Group IV: Rapid Growing Mycobacteria (RGM)

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Rapid-growing mycobacteria are a distinctive subset of the "atypical" or non-tuberculous mycobacteria. Widely distributed in the environment, they appear to be generally acquired from soil or water, but they are unfortunately common as agents of nosocomial infection.

MICROBIOLOGy

M. abscessus, M. chelonae, M. fortuitum and M. smegmatis are the RGM species most commonly associated with human disease. Other RGM which have been reported in association with human disease include M. peregrinum, M. mucogenicum and some rare exotic species (19).

Genetically the RGM are relatively remote from the various slow growing mycobacteria (42). The biological separation is reflected in several important clinical distinctions: (a) dosing schedules for RGM antimicrobial agents are more frequent, commensurate with the relatively shorter replication times, (b) therapy of the RGM typically involves agents without activity against other mycobacterial pathogens and (c) the RGMs commonly elicit a weakly granulomatous tissue response or a frankly dimorphic reaction (a combination of granulomatous and/or pyogenic features).

EPIDEMIOLOgY

These mycobacteria are widely distributed in water and soil and presumably are commonly acquired from these environmental sources (13). The great majority of RGM cases, both pulmonary and extra pulmonary have been reported from the southeast U.S., notably Texas and Florida (10,16,44,47-49); however, recent experience documents disease due to RGM in all the United States including Alaska and Hawaii. There is no evidence of human-to-human transmission. The capacity of the RGM to survive, even proliferate in water may partially explain their association with iatrogenic infections. M. chelonae in particular has been associated with water or other liquid-borne infections in a variety of medical settings including bronchoscopy (17), xenographic heart valves (27), otologic (29); and ophthalmologic (25) surgery, gentian violet used to mark skin lines for plastic surgery (34), cardiac surgery (20,26) augmentation mammaplasty prostheses (48) liposuction instruments (8,31) and DPTP vaccine (2). M. abscessus has also been reported in association with iatrogenic disease related to renal dialysis (1), sternotomy for cardiac surgery (24) unlicensed preparation of adrenal extract (7), contamination of pacemaker wires (11) acupuncture (50), body-piercing (40) and prosthetic valve endocarditis (41). Recent reports have also documented increased numbers of cases of soft tissue and bone infections due to M. fortuitum and M. smegmatis including those associated with cardiac surgery (20,26) mammaplasty (48) and peritoneal dialysis (18). Shower-born colonization of the respiratory tracts of 16 patients by M. fortuitum was seen in an East Coast Veterans Administration Hospital (6). Excellent reviews have recently been published on nosocomial outbreaks and pseudo-outbreaks due to NTM (43) and infections due to NTM (33). Both articles emphasized the predominant role of RGM in these settings.

Risk factors commonly associated with pulmonary disease due to the RGM include the unusual body habitus among females previously described in association with MAC disease-slender, mild thoracic scoliosis, pectus excavatum and/or narrowed anterior-posterior thoracic dimensions, with or without mitral valve prolapse (23). Another apparent but not well-documented risk factor for RGM pulmonary disease includes esophageal achalasia or other disorders of motility associated with vomiting (5,16). Additional predisposing host conditions include previously damaged or scarred lungs from disorders such as prior tuberculosis, MAC disease, sarcoidosis, rheumatoid arthritis/ankylosing spondylitis, lipoid pneumonia, and previous or co-existent disease due to M. avium complex. Inherited disorders including cystic fibrosis and deficiency of alpha-1 antitrypsin may also play a substantial role (12).

Common host conditions associated with multifocal or disseminated RGM disease includes renal failure, dialysis, organ transplantation, connective tissue disorders and other conditions treated with steroids and/or cytotoxic agents, leukemia and (1,22,39,44). Disseminated RGM infection with prominent lymphadenopathy was reported in 16 HIV negative patients from Thailand (9); although they were described as "Immunocompetent Hosts", the RGM disease and other opportunistic infections belie that appellation.

CLINICAL MANIFESTATION

Extrapulmonary disease due to the RGMs largely takes two forms--localized-direct inoculation, typically in normal hosts, and disseminated-multifocal disease, usually associated with an immunosuppressed state. Notable in the latter group is the relative paucity of disseminated RGM infection in persons with AIDS. Among nearly 2,000 cases of disseminated mycobacterial infections in persons with AIDS reported by the CDC in 1989 there were only 10 instances of RGM disease (21). Given the frequency with which the RGMs can be isolated from the environment, their infrequency in this group suggests possibly that an alternative immune mechanism is primarily responsible for defense against the RGMs. Direct inoculation disease with RGM occurs both with environmental puncture wounds (15, 30-32) and with iatrogenic procedures including the injection of inflamed joints or bursae with steroids (33). Endocarditis may evolve in the presence of chronic infection with RGMs elsewhere (14). One case of meningitis due to M. fortuitum has been reported in association with a puncture wound and foreign body, while another has been reported with AIDS (35).

LABORATORY DIAGNOSIS

The RGM predictably grow rapidly on culture medium when subcultured in the laboratory. However, on initial isolation from respiratory secretions, abscesses, or other body tissues, recovery may take several weeks. The usual method of diagnosis is mycobacterial blood cultures in patients with AIDS.

Pathogenesis

Mycobacteria are successful intracellular pathogens that not only penetrate host defense cells, but replicate within them. Organisms engulfed by the macrophages are taken into intracellular vacuoles and the prevention of acidification of the intracellular vacuole may be an important mechanism of mycobacterial evasion of host defenses and a virulence factor. If the mycobacteria persists and multiplies, within the macrophage, then a lymphocyte-mediated immune response including CD4+ T lymphocytes and natural killer (NK) cells is triggered by the infected macrophage. The infected macrophage and stimulated lymphocytes then produce soluble factors, including cytokines and prostaglandins that modulate a complicated immune interaction. The immune mediators include tumor necrosis factor (TNF)-a, interferon (IFN)-g, interleukins (IL) 2,6,10 and 12, and granulocyte-macrophage colony stimulating factor. Because most non tuberculous mycobacteria (NTM) are non pathogenic and those NTM that are pathogens frequently cause disease in limited circumstances, there is interest in identifying virulence factors for NTM. Plasmids may encode for virulence genes, as they are more common in MAC isolates from people who have AIDS than in environmental isolates. Other potential virulence factors are prevention of acidification of phagocytic vesicles, prevention of phagosome-lysosome fusion, delay in TNF secretion by infected host cells and catalase activity.

SUSCEPTIBILITY IN VITRO AND IN VIVO

The RGM generally show in vitro resistance to the standard anti-tuberculosis agents. In addition, RGM species show variable patterns of susceptibility to the drugs most likely to be active against that species, e.g., even wild strains (not previously exposed to antimicrobial therapy) do not have consistent patterns of in vitro susceptibility. Furthermore, it is common to find disparate results between different laboratories. The technique which appears most reliable is both microdilution (3,37,38). A recent study compared the reproducibility of Etest strips at various centers with various isolates of M. abscessus, M. chelonae, and M. fortuitum (51). Unfortunately, the Etest performed unreliably in this trial.

The probabilities of in vitro susceptibility to the three major pathogenic species of RGM are delineated in Table 1. Although these data may be assumed to be generally helpful in selecting drug regimens, it is important to emphasize that the validity of in vitro susceptibility testing (correlation with clinical outcomes) for RGM therapy has not been proven in rigorous trials. Important variables include the methodology of the in vitro susceptibility testing technique and the choice of "critical concentrations". No evidence documents in vitro synergistic or antagonistic drug interactions. Multidrug therapy is typically employed to prevent the evolution of acquired drug resistance; however, the utility of this practice has not been clearly demonstrated. No distinctions regarding optimal regimens in the setting of pulmonary, extrapulmonary, or disseminated disease have been made, although the understandable inference is commonly made that disseminated disease and/or immunocompromised hosts merit more aggressive treatment (more drugs, higher doses, and/or longer therapy).

ANTIMICROBIAL THERAPY

In large measure, treatment of RGM disease is empirical and derived from the principles enumerated above rather than randomized trials. For patients with disease due toM. abscessus a regimen of cefoxitin 2 grams IV every 8 hours and amikacin 15 mg/kg IV daily has been widely used. Clarithromycin 500 mg IV orally twice-daily or imipenem 500 mg IV every 8 hours may be substituted for Cefoxitin. The duration of treatment is usually in the range of 8 to 12 weeks depending upon extent and type of disease, response to therapy and tolerance; For those with M. chelonae disease, therapy might entail clarithromycin 500 mg orally twice-daily with amikacin 15 mg/kg IV daily. Although some cases have been rerouted of a curative response to mono-therapy to clarithromycin, it seems prudent to employ two-drug therapy when possible, to prevent or delay acquired drug resistance.

For cases with serious infection due to M. fortuitum initial therapy might included imipenem 500 mg IV every 8 hours and amikacin 15 mg/kg IV daily. Given the expanded list of agents active versus the usual strain of M. fortuitum, it may be possible to switch to an all-oral regimen after 4 to 8 weeks of intravenous treatment. The decision to modify chemotherapy in RGM cases is usually driven evidence of lack of efficacy (persistent or worsening constitutional symptoms or progressive local disease) or drug toxicity (rash and fever related to cefoxitin or 8th nerve dysfunction related to aminoglycosides).

The RGM have been reported to involve a variety of organs or tissues depending upon the route of infection and host defenses. Obviously, the most ominous forms include mediastinitis, endocarditis, and meningitis. In these situations aggressive therapy including expanded 3 or 4 drug regimens (until reliable susceptibility results from an established laboratory such as The University of Texas in Tyler or National Jewish Medical and Research Center in Denver are reported) and high-dosing are appropriate.

Alternative Therapy

In cases of in vitro resistance to or intolerance of the agents enumerated above, we should select agents based on the likelihood of activity (see Table 1) or demonstrated favorable MICs. A promising agent based on in vitro activity and a small clinical experience is linezolid (46). However, caution is warranted based on reports of rerouted hematologic complications (28) and painful peripheral neuritis (MD Iseman, unpublished data).

ADJUNCTIVE THERAPY

The role of surgery in the management of RGM disease varies according to the form and location of the infection. For cases of pulmonary disease in which there is anatomically localized disease, chemotherapy followed by resection may be useful in minimizing symptoms, slowing the progression, or--in a few cases--actually curing the disease (16) (MD Iseman, unpublished data). For extrapulmonary disease, drainage or debridement of necrotic debris may promote healing of localized abscesses. Aggressive debridement has proven particularly helpful in our care of RGM infections of the hand where tendinous damage may seriously threaten function. Also, we have observed the complimentary role of surgical debridement of lower extremity multinodular abscesses as described above. Topical heat may be useful in some superficial abscesses.

Immune modulation may be appropriate in some cases. Certainly for patients whose RGM disease appears related to immunosuppressive drug therapy (steroids, cytotoxic agents, anti-rejection medications), reducing these agents to their minimally required dosages is desirable. The role of IFN-g as an immunity-enhancing adjuvant for "normal hosts" with refractory pulmonary RGM disease has not been determined. Bronchial hygiene is an essential and often overlooked element of management of patients with bronchiectatic pulmonary RGM disease. Inhaled beta-agonists may be useful both for bronchodilating (a substantial portion of patients with bronchiectasis develop reversible obstructive airways dysfunction) and accelerating ciliary activity (to help clear secretions). Purulent secretions may be cleared more effectively with the use of the Flutter-Valve® or Pep-Valve® variously combined with postural drainage, clapping, or vibration techniques. In addition, attention should be directed toward the potential for non-mycobacterial bronchitis with organisms such as Pseudomonas aeruginosa or other gram-negative rods, which may require periodic intensive antibiotic therapy.

ENDPOINTS FOR MONITORING THERAPY

Patients with RGM disease should be monitored with a matrix of clinical, microbiological, radiographic and/or other laboratory techniques. The obvious desired endpoints are clinical and microbiological "cures", but these are difficult to achieve with most RGM disease. In particular, pulmonary disease due to M. abscessus and M. chelonae are extremely difficult to eliminate, with relapses occurring in the great majority of treated cases (16). M. fortuitum pulmonary disease, due in part to the availability of long-term suppressive therapy with oral agents, may be more amenable to medical cures (16).

Reduction of cough and phlegm are the most immediate markers of clinical response. Semi-quantitative enumeration of sputum smears and cultures also reflect the impact of drug therapy. Routine chest x-rays and computed tomographic radiography studies are useful adjuncts to stage and assess response to treatment.

Treatment for pulmonary RGM disease varies in duration. For M. fortuitum cases in which there is susceptibility to both oral and parenteral agents, treatment may consist of an initial intensive phase of "mixed" (oral and parenteral) treatment for six to twelve weeks followed by four to nine months of oral suppressive drugs. For M. abscessus or M. chelonae disease we typically treat for six to twelve weeks with a two-drug parenteral regimen directed at suppression of symptoms. Such treatment is initiated when patients find their cough, congestion, or malaise too severe to tolerate, but it is done so with the explicit understanding that treatment palliative, not curative. The patients are also informed that repeated use of these antibiotics entails the risk of acquired resistance to or toxicity from the agents employed. Also it must be emphasized that most patients do not have good insurance coverage for home intravenous therapy and that the arrangements are likely to be both expensive and awkward. Hence, such treatment is not entered into lightly.

Treatment of extrapulmonary or disseminated disease due to RGM varies according to the site and extent of infection. In some cases, simple drainage may be adequate to promote a cure of a local abscess. In other cases, protracted therapy with multiple antibiotics may be required to eradicate the infection. In most cases, inflammatory collections associated with RGM infection, should be drained surgically. In some cases radical debridement is necessary to affect cure. We have found magnetic resonance imaging to be a useful technique to delineate the boundaries of the inflamed tissue. MRI is generally superior to computed tomography in characterizing soft tissue or peri-osseous abscesses.

Toxicity monitoring must include periodic audiometric and vestibular testing as well as blood tests for renal dysfunction for persons receiving aminoglycosides. Pharmacokinetic assessment with aminoglycosides will help reduce the likelihood of oto-vestibular toxicity, nerve or renal injury. Symptomatic surveillance for diarrhea, a potential indicator of pseudomembranous colitis--especially for those receiving cefoxitin--and interval tests of hematologic function are required for all of the RGM agents.

VACCINES

There are no vaccines for RGM.

PREVENTION

There are no preventive measures for RGM. Most data suggest that nosocomial infections with RGM are acquired from the environment rather than primary contamination of devices or products (48).

REFERENCES

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45. Wallace RJ Jr., Brown BA, Onyi GO. Susceptibilities of Mycobacterium fortuitum biovar. fortuitum and the two subgroups of Mycobacterium chelonae to Imipenem, Cefmetazole, Cefoxitin, and Amoxicillin-Clavulanic acid. Antimicrob. Agents Chemother. 1991; 35:773-775. [PubMed]

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47. Wallace RJ Jr, Musser JM, Hull SI, Silcox VA, Steele LC, Forrester GD, Labidi A, Selander RK. Diversity and sources of rapidly growing mycobacteria associated with infections following cardiac surgery. J. Infect. Dis. 1989; 159:708-716. [PubMed]

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Table 1. The Probability of in vitro Susceptibility of the Major RGM Pathogens to Various Antimicrobial Agents (4,36,38,45,46).

SPECIES

Agents M. fortuitum M. abscessus M. chelonae

Amikacin (kanamycin)

100%

90%

80%

Cefoxitin

80%

70%

[0-90%]*

Imipenem

100%

50%

60%

Clarithromycin

80%

100%

100%

Ciprofloxacin

100%

-

20%

Sulfamethoxazole

100%

-

-

Trimethoprim/Sulfa

100%

-

-

Doxycycline

50%

-

25%

Tobramycin

-

-

100%

Linezolid

96%

48%

94%

Agents	M. fortuitum	M. abscessus	M. chelonae
Amikacin (kanamycin)	100%	90%	80%
Cefoxitin	80%	70%	[0-90%]*
Imipenem	100%	50%	60%
Clarithromycin	80%	100%	100%
Ciprofloxacin	100%	-	20%
Sulfamethoxazole	100%	-	-
Trimethoprim/Sulfa	100%	-	-
Doxycycline	50%	-	25%
Tobramycin	-	-	100%
Linezolid	96%	48%	94%

Wallace's laboratory in Texas describes resistance to cefoxitin as a phenotypic feature of M. chelonae. By contrast, Heifets’ laboratory at National Jewish reports in vitrosusceptibility in a high proportion of isolates identified as M. chelonae. In comparing these results it appears as though the discrepancy has to do mainly with species identification rather than variation in susceptibility testing.