Runyon’s Classification of Nontuberculous Mycobacterium
NTM can cause infections on all adnexal and ocular tissues including the cornea, iris, lens, retina, choroid and optic nerve. Most NTM infections are caused by
In this chapter, we will focus on keratitis caused by atypical mycobacterium, since a great number of recent clinical reports of NTM ocular infections are of keratitis. In common general ophthalmology procedures like refractive surgery, for example laser in situ keratomileusis (LASIK), Laser epithelial keratomileusis (LASEK), photorefractive keratectomy (PRK), and other specialized procedures such as penetrating keratoplasty (PKP), a transgression to natural barriers occurs, this constitutes a risk factor for infection by these organisms. In addition, LASIK is one of the most commonly performed procedures in ophthalmology practice.
Several factors may contribute to the development of mycobacterial keratitis following LASIK, making it difficult to determine the true origin of the infection in most cases. This procedure is often performed utilizing aseptic, but non sterile techniques.
Atypical Mycobacteria corneal infections are rare, but devastating complications. Although rare, are a diagnostic and therapeutic challenge. Mycobacterium have been involved in several isolated cases as well as in outbreaks.[4-12]
2. Microbiological and laboratory profile
The only genus of the
Other places where NTM have been isolated are: contaminated tap water, saline solutions, disinfectant solutions, and hemodialyzers. Mycobacteria influences a number of ocular structures, including the cornea,iris, lens,retina, choroid and optic nerve.
Clinical manifestations of the typical mycobacteria are : lupus vulgaris on eyelid, phlyctenule, scleritis, lacrimal gland involvement, orbital periostitis, granulomatous panuveitis, secondary glaucoma and cataract, chorioretinal plaque or nodule, nerve palsies.
The incidence of tuberculosis has increased due to the growth in homelessness, the upsurge of intravenous drug abuse, neglect of tuberculosis programs, acquired immunodeficiency syndrome.
Runyon classified nontuberculous mycobacteria into four groups, described in [Table 1]. Runyon Classification of tuberculous and non-tuberculous
Out of the more than 130 actually validated species of non-tuberculousmycobacteria, 60 are slowly growingmycobacteria
|M. fortuitum group|
M. chelonae-abscessus group
M. smegmatis group
3. Laboratory diagnosis and bacteriology
In ophthalmological infections traumatic or post-surgical in origin, are frequently involved in non-tuberculous or atypical fast growing
To identify the microorganism, its phenotypic characteristics were used, such as pigmentation of colonies growing in the darkness (presented in Table 1) on Lowenstein-Jensen media.
The most common species of rapidly growing
For genotypic characterization, the 16Sr RNA gene sequencing, high performance liquid chromatography and polymerase chain reaction has been used.
4. Clinical features
Nontuberculous Mycobacteria can cause infections of all adnexal and ocular tissues. Most atypical Mycobacteria infections are caused by
Dacryocystitis and Canaliculitis: Present as epiphora and erythematous swelling in the medial canthal area, purulent material can be expressed with massage of the lacrimal sac.
Orbital Infections: Present with a gradual development of periorbital edema, without a significant proptosis and a superficial skin lesion may be present. The visual acuity will depend on the involvement of the optic nerve. [18,19]
Conjuntivitis and Scleritis: Present as conjunctival or as scleral injection and tenderness accompanied with chronic redness, irritation, discharge and pain. Sometimes, marked scleral thinning may develop. Scleral abscesses manifest late in the course of the disease as subconjunctival nodules. [20,21]
Endoftalmitis: Present with severe pain, decreased vision, and redness and discharge, may exist hypopyon, and variable amounts of granulomatous keratitic precipitates. Moderate vitreous inflammation is present in most cases.
Keratitis: The greatest number of recent clinical reports of nontuberculous Mycobacteria ocular infections are of keratitis, as seen in our hospital (Asociación Para Evitar La Ceguera en México “Dr. Luis Sánchez Bulnes” I.A.P. [APEC]). Keratitis most commonly follows trauma or surgery and has been associated with penetrating keratoplasty and refractive surgery.
Nontuberculous Mycobacteria keratitis is characterized by a delayed onset of symptoms that range typically from 1 to 3 weeks following the exposing event. There is decreased vision and an indolent course and some cases various degrees of pain, ranging from indolent to severe.
Presenting symptoms can include any of the following: pain, redness, photophobia, decreased vision, foreign body sensation and/or mild irritation. Presenting clinical signs include infiltrates in the corneal interface that can either be multiple white granular opacities <0.5mm in diameter with well defined borders or radiating projections, or a single white round lesion (0.1-2 mm in diameter) which may progress to satellite lesions. These infiltrates spread subsequently into the corneal stroma posteriorly and anteriorly and can result in perforation though the flap to surface. [Table 2].A hypopyon is often found in untreated or poorly treated cases. [25,26]
Lazar and colleagues first described the presence of a “cracked windshield” appearance to the cornea around the edge of the central area of ulceration and infiltrate, seen transiently early in the course of the infection. [25,27,28] This sign consist of radiating lines from the central infiltrate in the middle third of the corneal stroma. It is important to mention that NTM keratitis has also been noted in the abscence of epithelial defect with deep stromal keratitis. The corneal infiltrate may show irregular margins.
|Single or multiple white granular opacities with well defined borders or radiating projections|
Mild or absent anterior chamber reaction
“Cracked windshield” appearance
Foreign body sensation
Decreased visual acuity
5. Predisposing factors
Nontuberculous Mycobacteria are opportunistic pathogens that require an alteration in the ocular barriers to produce infection. In nearly all reports, a previous history of minor to severe trauma is the common denominator.Men and women are equally affected among NTM keratitis patients who have had LASIK, in contrast to a 70% male preponderance among patients who have not had LASIK, the result of a higher prevalence of trauma in males. [Table 3] [5,29]
Laser in situ keratomileusis (LASIK)
Laser epithelial keratomileusis (LASEK)
Photorefractive keratectomy (PRK)
Penetrating keratoplasty (PKP)
Other ophthalmologic surgeries
Extracapsular cataract extraction
Small incision corneal cataract surgery
Contact lens wear
Improper aseptic technique or sterilization of surgical instrumentation
Innoculation of NTM to the flap-stromal interface probably takes place at the time of surgery, therefore, it is infrequent to find an epithelial defect, being present in less than half of cases. Corneal infiltrates appear to be entirely within the lamellar flap or at the flap interface and may be either multiple, tiny, white, granular opacities less than 0.5mm in diameter or a single white lesion ranging between 0.1-0.2mm in diameter. Anterior extension of infiltrate with ulceration or anterior perforation of the corneal flap or posterior extension into the stroma is a rare finding and is usually associated with a delay in diagnosis and the beginning of therapy. Anterior chamber reaction is not a common finding, occurring in only 20% of cases.[1,29]
6. Differential diagnosis
NTM keratitis can often be mistaken with other bacterial infections that cause nonsuppurative keratitis. Several authors suggest to keep in mind other causative organisms that may present, in the course of disease, similar clinical features such as fungal keratitis, infectious crystalline keratopathy, Nocardia keratitis, herpes simplex virus, and rarely Acanthamoeba keratitis. In our experience at APEC, the principal differential diagnosis must be made between fungal and Nocardia keratitis.
7. Our experience
Keratitis caused by atypical
In our hospital, our service found an incidence of 2025 cases of infectious keratitis in the last 10 years (2000-2010). We found that 83.03% corresponded to infections caused by bacteria, 6.67% mycotic, and 10.3% originated by virus. [Table 4] Out of this percentage of bacterial keratitis, we report a frequency of 73.57% caused by gram positive, 9.22% caused by gram negative and 0.24% originated by nontuberculous mycobacteria. [Table 5]
In 100% of cases, the causative agent was
Almost all our cases (4 out of 6) of nontuberculous mycobacterial keratitis had as common background, a previous history of surgical trauma, specifically speaking of LASIK and PKP. We report one case of a contact lens user. A clinical summary of all cases reported in APEC to date, has been compiled in [Table 6,7]
The average age in our patients was of 36.6 years with a range from 12 to 58 years.
The average time that took from the onset of symptoms to the stabishment of correct diagnosis in patients that underwent previous surgical therapy was 4.25 weeks, which results similar to the average of weeks reported in literature (3.5 weeks). [1,33,34]
In our hospital 15,028 LASIK surgeries were performed from 2001-2011. We report in our service a total of 4 cases ok infectious keratitis following a LASIK procedure, which resembles an incidence of 1 infection every 3,757 procedures (0.026%). 2 cases (50%) correspond to post-LASIK keratitis caused by
Velotta reported that nearly 90% of NTM keratitis after LASIK cases are unilateral, all of our cases presented in just one eye.
Infectious keratitis after penetrating keratoplasty (PKP) is not a frequent complication with an incidence ranging from 1.8% to 11.0%; however, this infection has a high risk of loss of corneal clarity. In our present analysis, the remaining 2 patients that underwent surgical procedures, developed nontuberculous mycobacterial keratitis posterior to penetrating keratoplasty. Both cases were promptly diagnosed after onset of symptoms, resulting in satisfactory outcomes and good final visual acuity [Table 7] [Figure 8,9]
Management of this type of infectious keratitis often traduces in a medical challenge. In cases of identified NTM corneal infection, there is considerable benefit from the use of combined antibiotics, since atypical mycobacteria have a slower growth rate compared to other bacteria and may become resistant to a single antibiotic class during the course of extended treatment.
The base of treatment consists of a double approach; appropriate antibiotic and judicious surgical intervention. Such antimicrobial choice becomes complicated since a poor correlation exists between
De La Cruz et al. suggest initial combined antibiotic therapy that includes at least 2 of the 3 most susceptible agents (clarithromycin, amikacin, and fourth-generation fluoroquinolones) for rapidly growing mycobacteria specially if known resistance has been documented. The initial therapy recommended for many years has been the use of topical Amikacin sulfate 20-40mg/mL.This antibiotic is the most frequently used agent in the treatment of NTM keratitis. In our institution we use amikacin sulfate (Amikin® 500mg injectable solution. Bristol-Myers Squibb de México S. de R.L. de C.V.)diluted to a concentration of 20mg/mL, one drop every hour and dose-response. Even though this antibiotic constitutes the first line of treatment against atypical mycobacterial keratitis, only a success rate of 30-40% has been reported. This therapeutic agent has also been associated with high epithelium toxicity when it is applied for a prolonged course.
We recommend the addition of two additional antibiotics to the drug scheme, such as a macrolide like clarithromycin and a fourth-generation fluoroquinolone like gatifloxacin.[Table 6] In our hospital we employ oral clarithromycin Klaricid H.P.® 500mg (Abbott Laboratories de México S.A. de C.V. México, D.F.) twice daily, and Zymar® (gatifloxacin 0.3% Allergan Labs, Irvine, CA).
Fluoroquinolone antibiotics are concentration-dependent killers. Therefore, they require a minimum inhibitory concentration (MIC) to be reached in order to be effective. In vitro studies have shown that fourth-generation fluoroquinolones are effective against atypical mycobacteria, inhibiting 90% of isolates after reaching its proper concentration.[23,43]
The fourth-generation fluoroquinolones have significant advantages over earlier generation fluoroquinolones in treating mycobacterial infections, including superior bactericidal activity, higher corneal concentrations, and decreased risk for bacterial resistance.
The reason for adding a fourth-generation fluoroquinolone to the therapeutic scheme is that 8-metoxy-fluoroquinolones such as gatifloxacin and moxifloxacin has shown better in vitro activity against these organisms, in comparison to second-generation fluoroquinolones like ciprofloxacin.
Furthermore, the molecular structures of moxifloxacin and gatifloxacin have a greater binding affinity for 2 of the enzymes necessary for bacterial DNA synthesis (deoxyribonucleic acid gyrase [also called topoisomerase II] and tipoisomerase IV) in both gram-negative and gram-positive microorganisms. By inhibiting such enzymes, these bacteria require to undergo two genetic mutations in order to create resistance. Older fluoroquinolones adequately inhibit tipoisomerase II in gram-negative microorganisms but are not as effective in inhibiting topoisomerase IV in gram-positive organisms.
The great effectiveness of fourth-generation fluoroquinolones rely due to their superior bactericidal activity, the ability to reach higher corneal concentration, and better resistance pattern.In a rabbit model, fourth-generation fluoroquinolones were found to be synergistic to our first-line drug options, amikacin and clarithromycin against
Lazar et al reported a torpid answer to the use of Rifampin in nontuberculous mycobacteria ocular infections. In our experience, we required to add a new antibiotic drug in patient 1 (Table 6), when we reached the three antibiotics suggested by diverse authors in literature (Amikacin, Clarythromicin and Gatifloxacin). We added topical rifampin to the scheme obtaining positive outcomes. We prepared a topical solution of Rifampin at our hospital by dissolving 300mg of Rifampin (Rifadin®) (SANOFI-AVENTIS de México, S.A. de C.V.) with 10mL of Sodium Hyaluronate (Lagricel® SOPHIA, S.A. de C.V., Laboratorios. Guadalajara, México) indicating a drop every hour and dose-response.
Management of mycobacterial keratitis usually requires a prolonged and intensive therapy consisting of topical and systemic medication. In our experience, medical treatment of NTM keratitis can prolong as long as 30 months. Shih et al have reported full months of therapy even when the appropriate antibiotic, chosen by drug sensitivity test results, is used. In [Table 8]we summarize our suggested treatment for the proper management of nontuberculous Mycobacterial keratitis.
|1. Amikacin 20 mg/mL|
2. Fourth-generation fluoroquinolone (gatifloxacin)
|3. Clarithromycin 500mg PO BID|
|SurgicalTherapy||1. Flap lift and irrigation|
2. Flap amputation in post-LASIK
3. Biopsy and culture
4. Penetrating keratoplasty
9. Modification to initial therapy
The medical response of mycobacterial keratitis to antibiotic therapy can be achieved by constant clinical observance. This can be difficult to appreciate in the first days of treatment due to increase in inflammation and local reaction to topical agents. The clinical response varies depending on the microorganism and pathogenicity of the mycobacteria, duration of the infection, risk factors involved and the patient’s individual response (immunosuppresion).
If the chosen therapy is effective, some response should manifest within the first of 24 to 72 hours of appropriate treatment. [Figure 10,11]. Said response manifests with the decrease of stromal infiltrates and less anterior chamber inflammation in case it exists. [Figure 12, 13]
If clinical improvement exists at 48 hours of initiation of treatment, we encourage to continue the same pharmacological agents, reducing the administration time to 1 drop every 2 hours until completion of 5 days with night rest. After the 5 days, if further improvement exists, antibiotic doses should be decreased progressively in function of clinical response, drug tolerance and sensitivity tests results. Antibiotic with the best sensitivity should be the one chosen to continue the treatment for 2-3 more weeks.
Special caution should be kept when therapy is suspended, as some microorganisms may remain in corneal tissue. In this case, a prolonged treatment may be required.
If lesion progression occurs after 48 hours of initiation of treatment, manifested by evident increase in size, stromal thinning or incomplete resolution of symptoms, the ophthalmologist should consider a lack of sensitivity to the chosen treatment or a failure in the patient’s attachment to the therapy. Culture results should be rechecked as well as sensitivity test results, as an addition of a different antimicrobial agent might be needed.[Table 9]
|Peripheral corneal clearance of infiltrates and density reduction.|
Decrease in stromal edema.
Less anterior chamber inflammation.
Corneal epithelial regeneration.
|Increase in size or depth.|
Partial resolution of symptoms.
10. Complementary therapy
Uncontrolled progression of the infection.
Imminent risk of corneal perforation
We recommend maximal antibiotic therapy for 48 hours prior to surgery to decrease the number of bacterial colonies as much as possible and consequently the diminish the risk of endophthalmitis. Additional to topical antibiotics, we suggest the use of systemic antimicrobial and antiinflammatory agents in the preoperative period. The trepan employed on the recipient’s cornea should be of enough size to extract the entire infected area, and the donor’s corneal graft should be 0.5mm bigger than the measurement made on the recipient’s cornea. It is advisable to obtain cultures from one half of the obtained cornea tissue (including stains and special culture media), and the other half should be sent for histopathological study. Sutures should be placed separately due to intense inflammatory reaction. In the postoperative period, corticosteroid therapy should be continued as well as specific antibiotics. Systemic therapy should continue. Posterior to the complete resolution of corneal infection, an optical PKP is an option of treatment to seek visual rehabilitation, as seen in out patient that appears on [Table 7]. As a consequence of the long term infectious process caused by mycobacterium keratitis, secondary cataract formation can be induced by the production of toxins, iridocyclitis, treatment toxicity and corticosteroid usage. For this complication, and optic PKP combined with a cataract extraction and Ahmed valve implantation can be considered as a treatment option, as seen in patient 1 who developed glaucoma.[Table 6,7]
We describe our experience in patients who developed keratitis caused by nontuberculous mycobacteria. As the most common cause of post-LASIK keratitis is NTM, a greater degree of suspicion, recognition of typical clinical course and presentation, and knowledge of similar cluster of NTM keratitis prompts rapid institution of appropriate antibiotic therapy, granting this cases with a better prognosis in comparison with those of late diagnosis. Antibiotic resistance continues to be an emerging problem, thus a limitation in the coverage of this pharmacological agents exists. We emphasize the need for vigilance in the follow-up of patients. Appropriate adjustment of antimicrobial therapy may be required based on cultures and sensitivity tests when atypical mycobacteria are responsible for corneal infection. We believe that fourth-fluoroquinolones adequately combined with first-line antibiotics constitute the best option so far to treat keratitis caused by atypical mycobacteria.
We express our gratitude to the cornea service and pathology service at Asociación Para Evitar La Ceguera en México “Hospital Dr. Luís Sánchez Bulnes” for their valuable contribution with images that helped making this chapter possible. Also to Miss. Elia Portugal for her assistance in the translation of this work.