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Antimicrobial Agents and Chemotherapy, April 2001, p. 1295-1297, Vol. 45, No. 4
Department of Microbiology, University of
Texas Health Center, Tyler,1 and
Microbiology Specialists, Inc.,
Houston,2 Texas
Received 15 May 2000/Returned for modification 29 December
2000/Accepted 18 January 2001
Linezolid was tested by broth microdilution against 140 clinical
Nocardia isolates belonging to seven species. The MIC at which 50% of the strains are inhibited (MIC50) and
MIC90 for all species other than Nocardia
farcinica were 2 and 4 µg/ml. Linezolid is the first
antimicrobial agent demonstrated to be active against all
Nocardia species.
Treatment of Nocardia
infections continues to be difficult, especially with central nervous
system or disseminated disease (1, 6, 7, 9, 10) and
species, such as Nocardia farcinica, that are highly drug
resistant (22). Most recent antimicrobial therapy of
complicated cases has involved the use of a sulfonamide or
trimethoprim-sulfamethoxazole plus the injectable agents amikacin and
imipenem or ceftriaxone (6, 10, 16, 18). The recent advent
of multiple new drug classes with activity against gram-positive bacteria offers the potential for new drugs useful against
Nocardia (3, 5, 11; M. C. Birmingham,
G. S. Zimmer, B. Hafkin, W. H. Todd, T. Leach, D. H. Batts, S. M. Flavin, C. R. Rayner, K. E. Welch, P. F. Smith, J. D. Root, N. E. Wilks, and J. J. Schentag, 39th Intersci. Conf. Antimicrob. Agents Chemother., poster 1098, 1999;
D. J. Stalker, C. P. Wajszczuk, and D. H. Batts, 5th
Int. Conf. Macrolides, Azalides, Streptogramins, Ketolides,
Oxazolidinones, poster 08-21, 2000; M. Wu, P. Aralor, K. Nash, L. E. Bermudez, C. B. Inderlied, and L. S. Young, Abstr. 38th
Intersci. Conf. Antimicrob. Agents Chemother., abstr. E-143, 1998.). We
studied the new oxazolidinone compound linezolid against all clinically important species of Nocardia including drug-resistant
species, such as N. farcinica and Nocardia
transvalensis (22, 23).
(Presented in part at the 99th Annual Meeting of the American Society
for Microbiology, Los Angeles, Calif., May 2000.)
Linezolid is a new class of synthetic antibiotics which prevent protein
synthesis by blocking the formation of a function initiation complex
(9, 11). The exact mechanism of action is unique, and no
cross-resistance has been discovered in strains of bacteria resistant
to other antimicrobial agents (11).
We tested 192 clinical Nocardia isolates submitted for
susceptibility testing from January 1999 through January 2000 to the Mycobacteria/Nocardia Research Laboratory at The University of Texas
Health Center for their susceptibility to linezolid. Isolates from 27 states and Mexico were tested, with 60% of the isolates from Texas,
Florida, North Carolina, Ohio, Massachusetts, and Connecticut.
Approximately 40% of the organisms were identified to the species
level by PCR restriction analysis of the 439-bp Telenti segment of the
65-kDa hsp gene (13-16, 23), and all were identified by their patterns of susceptibility (16, 17,
20-23) to approximately 15 other drugs, including
aminoglycosides, beta lactams, and quinolones. The test isolates
belonged to seven species (eight taxa) and included Nocardia
asteroides sensu stricto (n, 34), N. farcinica (n, 25), Nocardia
brasiliensis (n, 24), Nocardia nova (n, 41), Nocardia
pseudobrasiliensis (n, 8), Nocardia
otitidiscaviarum (n, 5), N. transvalensis complex (n, 7), and
Nocardia sp. (n, 2).
Susceptibility testing utilized three methods. The first was serial
twofold broth microdilution in cation-supplemented Mueller-Hinton broth
as previously described and recently approved by the NCCLS (4,
24). The second was the E-test (2) (generously
supplied by Pharmacia and Upjohn, Inc., and AB Biodisks) performed on
selected isolates on Mueller-Hinton agar using a 1-McFarland standard
inoculum. The third method was agar disk diffusion (20,
21) performed with Mueller-Hinton agar and 30-µg linezolid
disks generously supplied by the manufacturer, Pharmacia and Upjohn,
Inc. Susceptibilities to linezolid by all three methods were read after
incubation at 35°C in room air for 3 days. Two endpoints were
utilized: complete (100%) inhibition of visible growth (broth
microdilution and agar disk diffusion) and 80% inhibition of growth
(E-test) compared to the growth of controls.
Quality control for agar disk diffusion, the E-test, and broth
microdilution was performed with Staphylococcus aureus ATCC 29213. The values were within the acceptable range of inhibition for
this strain (MIC, 1 to 4 µg/ml).
The results are shown in Table 1 for the
140 isolates tested by broth microdilution. The isolates generally gave
sharp endpoints that were easy to read. Each species had a narrow
unimodal distribution of MICs, with >90% of the values falling within
1 dilution of the mode.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.4.1295-1297.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Activities of Linezolid against Multiple
Nocardia Species
ABSTRACT
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TABLE 1.
Susceptibilities of 140 Nocardia isolates to
linezolid determined by broth microdilution
Twenty random isolates were tested by the E-test. The zones of
inhibition were generally sharp, with a trailing endpoint that was
present for only 1 to 2 dilutions. The MICs for 12 of 14 (86%) isolates belonging to five species, N. nova (3 of 3),
N. asteroides complex (2 of 2), N. brasiliensis
(4 of 5), N. transvalensis complex (2 of 3), and N. pseudobrasiliensis (1 of 1), were 
1 µg/ml, and those for 8 of
14 (57%) isolates were 0.5 µg/ml. These MICs were 4- to 16-fold
lower than the MICs determined in broth. The E-test MICs for N. farcinica were higher and ranged from 1.5 to 3 µg/ml (6 of 6),
values which were two- to fourfold lower than the broth values.
Additionally, 192 consecutive isolates were tested by agar disk
diffusion. These included 140 isolates for which MICs were determined
by broth microdilution and 52 random isolates for which MICs were not
determined by broth microdilution. As with the E-test on agar, the
zones of inhibition were fairly sharp and trailed over only a 5- to
10-mm range. Of the 158 isolates from species other than N. farcinica, 154 (97.5%) had zones of complete (100%) inhibition
36 mm in diameter, and 71 (45%) had zones >45 mm in diameter. This
was in comparison to only 21 of 34 (62%) and 2 of 34 (6%) isolates of
N. farcinica, respectively, with similar zones.
One of the major limitations of the treatment of nocardiosis has been the absence of oral antimicrobials which are active against all Nocardia species (21). The sulfonamides or trimethoprim-sulfamethoxazole is active against most clinical isolates (21), but patients with central nervous system disease and severe disease do poorly with sulfonamide therapy only (7), and hypersensitivity reactions to sulfonamides are common. Other agents active against most strains and species are injectable agents, including amikacin, imipenem, and ceftriaxone (6, 7, 9, 10, 12, 16-18, 21). These agents work well alone or in combination with a sulfonamide but are limited by the need for intravenous administration, high cost, and significant toxicity. These are major limitations for pulmonary or central nervous system nocardiosis, for which the usual duration of therapy is 6 to 12 months. Amoxicillin-clavulanic acid, fluorinated quinolones, minocycline, and macrolides have limited activity (21) and are active at levels achievable in serum or tissue only against select species and isolates. The mean peak level of linezolid in serum with oral doses of 600 mg twice daily is 21.2 µg/ml (±5.8 µg/ml [standard deviation]) with a half-life of 5.4 h (Pharmacia and Upjohn, Inc., package insert for Zyvox, 2000). Linezolid is the first antimicrobial to be active against all clinically significant species of the genus Nocardia. Its clinical activity remains to be determined, although its use as a compassionate agent is ongoing. Because of its activity and availability as an oral agent and the current limitations of the sulfonamides, linezolid has the potential to be the primary drug for treatment of Nocardia disease. Its clinical efficacy and long-term toxicity in this setting, however, have yet to be determined.
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ACKNOWLEDGMENTS |
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We thank Joanne Woodring for her excellent clerical assistance.
This study was supported in part by a grant from Pharmacia and Upjohn Co.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology, The University of Texas Health Center, 11937 U.S. Hwy. 271, Tyler, TX 75708. Phone: (903) 877-7685. Fax: (903) 877-7652. E-mail: barbara.elliott{at}uthct.edu.
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REFERENCES |
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Abstract
Text
References
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|---|
| 1. | Bach, M. C., A. P. Monaco, and M. Finland. 1973. Pulmonary nocardiosis: therapy with minocycline and with erythromycin plus ampicillin. JAMA 224:1378-1381[CrossRef][Medline]. |
| 2. | Biehle, J. R., S. J. Cavalieri, M. A. Saubolle, and L. J. Getsinger. 1994. Comparative evaluation of the E test for susceptibility testing of Nocardia species. Diagn. Microbiol. Infect. Dis. 19:101-110[CrossRef][Medline]. |
| 3. |
Bowersock, T. L.,
S. A. Salmon,
E. S. Portis,
J. F. Prescott,
D. A. Robison,
C. W. Ford, and J. L. Watts.
2000.
MICs of oxazolidinones for Rhodococcus equi strains isolated from humans and animals.
Antimicrob. Agents Chemother.
44:1367-1369 |
| 4. | Brown, B. A., and R. J. Wallace, Jr. 1992. Broth microdilution MIC test for Nocardia spp., p. 5.12.1. In H. D. Isenberg (ed.), Clinical microbiology procedures handbook. American Society for Microbiology, Washington, D.C. |
| 5. |
Cynamon, M. H.,
S. P. Klemens,
C. A. Sharpe, and S. Chase.
1999.
Activities of several novel oxazolidinones against Mycobacterium tuberculosisin a murine model.
Antimicrob. Agents Chemother.
43:1189-1191 |
| 6. | Garlando, F., T. Bodmer, C. Lee, W. Zimmerli, and M. Pirovino. 1992. Successful treatment of disseminated nocardiosis complicated by cerebral abscess with ceftriaxone and amikacin: case report. Clin. Infect. Dis. 15:1039-1040[Medline]. |
| 7. | Geiseler, P. J., and B. R. Andersen. 1979. Results of therapy in systemic nocardiosis. Am. J. Med. Sci. 278:188-193[Medline]. |
| 8. |
Goldstein, E. J. C.,
D. M. Citron, and C. V. Merriam.
1999.
Linezolid activity compared to those of selected macrolides and other agents against aerobic and anaerobic pathogens isolated from soft tissue bite infections in humans.
Antimicrob. Agents Chemother.
43:1469-1474 |
| 9. |
Gombert, M. E.,
T. M. Aulicino,
L. duBouchet,
G. E. Silverman, and W. M. Sheinbaum.
1986.
Therapy of experimental cerebral nocardiosis with imipenem, amikacin, trimethoprim-sulfamethoxazole, and minocycline.
Antimicrob. Agents Chemother.
30:270-273 |
| 10. | Krone, A., P. Klaus, K. P. Schaal, A. Brawanski, and B. Schuknecht. 1989. Nocardial cerebral abscess cured with imipenem/amikacin and enucleation. Neurosurg. Rev. 12:333-340[CrossRef][Medline]. |
| 11. |
Noskin, G. A.,
F. Siddiqui,
V. Stosor,
D. Hacek, and L. R. Peterson.
1999.
In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci.
Antimicrob. Agents Chemother.
43:2059-2062 |
| 12. |
Ruimy, R.,
P. Riegel,
A. Carlotti,
P. Boiron,
G. Bernardin,
H. Monteil,
R. J. Wallace, Jr., and R. Christen.
1996.
Nocardia pseudobrasiliensis sp. nov., a new species of Nocardia which groups bacterial strains previously identified as Nocardia brasiliensis and associated with invasive disease.
Int. J. Syst. Bacteriol.
46:259-264 |
| 13. | Steingrube, V. A., B. A. Brown, J. L. Gibson, R. W. Wilson, J. Brown, Z. Blacklock, K. Jost, S. Locke, R. F. Ulrich, and R. J. Wallace, Jr. 1995. DNA amplification and restriction endonuclease analysis for differentiation of 12 species and taxa of Nocardia, including recognition of four new taxa within the Nocardia asteroides complex. J. Clin. Microbiol. 33:3096-3101[Abstract]. |
| 14. | Steingrube, V. A., R. W. Wilson, B. A. Brown, K. C. Jost, Jr., Z. Blacklock, J. L. Gibson, and R. J. Wallace, Jr. 1997. Rapid identification of clinically significant species and taxa of aerobic actinomycetes, including Actinomadura, Gordona, Nocardia, Rhodococcus, Streptomyces, and Tsukamurella isolates, by DNA amplification and restriction endonuclease analysis. J. Clin. Microbiol. 35:817-822[Abstract]. |
| 15. |
Telenti, A.,
F. Marchesi,
M. Balz,
F. Bally,
E. C. Böttger, and T. Bodmer.
1993.
Rapid identification of mycobacteria to the species level by polymerase chain reaction and restriction enzyme analysis.
J. Clin. Microbiol.
31:175-178 |
| 16. | Wallace, R. J., Jr., B. A. Brown, Z. Blacklock, R. Ulrich, K. Jost, J. M. Brown, M. M. McNeil, G. Onyi, V. A. Steingrube, and J. L. Gibson. 1995. New Nocardia taxon among isolates of Nocardia brasiliensis associated with invasive disease. J. Clin. Microbiol. 33:1528-1533[Abstract]. |
| 17. |
Wallace, R. J., Jr.,
B. A. Brown,
M. Tsukamura,
J. M. Brown, and G. Onyi.
1991.
Clinical and laboratory features of Nocardia nova.
J. Clin. Microbiol.
29:2407-2411 |
| 18. |
Wallace, R. J., Jr.,
D. R. Nash,
W. K. Johnson,
L. C. Steele, and V. A. Steingrube.
1987.
 -Lactam resistance in Nocardia brasiliensis is mediated by -lactamase and reversed in the presence of clavulanic acid.
J. Infect. Dis.
156:956-966.
|
| 19. | Wallace, R. J., Jr., E. J. Septimus, T. W. Williams, Jr., R. H. Conklin, T. K. Satterwhite, M. B. Bushby, and D. C. Hollowell. 1982. Use of trimethoprim-sulfamethoxazole for treatment of infections due to Nocardia. Rev. Infect. Dis. 4:315-325[Medline]. |
| 20. | Wallace, R. J., Jr., and L. C. Steele. 1988. Susceptibility testing of Nocardia species for the clinical laboratory. Diagn. Microbiol. Infect. Dis. 9:155-166[CrossRef][Medline]. |
| 21. |
Wallace, R. J., Jr.,
L. C. Steele,
G. Sumpter, and J. M. Smith.
1988.
Antimicrobial susceptibility patterns of Nocardia asteroides.
Antimicrob. Agents Chemother.
32:1776-1779 |
| 22. |
Wallace, R. J., Jr.,
M. Tsukamura,
B. A. Brown,
J. Brown,
V. A. Steingrube,
Y. Zhang, and D. R. Nash.
1990.
Cefotaxime-resistant Nocardia asteroides strains are isolates of the controversial species Nocardia farcinica.
J. Clin. Microbiol.
28:2726-2732 |
| 23. | Wilson, R. W., V. A. Steingrube, B. A. Brown, Z. Blacklock, K. C. Jost, Jr., A. McNabb, W. D. Colby, J. R. Biehle, J. L. Gibson, and R. J. Wallace, Jr. 1997. Recognition of a Nocardia transvalensis complex by resistance to aminoglycosides, including amikacin, and PCR-restriction fragment length polymorphism analysis. J. Clin. Microbiol. 35:2235-2242[Abstract]. |
| 24. | Woods, G. L., B. A. Brown-Elliott, E. P. Desmond, G. S. Hall, L. Heifets, G. E. Pfyffer, M. R. Plaunt, J. C. Ridderhof, R. J. Wallace, Jr., N. G. Warren, and F. G. Witebsky. 2001. Susceptibility testing of mycobacteria, nocardia, and other aerobic actinomycetes. Tentative standard, 2nd ed. NCCLS 20 (26); M24-T2. NCCLS, Wayne, Pa. |
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