Abstract
Rapidly growing mycobacteria, generally of low virulence, are capable of causing a wide spectrum of infections. Increasing reports in the literature, referral center experiences, and data from the Infectious Disease Society of America Emerging Infectious Disease Network suggest that greater numbers of infections are occurring. Epidemiological study is imperative in understanding the true incidence of these infections and preventing disease in vulnerable hosts. Especially problematic is pulmonary infection due to Mycobacterium abscessus, which is difficult to cure. New agents with enhanced activity against this group and other nontuberculous mycobacteria are needed. Here, we focus on the members of the rapidly growing mycobacteria because of their emerging importance in both sporadic infections and outbreak settings.
In contrast to Mycobacterium tuberculosis, there is no systematic reporting of nontuberculous mycobacterial infections; thus, precise incidence data are lacking. Several state health departments now report that the number of isolates of nontuberculous mycobacteria has surpassed the number of M. tuberculosis isolates. Our experience and published reports suggest that infections due to rapidly growing mycobacteria are particularly problematic. Here, we focus on the members of the rapidly growing mycobacteria because of their emerging importance in both sporadic infection and outbreak settings.
Biology Of Rapidly Growing Mycobacteria
Members of the genus Mycobacterium are relatively slow growing, compared with Escherichia coli, but “rapidly growing mycobacteria,” defined by Runyon [1, 2] as mycobacteria that form mature colonies on solid agar in 7 days (from subculture), remains a useful clinical and laboratory term. Genomics has defined the modern taxonomic era, and a dizzying array of new nontuberculous mycobacterial species has been described. This more accurate species-specific identification has become possible by sequencing a number of target genes, including the small subunit ribosomal (16S rRNA) gene, a robust, accurate, and reproducible method in use for years [3]. Although not all isolates within this highly conserved genus can be identified, exceptional-quality databases exist for the comparison of mycobacterial species (e.g., http://www.ridom.de) to provide a species-level distinction for the majority of species, using ribosomal operon sequences. When the species differ by only a small number of base pairs (e.g., Mycobacterium abscessus versus Mycobacterium chelonae), restriction digests of PCR products of the heat shock protein 65 gene (PCR restriction analysis) or other methods offer reliable and inexpensive means of differentiation [4]. Chromatographic patterns of mycolic acids or other identification methods can also be helpful. On the basis of ribosomal gene sequences, rapidly growing mycobacteria tend to group together in the phylogenetic tree of life, possibly suggesting common ancestry (figure 1).
Phylogenetic relationships of select mycobacterial species. The analysis is based on alignment of 16S rRNA gene sequences from GenBank (>1300 bp in length). Maximum likelihood and neighbor joining algorithms were used. The bar represents 5% sequence divergence. GenBank accession numbers are in parentheses. From the top of the tree, Mycobacterium tuberculosis to Mycobacterium xenopi are slow-growing mycobacteria and the remainder are rapidly growing mycobacteria, which tend to cluster together. Note that not all species presented in this tree represent pathogens and were described from environmental sources.
The Environment
Mycobacteria are ubiquitous in nature and can be found in soil, dust, rocks, bioaerosols, and water. These organisms have been increasingly identified from environments with harsh conditions (i.e., low nutrients, low pH, and temperature extremes). Biofilm formation is a successful survival strategy for these very hydrophobic organisms. In fact, their presence in early biofilms in water pipes may make them real biofilm “pioneers” [5–7]. Rapidly growing mycobacteria are difficult to eradicate with common decontamination practices and are relatively resistant (compared with coliforms) to standard disinfectants such as chlorine, organomercurials, and alkaline glutaraldehydes [8, 9]. Dispersal from biofilms may be a mechanism of shedding from a device or water pipe to infect the patient (e.g., while showering). In piped water systems, multiple mycobacterial species have been described. In hot water systems, several thermophilic mycobacteria can survive and have been reported to cause outbreaks or pseudo-outbreaks [10, 11]. In some cases, temperatures of up to 70°C are required to inhibit the organism. In cold water systems, Mycobacterium fortuitum, M. chelonae, M. abscessus, and Mycobacterium mucogenicum have been found. Because both cold and hot water temperatures exist in nosocomial settings, it is not surprising to see an array of species responsible for infection.
Infection Versus Pseudo-Infection
Laboratory cross-contamination, contaminated instruments, or contaminated solutions can result in a clinical specimen that yields positive results for nontuberculous mycobacteria by culture in the absence of clinical disease. Bronchoscopes and other instruments, especially those with small crevices that are difficult to sterilize, have been associated with pseudo-outbreaks, due not only to rapidly growing mycobacteria (M. abscessus and M. fortuitum) but also to slow-growing species (Mycobacterium avium complex, Mycobacterium gordonae, and Mycobacterium xenopi) [10, 12]. Pseudo-outbreaks should be considered, especially if a cluster of cases is recognized without a high clinical suspicion of true infection [10]. However, practitioners should consider the isolation of a rapidly growing mycobacterial species from normally sterile sites or multiple isolates from nonsterile sites to indicate a true infection until proven otherwise, and therapy should be considered, especially if a patient is immunocompromised or has an underlying lung disease.
Infection Due To Contaminated Materials And Invasive Procedures
Catheter infections. Rapidly growing mycobacterial infections of indwelling venous access catheters and vascular shunts have been increasingly reported [13, 14]. M. fortuitum, M. chelonae, M. abscessus, Mycobacterium smegmatis, and M. mucogenicum have been the most common, but other novel species of rapidly growing mycobacteria have been reported. Risks include immunosuppression, duration of catheter placement, and prior antimicrobial therapy [15, 16]. Symptoms include local manifestations of catheter infections, such as erythema, drainage at the site, and pain. There may also be a systemic inflammatory response, including fever, rigors, and other symptoms of mycobacteremia. Pocket infections involving pacemakers and defibrillators have also been seen with several rapidly growing mycobacteria, with M. abscessus predominating. Foreign bodies need to be removed to enhance cure.
Dialysis-acquired infections due to rapidly growing mycobacteria have been reported in both intravascular and peritoneal mechanisms of renal replacement therapy [17]. Contaminated aqueous solutions used to sterilize the reusable dialysis filters have been involved in many cases. Peritonitis can occur in patients undergoing long-term ambulatory peritoneal dialysis [18]. In this situation, the infection can involve the catheter insertion site, the tunneling tract, and/or the peritoneum itself. If routine cultures for bacteria yield negative results, one should consider the diagnosis of rapidly growing mycobacterial peritonitis.
Laser in situ keratomileusis (LASIK) surgery. An emerging scenario involves the development of mycobacterial infection after laser vision-correction surgery. One example is keratitis after LASIK surgery [19]. Even though mycobacteria are presumably of low virulence, a sight-threatening infection can occur. A typical case is one of indolent, slowly progressive corneal disease. Reports of crystalline opacities seen in the corneal stroma are thought to be highly suggestive of mycobacterial infection, and there is often a paucity of inflammation. The lack of inflammation may be secondary to routine postoperative topical corticosteroid use or the inherent properties of the rapidly growing mycobacteria.
Skin and soft tissue infections. Injection site abscesses have been caused by a variety of contaminated solutions, such as medications not approved by the US Food and Drug Administration, local anesthetic agents, and steroids dispensed in multiuse vials (figure 2). Postinjection infection with abscess formation occurred in a large number of persons who received adrenal cortex injections as part of naturopathic health and weight loss programs [20]. The solutions themselves may be contaminated; needles that are reused or rinsed in tap water have also been implicated.
Infections due to rapidly growing mycobacteria. A, disseminated infection to soft tissue after systemic steroid use; B, abscess after injection with contaminated adrenal cortex solution; C, breast reduction—associated infection; D, pedicure-associated infection; E, cosmetic surgery—associated facial infection.
Furunculosis after whirlpool footbaths has received much attention [21]. In one outbreak, risk included microabrasion from shaving the legs before the footbath [22]. Typing of strains of M. fortuitum in one case and Mycobacterium mageritense in another case obtained from the footbath and the patient revealed identical patterns. In these instances, it was concluded that contamination resulted from municipal water, which supplied the footbath. It was speculated that further growth on sloughed skin and other organic debris present in the drain resulted in high numbers of organisms. Infections ranged from mild to severe. Most patients were treated with antimicrobials, and the infection resolved in all, although some were left with disfigurement. It is important to note that new skin lesions can occur even during appropriate therapy.
Cosmetic surgery has emerged as an important source of rapidly growing mycobacterial infection [23]. Facial procedures, abdominoplasty, liposuction, breast reduction or augmentation, mammoplasty, and nipple piercing have all been associated with cases of postprocedure infection with rapidly growing mycobacteria. Contributing factors may include increased use of alternative medicine providers and increased numbers of procedures performed in freestanding surgical centers that are not routinely monitored by infection-control committees or equivalent oversight bodies. The recent outbreak of infection due to rapidly growing mycobacteria after cosmetic surgery done in the Dominican Republic and Venezuela underscores this issue [24]. To prevent skin and device-related infections, strict avoidance of tap (nonsterile) water for medical procedures and instrument cleaning is recommended.
Postsurgical wound infections have also been reported after the use of contaminated solutions, instrumentation, and implants (e.g., gentian violet, ice, lacrimal duct probes, tympanostomy tubes, epidural catheters, graft materials). There are also reports of postsurgical infections associated with contaminated suture material causing prolonged postoperative healing, wound breakdown, and intra-abdominal fistula formation. Mediastinitis and sternal wound infections due to M. fortuitum or M. chelonae have been reported after cardiothoracic surgery [25]. Skin infections due to rapidly growing mycobacteria usually produce painful red to violaceous nodules that can drain serosanguinous material, ulcerate, spread to deeper tissues, and form fistulous tracts. Culture material frequently yields negative results on smear testing for acid-fast bacilli and reveals abundant neutrophils [26, 27]. Granulomas may be caseating or noncaseating. The immunocompromised person may not display the typical histopathologic findings. Frequently a patient will present with an indolent inflammatory lesion that is partially or entirely unresponsive to antimicrobials commonly used for treatment of cellulitis. Corticosteroids are often administered before the definitive diagnosis is made, which may delay the diagnosis of rapidly growing mycobacterial infection because of their potent anti-inflammatory action and temporary relief of signs and symptoms of localized infection.
Pulmonary infection. The highest incidence of pulmonary disease appears to be in the southern and coastal regions of the United States, although sound epidemiological data are scarce. Risk factors include the underlying host conditions listed in table 1. More often than not, there are no identifiable risk factors for pulmonary infections due to rapidly growing mycobacteria. Pulmonary disease may be associated with structural lung disease and impaired clearance of the organisms, such as is seen in patients with cystic fibrosis. Clinically, rapidly growing mycobacterial infection can range from an asymptomatic, indolent disease with minimal clinical symptoms to severe bronchiectasis and cavitary lung disease with significant morbidity and mortality.
Predisposing factors for environmental mycobacteria lung disease.
Copathogens such as Staphylococcus aureus, molds, Pseudomonas aeruginosa, and other non—lactose fermenting organisms are often seen. Coinfection with multiple mycobacterial species is also being seen with increased frequency. Polymycobacterial infection may be underappreciated if liquid medium is the only one used for isolation. Before the 1990s, recovery of rapidly growing mycobacteria from sputum of patients with cystic fibrosis was rare. Olivier et al. [29] found a prevalence of nontuberculous mycobacteria of 13% in the sputum of patients with cystic fibrosis. Of these, M. avium complex accounted for 75% and rapidly growing mycobacterial isolates for 13%. Rates were higher in older patients. Whether this is a result of exposure, sequential antimicrobial pressure, or other host susceptibility is not known. However, the contribution to respiratory decline in patients with cystic fibrosis is disputed. With a follow-up of 15 months, Olivier et al. [29] found no effect on lung function, but high-resolution CT of chest abnormalities suggestive of infection with rapidly growing mycobacteria was predictive of disease progression, and we suspect that with longer follow-up, the significance of infection due to nontuberculous mycobacteria may indeed by greater than appreciated in the studies. Those harboring M. abscessus were more likely to meet the American Thoracic Society criteria for true microbiological disease than were those harboring M. avium complex [30, 31]. Given the severe disease and therapeutic difficulties with disease due to M. abscessus, these patients are likely to require therapy without delay [32]. Other rapidly growing mycobacteria are capable of causing pulmonary disease in patients with and without cystic fibrosis, particularly Mycobacterium immunogenum, M. mucogenicum, and Mycobacterium goodii, although infections related to these species seem to be relatively rare.
Hypersensitivity pneumonitis secondary to rapidly growing mycobacteria as an occupational lung disorder is seen most often in persons using metal-working fluids that are contaminated with mycobacteria, although indoor hot tubs, spas, and swimming pools are also environments that may predispose persons to develop hypersensitivity pneumonitis [33–35]. Symptoms of shortness of breath, decreased oxygen saturation, and fever are common. Chest CT reveals findings of inflammation of the small terminal (diameter, 1–5 mm) bronchioles (tree-in-bud appearance) with ill-defined centrilobular nodules. Tissue biopsy will often reveal granulomas that yield negative results on staining for acid-fast bacilli. Cultures may yield positive or negative results. The hydrophobic nature of mycobacteria makes them especially prone to aerosol formation, particularly from the biofilm found at the air-water interface [5, 6, 36]. Treatment involves removal of the patient from the offending environmental source in conjunction with glucocorticoid treatment. Antimycobacterial antibiotics are often required for a period of 6–12 months.
Disseminated infection. Rapidly growing mycobacteria can be isolated from blood and other sterile sites [37, 38]. A recent report of disseminated disease due to M. abscessus in 16 Thai patients manifested as lymphadenopathy and multiple-organ involvement. Sweet syndrome was reported in 9 of the patients. These patients were HIV seronegative. Suspicion of a defect in cell-mediated immunity was raised but not confirmed [39]. The finding of disseminated disease should alert the clinician to an immunocompromising condition, such as malignancy, transplantation, HIV infection, or defects in cytokine pathways (in particular, IL-12 and IFN-γ) [40]. A heightened suspicion is important, and biopsy should be performed for any isolated lesion in an immunosuppressed patient, with the sample sent for special stains and cultures.
Treatment
Identification to the species level is important, because there are predictable antimicrobial susceptibility patterns. In general, cefoxitin and amikacin are more active against M. abscessus, whereas tobramycin may have activity against M. chelonae but has little activity against M. abscessus. M. fortuitum is generally more drug susceptible than is M. chelonae or M. abscessus, and often oral regimens can be devised. M. abscessus typically shows susceptibility to amikacin, cefoxitin, imipenem, clarithromycin, and azithromycin. Interlaboratory imipenem susceptibility results are not reliable. The Infectious Diseases Society of America and American Thoracic Society [30] (unpublished data) statements regarding nontuberculous mycobacteria suggest that susceptibilities should be reported and used as a clinical guide for treatment, although M. fortuitum likely will be inhibited by tetracyclines, sulfamethoxazole, and quinolones and M. chelonae is often inhibited by macrolides, linezolid, and tobramycin. Rapidly growing mycobacteria can develop macrolide resistance by specific mutations in the peptidyltransferase region of the 23S ribosome gene [41]. A recent report has described a new rRNA methylase gene (erm) in M. fortuitum that is capable of induction and brings to a great concern the use of single-drug therapy with macrolides [42]. Because of this property, we do not recommend the use of monotherapy for infections due to rapidly growing mycobacteria, especially when there is a large organism burden or when macrolide MICs are in the 4–8-µg/mL range. Some experts in the field have shown that there is evidence in M. fortuitum of in vitro resistance to the macrolides, which therefore should not be used in empirical therapy. However, we have had good clinical results when macrolides are combined with at least 1 additional drug to which the organism appears to have in vitro susceptibility.
The 8-methoxy fluoroquinolones (gatifloxacin, moxifloxacin) may be effective in some rapidly growing mycobacterial infections [43]. Tigecycline, available only in an intravenous preparation, appears to have good in vitro activity, and susceptibility testing can be performed in reference laboratories. Preliminary clinical studies indicate that its use may be limited by its adverse effect profile, most notably nausea. Linezolid often shows some degree of in vitro response, and if used, there may be some benefit from concomitant pyridoxine administration for prevention of cytopenia (but not peripheral neuropathy) [44]. When risks for VIII cranial nerve toxicity or renal dysfunction preclude systemic aminoglycoside treatment, inhaled therapy (e.g., amikacin) can be tried, but there have been no controlled trials. Each agent has its own unique toxicity profile, and drug-drug interactions require close monitoring and informing patients of potential risks. On the horizon, newer agents hold some promise, and the field of treatment for rapidly growing mycobacteria may benefit from testing of newer antituberculous agents [45, 46].
In vitro susceptibility testing and guidelines of the Clinical and Laboratory Standards Institute [47] for microbroth dilution using a panel of antimicrobial agents, including macrolides, aminoglycosides, fluoroquinolones, cefoxitin, imipenem, linezolid, tigecycline, doxycycline, minocycline, and trimethoprim-sulfamethoxazole, should guide therapy. There are no results of controlled trials of treatment of rapidly growing mycobacterial infection. Although spontaneous healing of skin infection without antibiotics has been reported, most experts recommend antibiotics, usually in combination to avoid emergence of resistance [48]. Severe infections sometimes require cooperative management between those with infectious disease expertise and surgical colleagues to ensure adequate debridement of necrotic tissue. Therapy needs to be individualized. With such recalcitrant infections, it is strongly recommended that foreign bodies be removed.
Appropriate antibiotics are given for varying periods of time depending on disease severity and location. Skin and soft tissue infections may be successfully treated in 3–6 months with excellent chance for cure when medication either with or without concomitant surgical debridement is used. Pulmonary disease due to M. abscessus is currently considered “managed” but not cured. Most experts in the field practice intermittent intravenous therapy: intravenous imipenem or cefoxitin for 1 or 2 months plus a macrolide. Intravenous amikacin may also be used adjunctively in this pulsed fashion as long as there are no contraindications, such as renal insufficiency or evidence of damage to cranial nerve VIII. For the periods in between the pulsed intravenous therapy, “holding” regimens of a macrolide plus a quinolone may be helpful, even if in vitro susceptibility results reveal resistance to the quinolones. Pulmonary disease due to M. fortuitum generally has a much better outcome and in many cases can be considered cured after therapy for 12–24 months with at least 2 or 3 antibiotics with in vitro susceptibility. A commonly used regimen might include sulfamethoxazole, moxifloxacin, and minocycline. Antibiotics, both intravenous and oral, are administered as symptoms dictate. Short courses of intravenous antibiotics for 1–2 months plus an oral macrolide with a continuation phase using an oral macrolide and quinolone for 6–12 months is a regimen that is commonly used by experts in the field. Aminoglycosides are typically given during initial therapy for 2–8 weeks and longer if bone or other recalcitrant infection exists. For pulmonary disease due to M. abscessus, inhaled amikacin may also be considered but has not been used in clinical trials. Table 2 highlights recommendations for treatment of infection due to rapidly growing mycobacteria. A typical regimen for skin and soft tissue infection due to rapidly growing mycobacteria is intravenous imipenem or cefoxitin combined with amikacin as initial therapy accompanied by a macrolide.
Agents used to treat infections due to rapidly growing mycobacteria (assuming normal renal and liver function).
Acknowledgments
Kirk Harris provided assistance with figure 1.
Potential conflicts of interest. G.H. serves on the speakers' bureaus for Chiron and Hill-Rom. M.A.D.G.: no conflicts.
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