Nontuberculous Mycobacterial Endophthalmitis: Case Series and Review Literature

Background: To report three cases of nontuberculous mycobacterial (NTM) endophthalmitis following multiple ocular surgeries and to review previous literature in order to study the clinical pro�le, treatment modalities, and visual outcomes among patients with NTM endophthalmitis. Methods: Clinical manifestation and management of patients with NTM endophthalmitis in the Department of Ophthalmology


Background
Nontuberculous mycobacteria (NTM) are aerobic, gram-positive bacilli found in the soil, dust, and water.NTM infection in human can be both acquired from the environment and nosocomial [1].Based on in vitro culture properties, NTM have been divided into 4 groups by Runyon in 1959 [2].The photochromogens (Runyon group I) grow slowly over 2-4 weeks and produce yellow pigment after light exposure.M. marinum, M. kansasii, M. simiae, M. asiaticum are majority members in this group.The scotochromogens (Runyon group II) also grow over 2-4 weeks and produce yellow-orange pigment.They include M. scrofulaceum, M. szulgai, M. gordonae, M. xenophi and M. avescens.The nonphotochromogens (Runyon group III) grow over 2-4 weeks without producing pigment.The members in this group are M. Avium, M. malmoense, M. intracellulare, M. terrae, M. haemophilum, M. triviale, M. paratuberculosis, M. gastri, M. nonchromogenicum.The Rapid growers (Runyon group IV) include 3 subgroups; the M. fortuitum group, the M. chelonae/abscessus group, and the M. smegmatis group.They colony within 5 days and do not produce pigment [2].NTM ocular infections were rst reported in a case of M. fortuitum keratitis after corneal foreign body removal in 1965.Since then, the infections have been increasingly reported in a variety of ocular infections range from periocular, conjunctival, scleral, corneal, orbital and intraocular infections [1,3,4].
Endophthalmitis is a serious intraocular infection affecting the vitreous cavity and surrounding tissue.It can be categorized into exogenous or endogenous types.Exogenous endophthalmitis occurs when a pathogen enters the eye by direct inoculation, such as intraocular surgery, penetrating ocular trauma, or periocular tissue infection.On the other hand, endogenous endophthalmitis is a secondary infection in the eye resulting from hematogenous spread from distant infection.The pathogenic microbes are commonly bacteria or fungi; however, mycobacteria can rarely cause endophthalmitis.Being a rare intraocular infection, NTM endophthalmitis is a diagnostic and therapeutic challenge in clinical practice and the prognosis is usually poor accordingly.Herein, we reported three cases of postoperative endophthalmitis caused by different types of NTM at the Department of Ophthalmology, Faculty of Medicine, Siriraj hospital, Mahidol University, Bangkok, Thailand from January 2006 to September 2019.The rst case was M. abscessus endophthalmitis after a cataract surgery.The second patient developed M. fortuitum endophthalmitis after Baerveldt shunt implantation.The third patient was M. haemophilum endophthalmitis following multiple trabeculectomy surgeries.The last case was also previously reported in February 2018 [12].In addition, the literature review and summary of previous NTM endophthalmitis was performed in order to summarize the clinical pro le, treatment modalities, and visual outcomes in this rare intraocular infection worldwide.

Case 1
A 55-year-old man underwent an uneventful cataract surgery with intraocular lens (IOL) implantation of the left eye.One year postoperatively, he experienced painless visual loss in the operated eye.His vision was 6/36 in the left eye.Slit-lamp examination showed ciliary injection, 2+ cells in the anterior chamber, and posterior synechiae.There was white plague deposited on the posterior capsule which was noted as posterior capsule opacity.The fundus examination was normal.There was no other systemic abnormality identi ed from the physical examination.He had a previous history of sputum smearnegative pulmonary tuberculosis (TB) which was responsive to a 6-month anti-tuberculosis treatment from a local hospital 2 years ago.
Initially, chronic ocular in ammation was suspected so topical corticosteroid was prescribed, and laser capsulotomy was performed.One month later, his vision decreased to hand motion.The anterior chamber showed plasmoid reaction with 4+ cells and a 1.7-mm hypopyon.Fundus examination was obscured by grade 3 vitreous haze.The B-scan ultrasound revealed heterogenous vitreous echogenicity.
As a result, pars plana vitrectomy (PPV) with intravitreal injection of vancomycin was performed followed by topical vancomycin, ceftazidime, amikacin and oral cipro oxacin.The in ammation was gradually improved.Six weeks later, the vitreous culture was identi ed as M.abscessus.The treatment regimen was changed to intravenous injection of cefoxitin and intravitreal amikacin.After 14 days of intravenous antibiotics, the treatment was changed to a 6 month-course of oral clarithromycin and cipro oxacin.The nal best-corrected visual acuity (BCVA) was 6/9 in the left eye and intraocular pressure (IOP) became normal without antiglaucoma medications.

Case 2
A 61-year-old man with uncontrolled diabetes underwent Baerveldt shunt implantation in his left eye after failures from four trabeculectomy surgeries.One year later, tube shunt exposure was found and successfully repaired with scleral and buccal mucosal graft.One month after the reparation, he developed non-granulomatous anterior uveitis which partially responded to topical prednisolone.The investigations showed positive Quantiferon-TB gold result.He had been treated as TB anterior uveitis with a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months.The in ammation improved, so the regimen was changed to isoniazid and rifampicin.One months later, he complained of blurred vision and periocular pain in the left eye.The BCVA was 6/30.The anterior segment examination demonstrated marked circumcorneal injection, however there was no sign of blebitis.There was brinous material occluded in the tube and 4+ cells in the anterior chamber.Fundus examination revealed prominent anterior vitreous cells and vitreous opacity.
Since these ndings suggested either endophthalmitis or a progression of ocular tuberculosis, the patient underwent a diagnostic aqueous tapping.Aqueous cultures showed no organisms and the direct polymerase chain reaction (PCR) was negative for TB.Due to persistent intraocular in ammation, PPV was performed followed by multiple intravitreal injections of vancomycin and ceftazidime.Despite these treatments, the in ammation worsened with a development of hypopyon and subconjunctival pus around the tube (Figure 1).The Baerveldt shunt was removed.Three weeks later, M. fortuitum was identi ed from aqueous cultures in Mycobacteria Growth Indicator Tube (MGIT).The treatment regimen was switched to topical, subconjunctival, and intravitreous amikacin combined with intravenous amikacin, cefoxitin, levo oxacin, and oral clarithromycin.Home medication consisted of oral levo oxacin and clarithromycin for 6 months.The patient showed a good response to the treatment with the nal BCVA of 6/18.

Case 3
A 66-year-old man with uncontrolled diabetes had undergone three trabeculectomies in the left eye; the last surgery performing ve years ago.Four months before this presentation, he complained of blurred vision and pain in the left eye.The condition was treated with topical and systemic corticosteroids at a local hospital.The intraocular in ammation subsided but recurred after drug discontinuation.After 4month intermittent treatments, the patient stopped medications and sought for our opinion.At presentation, the left eye showed a poor response to light projection with plasmoid reaction in aqueous, mutton-fat keratic precipitates, and 4+ cells in the anterior chamber.The conjunctiva was injected with three at trabeculectomy blebs.Severe vitritis with a string-of-pearls appearance was seen from a fundus examination.A diagnosis of severe panuveitis was made.Oral prednisolone was started, and the in ammation subsided.
One month later, the inferior ltering bleb became in amed and iris brinous membrane and hypopyon were observed in the left eye (Figure 2).Aqueous and vitreous aspirations were performed along with 2 intravitreal injections of vancomycin and amikacin.Due to unsuccessful results, PPV was carried out.
The additional intravenous vancomycin and amikacin were given.Two days later, vitreous staining from vitrectomy sample demonstrated positive for acid-fast bacilli, however the PCR was negative for TB.The treatment was changed to intravenous imipenem, levo oxacin, and amikacin for two weeks combined with intravitreal, intracameral, and subconjunctival injections of amikacin and imipenem.The in ammation gradually improved but the vision worsened to no light perception.There was uveal tissue prolapsed through a scleral window of trabeculectomy wound.Eventually, vitreous cultures revealed M. haemophilum three months later.The treatment was changed to oral azithromycin, doxycycline, and rifampicin for 12 months.Over a follow-up period, the eye gradually became phthisical (Figure 3).

Methods
The literature review and summary of previous NTM endophthalmitis was performed in this study.We searched in MEDLINE, EMBASE, and CENTRAL for related articles by using the search terms "atypical mycobacteria", "non-tuberculous mycobacteria", "endophthalmitis", and "intraocular infection".All reports of patients with a diagnosis of endophthalmitis based on clinical presentation with culture-proven positive for NTM were included.Relevant articles published in English language were extracted and summarized.Patients whose microbiological investigations were negative, and articles with duplicated cases were excluded from data analyses.Our last search was performed in October 2020.We evaluated the methodological quality of published articles using the proposed tool by Murad and colleagues [13] and reported the quality as high, moderate, or low risk of bias.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was used to report the results of this review.
If available, demographic data including sex, age, systemic diseases, previous ocular trauma and surgery was collected.The information about detectable NTM species, medical and surgical treatment was obtained, as well as the BCVA and complications.All data analyses were performed using SPSS Statistics version 23 (SPSS, Inc.).Demographic data were summarized in descriptive statistics.Categorical data was shown as number and percentage, and continuous data was reported as mean ± standard deviation.

Results
Up to October 2020, there were 112 cases from 51 case reports and case series (Appendices 1 and 2) of culture positive NTM endophthalmitis reported in the literature apart from three cases of this current study [1, 5-7, 14-58].The search result was illustrated in Figure 4. Demographic data of all 115 cases were shown in Table 1.The age ranged from 13 to 89 years with mean age of 60.5±17.7 years.There were 54 males (47.0%), 58 females (50.4%), and the data were unavailable in three cases.The common symptoms were pain, decreased vision and redness.The clinical signs are conjunctival injection, hypopyon, anterior chamber in ammation, granulomatous keratic precipitates, vitreous in ammation, and paradoxical deterioration after steroid therapy [3,4,36].Of total, exogenous endophthalmitis and endogenous endophthalmitis occurred in 101 cases (87.8%) and 14 cases (12.2%), respectively.

Discussion
Since the rst reported case of NTM endophthalmitis in 1973, the organism had been increasingly reported because of improved microbiological diagnostic methods and enlarged immunocompromised hosts in recent years [40].
In this review, endophthalmitis caused by NTM equally occurred in both males and females.The age of onset was approximately in the fourth to sixth decades of life.NTM exogenous endophthalmitis could occur after uneventful ocular surgery, even in healthy hosts.The infection often occurred within 1 month after ocular surgery.Cataract surgery was accounted for the most common procedure related to the infection.On the other hand, NTM endogenous endophthalmitis mainly took place in immunocompromised patients especially those with history of mycobacterial systemic infection.
Overall demographic data did not change from previous reviews of ocular NTM infections.In 2015, Kheir et al reported that NTM endophthalmitis had no gender differences and the median age of presentation was 44 years.Among all exogenous endophthalmitis patients, the infection usually occurred after ocular intervention which 48.6% was cataract surgery with an average time of 11.5 weeks after ocular surgery [3].In 2012, Moorthy et al reported an average period of 1 month after a procedure, while all endogenous endophthalmitis cases were under immunosuppression [4].Likewise, Kheir et al reported that more than half (60.0%) of endogenous endophthalmitis cases was associated with immunode ciency status and previous disseminated mycobacterial infection [3].
The most common causative pathogens of ocular infections are rapidly growing NTMs.M. abscessus, M. chelonae, and M. fortuitum are responsible for the majority of cases [3,4].However, in this review, we found that most of exogenous endophthalmitis cases were caused by rapid growers, while slow growing NTMs were leading causes of endogenous endophthalmitis.According to different natures of NTMs, slow growers are generally found in pulmonary and lymph node diseases [59].Along with immunocompromised state of hosts leading to susceptibility for systemic spreading, this could explain why slow growing NTMs were apparently related with endogenous endophthalmitis in this study.
In addition to the published literature, there were three exogenous endophthalmitis cases reported from our hospital; M. abscessus, M. fortuitum, and M. haemophilum endophthalmitis.All of them were male in fth to sixth decade similar to previously reported cases.Two rapid growers (M.absecssus and M. fortuitum) were identi ed early after laser capsulotomy and reparation of exposed tube shunt respectively, while a slow grower NTM, M. haemophilum, was found late in a case with multiple trabeculectomies.Despite the types of organism, the onset of these cases was gradual, and the clinical manifestation was subtle at the beginning mimicking chronic uveitis.Their presentation misled the ophthalmologists resulting in delayed investigation and treatment.M. abscessus belongs to M. Chelonae/abscessus group.Its identi cation was relying on identi cation methods, such as PCR restriction analysis and DNA sequencing [60].Among the NTMs, M. chelonaeabscessus group was known as having the highest resistant rate to antibiotics and anti-tuberculous drugs due to the formation of bio lm [38,60].
The onset of M. chelonae/abscessus endophthalmitis varied from immediate to 3 years after operation and the infection generally presented with chronic granulomatous in ammation.In post-cataract surgery, corneal in ltration around the cataract wound and white plaque-like material on the intraocular lens implant had been observed [5].The same pattern was observed in our patient.In the previous literature, M. chelonae/abscessus group was generally associated with poor visual outcomes [5].Total of 82.3% of cases ended up with visual impairment, evisceration, enucleation, or phthisis.The poor prognosis is due to delay diagnosis and treatment and the organism's ability to form a bio lm [1,6,9].The diagnosis of our case was made within 6 weeks after capsulotomy which caused acute active in ammation.This presentation led to early vitrectomy resulting in a successful treatment.From literature review, there were only 11 eyes that showed nal BCVA of 6/60 or better [7,21,30,32,37,41,43,47,52].Stewart et al reported a case of M. abscessus endophthalmitis with a full visual recovery [50].
M. fortuitum endophthalmitis was reported in 26 cases previously.The incubation period ranged from 10 days to 20 months [1,7,22,28,41,44,45,56].As a rapid growing nature, our patient had the onset of 1 month postoperatively.The progression of disease and the clinical ndings were similar to almost all reported cases.At early stage, with surgical repair of exposed shunt, infectious uveitis could not be excluded.However, the treatment of this patient was misled by false positive Quantiferon-TB test and treated partially with standard anti-tuberculosis drugs.The suspicion of NTM infection was made after clinical worsening despite anti-tuberculosis and anti-bacterial treatment, and the organism was identi ed 3 weeks after aqueous aspiration.Despite the delay in diagnosis, our patient ended with favorable vision.
M. haemophilum endophthalmitis in our patient was previously reported to be the rst case of postoperative endophthalmitis in the literature [12].In 2007, Modi et al reported the rst case of disseminated M. haemophilum infection in a patient with immunosuppressive medication after a cardiac transplantation [42,61,62].He had the gradual course of ocular infection with multiple skin nodules before turning into a suppurative endophthalmitis and nally enucleated.Our patient also had similar clinical course which ended up with purulent endophthalmitis and visual loss despite combination of intraocular and systemic antimicrobial treatment.
NTM endophthalmitis has a variable of clinical syndrome which can mimic chronic intraocular in ammation and makes initial confusion with other low virulent bacterial and fungal infection [10].Misdiagnosis with other organisms has been commonly reported before the nal diagnosis [34].Clinical suspicion of NTM infections is necessary especially in immunocompromised patients, with chronic granulomatous intraocular in ammation and intermittent response with anti-in ammatory drugs.Repeat vitreous and aqueous cultures are required to identify the causative organism in which determines the choice of antibiotics.The treatment of NTM endophthalmitis includes the combination of local and systemic antibiotic therapy with or without surgical removal of the implants.The patient who does not response to medical treatment or has an ocular implant is considered surgical therapeutic interventions [3,10].Speci c guidelines for antibiotics and duration of treatment are still unestablished.The regimen is based on drug sensitivity information and clinical response.Standard anti-tuberculosis drugs such as isoniazid, rifabutin, rifampin, ethambutol, and streptomycin are commonly prescribed.However, NTM are often resistant to these regimens and alternative antimicrobials have emerging roles for NTMs infection due to the potency, pharmacokinetic property, and safety.Especially among rapidly growing NTM, a combination of aminoglycosides, uoroquinolones and macrolides has shown successful outcome [3,8,10].Gri th et al recommended the treatment for M. abscessus skin and soft tissue infections, based on in vitro susceptibility studies, should be a combination of macrolide and one or more medications including amikacin, cefoxitin, or imipenem for 4-6 months of therapy [63].Nevertheless, Pasipanodya et al showed poor clinical outcomes of macrolide-containing regimen in M. abscessus pulmonary infections, de ned by sustained sputum culture conversion and recurrent rates [64].The results from this meta-analysis were consistent with previous in vitro studies which reported that macrolides showed poor kill rates, even at maximal drug concentrations [65].On the other hand, slow growers are more sensitive to most of antituberculosis drugs [4].Thus, further studies of treatment regimen are still needed to gain the most favorable outcomes.
There are some mentionable limitations.As NTM endophthalmitis is an uncommon condition, this review was a collection of case reports and case series.Nevertheless, we summarized all available information and demonstrated the characteristics as well as the causative pathogens and the outcomes of NTM endophthalmitis.Lack of required details from the literature review and inaccessibility of non-English data could miss complete information.

Conclusions
NTM endophthalmitis is rare but can lead to vision-threatening complications.It can imitate chronic intraocular in ammation, so it usually is misdiagnosed as in ammatory uveitis or endophthalmitis caused by other common pathogens.Although the prognosis for NTM endophthalmitis is poor despite invasive treatment, appropriate samples for microbiological identi cation and suitable treatment regimen are required for preventing the infections from progression to detrimental outcomes.The recommended therapy is a combination of two or more antibiotics based on culture susceptibility.Surgical intervention can be done in case of failure medical treatment or infection control.However, the precise diagnostic yields and therapeutic managements for NTM are still challenging.

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Figure 4 Flow
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Table 1
Demographic information of patients with Non-tuberculous mycobacterium endophthalmitis days to 8 months.From all endophthalmitis cases, there were 4 patients (3.5%) with previous mycobacterial tuberculosis infection.There were one with a lymph node tuberculosis and one with pulmonary tuberculosis (case 1), which had been completely treated 2 years ago.The other two cases had recent ocular (case 2) and disseminated tuberculosis which were undergoing antimycobacterial treatment.
mellitus.Four of them received immunosuppressive agents due to autoimmune disease, organ transplantations, or cancers.Only one case was a healthy host.(Table1)Amongendogenousendophthalmitis cases, 4 (30.8%) had a clear evidence of disseminated NTM infection prior to intraocular infection.(Table2)Others had neither unmentioned systemic infection nor unavailable information.The median duration between the onset of systemic infection and ocular presentation was 3 months which ranged from 15

Table 2
Primary source of infection of Non-tuberculous mycobacterium endophthalmitis

Table 3
Non-tuberculous mycobacterium species identified in endophthalmitis

Table 4
Treatment summary of Non-tuberculous mycobacterium endophthalmitis

Table 5
Clinical outcome of Non-tuberculous mycobacterium endophthalmitis