Ethambutol

Ethambutol (EMB) is an important component of multidrug treatment regimens for Mycobacterium avium complex lung disease. Ocular toxicity is the most important potential EMB toxicity, especially in the elderly population with M. avium complex lung disease. Two hundred twenty-nine patients with M. avium complex lung disease, 55% women and 53% with nodular/bronchiectatic disease, received a mean of 16.1 ± 10.8 months of multidrug therapy that included EMB. Fifty patients (22%) were known to have preexisting ocular disease. While on EMB, 97 (42%) patients consulted an opthalmologist and 24 (10%) stopped EMB at least temporarily. Eight of 139 patients (6%) on daily therapy were diagnosed with EMB ocular toxicity, whereas 0 of 90 patients on intermittent therapy had EMB ocular toxicity (p = 0.05). All patients with EMB ocular toxicity developed symptoms between outpatient clinic appointments; none were diagnosed with routine visual acuity and color vision testing. All patients with EMB ocular disease returned to baseline ocular status after discontinuation of EMB. Intermittent EBM administration was associated with less ocular toxicity than daily EMB administration in this patient population.

Keywords: ethambutol; Mycobacterium avium complex

Ethambutol (EMB) is a very important element, second only to macrolides, in current drug regimens for treatment of patients with pulmonary and disseminated Mycobacterium avium complex (MAC) disease (1-6). Patients with disseminated MAC disease, for instance, can achieve 60% microbiologic conversion rates when treated with only a macrolide and EMB (5). EMB is a more critical component of routine therapy for MAC disease than for tuberculosis.

The most serious potential adverse effect of EMB is ocular toxicity manifested by optic or retrobulbar neuritis, which exists in two forms and may affect one or both eyes (7-11). The central fibers of the optic nerve are most commonly affected, causing blurred vision, decreased visual acuity, central scotomas, and often loss of the ability to detect green and sometimes red. The more unusual form of ocular toxicity involves the peripheral fibers of the optic nerve so that visual acuity and color vision may not be affected, but peripheral constriction of the visual fields occurs. Because the neuritis is retrobuibar in both forms, the fundus appears normal on opthalmoscopic examination. In the majority of cases, the visual abnormalities resolve on cessation of EMB. Occasionally, vision continues to deteriorate in the month or months after cessation of EMB and then improves in subsequent months (8, 12). In rare cases, visual symptoms and objective visual abnormalities do not improve (12, 13).

In the treatment of tuberculosis, the reported incidence of retrobulbar neuritis when EMB is taken for more than 2 months is 18% in subjects receiving more than 35 mg/kg/day, 5 to 6% with 25 mg/kg/day, and less than 1% with 15 mg/kg/day (8, 10, 11, 14). In two small series of subjects who received EMB at 50 mg/kg/dose on a twice-weekly basis for 18 months in combination with other agents, none developed visual symptoms (15-16). EMB is cleared by the kidney and the frequency of ocular side effects is increased in patients with decreased renal function (9). However, no study has shown a relationship between serum levels (peak, trough, or area under the curve) and toxicity, although such a relationship is suspected to be present.

Current recommendations for monitoring patients with tuberculosis who receive EMB suggest that these patients should have baseline visual acuity and color discrimination testing and should be questioned regarding visual disturbances at each monthly visit. Monthly visual acuity and color vision discrimination testing is recommended for patients taking EMB doses of greater than 15 to 20 mg/kg, patients receiving the drug for longer than 2 months, and patients with renal insufficiency. Patients should also be instructed to contact the physician with a change in vision (17). However, the efficacy of routine visual acuity and color vision discrimination monitoring for preventing EMB toxicity is not established (17, 18).

Patients with MAC lung disease are generally elderly and at risk for a variety of ocular diseases, and many patients have abnormal baseline visual acuity tests. These patients also usually have different companion drugs with EMB compared with patients with tuberculosis. The risk of EMB toxicity is not well defined for this population, although it may be substantial (19). Some of the results of these studies have been previously reported in the form of an abstract (20).

METHODS

Patients enrolled between 1996 and 2000 in six prospective treatment protocols for MAC lung disease that included EMB were eligible for inclusion in the study. Companion drugs in these protocols included clarithromycin or azithromycin, rifampin or rifabutin, and generally streptomycin in the first few months of therapy. Patients received medication either on a daily or intermittent (Monday-Wednesday-Friday [MWF]) basis. Patients on daily therapy received EMB at 25-mg/kg doses for the first 2 months, then 15 mg/kg for the remainder of therapy. Patients on MWF therapy received 25 mg/kg/dose, although the dosing was not always exact because EMB is available only in 400 and 100 mg formulations. Patients were older than 18 years, and signed, informed consent forms were approved by the Human Subjects Institutional Review Board. All patients met current American Thoracic Society diagnostic criteria for MAC lung disease (21).

Patients completed a symptom checklist, including visual symptoms, at each University of Texas Health Center, Tyler (UTHCT), pulmonary clinic visit. Patients had baseline visual acuity testing in each eye by Snellen chart and color vision testing by Ishihara color plate testing in each eye performed by clinic nursing personnel. Patients with corrective lenses were tested with them in place. Visual acuity and color vision testing was performed by these same methods at follow-up visits at 1- to 3-month intervals while the patients were receiving EMB. Patients were instructed to report any perceived change in color vision discrimination or visual acuity and encouraged to seek opthalmologic evaluation as soon as possible after reporting the development of visual changes. Patients were sometimes instructed to discontinue the EMB pending the ophthalmologic examination. EMB-related ocular toxicity was defined as a change, both subjectively and objectively, in visual acuity and/or color vision discrimination that could not be explained or corrected on another basis and that improved and/or returned to baseline or progressed with discontinuation of EMB. No patient was diagnosed with EMB-related ocular toxicity without the concurrence of an opthalmologist. If an explanation other than EMB toxicity for the patient's visual symptoms was identified by the opthalmologist, then EMB was reintroduced into the patient's treatment regimen.

The patients' chest radiographs and/or chest computed tomography scans were reviewed by the first author.

All patients had measurement of creatinine at baseline, at routine follow-up visits, and at the time of new ocular symptoms. Creatinine clearance was estimated by the following formula: calculated creatine clearance = ([140 - age] × weight in kg)/(72 × serum creatinine) (22).

Nonparametric analysis was used for most comparison statistics: Mann-Whitney two-sample tests were used for between-group comparisons of categoric variables (visual acuity) and continuous variables (age). Wilcoxon paired tests were done to examine changes from baseline to end of study. Fisher's exact test was used for 2 × 2 tables, and χ^sup 2^ tests were used for tables larger than 2 × 2. Miscellaneous analyses included multiple logistic regression for dichotomous outcomes, proportional hazards modeling for time-related events, and analysis of variance for comparison of groups. Two-sided p values were calculated for all tests.

RESULTS

Of 272 total patients eligible for evaluation, 39 (14%) had only one ocular exam at UTHCT, and 4 patients (1%) had no available records. The results of visual acuity and color vision testing were evaluated in the remaining 229 patients (85%). The mean number of vision checks at UTCHT for all 229 patients during the study period was 9.6 ± 5.7 (range, 2-37). Not all patients had monthly ocular toxicity monitoring at UTHCT because of joint follow-up with referring physicians.

The mean age of evaluated patients was 63.8 ± 13.6 years, including 127 (55%) women and 104 (45%) men. Seventy-nine patients (34%) were 70 years or older. As defined by characteristic computed tomography and/or chest radiographic changes, 53% of patients had nodular/bronchiectatic disease and 47% had upper lobe fibrocavitary disease (20). The mean baseline serum creatinine was 0.9 ± 0.7 mg/dl (range, 0.2-11.6 mg/dl; normal range, 0.4-1.1 mg/dl), and the mean calculated creatinine clearance was 84.0 ± 40.2 ml/minute (range, 5.3-185 ml/minute).

At entry into the study, 49 of 229 patients (21%) had known or preexisting ocular disease, including 36 patients (16%) with cataracts, 7 patients (3%) with macular degeneration, and 6 patients (3%) with glaucoma. At entry into the study, the mean visual acuity denominator (20/X) for all study patients, with either eye, was 31.0 ± 30.3 (range, 10-300). Eighty-one of 229 patients (35%) had visual acuity in one or both eyes of 20/30 or worse at baseline. The mean number of color vision plates read correctly, of a possible 14, was 13.7 ± 1.1 (range, 6-14). Thirty patients (13%) missed at least one or more color plates at baseline.

The mean duration of EMB administration for the entire study population was 16.1 ± 10.8 months (range, 1-67 months). One hundred thirty-nine patients received EMB at approximately 15 mg/kg on a daily basis, whereas 90 patients received EMB at 25 mg/kg on an intermittent (MWF) basis. The total weekly dose of EMB was 75 mg/kg on intermittent therapy versus 175 mg/kg for the first 2 months of daily therapy followed by 105 mg/kg for the remainder of daily therapy. There was no significant difference in the duration of EMB administration for patients on daily versus intermittent therapy, although the cumulative dose of EMB was significantly higher for patients receiving daily medication compared with patients who received intermittent medication (p = 0.0001).

Eight of 139 (6%) patients on daily EMB and 0 of 90 (0%) on MWF EMB (p = 0.05) had EMB ocular toxicity confirmed by an opthalmologist. All patients with ocular toxicity were undergoing monthly visual acuity and color vision testing at the time of onset of ocular symptoms, and ocular symptoms began in all eight patients between routine clinic appointments. None of the eight patients was diagnosed with EMB ocular toxicity at a routine appointment. Clinical details about these eight patients are presented in Table 1. One patient was receiving plaquenil; otherwise, no patients were receiving concomitant medications associated with ocular toxicity. Two cases of ocular toxicity occurred in patients in the sixth decade of life, three cases in the seventh, two cases in the eighth, and one case in a patient in the ninth decade of life. Patients with EMB toxicity had a mean daily EMB dose of 17.8 ± 4.2 mg/kg/day (range, 14-24 mg/kg/day; five of eight patients were on 17 mg/kg/day or less) and were on EMB a mean of 6.7 ± 5.8 months (range, 1-16 months) and had ocular complaints a mean of 4.2 ± 3.1 weeks (range, 1-10 weeks) before stopping EMB. Patients frequently developed visual symptoms before a measurable change in visual acuity or color vision. No patient was found to have visual field abnormalities on examination by an opthalmologist. No patient had permanent visual acuity loss, and all patients returned to baseline visual acuity after stopping EMB. The time to improvement in visual acuity and color vision after discontinuation of EMB was 3.7 ± 2.0 months (range, 1-6 months).

No demographic or clinical factors, such as age, sex, race, type of disease (cavitary or nodular/bronchiectatic), or renal function, were predictive of EMB ocular toxicity risk. There was no significant correlation between the EMB-related ocular disease and the use of any of the companion medications.

Ninety-nine of 229 patients (43%) consulted an opthalmologist during therapy and 24 patients (10%) stopped EMB at least temporarily. Ninety-one patients (40%) had ocular symptoms not related to EMB (Table 2). This group of patients almost universally complained of blurred vision. These patients were significantly more likely to be older and female with nodular/ bronchiectatic MAC disease compared with patients with EMB toxicity (Table 2). The variability of visual acuity and color discrimination testing for patients with ocular complaints without EMB ocular toxicity is also shown in Table 2. Patients with ocular symptoms without EMB toxicity had significantly worse baseline visual acuity than patients with EMB toxicity and patients without ocular symptoms and significantly greater worst visual acuity than patients without ocular symptoms (Table 2). Patients with EMB toxicity had significantly greater worst visual acuity and worst color vision discrimination than both comparison groups. Overall, among all patients who did not have EMB-related ocular toxicity (with or without symptoms), the mean variation of visual acuity (worst visual acuity denominator minus best visual acuity denominator, i.e., worst visual acuity 20/30 minus best visual acuity 20/20 equals 10) while receiving EMB was 20/17.8 ± 33.0. The mean variation in color vision testing (most number of color plates correct minus least number of color plates correct, i.e., best 14/14 correct minus worst 10/14 correct equals a difference of 4) was much less, however, at 0.5 ± 1.3.

No patient who continued on EMB after it was determined that ocular symptoms were not caused by EMB toxicity developed progressive visual loss or loss of color vision discrimination compatible with progressive EMB ocular toxicity. Four of eight patients with ocular toxicity while on daily EMB therapy were successfully rechallenged with MWF EMB at 25 mg/kg/dose after return of their vision to baseline. None of these patients developed recurrence of EMB-related toxicity and all remained on EMB for the duration of their therapy.

DISCUSSION

EMB toxicity was more common for patients receiving EMB daily for MAC lung disease compared with patients receiving intermittent (MWF) EMB therapy. No demographic or clinical factors were predictive for, or correlated with, EMB toxicity. Ocular symptoms prompting opthalmology consultations were common in the elderly patient population treated for MAC lung disease. One fortuitous aspect of the high incidence of preexisting ocular abnormalities in this population is that many patients with MAC lung disease had established relationships with opthalmologists.

There are potential limitations of this study in the evaluation of EMB ocular toxicity. First, we did not routinely perform visual field examinations during initial or follow-up visits to our facility. We therefore did not monitor for abnormalities in the peripheral fields of the optic nerves. It is possible that some patients with subtle abnormalities in peripheral vision caused by EMB were missed in our study.

Second, there is usually no single simple diagnostic test that can be performed, even by an opthalmologist, that is confirming or diagnostic for EMB toxicity. For our patients, the diagnosis of EMB-related ocular toxicity was based on several factors, including the new onset of ocular symptoms compatible with EMB-related toxicity (usually both diminished visual acuity and altered color vision perception), the lack of identification of an alternative explanation for the new ocular symptoms after consultation with an opthalmologist, and improvement and ultimately resolution of the ocular abnormalities with discontinuation of EMB and in the absence of other therapeutic interventions.

The basis of EMB-related ocular toxicity is not known (i.e., high peak serum levels, high trough levels, or high mean serum levels), although on a daily administration basis, it appears to be dose-related (8, 10, 11, 14). Data from this study with MWF dosing and from the twice-weekly 50-mg/kg EMB dose study suggest it is not related to peak dose alone, but perhaps a cumulative dose within a given time span (15, 16). The patients in this study on intermittent therapy received a significantly lower cumulative EMB dose compared with patients on daily therapy. We also successfully reintroduced intermittent EMB to patients with a history of EMB ocular toxicity associated with daily EMB administration. The reduction in weekly dosing of the EMB (~30%) was apparently sufficient to prevent recurrence of the ocular toxicity in these patients.

It is unclear why we observed such a high percentage of patients on daily therapy who developed EMB ocular toxicity. In a recent study evaluating serious side effects from first-line antituberculosis drugs, EMB given daily at a comparable mean dose (16.8 mg/kg) was the least toxic of any first-line antituberculosis drug, with only one episode of ocular toxicity out of 329 patients, an incidence of 0.07 events per 100 person-months of treatment (23). In an analysis of 2,184 patients from Great Britain who received EMB at 25 mg/kg/day for 2 months, then 15 mg/kg/day for tuberculosis, ocular toxicity was reported in only 10 patients (

In our patients, routine clinical monitoring of visual acuity and color vision did not detect any patients with asymptomatic EMB ocular toxicity. Visual acuity testing was, however, difficult to interpret for two reasons. First, there was considerable variability in visual acuity test results from visit to visit. This variability was most pronounced in older, female patients with nodular/bronchiectatic MAC disease, the population of patients with MAC dis ease most commonly encountered by clinicians. Compared with visual acuity testing, there was much less variability in color discrimination testing, which appears to be a more specific indicator of EMB ocular toxicity. second, visual symptoms caused by EMB toxicity commonly preceded any measurable decrease in visual acuity or change in color vision discrimination.

In the previously mentioned analysis from Great Britain, 8 (80%) of 10 patients diagnosed with ocular toxicity were detected as a result of routine eye examinations at follow-up appointments and only 2 of these patients were symptomatic (24). In this study, however, no patients were diagnosed by routine ocular exam. This study was conducted by health care workers experienced with EMB therapy, and patients were repeatedly educated about what to watch for and what to do while on EMB. Routine visual acuity and color discrimination monitoring may have contributed to patient awareness and reinforced the need for ongoing vigilance for symptoms of EMB ocular toxicity. The most important element of EMB toxicity monitoring in this study was immediate notification of the investigator by the patient with new ocular symptoms.

Given the advanced age of patients with frequent preexisting ocular abnormalities and the frequency of ocular complaints during MAC lung disease therapy, it still appears appropriate to monitor visual acuity and color discrimination during the course of EMB therapy. Serial visual acuity tests are helpful for establishing a baseline for individual patients. In addition, changes in color vision discrimination appear to be a relatively specific indicator of EMB ocular toxicity. Perhaps more importantly, the testing serves as a tangible reminder to the patient and provider about the risks of EMB ocular toxicity. Last, maintaining EMB in the treatment regimen for MAC is a high priority, compared with tuberculosis, because there are few other effective alternative drugs. Aggressive monitoring and assessment of visual complaints in the MAC lung disease population may have resulted in the continuation of EMB in the treatment regimen after other causes for the ocular complaints were identified. Although intermittent EMB appears to be associated with less ocular toxicity than daily EMB, pending further studies, the most recent American Thoracic Society recommendations for routine visual testing for patients with tuberculosis receiving EMB seem reasonable in the MAC lung disease population as well (17). Intermittent (MWF) EMB therapy may be a treatment option in patients who develop EMB toxicity on daily therapy.

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

1. Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT. Clarithromycin regimens for pulmonary Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med 1996;153(6):1766-1772.

2. Griffith DE, Brown BA, Girard WM, Griffith BE, Couch LA, Wallace RJ Jr. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 2001;32(11):1547-1553.

3. Tanaka E, Kimoto T, Tsuyuguchi K, Watanabe I, Matsumoto H, Niimi A, Suzuki K, Murayama T, Amitani R, Kuze F. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 1999;160(3):866-872.

4. Shafran SD, Singer J, Zarowny DP, Phillips P, Salit I, Walmsley SL, Fong IW, Gill MJ, Rachlis AR, Lalonde RG, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group. N Engl J Med 1996;335:377-383.

5. Gordin FM, Sullam PM, Shafran SD, Cohn DL, Wynne B, Paxton L, Perry K, Horsburgh CR Jr. A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis 1999;28(5):1080-1085.

6. Benson CA, Williams PL, Currier JS, Holland F, Mahon LF, MacGregor RR. Inderlied CB, Flexner C, Neidig J, Chaisson R, et al., for the AIDS Clinical Trials Group 223 Protocol Team. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis 2003;37:1234-1243.

7. Schild HS, Fox BC. Rapid-onset reversible ocular toxicity from ethambutol therapy. Am J Med 1991;90(3):404-406.

8. Kahana LM. Toxic ocular effects of ethambutol. Can Med Assoc J 1987;137:213-216.

9. Alvarez KL, Krop LC. Ethambutol-induced ocular toxicity revisited. Ann Pharmacother 1993;27(1):102-103.

10. Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann NY Acad Sci 1966;135:904-909.

11. Russo PA, Chaglasian MA. Toxic neuropathy associated with ethambtuol: implications for current therapy. J Am Optom Assoc 1994;65:332-338.

12. Kumar A, Sandramouli S, Verma L, Tewari HK, Khosla PK. Ocular ethambutol toxicity: is it reversible? J Clin Neuroopthalmol 1993;13:15-17.

13. Chatterjee VK, Buchanan DR, Friedmann AI, Green M. Ocular toxicity following ethambutol in standard dosage. Br J Dis Chest 1986;80(3):288-291.

14. Addington WW. The side effects and interactions of antituberculosis drugs. Chest 1979;76(Suppl):782-784.

15. Sbarbaro JA, Hudson LD. High dose ethambutol: an oral alternate for intermittent chemotherapy. Am Rev Respir Dis 1974;110(1):91-94.

16. Albert RK, Sbarbaro JA, Hudson LD, Iseman M. High-dose ethambutol: its role in intermittent chemotherapy: a six-year study. Am Rev Respir Dis 1976;114(4):699-704.

17. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-662.

18. Bass JB Jr, Farer LS, Hopewell PC, O'Brien R, Jacobs RF, Ruben F, Snider DE Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children: American Thoracic Society and the Centers for Disease Control and Prevention. Am J Respir Crit Care Med 1994;149(5):1359-1374.

19. Pierce JR, Denison AV. Letter to the editor. JAMA 1994;271:104-105.

20. Griffith DE, Elliott-Brown B, Shephard S, McLarty J, Griffith L, Wallace RJ Jr. Ethambutol ocular toxicity in multidrug treatment regimens for Mycobacterium avium complex lung disease [abstract]. Am J Respir Crit Care Med 2001;163:A763.

21. Wallace RJ Jr, Glassroth J, Griffith DE, Olivier KN, Cook JL, Gordin F. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156(2):S1-S25.

22. Humes HD, editor. Kelley's textbook of internal medicine. 4th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

23. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167:1472-1477.

24. Citron KM, Thomas GO. Ocular toxicity from ethambutol. Thorax 1986;41(10):737-739.

David E. Griffith, Barbara A. Brown-Elliott, Sara Shepherd, Jerry McLarty, Lee Griffith, and Richard J. Wallace, Jr.

Departments of Medicine and Microbiology, University of Texas Health Center, Tyler, Texas; and Louisiana State University Health Science Center, Shreveport, Louisiana

(Received in original from July 5, 2004; accepted in final form April 25, 2005)

Correspondence and requests for reprints should be addressed to David E. Griffith, M.D., Professor of Medicine, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708. E-mail: david.griffith@uthct.edu

Am J Respir Crit Care Med Vol 172. pp 250-253, 2005

Originally Published in Press as DOI: 10.1164/rccm.200407-863OC on April 28, 2005

Internet address: www.atsjournals.org

Copyright American Thoracic Society Jul 15, 2005
Provided by ProQuest Information and Learning Company. All rights Reserved