoside 2'-N-acetyltransferase (AAC [2']), which confers resistance to cell wall degradative enzymes.[28]

Disulfiram has been studied as a novel antibiotic against rapidly growing mycobacteria; it showed concentration- and time-dependent bactericidal activity against M fortuitum. Additionally, disulfiram reduced the intra-macrophage bacterial load better than amikacin.[29]

Topical amikacin and ciprofloxacin have been used successfully for ocular disease, both alone and in combination with parenteral or oral antibiotics. Topical ofloxacin is expected to be effective.[30, 31]

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Deferring therapy until sensitivity results are available may be prudent.

Amikacin (Amikin)

Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. Use patient's IBW for dosage calculation. Often used with cefoxitin or imipenem for severe pulmonary or disseminated disease.

Cefoxitin (Mefoxin)

Usually used with amikacin for severe pulmonary or disseminated disease.

Imipenem/cilastatin (Primaxin)

Usually used with amikacin for severe pulmonary or disseminated disease.

TMP-SMZ; cotrimoxazole (Septra, Bactrim)

Use alone or in combinations. Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Ciprofloxacin (Cipro)

Use alone or in combinations. Inhibits bacterial DNA synthesis and, consequently, growth.

Tigecycline (Tygacil)

Good in vitro activity but no documented clinical use. A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of amino-acyl tRNA molecules in ribosome A site.

Levofloxacin (Levaquin)

Used alone or in combination. Second-generation quinolone. Acts by interfering with DNA gyrase in bacterial cells. Bactericidal. Highly active against gram-negative and gram-positive organisms, including Pseudomonas aeruginosa. Probably fluoroquinolone of choice.

Doxycycline (Vibramycin, Doryx)

Because doxycycline has activity against approximately one third of isolates, generally not used as part of initial empiric regimen. Use should be guided by sensitivity data.

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Use alone or in combinations.

Azithromycin (Zithromax)

Use alone or in combinations. Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections.

Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life.

Ofloxacin ophthalmic (Ocuflox)

For use with or without systemic antibiotics (either oral or parenteral). Pyridine carboxylic acid derivative with broad-spectrum bactericidal effect. Inhibits bacterial growth by inhibiting DNA gyrase. Indicated for superficial ocular infections of the conjunctiva or cornea caused by strains susceptible to ofloxacin.

Ciprofloxacin ophthalmic (Ciloxan)

For use with or without systemic antibiotics (either oral or parenteral). Inhibits bacterial growth by inhibiting DNA gyrase. Indicated for superficial ocular infections of the conjunctiva or cornea caused by strains susceptible to ciprofloxacin.

Moxifloxacin (Avelox)

Good in vitro activity but no documented clinical use.

Inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription.

Linezolid (Zyvox)

Good in vitro activity. No documented use in M fortuitum infections but has been used successfully against other rapidly growing mycobacteria.

Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process.