1107
regional nodes and concentration in mucosal mast cells. Eur J Immunol 1976; 6: 537-45. 16. Gustowska L, Ruitenberg EJ, Elgersma A, Kociecka W. Increase in mucosal mast cells in the jejunum of patients infected with Trichinella spiralis. Int Arch Allergy Appl Immunol 1983; 71: 304-08. 17. Crow J, Howe S. Mast cell numbers in appendices with threadworm infestation. J Pathol 1988; 154: 347-51. 18. Jenkins HR, Pincott JR, Soothill JF, Milla PJ, Harries JT. Food allergy: the major cause of infantile colitis. Arch Dis Child 1984; 59: 326-29. 19. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol 1986; 10: 75-86. 20. Gray I, Harten M, Walzer M. Studies in mucous membrane hypersensitivities. IV. The allergy reactions in the passively sensitized mucous membranes of the ileum and colon in humans. Ann Intern Med 1940; 13: 2050-56.
21. Reinmann
H-J, Ring J, Ultsch B, et al. Release of gastric histamine in patients with urticaria and food allergy. Agents Actions 1982; 12:
111-13. 22. Moneret-Vautrin DA, De Korwin JD, Tisserant J, Grignon M, Claudot N. Ultrastructural study of the mast cells of the human duodenal mucosa. Clin Allergy 1984; 14: 471-81. 23. Lake AM, Bloch KJ, Sinclair KJ, Walker WA. Anaphylactic release of intestinal goblet cell mucus. Immunology 1980; 39: 173-78. 24. Perdue MH, Forstner JF, Roomi NW, Gall DG. Epithelial response to intestinal anaphylaxis in rats; goblet cell secretion and enterocyte damage. Am J Physiol 1984; 247: G632-37. 25. Forbes D, Patrick M, Perdue M, Buret A, Gall AG. Intestinal anaphylaxis: in vivo and in vitro studies on the rat proximal colon. Am J Physiol 1988; 255: G201-05. 26. Ogilvie BM, Love RJ. Co-operation between antibodies and cells in immunity to a nematode parasite. Transplant Rev 1974; 19: 147-68.
SHORT REPORTS
Azithromycin for treatment of Mycobacterium aviumintracellulare complex infection in patients with AIDS
Mycobacterium avium complex infection is common in patients with AIDS. Experimentally infected mice have been treated successfully with azithromycin, a macrolide antibiotic. We report an uncontrolled phase I study in which male homosexuals with AIDS and M avium complex disease were given 500 mg azithromycin per day orally for 10, 20, or 30 days. Quantitative blood cultures
a mean in showed reduction mycobacteraemia from 118 colony forming units (cfu)/ml to 43 cfu/ml in 3 patients treated for 10 days, and from 2028 cfu/ml to 136 cfu/ml in 21 patients treated for 20 or 30 days. Of the patients treated for 20 or 30 days, 15 of 21 with fever pretreatment and 12 of 18 with night sweats pretreatment reported resolution of these symptoms. The principal side-effects were loose stools or diarrhoea, but these did not result in cessation of therapy. Azithromycin, as a single oral agent, safely reduced M avium complex bacteraemia and associated symptoms in almost 75% of patients treated for at least 20 days. Further studies are needed to assess emergence of resistance.
Mycobacterium avium-Mycobacterium intracellulare complex (M avium complex) bacteria are the most common cause of disseminated bacterial infection in patients with the late stages of the acquired immunodeficiency syndrome (AIDS).1 It is unclear whether or not this opportunistic infection can or should be treated. Multiple-drug regimens reduce M avium complex bacteraemia, and significant reductions in bacteraemia parallel clinical improvement in a small number of AIDS patientsAggressive therapeutic regimens are, however, not practical for long-term use and
expensive. Thus, compounds have been sought that might be therapeutically active against the M avium complex. Azithromycin is a semi-synthetic macrolide (azalide) antibiotic. Azithromycin has a prolonged polyphasic halflife and an initial distribution-phase half-life of about 20 h.4 As a consequence, azithromycin accumulates at high concentrations in phagocytes and tissue.Encouraged by the results of an animal study, we initiated a trial of the safety and efficacy of azithromycin monotherapy for the treatment of M avium complex bacteraemia in patients with AIDS. are
All patients had blood-culture-proven M avium complex bacteraemia or had symptoms of disseminated M avium complex infection that could not be attributed to any other opportunistic infection. Antimicrobial therapy that included any agent that was potentially active against the M avium complex was stopped at least 72 h before treatment with azithromycin. Patients who had received such agents were evaluable for assessment of efficacy only if they had a blood culture positive for M avium complex at the time of entry into the trial. Pretreatment investigations included measurement of vital signs, weight, standard haematologic parameters, erythrocyte sedimentation rate, liver function, serum electrolytes, CD4 lymphocytes, serum p24 HIV-1 antigen, and urinalysis. Entry criteria required that serum chemistry test results and liver function test results were within a factor of three or less of accepted normal ranges. Blood was taken for quantitative culture before azithromycin was given, then once each week for 4 weeks, and again 6 weeks after the start of therapy. Blood specimens were serially diluted in Middlebrook 7H9 broth before quantitative culture on 7H11 agar. Cultures were examined weekly for up to 6 weeks for colony forming units (cfu). In vitro susceptibility of mycobacterial isolates to azithromycin was tested by the T100 method.’ Initially, 5 patients were treated for 10 days (group I) with a single daily dose of 500 mg azithromycin and monitored for untoward effects. After the initial evaluation, therapeutic trials of 20 days (group II) and 30 days (group III) of 500 mg per day azithromycin were begun. Results of the safety and tolerance trial (group I) were available and evaluated before patients in group II began their 20 days of treatment. Similarly, patients in group III began treatment only after establishing there were no untoward effects in groups I and II. At the completion of treatment patients were followed weekly and then monthly for evidence of rebound mycobacteraemia and return of symptoms.
All patients were homosexual males with AIDS (median age 35 years). 2 patients in group I were not evaluable: M avium bacteraemia was not confirmed by blood culture in 1 patient, and a second patient had an acute anxiety reaction after administration of the first dose of drug and withdrew. The mean (SE) concentration of mycobacteria in blood decreased from 118 (93) cfu/ml to 43 (36) cfu/ml in the
1108
remaining 3 patients in group I over 10 days of treatment. The 5 evaluable patients in group II had a mean (SE) reduction in mycobacteraemia from 3580 (3021) cfu/ml to 243 (154) cfu/ml over 20 days of treatment. Mean (SE)
colony counts in the 16 patients in group IIIdeclined from 1546 (960) cfu/ml to 101 (61) cfu/ml over 30 days of treatment (figure). 10 patients in group III continued suppressive treatment after day 30 with 250 mg per day azithromycin (figure), and only 1 patient has had rebound bacteraemia of greater than 30% of the initial colony count. Median follow-up in this group is now 140 days and 7 patients remain on azithromycin. M avium complex bacteria isolated from the blood of 8 patients before and after treatment tested for in-vitro sensitivity to were azithromycin; minimum inhibitory concentrations were not significantly changed by treatment. All patients had CD4 lymphocyte counts of less than 50 cells/ul before treatment, and only 1 patient showed an increase to above 50 cells/ul by the end of treatment. The clinical features of 19 patients in groups IIand IIIare shown in the table. Some patients showed clinical improvement after only 4 days of treatment, whereas others improved after 10 to 20 days of treatment. Most patients had resolution of fever and night sweats and there was an modest overall improvement in patients’ performance status (Karnofsky scale), but fatigue, weight loss, and appetite were largely unchanged. 1 patient had mild abdominal pain before treatment and 4 reported this symptom after treatment. 4 patients had loose stools and 3 had diarrhoea associated with treatment; however, it was not necessary to discontinue treatment because of these symptoms. Some patients reported mild abdominal discomfort after taking two 250 mg azithromycin tablets, but these symptoms were ameliorated by an interval of 1 h between tablets. All patients were initially mildly anaemic and most had abnormal baseline alkaline phosphatase and aspartate aminotransferase levels. 1 patient was withdrawn from suppressive treatment at day 56 because of adverse changes in liver function. Serial liver-function
tests
revealed 2
patients with a twofold increase in aminotransferase. No other significant changes were noted in the liver function of patients treated for 20 or 30 days.
DAYS in the concentration of M avium complex bacteria in the blood of 16 patients during and after 30 days of treatment with azithromycin.
Change
Points represent mean and SE concentration of mycobactena in blood. At the conclusion of treatment, 10 patients elected to receive a suppressive dose of 250 mg per day oral azithromycin (dotted line)
NUMBER OF PATIENTS WITH VARIOUS SIGNS AND SYMPTOMS BEFORE AND AFTER TREATMENT WITH AZITHROMYCIN FOR 20 OR 30 DAYS
Based
in-vitro activity, macrolides such as azithromycin appear to be inappropriate agents for treatment of M avium complex disease, because minimum inhibitory concentrations against the M avium complex are in excess of achievable serum concentrations. However, macrolides concentrate in tissues, particularly phagocytic cells, at concentrations up to two-hundred-fold higher than serum concentrations.s Thus, azithromycin accumulates within the cells where mycobacteria persist and multiply. There is good evidence that, like M tuberculosis, M avium complex bacteria block phagolysosome fusion, which contributes to their ability to survive within macrophages.8,9 Inhibition of phagolysosome fusion prevents acidification of the phagosome and this may enhance macrolide activity, which is higher at a more alkaline pH. We have shown that a single dose of 500 mg azithromycin per day for 10 to 30 days gives consistent reduction of mycobacteraemia and clinical improvement in threequarters of patients. The magnitude of the reduction in mycobacteraemia appears to be related to the duration of therapy and the level of the starting bacteraemia. We were cautious about extending treatment because animal studies have shown that azithromycin can complex with phospholipids especially in the liver (C. L. Holmes, personal communication); however, we observed no significant evidence of hepatic toxicity when treatment was extended to 30 days. The major side-effects were diarrhoea or loose stools, but in no instance did this result in the discontinuation of treatment. We recognise that this was an uncontrolled study. However, patients in group III showed a direct relation between duration of treatment with azithromycin and reduction in numbers of M avium in blood. The overall improvement of symptoms in patients treated for 20 days or more strongly suggests an attributable clinical response. Comparative trials with other regimens are clearly desirable, as are studies that will identify the optimal therapeutic dose. It is of concern that use of a single agent may result in emergence of a resistant subpopulation of mycobacteria. Long periods of therapy are necessary to successfully treat mycobacterial diseases; thus, we expect that as the length of azithromycin treatment is extended beyond 30 days, drug resistance will become a problem. We are therefore actively investigating drug combinations that will have enhanced antimicrobial effect and will prevent the emergence of resistance. on
This study was supported by contract AI-72637 from the National Institute of Allergy and Infectious Diseases and a grant from Pfizer Inc. We gratefully acknowledge Dr Lawrence Boly, Dr Michael Bunim, Dr James Campbell, Dr James Clever, Dr Jeffrey Fessel, Dr Charles Gherman, Dr Michaela Glenn, Dr Debbie Gold, Dr Joel Klompus, Dr Jay Lalezari, Dr
1109
William Lang, Dr Alison LaVoy, Dr Brian Lewis, Dr Elliot Liff, Dr Martin Mass, Dr Charles McDonald, Dr Robert Mithun, Dr Michael Pawlik, Dr Lester Solomon, and Dr Frederick Whinery who referred patients to the
study. REFERENCES
1. Horsburgh CR Jr. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 1332-38. et al. Quadruple-drug therapy for Mycobacterium avium-intracellulare bacteremia in AIDS patients. J Infect Dis 1990; 161: 801-05. 3. Benson CS, Kessler HA, Pottage JC Jr, et al. Successful treatment of acquired immunodeficiency syndrome-related Mycobacterium avium complex disease with a multiple drug regimen including amikacin.
2. Hoy J, Mijch A, Sandland M,
Arch Intern Med 1991; 151: 582-85. AE, Girard D, English AR, et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 5. Gladue RP, Snider ME. Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother 1990; 34: 1056-60. 6. Inderlied CB, Kolonoski P, Wu M, et al. In vitro and in vivo activity of azithromycin (CP 62,993) against the Mycobacterium avium complex. J Infect Dis 1989; 159: 994-97. 7. Inderlied CB, Young LS, Yamada J. Determination of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob Agents Chemother 1987; 31: 1697-702. 8. Crowle AJ, Dahl R, Ross E, et al. Evidence that vesicles containing living, virulent Mycobacterium tuberculosis or Mycobacterium avium in cultured human macrophages are not acidic. Infect Immun 1991; 59: 1823-31. 9. Black CM, Bermudez LEM, Young LS, et al. Co-infection of macrophages modulates interferon gamma and tumor necrosis factorinduced activation against intracellular pathogens. J Exp Med 1990; 172: 977-80. 4. Girard
ADDRESSES: Kuzell Institute for Arthritis and Infectious Diseases, Medical Research Institute of San Francisco, San Francisco, California, USA (Prof L. S Young, MD, M. Wu, BA, P. Kolonoski, BA, R Bolan, MD, C. B. Inderlied, PhD); Pacific Presbyterian Medical Center, San Francisco (L. S. Young, L. Wiviott, MD, M Wu, R Bolan); and Department of Pathology and Laboratory Medicine, Children’s Hospital, University of Southern California, Los Angeles, California (C. B. Inderlied). Correspondence to Prof Lowell S. Young, Kuzell Institute, 2200 Webster Street, Suite 305, San Francisco, California 94115, USA
Yellow spectacles to improve vision in children with binocular
amblyopia
Yellow spectacles were given to 20 children who had binocular amblyopia. Immediately, their vision improved. Furthermore, in the younger children, after they had worn the yellow lenses for up to nine months, this improvement persisted even when they were not wearing the spectacles. Yellow filters may help these children with binocular amblyopia because they remove the blue fringes that are due to chromatic aberration of the eye.
Binocular amblyopia is said
suppression, amblyopia,
to be rare. Cortical which is the usual cause of monocular is unlikely if both eyes are equally
disadvantaged. At the orthoptic department, Royal Berkshire Hospital, we see about 600 new children aged between 6 and 14 years each year; 400 are referred for learning difficulties and 200 for squints, blurred vision, and other visual disorders. In view of the rarity of binocular amblyopia, we were surprised to find that we were seeing about 1 child every two months (ie, 1 % of these referrals) with reduced vision in both eyes without a clear cause. There have been claims that tinted lenses alleviate a wide range of visual disorders. Yellow filters cut out the short (ultraviolet and blue) wavelengths which not only are potentially damaging but also cause the blurring effects of chromatic aberration. The wearing of yellow filters improves several aspects of vision, including the contrast sensitivity in normal individuals, especially at lower spatial frequencies,2,3 and the apparent brightness of large targets under daylight conditions.4 Furthermore, Kinney et al5 showed that the response to the appearance of a black and white striped grating stimulus was faster when subjects were wearing yellow filters. We therefore decided to investigate whether coloured filters, especially yellow, might benefit children with binocular amblyopia. 20 children (9 boys, 11 girls) with binocular amblyopia were referred from 1988 to 1990. Full medical and ophthalmological histories were taken, with special attention to possible psychological influences. Each child was refracted by an ophthalmologist, with cycloplegics if necessary. Fundi were also carefully inspected; no abnormalities were seen. In 3 children flash electroretinograms were recorded, these were also normal. A full orthoptic examination consisted of: (1) monocular and binocular visual acuities (Snellen chart with and without pinholes); (2) binocular function (cover test); (3) monocular and binocular accommodation and near-point for convergence ("RAF rule"), and
convergence eye movements (infrared eye movement recorder); (4)
depth perception (Randot test); (5) contrast sensitivity function (Vistech chart and, in 3 children, a ’Joyce’ screen [p4 phosphor] by which contrast sensitivities were measured through neutral density, yellow and blue filters, which were carefully matched to transmit the same amount of light); (6) colour vision (Ishihara plates [all children], ‘Farnsworth-Munsell 100 Hue Colour Vision Test’ [10], Rayleigh colour matching [7]). Various methods were used to exclude the possibility that symptoms were psychosomatic. For example, the children were asked to look through a magnifying lens, which was then cancelled out with one of opposite power. In no instance did a child’s vision improve. Each child was then asked to attempt to read normal print through four coloured overlays presented in a random order: yellow (Wratten filter 4), green (Wratten filter 58), red (Wratten filter 25), and blue (Wratten filter 47). A neutral density filter which cut out 50% of the light at all wavelengths was also presented. The children were asked which condition they found clearest. The mean visual acuity for our group was 6/10-5 (range 6/5-6/18). 6/6 is ’normal’, but 6/4 is common for children of this age. 4 children had acuities as low as 6/18. Pinholes did
improve acuity. In 17 children acuity was reduced equally in both eyes; in the other 3 the difference between the eyes was only one line. Although all children had reduced acuity, no child had a refractive error greater than ± 0-5 dioptres. All the children had normal binocular single vision (bifoveal fixation, no squint, and normal fusion), not
normal binocular function, and normal binocular control. The accommodation of all the children was reduced. With N5 or N8 sized print, depending on acuity, the near-point for clear vision averaged 17-8 cm (range 8-28; normal 6) on the RAF rule. In the Randot test, 7 children could not even detect the largest disparity used (400 arc") and the other showed reduced responses (mean 171", range 40-400;
regional nodes and concentration in mucosal mast cells. Eur J Immunol 1976; 6: 537-45. 16. Gustowska L, Ruitenberg EJ, Elgersma A, Kociecka W. Increase in mucosal mast cells in the jejunum of patients infected with Trichinella spiralis. Int Arch Allergy Appl Immunol 1983; 71: 304-08. 17. Crow J, Howe S. Mast cell numbers in appendices with threadworm infestation. J Pathol 1988; 154: 347-51. 18. Jenkins HR, Pincott JR, Soothill JF, Milla PJ, Harries JT. Food allergy: the major cause of infantile colitis. Arch Dis Child 1984; 59: 326-29. 19. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol 1986; 10: 75-86. 20. Gray I, Harten M, Walzer M. Studies in mucous membrane hypersensitivities. IV. The allergy reactions in the passively sensitized mucous membranes of the ileum and colon in humans. Ann Intern Med 1940; 13: 2050-56.
21. Reinmann
H-J, Ring J, Ultsch B, et al. Release of gastric histamine in patients with urticaria and food allergy. Agents Actions 1982; 12:
111-13. 22. Moneret-Vautrin DA, De Korwin JD, Tisserant J, Grignon M, Claudot N. Ultrastructural study of the mast cells of the human duodenal mucosa. Clin Allergy 1984; 14: 471-81. 23. Lake AM, Bloch KJ, Sinclair KJ, Walker WA. Anaphylactic release of intestinal goblet cell mucus. Immunology 1980; 39: 173-78. 24. Perdue MH, Forstner JF, Roomi NW, Gall DG. Epithelial response to intestinal anaphylaxis in rats; goblet cell secretion and enterocyte damage. Am J Physiol 1984; 247: G632-37. 25. Forbes D, Patrick M, Perdue M, Buret A, Gall AG. Intestinal anaphylaxis: in vivo and in vitro studies on the rat proximal colon. Am J Physiol 1988; 255: G201-05. 26. Ogilvie BM, Love RJ. Co-operation between antibodies and cells in immunity to a nematode parasite. Transplant Rev 1974; 19: 147-68.
SHORT REPORTS
Azithromycin for treatment of Mycobacterium aviumintracellulare complex infection in patients with AIDS
Mycobacterium avium complex infection is common in patients with AIDS. Experimentally infected mice have been treated successfully with azithromycin, a macrolide antibiotic. We report an uncontrolled phase I study in which male homosexuals with AIDS and M avium complex disease were given 500 mg azithromycin per day orally for 10, 20, or 30 days. Quantitative blood cultures
a mean in showed reduction mycobacteraemia from 118 colony forming units (cfu)/ml to 43 cfu/ml in 3 patients treated for 10 days, and from 2028 cfu/ml to 136 cfu/ml in 21 patients treated for 20 or 30 days. Of the patients treated for 20 or 30 days, 15 of 21 with fever pretreatment and 12 of 18 with night sweats pretreatment reported resolution of these symptoms. The principal side-effects were loose stools or diarrhoea, but these did not result in cessation of therapy. Azithromycin, as a single oral agent, safely reduced M avium complex bacteraemia and associated symptoms in almost 75% of patients treated for at least 20 days. Further studies are needed to assess emergence of resistance.
Mycobacterium avium-Mycobacterium intracellulare complex (M avium complex) bacteria are the most common cause of disseminated bacterial infection in patients with the late stages of the acquired immunodeficiency syndrome (AIDS).1 It is unclear whether or not this opportunistic infection can or should be treated. Multiple-drug regimens reduce M avium complex bacteraemia, and significant reductions in bacteraemia parallel clinical improvement in a small number of AIDS patientsAggressive therapeutic regimens are, however, not practical for long-term use and
expensive. Thus, compounds have been sought that might be therapeutically active against the M avium complex. Azithromycin is a semi-synthetic macrolide (azalide) antibiotic. Azithromycin has a prolonged polyphasic halflife and an initial distribution-phase half-life of about 20 h.4 As a consequence, azithromycin accumulates at high concentrations in phagocytes and tissue.Encouraged by the results of an animal study, we initiated a trial of the safety and efficacy of azithromycin monotherapy for the treatment of M avium complex bacteraemia in patients with AIDS. are
All patients had blood-culture-proven M avium complex bacteraemia or had symptoms of disseminated M avium complex infection that could not be attributed to any other opportunistic infection. Antimicrobial therapy that included any agent that was potentially active against the M avium complex was stopped at least 72 h before treatment with azithromycin. Patients who had received such agents were evaluable for assessment of efficacy only if they had a blood culture positive for M avium complex at the time of entry into the trial. Pretreatment investigations included measurement of vital signs, weight, standard haematologic parameters, erythrocyte sedimentation rate, liver function, serum electrolytes, CD4 lymphocytes, serum p24 HIV-1 antigen, and urinalysis. Entry criteria required that serum chemistry test results and liver function test results were within a factor of three or less of accepted normal ranges. Blood was taken for quantitative culture before azithromycin was given, then once each week for 4 weeks, and again 6 weeks after the start of therapy. Blood specimens were serially diluted in Middlebrook 7H9 broth before quantitative culture on 7H11 agar. Cultures were examined weekly for up to 6 weeks for colony forming units (cfu). In vitro susceptibility of mycobacterial isolates to azithromycin was tested by the T100 method.’ Initially, 5 patients were treated for 10 days (group I) with a single daily dose of 500 mg azithromycin and monitored for untoward effects. After the initial evaluation, therapeutic trials of 20 days (group II) and 30 days (group III) of 500 mg per day azithromycin were begun. Results of the safety and tolerance trial (group I) were available and evaluated before patients in group II began their 20 days of treatment. Similarly, patients in group III began treatment only after establishing there were no untoward effects in groups I and II. At the completion of treatment patients were followed weekly and then monthly for evidence of rebound mycobacteraemia and return of symptoms.
All patients were homosexual males with AIDS (median age 35 years). 2 patients in group I were not evaluable: M avium bacteraemia was not confirmed by blood culture in 1 patient, and a second patient had an acute anxiety reaction after administration of the first dose of drug and withdrew. The mean (SE) concentration of mycobacteria in blood decreased from 118 (93) cfu/ml to 43 (36) cfu/ml in the
1108
remaining 3 patients in group I over 10 days of treatment. The 5 evaluable patients in group II had a mean (SE) reduction in mycobacteraemia from 3580 (3021) cfu/ml to 243 (154) cfu/ml over 20 days of treatment. Mean (SE)
colony counts in the 16 patients in group IIIdeclined from 1546 (960) cfu/ml to 101 (61) cfu/ml over 30 days of treatment (figure). 10 patients in group III continued suppressive treatment after day 30 with 250 mg per day azithromycin (figure), and only 1 patient has had rebound bacteraemia of greater than 30% of the initial colony count. Median follow-up in this group is now 140 days and 7 patients remain on azithromycin. M avium complex bacteria isolated from the blood of 8 patients before and after treatment tested for in-vitro sensitivity to were azithromycin; minimum inhibitory concentrations were not significantly changed by treatment. All patients had CD4 lymphocyte counts of less than 50 cells/ul before treatment, and only 1 patient showed an increase to above 50 cells/ul by the end of treatment. The clinical features of 19 patients in groups IIand IIIare shown in the table. Some patients showed clinical improvement after only 4 days of treatment, whereas others improved after 10 to 20 days of treatment. Most patients had resolution of fever and night sweats and there was an modest overall improvement in patients’ performance status (Karnofsky scale), but fatigue, weight loss, and appetite were largely unchanged. 1 patient had mild abdominal pain before treatment and 4 reported this symptom after treatment. 4 patients had loose stools and 3 had diarrhoea associated with treatment; however, it was not necessary to discontinue treatment because of these symptoms. Some patients reported mild abdominal discomfort after taking two 250 mg azithromycin tablets, but these symptoms were ameliorated by an interval of 1 h between tablets. All patients were initially mildly anaemic and most had abnormal baseline alkaline phosphatase and aspartate aminotransferase levels. 1 patient was withdrawn from suppressive treatment at day 56 because of adverse changes in liver function. Serial liver-function
tests
revealed 2
patients with a twofold increase in aminotransferase. No other significant changes were noted in the liver function of patients treated for 20 or 30 days.
DAYS in the concentration of M avium complex bacteria in the blood of 16 patients during and after 30 days of treatment with azithromycin.
Change
Points represent mean and SE concentration of mycobactena in blood. At the conclusion of treatment, 10 patients elected to receive a suppressive dose of 250 mg per day oral azithromycin (dotted line)
NUMBER OF PATIENTS WITH VARIOUS SIGNS AND SYMPTOMS BEFORE AND AFTER TREATMENT WITH AZITHROMYCIN FOR 20 OR 30 DAYS
Based
in-vitro activity, macrolides such as azithromycin appear to be inappropriate agents for treatment of M avium complex disease, because minimum inhibitory concentrations against the M avium complex are in excess of achievable serum concentrations. However, macrolides concentrate in tissues, particularly phagocytic cells, at concentrations up to two-hundred-fold higher than serum concentrations.s Thus, azithromycin accumulates within the cells where mycobacteria persist and multiply. There is good evidence that, like M tuberculosis, M avium complex bacteria block phagolysosome fusion, which contributes to their ability to survive within macrophages.8,9 Inhibition of phagolysosome fusion prevents acidification of the phagosome and this may enhance macrolide activity, which is higher at a more alkaline pH. We have shown that a single dose of 500 mg azithromycin per day for 10 to 30 days gives consistent reduction of mycobacteraemia and clinical improvement in threequarters of patients. The magnitude of the reduction in mycobacteraemia appears to be related to the duration of therapy and the level of the starting bacteraemia. We were cautious about extending treatment because animal studies have shown that azithromycin can complex with phospholipids especially in the liver (C. L. Holmes, personal communication); however, we observed no significant evidence of hepatic toxicity when treatment was extended to 30 days. The major side-effects were diarrhoea or loose stools, but in no instance did this result in the discontinuation of treatment. We recognise that this was an uncontrolled study. However, patients in group III showed a direct relation between duration of treatment with azithromycin and reduction in numbers of M avium in blood. The overall improvement of symptoms in patients treated for 20 days or more strongly suggests an attributable clinical response. Comparative trials with other regimens are clearly desirable, as are studies that will identify the optimal therapeutic dose. It is of concern that use of a single agent may result in emergence of a resistant subpopulation of mycobacteria. Long periods of therapy are necessary to successfully treat mycobacterial diseases; thus, we expect that as the length of azithromycin treatment is extended beyond 30 days, drug resistance will become a problem. We are therefore actively investigating drug combinations that will have enhanced antimicrobial effect and will prevent the emergence of resistance. on
This study was supported by contract AI-72637 from the National Institute of Allergy and Infectious Diseases and a grant from Pfizer Inc. We gratefully acknowledge Dr Lawrence Boly, Dr Michael Bunim, Dr James Campbell, Dr James Clever, Dr Jeffrey Fessel, Dr Charles Gherman, Dr Michaela Glenn, Dr Debbie Gold, Dr Joel Klompus, Dr Jay Lalezari, Dr
1109
William Lang, Dr Alison LaVoy, Dr Brian Lewis, Dr Elliot Liff, Dr Martin Mass, Dr Charles McDonald, Dr Robert Mithun, Dr Michael Pawlik, Dr Lester Solomon, and Dr Frederick Whinery who referred patients to the
study. REFERENCES
1. Horsburgh CR Jr. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 1332-38. et al. Quadruple-drug therapy for Mycobacterium avium-intracellulare bacteremia in AIDS patients. J Infect Dis 1990; 161: 801-05. 3. Benson CS, Kessler HA, Pottage JC Jr, et al. Successful treatment of acquired immunodeficiency syndrome-related Mycobacterium avium complex disease with a multiple drug regimen including amikacin.
2. Hoy J, Mijch A, Sandland M,
Arch Intern Med 1991; 151: 582-85. AE, Girard D, English AR, et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 5. Gladue RP, Snider ME. Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother 1990; 34: 1056-60. 6. Inderlied CB, Kolonoski P, Wu M, et al. In vitro and in vivo activity of azithromycin (CP 62,993) against the Mycobacterium avium complex. J Infect Dis 1989; 159: 994-97. 7. Inderlied CB, Young LS, Yamada J. Determination of in vitro susceptibility of Mycobacterium avium complex isolates to antimycobacterial agents by various methods. Antimicrob Agents Chemother 1987; 31: 1697-702. 8. Crowle AJ, Dahl R, Ross E, et al. Evidence that vesicles containing living, virulent Mycobacterium tuberculosis or Mycobacterium avium in cultured human macrophages are not acidic. Infect Immun 1991; 59: 1823-31. 9. Black CM, Bermudez LEM, Young LS, et al. Co-infection of macrophages modulates interferon gamma and tumor necrosis factorinduced activation against intracellular pathogens. J Exp Med 1990; 172: 977-80. 4. Girard
ADDRESSES: Kuzell Institute for Arthritis and Infectious Diseases, Medical Research Institute of San Francisco, San Francisco, California, USA (Prof L. S Young, MD, M. Wu, BA, P. Kolonoski, BA, R Bolan, MD, C. B. Inderlied, PhD); Pacific Presbyterian Medical Center, San Francisco (L. S. Young, L. Wiviott, MD, M Wu, R Bolan); and Department of Pathology and Laboratory Medicine, Children’s Hospital, University of Southern California, Los Angeles, California (C. B. Inderlied). Correspondence to Prof Lowell S. Young, Kuzell Institute, 2200 Webster Street, Suite 305, San Francisco, California 94115, USA
Yellow spectacles to improve vision in children with binocular
amblyopia
Yellow spectacles were given to 20 children who had binocular amblyopia. Immediately, their vision improved. Furthermore, in the younger children, after they had worn the yellow lenses for up to nine months, this improvement persisted even when they were not wearing the spectacles. Yellow filters may help these children with binocular amblyopia because they remove the blue fringes that are due to chromatic aberration of the eye.
Binocular amblyopia is said
suppression, amblyopia,
to be rare. Cortical which is the usual cause of monocular is unlikely if both eyes are equally
disadvantaged. At the orthoptic department, Royal Berkshire Hospital, we see about 600 new children aged between 6 and 14 years each year; 400 are referred for learning difficulties and 200 for squints, blurred vision, and other visual disorders. In view of the rarity of binocular amblyopia, we were surprised to find that we were seeing about 1 child every two months (ie, 1 % of these referrals) with reduced vision in both eyes without a clear cause. There have been claims that tinted lenses alleviate a wide range of visual disorders. Yellow filters cut out the short (ultraviolet and blue) wavelengths which not only are potentially damaging but also cause the blurring effects of chromatic aberration. The wearing of yellow filters improves several aspects of vision, including the contrast sensitivity in normal individuals, especially at lower spatial frequencies,2,3 and the apparent brightness of large targets under daylight conditions.4 Furthermore, Kinney et al5 showed that the response to the appearance of a black and white striped grating stimulus was faster when subjects were wearing yellow filters. We therefore decided to investigate whether coloured filters, especially yellow, might benefit children with binocular amblyopia. 20 children (9 boys, 11 girls) with binocular amblyopia were referred from 1988 to 1990. Full medical and ophthalmological histories were taken, with special attention to possible psychological influences. Each child was refracted by an ophthalmologist, with cycloplegics if necessary. Fundi were also carefully inspected; no abnormalities were seen. In 3 children flash electroretinograms were recorded, these were also normal. A full orthoptic examination consisted of: (1) monocular and binocular visual acuities (Snellen chart with and without pinholes); (2) binocular function (cover test); (3) monocular and binocular accommodation and near-point for convergence ("RAF rule"), and
convergence eye movements (infrared eye movement recorder); (4)
depth perception (Randot test); (5) contrast sensitivity function (Vistech chart and, in 3 children, a ’Joyce’ screen [p4 phosphor] by which contrast sensitivities were measured through neutral density, yellow and blue filters, which were carefully matched to transmit the same amount of light); (6) colour vision (Ishihara plates [all children], ‘Farnsworth-Munsell 100 Hue Colour Vision Test’ [10], Rayleigh colour matching [7]). Various methods were used to exclude the possibility that symptoms were psychosomatic. For example, the children were asked to look through a magnifying lens, which was then cancelled out with one of opposite power. In no instance did a child’s vision improve. Each child was then asked to attempt to read normal print through four coloured overlays presented in a random order: yellow (Wratten filter 4), green (Wratten filter 58), red (Wratten filter 25), and blue (Wratten filter 47). A neutral density filter which cut out 50% of the light at all wavelengths was also presented. The children were asked which condition they found clearest. The mean visual acuity for our group was 6/10-5 (range 6/5-6/18). 6/6 is ’normal’, but 6/4 is common for children of this age. 4 children had acuities as low as 6/18. Pinholes did
improve acuity. In 17 children acuity was reduced equally in both eyes; in the other 3 the difference between the eyes was only one line. Although all children had reduced acuity, no child had a refractive error greater than ± 0-5 dioptres. All the children had normal binocular single vision (bifoveal fixation, no squint, and normal fusion), not
normal binocular function, and normal binocular control. The accommodation of all the children was reduced. With N5 or N8 sized print, depending on acuity, the near-point for clear vision averaged 17-8 cm (range 8-28; normal 6) on the RAF rule. In the Randot test, 7 children could not even detect the largest disparity used (400 arc") and the other showed reduced responses (mean 171", range 40-400;
