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
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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
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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.
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