clinical experience 6 cases 2003

Nocardia Infection and Linezolid • CID 2003:36 (1 February) • 313

M A J O R A R T I C L E

Clinical Experience with Linezolidfor the Treatment of Nocardia Infection

Edina H. Moylett,1 Susan E. Pacheco,1 Barbara A. Brown-Elliott,2 Tracy R. Perry,3 E. Stephen Buescher,4

Mary C. Birmingham,5 Jerome J. Schentag,6 Joseph F. Gimbel,7 Aaron Apodaca,8 Margot A. Schwartz,9

Robert M. Rakita,9 and Richard J. Wallace, Jr.2

1Department of Pediatrics, Section of Allergy and Immunology, Texas Children’s Hospital, Houston, and 2Department of Microbiology, Universityof Texas Health Center, Tyler, Texas; 3Department of Pharmacy, Kindred Hospital, Indianapolis, Indiana; 4Center for Pediatric Research, EasternVirginia Medical School, Norfolk; 5Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital and 6University at Buffalo School of Pharmacyand Pharmaceutical Sciences, Buffalo, New York; 7Arizona Research Center, Phoenix; and Sections of 8General Internal Medicine and 9InfectiousDiseases, Virginia Mason Medical Center, Seattle, Washington

Linezolid is an oxazolidinone that has activity against most gram-positive bacteria, including in vitro activity

against all Nocardia species and strains. We describe 6 clinical cases of nocardiosis that were successfully

treated with linezolid. Two patients had underlying X-linked chronic granulomatous disease, and 2 patients

were receiving chronic corticosteroid therapy. Four of 6 patients had disseminated disease, and 2 of these 4

patients had multiple brain abscesses. Four patients primarily received monotherapy; for the fifth patient,

linezolid was added to a failing multiple-drug regimen, and, for the sixth patient, it was used as part of

combination therapy. All 6 patients were successfully treated, although 1 patient had a presumed relapse of

central nervous system infection after premature discontinuation of the drug. Linezolid appears to be an

effective alternative for the treatment of nocardiosis.

Linezolid is a synthetic antibacterial agent of a novel

class of antibiotics, the oxazolidinones, which has clin-

ical usefulness in the treatment of infections caused by

aerobic gram-positive bacteria. Linezolid binds to a site

on the bacterial 23S rRNA of the 50S subunit and pre-

vents the formation of a functional 70S-initiation com-

plex, which is an essential component of the bacterial

translation process [1]. This mechanism of action is

different from that of other antimicrobial agents; there-

fore, cross-resistance with other classes of antimicro-

bials has not been encountered. Linezolid is primarily

Received 24 July 2002; accepted 26 October 2002; electronically published 13January 2003.

Presented in part: 39th Annual Meeting of the Infectious Diseases Society ofAmerica, San Francisco, California, 25–28 October 2001 (abstract 173).

Financial support: Pharmacia (Peapack, NJ), which provided the treatment drug.

Reprints or correspondence: Dr. Edina H. Moylett, Texas Children’s Hospital,Dept. of Allergy and Immunology, 6621 Fannin St., 3rd Fl. (MC: FC330.01), Houston,TX 77030 ([email protected]).

Clinical Infectious Diseases 2003; 36:313–8� 2003 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2003/3603-0011$15.00

targeted at the treatment of infections secondary to

resistant gram-positive organisms, especially methicil-

lin-resistant Staphylococcus aureus and vancomycin-

resistant Enterococcus species. However, linezolid also

has in vitro activity against some gram-negative anaer-

obes as well as some atypical organisms [1].

Nocardia species cause infection in humans and an-

imals. Twelve species (or taxa) within the genus No-

cardia have been identified using advanced laboratory

techniques. Of these species, the best known is Nocardia

asteroides sensu stricto. The latter term specifies that

the current species grouping excludes Nocardia nova,

Nocardia farcinica, and Nocardia transvalensis, which,

in older studies, were not recognized as species and

were included in what was called “N. asteroides” or “N.

asteroides complex.” N. farcinica, N. nova, Nocardia

brasiliensis, Nocardia otitidiscaviarum, and N. transva-

lensis complex are other species frequently associated

with infection in humans [2]. Members of the N. as-

teroides complex (older definition) are responsible for

∼80% of noncutaneous invasive disease and for most

systemic and CNS disease. N. farcinica is most often

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Table 1. Clinical features of disease, indications for linezolid use, and outcomes for 6 patients with nocardiosis treated with linezolid.

Patient

Agein years,

sex

Underlyingmedical

conditionor drug use

Type of clinicalnocardiosis syndrome

Previous antibiotictherapy (duration)

Indication(s)for starting Lzd Lzd dosage

Duration ofLzd therapy,

months

Adverse eventsattributed to Lzd

therapy Outcome

1 45, M Silicosis andsteroid use

Disseminated (skin pus-tules and multiplebrain abscesses [fig-ure 1])

TMP-SMX and Ctri(3 weeks)

Diffuse rash, fever, and elevatedtransaminase levels that re-solved with discontinuationof TMP-SMX; long-term ivtherapy is not an option

600 mg po b.i.d. 12 None Clinical cure (figure 2)

2 63, M Silicosis andsteroid use

Disseminated (skin pus-tules and pulmonarynodules)

None History of sulfonamide allergy(skin rash)

600 mg po b.i.d. 3 Anemia Suspected recurrence of CNSinfectiona

3 54, F None Facial cellulitis andpustules

Dcl (3 weeks) Clinical failure as part of phase-3 Lzd skin and skin structureinfection protocol

600 mg po b.i.d. 2b Anemia Clinical cure

4 52, F None Disseminated (brain,lung, mediastinalnodes, liver, kidney,and adrenal glands)

TMP-SMX (4weeks); switchedto Mino and Cpfx(1 week)

Diffuse rash, myelosuppression,and elevated transaminaselevels that resolved with dis-continuation of TMP-SMX;after the switch: severe clini-cal disease, intermediate invitro susceptibility to Minoand Cpfx

600 mg po oriv b.i.d.

4 Anemia, thrombo-cytopenia, lacticacidosis, andperipheral neu-ropathy [16]

Clinical cure; patient com-pleted 8 weeks of Lzd andClmc as well as 7 weeksof Lzd and Gati; completedtherapy with Moxi as aresult of adverse eventsattributed to Lzd

5 6, M CGD Pulmonary (new-onsetcavitary pneumonia[figure 3]); history ofN. brasiliensis pneu-monia necessitatingright pneumonectomy

TMP-SMX and Tic/Clv (10 days);Amik added onday 10; Lzd andMero added onday 28

Rapidly worsening lung disease,daily spiking fever, doublingin size of initial pulmonarylesion while following theinitial antibiotic regimen

10 mg/kg iv b.i.d. 1.5d or 24.5e None Clinical cure (figure 4); patientcompleted 10 weeks ofTMP-SMX iv, 7 weeks ofAmik and Tic/Clv, 6 weeksof Lzd iv, and 5 weeks ofMero; patient received 6granulocyte transfusions

6 9, M CGD Disseminated (nasalabscess and bilateralnodular pneumonia)

TMP-SMX andAmik (7 days);TMP-SMX alone(3 days)

With TMP-SMX alone, exten-sive erythema and conjuncti-val injection 10 days afterrapid oral desensitization

300 mg po b.i.d. 12 None Clinical cure

NOTE. Amik, amikacin; CGD, chronic granulomatous disease; Clm, clarithromycin; Cpfx, ciprofloxacin; Ctri, ceftriaxone; Dcl, dicloxacillin; Gati, gatifloxacin; Lzd, linezolid; Mero, meropenem; Mino,minocycline; Moxi, moxifloxacin; N. brasiliensis, Nocardia brasiliensis; Tic/Clv, ticarcillin-clavulanate; TMP-SMX, trimethoprim-sulfamethoxazole.

a Within 3 weeks of discontinuing linezolid, the patient developed fever and an abnormal affect, which necessitated admission to the hospital. MRI of the brain revealed no abnormal findings, and feverand neurological findings resolved synchronously. Suspected relapse of Nocardia infection was treated with 6 weeks of therapy with ceftriaxone and TMP-SMX (after successful desensitization), and 12months of therapy with TMP-SMX were completed.

b Lzd therapy was followed by long-term suppressive oral therapy with TMP-SMX.c Clm was switched to Gati as a result of severe nausea and vomiting.d For intravenous therapy.e For oral therapy.

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Figure 1. Gadolinium-enhanced MRI of the brain (patient 1). Multiplelesions throughout the cerebral hemispheres are revealed (arrows), in-dicating multiple abscesses.

Figure 2. Follow-up MRI of the brain of patient 1 after he completed12 months of linezolid therapy. The previously demonstrated CNS lesionshave resolved.

associated with antibiotic resistance [3], and 150% of cases

involve disseminated infection [4]. The relative virulence of N.

asteroides complex correlates with the ability to inhibit impor-

tant phagocyte functions, thereby enabling the organism to exist

indefinitely within the host [5].

Nocardia species are primarily opportunists, and infection

occurs more frequently in patients with an underlying im-

munocompromised status. Procedures, conditions, and ther-

apies associated with nocardiosis include organ transplantation,

malignancy, diabetes mellitus, alcoholism, AIDS, and long-term

use of corticosteroids [6]. Nocardia infection has been reported

in patients with underlying chronic granulomatous disease [7].

Sulfonamides have comprised the cornerstone for the treat-

ment of nocardiosis since the 1940s [8]. Combination therapy

with a carbapenem or a third-generation cephalosporin with

or without amikacin usually is recommended for severely ill

patients or for those with CNS involvement [2], for whom the

mortality rate approaches 50% when a sulfonamide alone is

received. New antimicrobial agents are desirable, given the in-

creasing number of reports of resistance to sulfonamides [9,

10], the relatively high incidence of adverse events occurring

during sulfonamide therapy (most notably, among HIV-

infected patients) [11], and the lack of alternative highly active

oral agents.

In vitro studies of the antimicrobial activity of linezolid

against clinical strains of Nocardia species have revealed that

all strains are inhibited by a concentration of �8 mg/mL [12,

13]. However, data from in vivo studies are lacking. We describe

the successful use of linezolid for the treatment of Nocardia

infection in 6 patients (4 adults and 2 children). To our knowl-

edge, this is the first report in the medical literature that de-

scribes the use of linezolid for patients with Nocardia infection.

PATIENTS AND METHODS

Patients with nocardiosis were identified through referral of

clinical isolates to the University of Texas Health Center at Tyler

for susceptibility testing. A diagnosis of Nocardia infection re-

quired a positive culture result for a sample obtained from a

clinically affected site. Clinical isolates were tested at the My-

cobacteria/Nocardia Research Laboratory at the University of

Texas Health Center at Tyler. Species identification of each iso-

late was accomplished using PCR and restriction frag-

ment–length polymorphism analysis of a 439-bp segment of

the 65-kDa heat-shock protein gene, as described elsewhere

[14]. Susceptibility testing was performed using serial 2-fold

microdilution in cation-supplemented Mueller-Hinton broth,

as previously described and recommended by the National

Committee for Clinical Laboratory Standards [15].

Table 1 shows the demographic characteristics, clinical man-

ifestations, previous antimicrobial therapy, indications for li-

nezolid use, and outcomes for the 6 patients with confirmed

nocardiosis who were treated with linezolid; figures 1 and 2

provide a comparison of the MRIs of patient 1, and figures 3

and 4 provide a comparison of the CT scans of patient 5. Table

2 shows the antibiograms for each clinical isolate.

DISCUSSION

To our knowledge, this is the first report that describes the use

of linezolid for the treatment of Nocardia infection. Four of

the 6 patients described had underlying predisposing factors,

as is frequently observed with this pathogen [2, 6]. In addition,

patient 5, who had underlying chronic granulomatous disease,

experienced recurrent Nocardia pneumonia (due to N. brasi-

liensis, followed by N. asteroides sensu stricto), despite receiving



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316 • CID 2003:36 (1 February) • Moylett et al.

Figure 3. CT scan of the chest of patient 5 revealing a large leftupper lobe pneumonia with evidence of central cavitation as well as aprevious right pneumonectomy.

Figure 4. Follow-up CT scan of the chest of patient 5 after he hadreceived linezolid therapy for 6 months. Significant resolution of the leftupper lobe cavitary pneumonia is revealed. Previous right pneumonectomyis again apparent.

appropriate prophylaxis with trimethoprim-sulfamethoxazole

(TMP-SMX). A clinical cure was obtained for all patients, al-

though patient 2, for whom therapy was discontinued pre-

maturely, had a probable recurrence of CNS infection. Linezolid

was generally well tolerated by each patient (most notably, by

patient 5, for whom therapy was continued for 12 years). How-

ever, patient 4 developed significant adverse effects, including

lactic acidosis and peripheral neuropathy, which resolved when

linezolid therapy was discontinued, as recently reported [16].

Anemia developed in 3 patients, necessitating discontinuation

of linezolid therapy for 2 patients (patients 2 and 4). CNS

disease, a complication for which increased associated mortality

is recognized [17], was documented in patients 1 and 4, for

whom a clinical cure was documented after linezolid mono-

therapy (patient 1) and before switching to an alternative ther-

apy (patient 4). Little is known about the adverse effects of

long-term linezolid therapy. The drug is currently approved for

short treatment courses only. However, treatment of nocar-

diosis requires therapy for 6–12 months. Knowledge of the

toxicity associated with long-term linezolid therapy, its fre-

quency, and its severity may help determine what role this drug

or other, as-yet-to-be-developed oxazolidinones will play in the

treatment of Nocardia infection.

Despite the development of numerous new drugs and classes

of drugs during the past 60 years, sulfonamides continue to be

the recommended treatment option for most cases of nocar-

diosis [2, 8]. The drug of choice most typically is TMP-SMX

[18]. However, the principal reason for initiating linezolid ther-

apy in this case series was a history of, or development of,

intolerance to TMP-SMX (4 of 6 patients [67%]). For patients

with a history of drug intolerance, desensitization to TMP-

SMX is a therapeutic option, but it has been our experience

that desensitization with sulfonamides generally has been un-

successful and that it often has been followed by severe reac-

tions, as demonstrated by patient 6 in this series. In addition,

adverse effects of long-term use of TMP-SMX, including fever,

rash, myelosuppression, and renal toxicity, are well recognized

and are commonly problematic, especially among HIV-infected

patients [11, 19, 20]. Antimicrobial agents that are alternatives

to TMP-SMX should be considered for patients with infections

caused by N. farcinica or N. otitidiscaviarum, which demon-

strate inconsistent susceptibility to sulfonamides [21].

Isolated reports describing the use of alternative or additive

oral antimicrobials for the treatment of nocardiosis, such as

amoxicillin-clavulanate, minocycline, and fluoroquinolones,

have appeared in the medical literature [22–25]. However, a

narrow therapeutic margin or the absence of activity against

all Nocardia species has severely limited the use of these po-

tential alternative oral agents. The agents active against most

Nocardia species are intravenously administered drugs, such as

amikacin and ceftriaxone; however, not all Nocardia species are

susceptible (N. transvalensis isolates are amikacin resistant, and

N. farcinica isolates are ceftriaxone resistant). In addition, con-

cerns related to cost, mode of administration, and toxicity often

limit the use of these agents. For severely ill patients or patients



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Table 2. Antibiograms and species identification of the case isolates of Nocardia species recovered from 6 patients withconfirmed nocardiosis.

Antibiotic

Antibiotic MICa (susceptibility determination) for each Nocardia isolate recovered,as per National Committee for Clinical Laboratory Standards guidelines [11]

N. asteroidesb

frompatient 1

N. asteroidesb

frompatient 2

N. brasiliensisfrom

patient 3

N. otitidiscaviarumfrom

patient 4

N. asteroidesb

frompatient 5

N. otitidiscaviarumfrom

patient 6

Amikacin �0.5 (S) 1 (S) 2 (S) 8 (S) 1 (S) 8 (S)

Amox/Clv �1/2 (S) 1128/2 (R) �2/2 (S) 1128/2 (R) 1128/2 (R) 1128/2 (R)

Cefepime 4 (S) 32 (R) 164 (R) Not done 16 (I) 132 (R)

Cefotaxime 4 (S) 32 (I) 32 (I) 132 (R) 32 (I) 132 (R)

Ceftriaxone 2 (S) 32 (I) 32 (I) 132 (R) 32 (I) 132 (R)

Ciprofloxacin 8 (R) 18 (R) 8 (R) 2 (I)c 18 (R) 2 (I)

Clarithromycin 116 (R) 116 (R) 116 (R) �0.25 (S) 116 (R) 2 (S)

Imipenem 16 (R) 8 (I) 132 (R) 132 (R) 8 (I) 132 (R)

Linezolid 1 (S) 2 (S) 4 (S) 2 (S) 2 (S) 4 (S)

Minocycline �1 (S) 2 (S) 8 (R) 2 (I) 4 (I) 4 (I)

Sulfamethoxazole 2 (S) 4 (S) 16 (S) 8 (S) 4 (S) 16 (S)

Tobramycin 1 (S) �0.25 (S) 1 (S) 4 (S) �0.25 (S) 4 (S)

NOTE. Amox/Clv, amoxicillin/clavulanate; I, intermediately susceptible; R, resistant; S, susceptible.a In micrograms per milliliter.b Nocardia asteroides sensu stricto.c Susceptibility to moxifloxacin and gatifloxacin was determined by MICs of 0.5 mg/mL.

with CNS disease, �2 or more drugs, which may include sul-

fonamides, are frequently prescribed, despite the lack of con-

trolled clinical trials, because of the poor results seen with the

use of a sulfonamide or TMP-SMX alone [26].

In this case series, the oral antibiotic options considered to

be alternatives on the basis of the results of the available an-

tibiograms included minocycline for 3 of 6 patients, amoxi-

cillin-clavulanate for 2 of 6 patients, and clarithromycin for 2

of 6 patients. Minocycline and amoxicillin-clavulanate have a

low therapeutic index that makes their use as a single agent,

especially for the treatment of patients with CNS disease, highly

problematic. Clarithromycin may have been an alternative

agent for patient 6; however, success with macrolides for the

treatment of patients with nocardiosis primarily has been re-

ported in association with N. nova (MIC, �0.25 mg/mL). Pa-

tient 4 received clarithromycin for 6 weeks before the onset of

severe nausea and vomiting, which necessitated discontinuation

of such therapy.

Thus, the major limitation in the treatment of nocardiosis

has been the absence of a second oral antimicrobial with activity

against all Nocardia species. Linezolid possesses a broad spec-

trum of in vitro and in vivo activity against a range of gram-

positive bacteria [1] and is available in both intravenous and

oral preparations. Brown-Elliott et al. [12] tested the suscep-

tibility of 140 clinical isolates of Nocardia (7 species) to line-

zolid, including 25 isolates of N. farcinica, 6 isolates of N.

transvalensis complex, and 4 isolates of N. otitidiscaviarum. By

broth microdilution, the MIC 50 and MIC90 for all species other

than N. farcinica were determined to be 2 mg/mL and 4 mg/

mL, respectively. The MIC50 and the MIC90 for N. farcinica were

both 4 mg/mL. Vera-Cabrera et al. [13] examined the activity

of linezolid against 25 strains of N. brasiliensis and obtained

similar results. Susceptibility breakpoints have been suggested

for linezolid at an MIC of �8 mg/mL [12, 15]. To date, no

Nocardia isolates with an MIC of 18 mg/mL have been reported;

therefore, no resistance breakpoints have been proposed.

CNS nocardiosis is associated with significant morbidity and

mortality. A number of recent reports have highlighted the

excellent penetration of the CSF by linezolid after intravenous

administration of the drug every 12 h [27, 28]. Villani et al.

[27] reported the CSF levels of linezolid in patients with gram-

positive CNS infection. In the latter study, the ratio of CSF and

plasma linezolid trough concentrations always exceeded 1, and

of more importance, the CSF linezolid trough concentration

largely exceeded the MICs of the gram-positive isolates being

studied. Similar data concerning Nocardia CNS infection are

not currently available; however, patients 1 and 4 in the present

series demonstrate the efficacy of linezolid for the treatment of

CNS nocardiosis.

Given linezolid’s excellent in vitro susceptibility profile

against a range of Nocardia species, its 100% oral bioavailability,

and its successful treatment of the 6 patients described in the

present study, it would appear to be a valid alternative for the

treatment of Nocardia infections in cases in which TMP-SMX

has failed, where its use is contraindicated, or where a second

agent is indicated. The drug may also be especially useful as



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318 • CID 2003:36 (1 February) • Moylett et al.

initial therapy until susceptibility results for other potential

agents are available. In addition, the cytochrome P-450 enzy-

matic complex neither participates in linezolid metabolism nor

undergoes induction or inhibition by linezolid or its metabo-

lites, making drug interactions less of a concern. The latter is

particularly beneficial with regard to the treatment of patients

already following complex medical regimens, such as patients

with HIV/AIDS or organ transplant recipients. However, a po-

tential disadvantage to prescribing long-term suppressive oral

linezolid therapy is the cost (∼$35,000 for 12 months of treat-

ment, on the basis of twice-daily administration). In addition,

the adverse effects of long-term therapy have not been fully

delineated at this time. Therefore, although linezolid is a wel-

come and useful addition to the armamentarium for the treat-

ment of nocardiosis, at this time, it is an excellent potential

second-line agent.

Acknowledgment

We thank Pharmacia (Peapack, NJ), which provided the drug

used in the treatment of the patients in this study.

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