Download Report

120
Successful Treatment of Pulmonary Mycobacterium xenopi Infection in a Natural
Killer Cell–Deficient Patient with Clarithromycin, Rifabutin, and Sparfloxacin
Hans Schmitt, Norbert Schnitzler, Jochen Riehl,
Gerhard Adam, Heinz-Gu¨nter Sieberth, and
Gerhard Haase
From the Departments of Internal Medicine II and Diagnostic
Radiology, and the Institutes of Medical Immunology and Medical
Microbiology, University Hospital Rheinisch–Westfa¨lische Technische
Hochschule Aachen, Aachen, Germany
Mycobacterium xenopi is a ubiquitous thermophilic bacterium occurring predominantly in water; its detection in clinical
samples is usually associated with contamination or asymptomatic transient colonization [1– 4]. However, in the past few
years an increasing number of clinically relevant M. xenopi
infections, including nosocomial transmissions, have been reported [5–9]. A common route of infection is aerosol spread via
inhalation of contaminated water. Clinical and radiological
examinations reveal pulmonary inflammation with cavitary
lesions, not easily distinguishable from tuberculosis [2, 3,
7–17].
Patients with a serious history of lung disease or severe
immunodeficiency due to different causes (e.g., AIDS or organ
transplantation) are most commonly affected [5, 9, 18 –26].
Disseminated M. xenopi infection is rarely observed [27, 28].
In a recently published study, clinically relevant disease was
diagnosed for 10 of 103 patients from whom M. xenopi was
isolated [5]. Therefore, it is difficult to determine the etiologic
role of this bacterium and the resulting therapeutic indications.
We report herein a young man with severe pulmonary M. xenopi infection successfully treated with a novel combination
therapy. Although severe immunodeficiency could be excluded, there was a great reduction in the number of natural
killer cells (NKCs).
Received 27 August 1998; revised 12 February 1999.
H.S. and N.S. made equal contributions to the manuscript and thus are both
considered first authors.
Reprints or correspondence: Dr. Gerhard Haase, Institute of Medical Microbiology, University Hospital RWTH Aachen, D-52057 Aachen, Germany
([email protected]).
Clinical Infectious Diseases 1999;29:120 – 4
© 1999 by the Infectious Diseases Society of America. All rights reserved.
1058 – 4838/99/2901– 0019$03.00
Case Report
A 36-year-old man underwent surgery of the left lung in
1985 because of spontaneous pneumothorax. In 1987 he developed Crohn’s disease, and in 1990 he underwent a subtotal
colectomy. He was treated continuously with mesalazine and
temporarily with corticosteroids. Bilateral apical pleural fibrosis (right . left) and cavernous changes in the left apical region
were first detected on a chest radiograph in December 1993.
Despite a history of smoking 30 cigarettes per day since
1977, there was no evidence of chronic obstructive lung disease or prior pulmonary tuberculosis. Because of increased
activity of the Crohn’s disease, 30 mg of methylprednisolone
per day was administered between July and October 1995. In
September recurrent coughing and night sweats occurred, leading to admittance to the hospital in December due to progressive deterioration (e.g., subfebrile temperature and loss of
weight [5 kg over 4 months]).
Radiological examinations revealed extensive infiltrative
and fibrous opacification and additional cavernous changes in
the upper lobe of the left lung (figure 1, left). Since the
tuberculin skin reaction was positive and acid-fast rod-shaped
bacteria were detected upon microscopic examination in five
sputum specimens obtained on subsequent days, antituberculous therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide was initiated. The cultivated slowly growing, scotochromogenic mycobacterium could be unequivocally identified
as M. xenopi by determination of the signature sequence of
both the 16S-rDNA and the dnaJ gene [29, 30].
With use of the radiometric BACTEC method (Becton Dickinson, Heidelberg, Germany) at 42°C (the optimal growth
temperature for M. xenopi), drug-susceptibility testing showed
susceptibility to rifampicin and streptomycin but revealed resistance to isoniazid, ethambutol, and pyrazinamide. Etests
(AB Biodisk, Solna, Sweden) performed on Middlebrook 7H10
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
Isolation of Mycobacterium xenopi from the respiratory tract may indicate pneumonia, often
clinically indistinguishable from tuberculosis. Resistance to the classic antituberculous drugs renders
the treatment of these infections problematic. We report on a case of cavernous pneumonia caused
by M. xenopi in a 36-year-old male with natural killer cell deficiency but without severe immunodeficiency. He was successfully treated with a novel triple-drug combination comprising clarithromycin, sparfloxacin, and rifabutin. An impressive subsequent regression of pathological pulmonary
changes was observed, and mycobacteria could no longer be detected. The therapeutic potential of
clarithromycin and sparfloxacin in the treatment of M. xenopi infections is discussed.
CID 1999;29 (July)
Pulmonary M. xenopi Infection
121
agar at 42°C revealed a very low MIC for clarithromycin
(0.016 mg/L) and sparfloxacin (0.003 mg/L) but a high MIC of
6.0 mg/L for ciprofloxacin.
HIV serology was negative. Mild leukocytosis (11,600
lymphocytes/mL), with 1,276 lymphocytes /mL detected before
initiation of therapy, was due mainly to (1) a reduction of
CD8/CD11b coexpressing suppressor T lymphocytes (STLs)
and (2) a reduction of CD16/CD56 coexpressing NKCs. The
number of CD41 T cells was normal. Because of the deficiency
of STLs, the CD4/CD8 ratio and the ratio of CD81/CD11b2
cytotoxic T lymphocytes (CTLs) to STLs were elevated (table
1). At this time, the 3H-thymidine incorporation rate by the
patient’s cultured lymphocytes was five times higher than that
of healthy controls.
The mitogens phytohemagglutinin and concanavalin A and
the recall antigen zymosan increased the 3H-thymidine incorporation rate of these basally stimulated lymphocytes by a
much lower factor in the patient than in healthy controls.
Conversely, the 3H-thymidine incorporation by the patient’s
lymphocytes increased dose-dependently after stimulation with
tuberculin by up to 8 times the basal incorporation rate.
After species identification and drug-susceptibility testing,
the treatment was switched to an alternative triple-drug regimen in January 1996, involving daily doses of 500 mg of
clarithromycin, 200 mg of sparfloxacin, and 300 mg of rifabutin. Smears became negative within 6 weeks, and a negative
sputum culture was achieved within 3 months. The overall
12-month antibiotic treatment led to an impressive regression
of the laboratory and radiological changes (table 1 and figure 1,
right). All 3H-thymidine incorporation rates normalized, but
numbers of NKCs and STLs remained as low as in the baseline
tests (table 1).
The drug regimen was tolerated well. Photosensitization,
a well-known side effect of sparfloxacin, was managed by
Table 1. Immunologic findings at the time of diagnosis and after cure of severe pulmonary infection due to Mycobacterium xenopi in a young
man.
Parameter
Erythrocyte sedimentation rate (mm/h), 1 h/2 h
C-reactive protein (mg/mL)
Cells
Leukocytes (/mL)
Lymphocytes (/mL)
B cells (/mL)
T cells (CD31) (/mL)
T helper cells (CD31/CD41) (/mL)
CD4/CD8 cell ratio
Suppressor/cytotoxic T lymphocytes (CD31/CD81) (/mL)
Cytotoxic T lymphocytes (CD81/CD11b2) (/mL)
Suppressor T lymphocytes (CD81/CD11b1) (/mL)
Cytotoxic/suppressor cell ratio
Natural killer cells (CD161/CD561) (/mL)
Diagnosis: December 1995
Cure: February 1997
38/70
72
5/19
10
11,600
1,276
179
1,059
766
3.00
255
217
38
5.71
64
7,200
1,512
423
1,013
771
2.83
272
197
45
4.38
60
Normal range
5/10
,7
4,600–7,100
1,600–2,400
200–400
1,100–1,700
700–1,100
1.0–1.5
500–900
...
...
,3.0
200–400
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
Figure 1. CT scans of the lung of a young man with severe pulmonary infection due to Mycobacterium xenopi, from the time of diagnosis
in November 1995 (left) and of cure in February 1997 (right) (window, 1900 HU [Hounsfield unit]; center, 2600 HU). At left, dense
opacification with cavitary changes are visible. After therapy (right), scarring and thickening of the bronchial walls but no persisting
inflammatory lesions were evident.
122
Schmitt, Schnitzler, et al.
light protection. Activity of Crohn’s disease was controlled
by mesalazine monotherapy. Because of the favorable clinical course, therapy was stopped after 12 months. No evidence of recurrence was found in the subsequent follow-up
period (2 years).
Discussion
therapy is variable and difficult to predict, and no proven
correlation with in vitro test results could be found [1, 10, 11].
Surgery therefore represents an important alternative to drug
therapy for patients with localized pulmonary disease [10, 11,
32, 45].
The prophylactic and therapeutic efficacy of rifabutin and
newer macrolides such as clarithromycin and azithromycin
against nontuberculous mycobacteria has been convincingly
demonstrated [46 –55]. Therefore, they are used in many combination regimens for nontuberculous mycobacterial infections,
including those due to M. xenopi [50 –52]. In vitro findings
have shown excellent activity of sparfloxacin against nontuberculous mycobacteria, including strains of M. xenopi [56, 57].
High tissue concentrations of sparfloxacin are achieved by oral
administration [58].
Pronounced synergy between sparfloxacin and clarithromycin as well as rifabutin has been observed in vitro [55,
59]. MICs of sparfloxacin were much lower than those of
ofloxacin, levofloxacin, and, as also seen in our case, ciprofloxacin [59 – 61], a finding indicating that sparfloxacin
may be the most potent quinolone against susceptible mycobacteria [62].
The triple-drug combination of clarithromycin, rifabutin, and
sparfloxacin used in the present case has not been reported so
far for nontuberculous mycobacterial infections. However, successful treatment of an extrapulmonary infection with clarithromycin and sparfloxacin has recently been described [63]. Despite its photosensitization side effect, sparfloxacin may be a
valuable drug for treatment of M. xenopi infections.
Acknowledgments
The authors thank Dr. E. C. Bo¨ttger for performing the 16S
rDNA signature sequence determination and Sabine Ba¨tge for
excellent technical assistance.
References
1. American Thoracic Society. Diagnosis and treatment of disease caused by
non-tuberculous mycobacteria. Am J Respir Crit Care Med 1997;
156(suppl):S1–25.
2. Woods GL, Washington JA. Mycobacteria other than Mycobacterium
tuberculosis: review of microbiologic and clinical aspects. Rev Infect
Dis 1987;9:275–94.
3. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am
Rev Respir Dis 1979;119:107–59.
4. Wayne LG, Sramek HA. Agents of newly recognized or infrequently
encountered mycobacterial diseases. Clin Microbiol Rev 1992;5:1–25.
5. Jiva TM, Jacoby HM, Weymouth LA, Kaminski DA, Portmore AC.
Mycobacterium xenopi: innocent bystander or emerging pathogen? Clin
Infect Dis 1997;24:226 –32.
6. Wolinsky E. Editorial response: is Mycobacterium xenopi an emerging
pathogen? Clin Infect Dis 1997;24:233– 4.
7. Costrini AM, Mahler DA, Gross WM, et al. Clinical and roentgenographic
features of nosocomial pulmonary disease due to Mycobacterium xenopi. Am Rev Respir Dis 1981;123:104 –9.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
M. xenopi was clearly proven to be the etiologic agent of the
cavitary pulmonary changes found in the present case. The
possibility of misidentification of M. xenopi as Mycobacterium
celatum was unequivocally excluded [29 –31]. Because of the
repeated isolation of M. xenopi and the exclusion of a simultaneous Mycobacterium tuberculosis infection, the diagnostic
criteria for a nontuberculous infection were fulfilled [1]. The
high reactivity of the patient’s lymphocytes to tuberculin could
be explained by the well-known cross-reactivity in cases of
M. xenopi infections [32]. However, an earlier infection with
M. tuberculosis could not be definitively excluded.
The long-term corticosteroid therapy certainly represents a
risk for secondary infections [33], but the subset of CD4 T cells
responsible for regulating the immune response to M. tuberculosis [34 –36] was not impaired; our patient had normal CD4
cell counts and a strong reaction to PPD. The CD8 T cell
subpopulation involved in immune response to M. tuberculosis
is the CD11b2 CTLs [36 – 41]. It is notable that in our patient
the reduction of CD8 T cells was not due to the CTLs but to the
T suppressor cells.
NKCs are also known to contribute to the immune response
to mycobacteria, mainly mediated by a T cell–independent
IFN-g secretion [42]. In patients with active ileocecal Crohn’s
disease, oral corticosteroids are known to cause a temporary
suppression of activity in peripheral blood NKCs [43] by
repression of the synthesis of perforin mRNA and granzyme A
and reduced adhesion to target cells [44]. Therefore, in our
patient temporary suppression of the NKC function by corticosteroids might have contributed to development of the
M. xenopi infection.
Despite the lack of clinical signs of obstructive lung disease,
the presence of further pulmonary damage has to be assumed in
view of the patient’s long-term nicotine abuse. Malnutrition
(body mass index, 18.3 kg/m2) associated with Crohn’s disease
might have been a further risk factor. Our case demonstrates
that young adults without evidence of severe immunodeficiency may develop a clinically relevant pulmonary M. xenopi
infection if other predisposing factors exist.
Chemotherapeutic combination protocols with three to four
drugs and an overall treatment duration of 18 –24 months
usually are recommended in cases of M. xenopi infection [1, 5,
12–16]. On the basis of results of vitro susceptibility testing,
we selected a combination of clarithromycin, rifabutin, and
sparfloxacin for therapy. However, clinical response to chemo-
CID 1999;29 (July)
CID 1999;29 (July)
Pulmonary M. xenopi Infection
31. Zurawski CA, Cage GD, Rimland D, Blumberg HM. Pneumonia and
bacteremia due to Mycobacterium celatum masquerading as Mycobacterium xenopi in patients with AIDS: an underdiagnosed problem? Clin
Infect Dis 1997;24:140 –3.
32. Parrot RG, Grosset JH. Post-surgical outcome of 57 patients with Mycobacterium xenopi pulmonary infection. Tubercle 1978;69:47–55.
33. Wallace RJ Jr, Brown BA, Onyi GO. Skin, soft tissue, and bone infections
due to Mycobacterium chelonae chelonae: importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to
oral antimicrobials other than clarithromycin. J Infect Dis 1992;166:
405–12.
34. Flesch I, Kaufmann SHE. Activation of tuberculostatic macrophage functions by interferon-g, interleukin 4 and tumor necrosis factor. Infect
Immun 1990;58:2675–7.
35. Kaufmann SHE. Immunity to intracellular bacteria. Annu Rev Immunol
1993;11:129 – 63.
36. Orme IM, Andersen P, Boom WH. T cell response to Mycobacterium
tuberculosis. J Infect Dis 1993;167:1481–97.
37. Bothamley GH, Festenstein F, Newland A. Protective role of CD8 cells in
tuberculosis. Lancet 1992;339:315– 6.
38. Flynn JL, Goldstein MM, Triebold KJ, et al. Major histocompatibility
complex class-I–restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 1992;89:
12013–7.
39. Orme IM. The kinetics of emergence and loss of mediator T lymphocytes
acquired in response to infection with Mycobacterium tuberculosis.
J Immunol 1987;138:293– 8.
40. Orme IM, Miller ES, Roberts AD, et al. T lymphocytes mediating protection and cellular cytolysis during the course of Mycobacterium tuberculosis infection. J Immunol 1992;148:189 –96.
41. Kaufmann SHE. CD81 T lymphocytes in intracellular microbial infections. Immunol Today 1988;9:168 –74.
42. Smith D, Hansch H, Bancroft G, et al. T-cell-independent granuloma
formation in response to Mycobacterium avium: role of tumour necrosis
factor-alpha and interferon-gamma. Immunology 1997;92:413–21.
43. van Ierssel GJHM, van der Sluys-Veer A, Verspaget HW, Griffioen G, van
Hogezand RA, Lamers CBHW. Contribution of plasma cortisol to
corticosteroid-suppressed peripheral blood natural killer cell activity in
Crohn’s disease. Immunopharmacology 1995;29:11–7.
44. Zhou J, Olsen S, Moldovan J, et al. Glucocorticoid regulation of natural
cytotoxicity: effects of cortisol on the phenotype and function of a
cloned human natural killer cell line. Cell Immunol 1997;178:108 –16.
45. Jouveshomme S, Dautzenberg B, Bakdach H, Derenne JP. Preliminary
results of collapse therapy with plombage for pulmonary disease caused
by multidrug-resistant mycobacteria. Am J Respir Crit Care Med 1998;
157:1609 –15.
46. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency
syndrome. N Engl J Med 1996;335:384 –91.
47. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated
Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392– 8.
48. Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens
for the treatment of Mycobacterium avium complex bacteremia in
AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin,
ethampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med
1996;335:377– 83.
49. Koletar SL. Treatment of Mycobacterium avium in human immunodeficiency virus–infected individuals. Am J Med 1997;102:16 –21.
50. Amsden GW, Peloquin CA, Berning SE. The role of advanced generation
macrolides in the prophylaxis and treatment of Mycobacterium avium
complex (MAC) infections. Drugs 1997;54:69 – 80.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
8. Yuen K, Fam AG, Simor A. Mycobacterium xenopi arthritis. J Rheumatol
1998;25:1016 – 8.
9. Jacoby HM, Jiva TM, Kaminski DA, Weymouth LA, Portmore AC.
Mycobacterium xenopi infection masquerading as pulmonary tuberculosis in two patients infected with the human immunodeficiency virus.
Clin Infect Dis 1995;20:1399 – 401.
10. Banks J, Hunter AM, Campbell IA, Jenkins PA, Smith AP. Pulmonary
infection with Mycobacterium xenopi: review of treatment and response. Thorax 1984;39:376 – 82.
11. Smith MJ, Citron KM. Clinical review of pulmonary disease caused by
Mycobacterium xenopi. Thorax 1983;38:373–7.
12. Bogaerts Y, Elinck W, van Renterghem D, Pauwels R, van der Straeten M.
Pulmonary disease due to Mycobacterium xenopi: report of two cases.
Eur J Respir Dis 1982;63:298 –304.
13. Koizumi JH, Sommers HM. Mycobacterium xenopi and pulmonary disease. Am J Clin Pathol 1980;73:826 –30.
14. Simor AE, Salit IE, Vellend H. The role of Mycobacterium xenopi in
human disease. Am Rev Respir Dis 1984;129:435– 8.
15. Contreras MA, Cheung OT, Sanders DE, Goldstein RS. Pulmonary infection with nontuberculous mycobacteria. Am Rev Respir Dis 1988;137:
149 –52.
16. Terashima T, Sakamaki F, Hasegawa N, Kanazawa M, Kawashiro T.
Pulmonary infection due to Mycobacterium xenopi. Int Med 1994;33:
536 –9.
17. Wittram C, Weisbrod GL. Mycobacterium xenopi pulmonary infection:
evaluation with CT. J Comput Assist Tomogr 1998;22:225– 8.
18. Shafer RW, Sierra MF. Mycobacterium xenopi, Mycobacterium fortuitum,
Mycobacterium kansasii, and other nontuberculous mycobacteria in an
area of endemicity for AIDS. Clin Infect Dis 1992;15:161–2.
19. Tenholder MF, Moser RJ, Telli CJ. Mycobacteria other than tuberculosis:
pulmonary involvement in patients with acquired immunodeficiency
syndrome. Arch Intern Med 1988;148:953–5.
20. Ausina V, Barrio J, Luquin M, Sambeat MA, et al. Mycobacterium xenopi
infections in the acquired immunodeficiency syndrome. Ann Intern Med
1988;108:927– 8.
21. Lichtenstein IH, MacGregor RR. Mycobacterial infections in renal transplant recipients: report of five cases and review of the literature. Rev
Infect Dis 1983;5:216 –26.
22. Weber J, Mettang T, Staerz E, Machleidt C, Kuhlmann U. Pulmonary
disease due to Mycobacterium xenopi in a renal allograft recipient:
report of a case and review. Rev Infect Dis 1989;6:964 –9.
23. Branger B, Gouby A, Ouleˆs R, Balducchi JP, et al. Mycobacterium
haemophilum and Mycobacterium xenopi associated infection in a renal
transplant patient. Clin Nephrol 1985;23:46 –9.
24. Damsker B, Bottone EJ, Deligdisch L. Mycobacterium xenopi: infection in
an immunocompromised host. Hum Pathol 1982;13:866 –70.
25. el-Helou P, Rachlis A, Fong I, Walmsley S, Phillips A, Salit I, Simor AE.
Mycobacterium xenopi infections in patients with human immunodeficiency virus infection. Clin Infect Dis 1997;25:206 –10.
26. De Coster C, Verstraeten JM, Dumortier P, De Vuyst P. Atypical mycobacteriosis as a complication of talc pneumoconiosis. Eur Respir J
1996;9:1757–9.
27. Weinberg JR, Dootson G, Gertner D, Chambers ST, Smith H. Disseminated Mycobacterium xenopi infection. Lancet 1985;1:1033– 4.
28. Price AB, Owen R, Sowter G, Weinberg J, Smith H. Disseminated
Mycobacterium xenopi infection [letter]. Lancet 1985;2:383.
29. Kirschner PB, Springer B, Vogel A, et al. Genotypic identification of
mycobacteria by nucleic acid sequence determination: report of a 2-year
experience in a clinical laboratory. J Clin Microbiol 1993;31:2882–9.
30. Takewaki S, Okuzumi K, Manabe I, et al. Nucleotide sequence comparison of the mycobacterial dnaJ gene and PCR–restriction fragment
length polymorphism analysis for identification of mycobacterial species. Int J Syst Bacteriol 1994;44:159 – 66.
123
124
Schmitt, Schnitzler, et al.
57. Martin-Luengo F, Sempere M. Activity of sparfloxacin and other quinolones against mycobacteria. Drugs 1993;45(suppl 3):219 –20.
58. Gevaudan MJ, Bollet C, Mallet MN, et al. Extracellular and intracellular
activities of sparfloxacin against Mycobacterium avium complex and
Mycobacterium xenopi. Pathol Biol 1992;40:443–9.
59. Truffot-Pernot C, Ji B, Grosset J. In vitro activity of sparfloxacin against
tuberculous and non-tuberculous mycobacteria. Eur J Clin Microbiol
Infect Dis 1991;Special issue:561–2.
60. Garcia-Rodriguez JA, Garcia ACG. In vitro activities of quinolones
against mycobacteria. J Antimicrob Chemother 1993;32:797– 808.
61. Rastogi N, Goh KS, Bryskier A, Devallois A. Spectrum of activity of
levofloxacin against nontuberculous mycobacteria and its activity
against the Mycobacterium avium complex in combination with ethambutol, rifampin, roxithromycin, amikacin, and clofazimine. Antimicrob
Agents Chemother 1996;40:2483–7.
62. Alangaden GJ, Lerner SA. The clinical use of fluoroquinolones for
the treatment of mycobacterial diseases. Clin Infect Dis 1997;25:
1213–21.
63. Roche B, Rozenberg S, Cambau E, Desplaces N, et al. Efficacy of
combined clarithromycin and sparfloxacin therapy in a patient with
discitis due to Mycobacterium xenopi [letter]. Rev Rhum Engl Ed
1997;64:64 –5.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
51. Hardly DJ. Extent and spectrum of the antimicrobial activity of clarithromycin. Pediatr Infect Dis J 1993;12(suppl 3):S99 –105.
52. Dautzenberg B, Papillon F, Lepitre M, Truffot-Pernod CH, Chauvin JP.
Mycobacterium xenopi infections treated with clarithromycin containing
regimens [abstract no 1125]. In: Program and abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (New
Orleans). Washington, DC: American Society for Microbiology, 1993:417.
53. Gevaudan MJ, Bollet C, Mallet MN, Gulian G, Tissot-Dupont H, de Micco
P. Etude de l’activite´ de l’azithromycine et de la roxithromycine seules
et en associations vis-a-vis de Mycobacterium avium et Mycobacterium
xenopi. Pathol Biol 1990;38:413–9.
54. Piersimoni C, Tortoli E, Mascellino MT, et al. Activity of seven antimicrobial agents, alone and in combination, against AIDS-associated isolates of Mycobacterium avium complex. J Antimicrob Chemother 1995;
36:497–502.
55. Rastogi N, Bauriaud RM, Bourgoin A, et al. French multicenter study
involving eight test sites for radiometric determination of activities of 10
antimicrobial agents against Mycobacterium avium complex. Antimicrob Agents Chemother 1995;39:6l38 – 44.
56. Sanchez-Carillo C, Cotarelo M, Cercenado E, Vincente T, Blazquez R,
Bouza E. Comparative in vitro activity of sparfloxacin and eight other
antimicrobial agents against clinical isolates of non-tuberculous mycobacteria. J Antimicrob Chemother 1996;37:151– 4.
CID 1999;29 (July)