**7. Our experience**

Keratitis caused by atypical *Mycobacteria* is characterized by an indolent course and poor re‐ sponse to antibiotics. The diagnosis requires a high index of suspicion and their treatment is usually very difficult. The early diagnosis of nontuberculous mycobacterial keratitis follow‐ ing LASIK is not easy, because the overlying, noninvolved stroma hinders the collection of sufficient material for culture. In addition, such organisms are only detectable by culture in special media, such as Lowenstein-Jensen, and special stains like Ziehl-Neelsen, which may not be included among routine cultures in the microbiology service.

**Table 4.** Profile of microorganisms causing infectious keratitis; 2025 cases, during 10 years (2000-2010). Data of Asociación Para Evitar La Ceguera en México "Dr. Luis Sánchez Bulnes" I.A.P.

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 *Mycobacterium chelonae*, correlating with the report‐ ed in literature.

**Herpetic keratitis.** In necrotizing stromal keratitis, herpetic keratitis can cause dense white stromal infiltrates that may be confused with NTM keratitis. Special features that are more typically found in herpetic keratitis are decreased corneal sensation and previous or con‐ comitant history of herpes labialis lesions. NTM keratitis may simulate a non-suppurative herpetic keratitis, especially in cases caused by Mycobacterium marinum. There may also be a dendritic or geographic epithelial defect with minimal stromal infiltration, misleading the clinician and prompting treatment with antivirals. This can lead to the development of a se‐

Keratitis caused by atypical *Mycobacteria* is characterized by an indolent course and poor re‐ sponse to antibiotics. The diagnosis requires a high index of suspicion and their treatment is usually very difficult. The early diagnosis of nontuberculous mycobacterial keratitis follow‐ ing LASIK is not easy, because the overlying, noninvolved stroma hinders the collection of sufficient material for culture. In addition, such organisms are only detectable by culture in special media, such as Lowenstein-Jensen, and special stains like Ziehl-Neelsen, which may

**Table 4.** Profile of microorganisms causing infectious keratitis; 2025 cases, during 10 years (2000-2010). Data of

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

Asociación Para Evitar La Ceguera en México "Dr. Luis Sánchez Bulnes" I.A.P.

negative and 0.24% originated by nontuberculous mycobacteria. [Table 5]

not be included among routine cultures in the microbiology service.

vere, wide corneal infiltrate.

**7. Our experience**

156 Common Eye Infections

Several authors reported an incidence between 0% and 1.5% of mycobacterial keratitis post-LASIK, our results (0.24%) correlate with these values. [29,31,32]

**Table 5.** The spectrum of bacterial agents causing keratitis. Data of Asociación Para Evitar La Ceguera en México "Dr. Luis Sánchez Bulnes" I.A.P

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 diag‐ nosis 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 resem‐ bles an incidence of 1 infection every 3,757 procedures (0.026%). 2 cases (50%) correspond to post-LASIK keratitis caused by *Mycobacterium chelonae, a*nd the remaining 2 cases (50%) by gram positive bacteria (*Streptococcus pneumoniae*). These findings correlate with the reported by Solomon et al. (year 2003)of 1 infection for every 2919 procedures (0.034%), Donnenfeld et al. (year 2005) who reported an incidence of 1 in every 2131 (0.04%) LASIK procedures and LLovet et al. (year 2010) with an incidence of 1 in every 2841 cases (0.035%). The study also mentions that 65.5% (76 cases) of the infections reported, presented in the first week postoperatively. 6.03% (7 cases) presented in the second week, 14.65% (17 cases) presented between the second and fourth week and lastly 13.79% (16 cases) presented after 1 month. 2 of our cases, the ones caused by *Streptococcus pneumoniae,* presented in the first week postop‐ eratively. 1 nontuberculous mycobacterial case presented between the second and fourth week (3 weeks), and lastly the remaining NTM keratitis case presented presented after 1 month (7 weeks). Speaking of ethiological factors, Solomon et al. reported that the most common microorganisms involved in post-LASIK keratitis are mycobacteria (48%) and coc‐ cus (33%), we found similar data in our retrospective analysis; Mycobacterial keratitis 50% and Streptococcus 50%.[30,39,40]


F=female, M=male, CF=count fingers, OS=left eye, OD=right eye, PO=per oral, BID=twice daily, DM=Diabetes Mellitus, VA= visual acuity, PKP=penetrating keratoplasty, LASIK=laser in situ keratomileusis

**Table 6.** Nontuberculousmycobacterialkeratitis in patients of Asociación Para Evitar La Ceguera en México "Dr. Luis Sánchez Bulnes" I.A.P.

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 kera‐ toplasty. Both cases were promptly diagnosed after onset of symptoms, resulting in satisfac‐ tory outcomes and good final visual acuity [Table 7] [Figure 8,9]


PKP=penetrating keratoplasty, ECCE=extracapsular, IOL=intraocular lens.

**Table 7.** Surgical treatment and outcome in nontuberculousmycobacterial keratitis in patients of Asociación Para Evitar La Ceguera en México "Dr. Luis Sánchez Bulnes" I.A.P.

**Figure 8.** Patient 2, clinical examination 4 weeks after penetrating keratoplasty with conjunctival hyperemia and cor‐ neal infiltrate (3.0 x 2.0 mm) in graft-host junction caused by *Mycobacterium chelonae*.

#### **8. Treatment**

postoperatively. 6.03% (7 cases) presented in the second week, 14.65% (17 cases) presented between the second and fourth week and lastly 13.79% (16 cases) presented after 1 month. 2 of our cases, the ones caused by *Streptococcus pneumoniae,* presented in the first week postop‐ eratively. 1 nontuberculous mycobacterial case presented between the second and fourth week (3 weeks), and lastly the remaining NTM keratitis case presented presented after 1 month (7 weeks). Speaking of ethiological factors, Solomon et al. reported that the most common microorganisms involved in post-LASIK keratitis are mycobacteria (48%) and coc‐ cus (33%), we found similar data in our retrospective analysis; Mycobacterial keratitis 50%

F=female, M=male, CF=count fingers, OS=left eye, OD=right eye, PO=per oral, BID=twice daily, DM=Diabetes Mellitus,

**Table 6.** Nontuberculousmycobacterialkeratitis in patients of Asociación Para Evitar La Ceguera en México "Dr. Luis

Velotta reported that nearly 90% of NTM keratitis after LASIK cases are unilateral, all of our

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 kera‐ toplasty. Both cases were promptly diagnosed after onset of symptoms, resulting in satisfac‐

VA= visual acuity, PKP=penetrating keratoplasty, LASIK=laser in situ keratomileusis

tory outcomes and good final visual acuity [Table 7] [Figure 8,9]

and Streptococcus 50%.[30,39,40]

158 Common Eye Infections

Sánchez Bulnes" I.A.P.

cases presented in just one eye.

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 antibi‐ otics, 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.

**Figure 9.** Patient 2, eighteen months after therapy discontinuation. Corneal graft is infection-free and clear in the vis‐ ual axis; best-corrected vision of 20/30 was attained with a +3.50-D contact lens.

The base of treatment consists of a double approach; appropriate antibiotic and judicious surgical intervention. Such antimicrobial choice becomes complicated since a poor correla‐ tion exists between *in vitro* susceptibility profiles and the final clinical response. We recom‐ mend surgical debridement, depending on the case, to facilitate drug penetration to the interlamellar space. In some cases, flap amputation may be necessary, the rationale for this procedure is to lower the bacterial load, remove necrotic as well as infected tissue, and per‐ mit better antibiotic penetration. We recommend this surgical procedures in recalcitrant post-LASIK NTM keratitis to maintain the infection under control.

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 kera‐ titis. 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 treat‐ ment against atypical mycobacterial keratitis, only a success rate of 30-40% has been report‐ ed. 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.[Ta‐ ble 6] In our hospital we employ oral clarithromycin Klaricid H.P.® 500mg (Abbott Labora‐ tories 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 stud‐ ies have shown that fourth-generation fluoroquinolones are effective against atypical myco‐ bacteria, 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 activi‐ ty, 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 bind‐ ing 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 under‐ go two genetic mutations in order to create resistance. Older fluoroquinolones adequately inhibit tipoisomerase II in gram-negative microorganisms but are not as effective in inhibit‐ ing topoisomerase IV in gram-positive organisms.

**Figure 9.** Patient 2, eighteen months after therapy discontinuation. Corneal graft is infection-free and clear in the vis‐

The base of treatment consists of a double approach; appropriate antibiotic and judicious surgical intervention. Such antimicrobial choice becomes complicated since a poor correla‐ tion exists between *in vitro* susceptibility profiles and the final clinical response. We recom‐ mend surgical debridement, depending on the case, to facilitate drug penetration to the interlamellar space. In some cases, flap amputation may be necessary, the rationale for this procedure is to lower the bacterial load, remove necrotic as well as infected tissue, and per‐ mit better antibiotic penetration. We recommend this surgical procedures in recalcitrant

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 kera‐ titis. 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 treat‐ ment against atypical mycobacterial keratitis, only a success rate of 30-40% has been report‐ ed. This therapeutic agent has also been associated with high epithelium toxicity when it is

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.[Ta‐ ble 6] In our hospital we employ oral clarithromycin Klaricid H.P.® 500mg (Abbott Labora‐ tories de México S.A. de C.V. México, D.F.) twice daily, and Zymar® (gatifloxacin 0.3%

ual axis; best-corrected vision of 20/30 was attained with a +3.50-D contact lens.

post-LASIK NTM keratitis to maintain the infection under control.

applied for a prolonged course.

160 Common Eye Infections

Allergan Labs, Irvine, CA).

The great effectiveness of fourth-generation fluoroquinolones rely due to their superior bactericidal activity, the ability to reach higher corneal concentration, and better resist‐ ance pattern.In a rabbit model, fourth-generation fluoroquinolones were found to be syn‐ ergistic to our first-line drug options, amikacin and clarithromycin against *M. chelonae.* Lastly, considering antibiotic resistance as an emerging problem; Ford et al. reported in their study that more than 60% of atypical mycobacteria are unresponsive to second-gen‐ eration fluoroquinolones. [5,34]

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 ob‐ taining 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 [Ta‐ ble 8]we summarize our suggested treatment for the proper management of nontuberculous Mycobacterial keratitis.


**Table 8.** We suggest a triple antibiotic treatment combined if needed with surgical therapy.
