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Case Series Report of a Linezolid-Containing Regimen for Extensively Drug-Resistant Tuberculosis* FREE TO VIEW

Rany Condos, MD; Nicos Hadgiangelis, MD; Eric Leibert, MD, FCCP; Germaine Jacquette, MD; Timothy Harkin, MD, FCCP; William N. Rom, MD, MPH, FCCP
Author and Funding Information

Affiliations: *From the Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, NY.,  Current address: Odyssey House, New York, NY.,  Current address: Division of Pulmonary and Critical Care Medicine, Mt. Sinai School of Medicine, New York, NY.

Correspondence to: Rany Condos, MD, Bellevue Chest Service, Division of Pulmonary and Critical Care Medicine, NYU School of Medicine, 550 1st Ave, NBV 7N24, New York, NY 10016; e-mail: Rany.Condos@nyumc.org


Chest. 2008;134(1):187-192. doi:10.1378/chest.07-1988
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Published online

Objective: To determine whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB).

Materials and methods: The was conducted in a specialized tuberculosis ward for multidrug-resistant tuberculosis (MDR-TB) on the Chest Service of Bellevue Hospital Center, which is a 768-bed public hospital in New York City. Seven patients with confirmed MDR-TB or XDR-TB who were still culture positive despite appropriate directly observed therapy were treated with a regimen containing linezolid and at least one other active agent.

Results: The linezolid-containing regimen led to sustained negative conversion of sputum cultures and radiographic improvement in all patients. Long-term therapy (longest duration of therapy, 28 months) was well tolerated in most patients. Neutropenia developed in three patients, but was reversible, and peripheral neuropathy developed in two patients.

Conclusions: Linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB. Linezolid is associated with side effects that can be adequately managed. Further studies to define the mechanism of action and optimum dose should be performed.

The treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging, with an overall response rate of 56% in 171 patients reported at a specialty hospital in the pre-HIV era.1We reported a 65% response rate in 173 MDR-TB patients who were treated in the Bellevue Hospital Center Chest Service from 1983 to 1993.2At the 60-month follow-up, the survival rate was 80% in HIV-1–negative patients vs only 5% in those coinfected with HIV-1. The institution of appropriate therapy was a positive predictor of survival and extrapulmonary involvement was a negative predictor. Cure rates as high as 81% have been reported3 in case series with ofloxacin/levofloxacin-containing regimens, and a fluoroquinolone agent now is routinely used in second-line therapy, depending on drug-susceptibility patterns.

The currently available second-line antibiotics that are used to treat MDR-TB are 4 to 10 times more likely to fail to elicit a response than the standard therapy for drug-susceptible tuberculosis (TB) and are about 100 times more costly.4 New drug development has been hampered by the enormous resources required for large-scale studies, the difficulties in evaluating a drug of interest in a multidrug regimen, and the lack of incentive on the part of pharmaceutical companies in developing a drug for a resource-poor population.

Linezolid is an oral antibiotic that is the first to be approved from the oxazolidinone class with demonstrated in vitro activity against both drug-susceptible and drug-resistant isolates of Mycobacterium tuberculosis without cross-resistance with the standard antituberculous agents.5Linezolid reaches microbicidal levels in the epithelial lining fluid of the lung and has been shown to have activity against M tuberculosis in a murine model.6 Two reports78 regarding MDR-TB have emphasized the treatment-limiting toxicities of the drug, which include peripheral neuropathy and myelosuppression. Despite these toxicities, cures were described by both groups in patients treated with a linezolid-containing regimen. We used linezolid in a second-line regimen for the treatment of XDR-TB according to drug sensitivities where no acceptable alternative existed among the available drugs, and we reported on its safety, tolerability, and efficacy in seven patients.

Bellevue Hospital Center, which is a 768-bed New York City municipal hospital, is a referral center for difficult-to-treat patients with MDR-TB. Most patients are referred from the New York City Department of Health (NYCDOH) because of lack of response to treatment and/or drug intolerance. Starting in January 2000 and lasting until June 2007, in collaboration with the NYCDOH we began to use linezolid as a component of second-line therapy in patients for whom no adequate alternate treatment could be found. All patients signed informed consent forms for participation in this phase I clinical trial of an off-label use of linezolid. This included all patients treated in the Bellevue Hospital Center Chest Service with linezolid during this time period. Linezolid was used as part of a “salvage” regimen in drug-resistant patients who were not responding to therapy.

In addition to linezolid, all patients received a regimen that included at least one other drug that was likely to retain activity against their isolate. Linezolid was administered orally at the US Food and Drug Administration-approved dose (600 mg bid) to all adult patients. Our pediatric patient received 600 mg/d. Patients were not receiving monoamine oxidase inhibitors, and each patient was counseled to maintain a low tyramine diet. Four of seven patients also received recombinant human interferon (IFN)-γ in an aerosol dose of 500 μg administered three times weekly as part of their regimen. We previously showed that therapy with IFN-γ was a well-tolerated treatment that may be useful as adjunctive therapy in patients with MDR-TB.9 The NYCDOH provided the IFN-γ for these patients. The M tuberculosis isolate and the drug sensitivity and resistance patterns for all patients were verified through NYCDOH records. All samples had susceptibility testing performed either through the NYCDOH or through the Bellevue Hospital Mycobacteriology Laboratory. Linezolid sensitivity testing is not routinely performed by our laboratory. The safety and tolerability of linezolid were assessed using clinical data (ie, medical history findings, physical examination findings, and serum chemistry levels from inpatient and outpatient records). Efficacy was evaluated by clinical and radiographic improvement, and by sputum culture conversion.

Seven patients (six female patients) were treated, and their demographic data are summarized in Table 1 . The patients’ ages ranged from 10 to 50 years at the time of the diagnosis. One patient was coinfected with HIV-1, and one patient was a liver transplant recipient.

The drugs added to the regimen to which patients had not responded are outlined in Table 1. In each case, we attempted to add a minimum of two drugs to that regimen, of which one was linezolid. The companion drug was tailored to the drug susceptibilities of the M tuberculosis isolate whenever possible. Therapy with linezolid, 600 mg po bid, and aerosol IFN-γ, three times a week, was added to the failing regimen in four patients. Patients 4, 5, and 7 received linezolid, 600 mg/d, and patients 5 to 7 did not receive any IFN-γ therapy. Because of the complexity of each patient’s course of treatment, we have provided brief clinical vignettes to better illustrate the types of patients who received this therapy.

Patient 1

A 41-year-old HIV-negative woman with brittle insulin-dependent diabetes mellitus had cavitary TB in 1993 that was treated with a second-line TB regimen and left pneumonectomy. She relapsed in 1996 with cavitary disease of the right lung due to noncompliance with therapy. Despite improved adherence with directly observed therapy, she remained culture positive, and in 2000 linezolid, IFN-γ, clofazimine, and para-aminosalicylic acid were added to her failing regimen. She converted her sputum culture to negative within 2 months of starting to receive the linezolid-containing regimen and had completed all TB treatments after 26 months. She relapsed 7 months later with evidence of active TB, but died shortly thereafter of unrelated causes. Her clinical isolates in 2000 and 2002 had the same IS6110 pattern. The isolate from the time of relapse was still extensively drug-resistant TB (XDR-TB), although it was not tested for continued sensitivity to linezolid.

Patient 2

A 27-year-old HIV-negative Tibetan women who was in the United States for 1 year, had right upper lobe cavitary TB and MDR-TB diagnosed in May 2001. She was begun on therapy with isoniazid, cycloserine, capreomycin, and levofloxacin. Despite adequate directly observed therapy, her sputum acid-fast bacillus smears and cultures remained positive for M tuberculosis, and she continued to lose weight. She underwent a right pneumonectomy in November 2001, and ethionamide, linezolid and IFN-γ aerosol were added to her failing regimen. She became culture negative 7 days after beginning treatment with the linezolid-containing regimen and completed an 18-month course in July of 2003. She has undergone 4 years of follow-up without signs of relapse or recurrence of the disease.

Patient 3

A 42-year-old, HIV-negative, African-American woman received a diagnosis of noncavitary, drug-resistant TB in 1993. She was initially poorly adherent and remained culture positive for M tuberculosis until 1995 when she underwent a left pneumonectomy. She relapsed in 1997 and received various treatment regimens, including high-dose isoniazid, sparfloxacin, and amoxicillin, without response. In 2000, she was started on therapy with linezolid and IFN-γ aerosol. Her acid-fast bacillus sputum cultures converted to negative 5 months after she had started on therapy with a linezolid-containing regimen, and her cultures remained negative for TB while receiving therapy when she died suddenly 21 months after culture conversion. Autopsy revealed granulomatous inflammation, but cultures grew only Mycobacterium avium. Her sudden death was thought to be unrelated to her TB or her treatment.

Patient 4

A 10-year-old HIV-1–positive (CD4+ count, 458 cells/μL; viral load, 110,000) girl received a diagnosis of cavitary, drug-resistant TB involving her left upper lobe and pericardium in December 2000. By September 2001, despite in-hospital therapy with 100% adherence, she had positive cultures for M tuberculosis and progression of her disease seen on chest radiographs. Linezolid, imipenem, and IFN-γ aerosol were added to her therapeutic regimen. She became culture negative after 1 month of receiving treatment with the linezolid-containing regimen and completed 24 months of treatment in August 2003. She has been asymptomatic and relapse-free since then.

Patient 5

A 50-year-old woman with a history of hepatitis C complicated by cirrhosis had received a liver transplant in 1996 presented with right upper lobe consolidation and MDR-TB in 2002. The patient was receiving immunosuppressant therapy, including tacrolimus and low-dose prednisone. ARDS developed due to sepsis with smears and cultures that were persistently positive for M tuberculosis. Linezolid, capreomycin, and ethionamide were added to her failing regimen, and she became culture negative for M tuberculosis. She received a total of 9 months of therapy with the linezolid-containing regimen and died of non–TB-related causes without evidence of recurrence or relapse.

Patient 6

A 38-year-old HIV-negative, Tibetan man received a diagnosis of cavitary, drug-resistant TB in November 2005. His smears and cultures remained positive for M tuberculosis while receiving therapy with a regimen of ethionamide, levofloxacin, and cycloserine. In June 2006, he was admitted to the hospital for medication intolerance and diarrhea, and declined further use of ethionamide. In his therapeutic regimen, moxifloxacin was substituted for levofloxacin, and linezolid and clofazimine were added. Cultures converted to negative in 74 days. Ethionamide was reintroduced successfully with antacids and antiemetics after culture conversion. He has completed 18 months of therapy to date with weight gain and radiographic improvement. His course of linezolid has been complicated by anemia and neutropenia, which responded to colony-stimulating factors; by hair thinning; and by mild peripheral neuropathy. Peripheral neuropathy consisted of mild sensory dysesthesia in a stocking distribution, and has been self-limited and nonprogressive. Symptoms predated the addition of linezolid to the regimen.

Patient 7

A 21-year-old Tibetan woman with a history of treatment in India was referred to Bellevue Hospital for the management of XDR-TB with bilateral disease, including extensive left lung fibrocavitary disease. Because drug resistance was recognized early, there was no lack of response to MDR-TB treatment. She was treated with a regimen of cycloserine, moxifloxacin, capreomycin, ethambutol, linezolid, and clofazimine. Her course was complicated by peripheral eosinophilia to 55% and eosinophilic gastroenteritis. These conditions resolved within 1 month of stopping therapy with clofazimine. Her course of linezolid has been complicated by mild peripheral neuropathy confirmed by electromyogram. Her symptoms improved with a reduction in dosage to 600 mg/d. Her culture converted on day 101. She underwent a left pneumonectomy on day 204, which was several months after the culture conversion. She has completed 18 months of therapy, with cultures remaining negative, weight gain, and significant radiographic improvement.

The linezolid regimen led to sustained sputum cultures that were negative for M tuberculosis in all patients (Table 2) . The time to sputum culture conversion while receiving linezolid ranged from 0 to 118 days. Patients 2 and 5 had rapid culture conversion with the addition of linezolid following pneumonectomy in the first case and after an episode of ARDS in the second case. Patient 2 completed an 18-month course of linezolid since XDR-TB is treated as a systemic chronic disease, and patient 5 completed 9 months prior to her death. Sputum conversion was accompanied by radiographic improvement in six of seven patients.

Long-term therapy (longest duration, 28 months) was well tolerated in most patients. Patients 2, 5, and 6 experienced reversible neutropenic episodes. The episodes resolved completely after medication withdrawal and did not recur when linezolid therapy was restarted at a lower dose (600 mg/d). In patient 6, anemia and neutropenia, which responded to therapy with colony-stimulating factors, and hair thinning, tooth discoloration, and mild peripheral neuropathy developed. Patient 7 also experienced mild peripheral neuropathy that was confirmed by electromyogram, and his condition improved after receiving a lower dose of linezolid (600 mg). No other patients experienced adverse events (eg, anemia, peripheral neuropathy, hepatotoxicity, lactic acidosis, or pancreatitis).

Patient 1 had severe upper and lower GI distress that was attributed to para-aminosalicylic acid throughout her 28-month course. She was often excused from receiving medication, and she received only about 60% of her planned doses. Three of the five patients (patients 1, 2, and 4) completed 24 months of therapy after sputum culture conversion. Patients 2, 4, 6, and 7 remain well with no evidence of recurrence. Patient 3 died suddenly 22 months after culture conversion, while still receiving therapy. The autopsy revealed no evidence of active TB. Patients 6 and 7 have had cultures that have been persistently positive for M tuberculosis for the past 18 months and are tolerating the linezolid regimen.

Incomplete and inadequate treatment is the most important factor leading to the development of MDR-TB.10MDR-TB, which is defined as resistance to at least isoniazid and rifampin, historically has had a poor prognosis despite treatment.11 Success rates as high as 90% have been reported with the use of fluoroquinolone agents.3 Resistance to fluoroquinolone agents ranges from 0.15% in the United States12to 35% in the Philippines.13We found resistance to a fluoroquinolone in 12% of MDR-TB isolates at Bellevue Hospital during the period from 1992 to 2001.14 Six of the seven patients in this report experienced fluoroquinolone resistance (the other patient did not respond to a regimen that included a fluoroquinolone), and all patients were resistant to aminoglycosides, capreomycin, or both. We have shown that an individualized regimen with linezolid therapy, immunomodulation, and surgery can be successful. All patients were not responding to optimal drug regimens that had been tailored to patients based on their sensitivities and tolerance. These circumstances led us to add linezolid plus at least one additional new drug to therapy.

Linezolid is a synthetic antibacterial agent from the oxazolidinone class that inhibits bacterial protein synthesis at an early stage of translation.15 The oral bioavailability of linezolid is almost 100%, with a high volume of distribution and high concentrations in alveolar macrophages.5,1617 Linezolid and a related oxazolidinone (PNU-100480) have shown efficacy, slightly less than that of isoniazid, in the treatment of a murine model of TB.6 Disseminated Mycobacterium chelonae was successfully treated using linezolid as a single agent in a 90-day regimen for a clarithromycin-resistant isolate.,18Linezolid was also successfully employed by Valencia et al19 for three MDR-TB patients in combination with other drugs. Fortun et al8 reported on five TB patients (both MDR-TB and resistant Mycobacterium bovis) who had been treated successfully with linezolid. Only one MDR-TB patient had undergone long-term follow-up while receiving the linezolid-containing regimen.,8 von der Lippe et al7 reported on treatment-limiting toxicities in 10 patients with MDR-TB who had been treated with linezolid. These patients were all multidrug resistant, but only one patient was treated with linezolid as part of a second-line regimen after having not responded to prior treatment for 42 months. Most of the other patients (7 of 10 patients) were treated with a linezolid-containing regimen within 2 months of diagnosis and were receiving a fluoroquinolone-containing regimen to which they were susceptible. Seven of the 10 patients experienced serious adverse events leading to the discontinuation of the linezolid treatment. Non-treatment-limiting adverse events developed in our patients. They were treated on a specialized TB unit with close inpatient and outpatient follow-up. Our improved safety profile may reflect the close follow-up and experience of the Bellevue Hospital Center Chest Service in treating these patients with difficult conditions.

We have reported on seven patients who were treated with linezolid as part of their therapy for XDR-TB resulting in sputum conversion. The most common side effect experienced in our group of linezolid-treated patients was neutropenia, which quickly (ie, within 1 week) began to resolve following discontinuation of the medication and did not recur in two patients after being rechallenged with a lower dose. Myelosuppression has been reported2021 at rates of 0.1 to 2.4% in patients receiving at least 14 days of therapy with linezolid. In addition, Meissner et al22 reported no difference in the occurrence of hematologic events in children with Gram-positive infections who had been treated with linezolid compared with those who had been treated with vancomycin. In a similar group of TB patients, von der Lippe et al7 found treatment-limiting toxicities in 70% of the patients. Peripheral neuropathy (6 of 10 patients) and/or bone marrow suppression (5 of 10 patients) developed in most patients. Three patients required transfusion for the treatment of symptomatic anemia. In our series, two patients had evidence of peripheral neuropathy, despite the fact that most of our patients had comorbid diseases, such as diabetes, that may predispose patients to such complications. More than 20 cases of peripheral and/or optic neuropathy have been reported since 2002.23 In most cases, linezolid therapy was discontinued at the appearance of neuropathic symptoms. Both of our patients continued to receive treatment with stable or improving symptoms. Close follow-up is essential in any patient who receives long-term treatment. Overall, we found linezolid to be tolerated in patients receiving long-term therapy (longest duration of therapy, 28 months) without serious adverse events. One reason that we were able to continue treatment despite the appearance of side effects may be that most of our patients were in the hospital or a specialized TB unit, or were closely observed in the DOT Program for adverse events and concomitant medication use.

The efficacy of the linezolid-containing regimen was assessed by sputum conversion times that averaged 53 days (range, 0 to 118 days). Radiographic and clinical improvement was seen in all seven patients. In 158 consecutive MDR-TB patients who were treated in Turkey, cultures became negative after a mean time of 1.9 months, with better results occurring in younger patients who had not been treated previously with fluoroquinolones.24 As cases of XDR-TB have emerged, the need for alternative treatment regimens has become obvious. The addition of linezolid to the regimen not being responded to in our series led to persistent sputum culture conversion followed by radiographic improvement. The tolerability of the therapy was adequate, and, as such, linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB.

Abbreviations: IFN = interferon; MDR-TB = multidrug-resistant tuberculosis; NYCDOH = New York City Department of Health; TB = tuberculosis; XDR-TB = extensively drug-resistant tuberculosis

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Table Graphic Jump Location
Table 1. Demographic and Treatment Data for Seven Patients With XDR-TB Treated With a Salvage Regimen Including Linezolid*
* 

CIP = ciprofloxacin; CLO = clofazimine; INH = isoniazid; AUG = amoxicillin; KAN = kanamycin; PZA = pyrazinamide; EMB = ethambutol; MOX = moxifloxacin; AMI = amikacin; ETA = ethionamide; RBT = rifabutin; CAP = capreomycin; CYC = cycloserine; LEV = levofloxacin; PAS = para-aminosalicylic acid; IRPES = isoniazid, rifampin, pyrazinimide, ethambutol, streptomycin.

Table Graphic Jump Location
Table 2. Mycobacteriology Data for Seven XDR-TB Patients Treated With Linezolid*
* 

Time to culture conversion ranged from 0 to 118 days. Negative = no acid-fast bacilli in 100 high-power fields; + = 1 to 9 acid-fast bacilli in 100 high-power fields; ++ = 1 to 9 acid-fast bacilli in 10 high-power fields; +++ = 1 to 9 acid-fast bacilli in 1 high-power field; ++++ = > 9 acid-fast bacilli in 1 high-power field.

Goble, M, Iseman, MD, Madsen, LA, et al (1993) Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin.N Engl J Med328,527-532
 
Park, MM, Davis, AL, Schluger, NW, et al Outcome of MDR-TB patients, 1983–1993: prolonged survival with appropriate therapy.Am J Respir Crit Care Med1996;153,317-324
 
Yew, WW, Chan, CK, Leung, CC, et al Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong.Chest2003;124,1476-1481
 
Horsburgh, CR, Jr The global problem of multidrug-resistant tuberculosis: the genie is out of the bottle.JAMA2000;283,2575-2576
 
Zurenko, GE, Yagi, BH, Schaadt, RD, et al In vitroactivities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother1996;40,839-845
 
Cynamon, MH, Klemens, SP, Sharpe, CA, et al Activities of several novel oxazolidinones againstMycobacterium tuberculosisin a murine model.Antimicrob Agents Chemother1999;43,1189-1191
 
von der Lippe, B, Sandven, P, Brubakk, O Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB): a report of ten cases.J Infect2006;52,92-96
 
Fortun, J, Martin-Davila, P, Navas, E, et al Linezolid for the treatment of multidrug-resistant tuberculosis.J Antimicrob Chemother2005;56,180-185
 
Condos, R, Rom, WN, Schluger, NW Treatment of multidrug-resistant pulmonary tuberculosis with interferon-γ via aerosol.Lancet1997;349,1513-1515
 
Sharma, SK, Mohan, A Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control.Chest2006;130,261-272
 
Iseman, MD Treatment of multidrug-resistant tuberculosis.N Engl J Med1993;329,784-790
 
Bozeman, L, Burman, W, Metchock, B, et al Fluoroquinolone susceptibility amongMycobacterium tuberculosisisolates from the United States and Canada.Clin Infect Dis2005;40,386-391
 
Grimaldo, ER, Tupasi, TE, Rivera, AB, et al Increased resistance to ciprofloxacin and ofloxacin in multidrug-resistantMycobacterium tuberculosisisolates from patients seen at a tertiary hospital in the Philippines.Int J Tuberc Lung Dis2001;5,546-550
 
Shih, PH, Bonk, S, Rom, WN, et al Incidence of quinolone resistance in multidrug-resistant tuberculosis [abstract].Am J Respir Crit Care Med2003;167,A869
 
Shinabarger, DL, Marotti, KR, Murray, RW, et al Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions.Antimicrob Agents Chemother1997;41,2132-2136
 
Honeybourne, D, Tobin, C, Jevons, G, et al Intrapulmonary penetration of linezolid.J Antimicrob Chemother2003;51,1431-1434
 
Pascual, A, Ballesta, S, Garcia, I, et al Uptake and intracellular activity of linezolid in human phagocytes and nonphagocytic cells.Antimicrob Agents Chemother2002;46,4013-4015
 
Brown-Elliott, BA, Crist, CJ, Mann, LB, et al In vitroactivity of linezolid against slowly growing nontuberculous Mycobacteria.Antimicrob Agents Chemother2003;47,1736-1738
 
Valencia, ME, Moreno, V, Laguna, F, et al Multiresistant tuberculosis caused byMycobacterium bovisand human immunodeficiency virus infection: are there new therapeutic possibilities?Enferm Infecc Microbiol Clin2001;19,37-39
 
Rubinstein, E, Isturiz, R, Standiford, HC, et al Worldwide assessment of linezolid’s clinical safety and tolerability: comparator-controlled phase III studies.Antimicrob Agents Chemother2003;47,1824-1831
 
French, G Safety and tolerability of linezolid.J Antimicrob Chemother2003;51(suppl),ii45-ii53
 
Meissner, HC, Townsend, T, Wenman, W, et al Hematologic effects of linezolid in young children.Pediatr Infect Dis J2003;22(suppl),S186-S192
 
Narita, M, Tsuji, BT, Yu, VL Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome.Pharmacotherapy2007;27,1189-1197
 
Tahaoglu, K, Torun, T, Sevim, T, et al The treatment of multidrug-resistant tuberculosis in Turkey.N Engl J Med2001;345,170-174
 

Figures

Tables

Table Graphic Jump Location
Table 1. Demographic and Treatment Data for Seven Patients With XDR-TB Treated With a Salvage Regimen Including Linezolid*
* 

CIP = ciprofloxacin; CLO = clofazimine; INH = isoniazid; AUG = amoxicillin; KAN = kanamycin; PZA = pyrazinamide; EMB = ethambutol; MOX = moxifloxacin; AMI = amikacin; ETA = ethionamide; RBT = rifabutin; CAP = capreomycin; CYC = cycloserine; LEV = levofloxacin; PAS = para-aminosalicylic acid; IRPES = isoniazid, rifampin, pyrazinimide, ethambutol, streptomycin.

Table Graphic Jump Location
Table 2. Mycobacteriology Data for Seven XDR-TB Patients Treated With Linezolid*
* 

Time to culture conversion ranged from 0 to 118 days. Negative = no acid-fast bacilli in 100 high-power fields; + = 1 to 9 acid-fast bacilli in 100 high-power fields; ++ = 1 to 9 acid-fast bacilli in 10 high-power fields; +++ = 1 to 9 acid-fast bacilli in 1 high-power field; ++++ = > 9 acid-fast bacilli in 1 high-power field.

References

Goble, M, Iseman, MD, Madsen, LA, et al (1993) Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin.N Engl J Med328,527-532
 
Park, MM, Davis, AL, Schluger, NW, et al Outcome of MDR-TB patients, 1983–1993: prolonged survival with appropriate therapy.Am J Respir Crit Care Med1996;153,317-324
 
Yew, WW, Chan, CK, Leung, CC, et al Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong.Chest2003;124,1476-1481
 
Horsburgh, CR, Jr The global problem of multidrug-resistant tuberculosis: the genie is out of the bottle.JAMA2000;283,2575-2576
 
Zurenko, GE, Yagi, BH, Schaadt, RD, et al In vitroactivities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother1996;40,839-845
 
Cynamon, MH, Klemens, SP, Sharpe, CA, et al Activities of several novel oxazolidinones againstMycobacterium tuberculosisin a murine model.Antimicrob Agents Chemother1999;43,1189-1191
 
von der Lippe, B, Sandven, P, Brubakk, O Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB): a report of ten cases.J Infect2006;52,92-96
 
Fortun, J, Martin-Davila, P, Navas, E, et al Linezolid for the treatment of multidrug-resistant tuberculosis.J Antimicrob Chemother2005;56,180-185
 
Condos, R, Rom, WN, Schluger, NW Treatment of multidrug-resistant pulmonary tuberculosis with interferon-γ via aerosol.Lancet1997;349,1513-1515
 
Sharma, SK, Mohan, A Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control.Chest2006;130,261-272
 
Iseman, MD Treatment of multidrug-resistant tuberculosis.N Engl J Med1993;329,784-790
 
Bozeman, L, Burman, W, Metchock, B, et al Fluoroquinolone susceptibility amongMycobacterium tuberculosisisolates from the United States and Canada.Clin Infect Dis2005;40,386-391
 
Grimaldo, ER, Tupasi, TE, Rivera, AB, et al Increased resistance to ciprofloxacin and ofloxacin in multidrug-resistantMycobacterium tuberculosisisolates from patients seen at a tertiary hospital in the Philippines.Int J Tuberc Lung Dis2001;5,546-550
 
Shih, PH, Bonk, S, Rom, WN, et al Incidence of quinolone resistance in multidrug-resistant tuberculosis [abstract].Am J Respir Crit Care Med2003;167,A869
 
Shinabarger, DL, Marotti, KR, Murray, RW, et al Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions.Antimicrob Agents Chemother1997;41,2132-2136
 
Honeybourne, D, Tobin, C, Jevons, G, et al Intrapulmonary penetration of linezolid.J Antimicrob Chemother2003;51,1431-1434
 
Pascual, A, Ballesta, S, Garcia, I, et al Uptake and intracellular activity of linezolid in human phagocytes and nonphagocytic cells.Antimicrob Agents Chemother2002;46,4013-4015
 
Brown-Elliott, BA, Crist, CJ, Mann, LB, et al In vitroactivity of linezolid against slowly growing nontuberculous Mycobacteria.Antimicrob Agents Chemother2003;47,1736-1738
 
Valencia, ME, Moreno, V, Laguna, F, et al Multiresistant tuberculosis caused byMycobacterium bovisand human immunodeficiency virus infection: are there new therapeutic possibilities?Enferm Infecc Microbiol Clin2001;19,37-39
 
Rubinstein, E, Isturiz, R, Standiford, HC, et al Worldwide assessment of linezolid’s clinical safety and tolerability: comparator-controlled phase III studies.Antimicrob Agents Chemother2003;47,1824-1831
 
French, G Safety and tolerability of linezolid.J Antimicrob Chemother2003;51(suppl),ii45-ii53
 
Meissner, HC, Townsend, T, Wenman, W, et al Hematologic effects of linezolid in young children.Pediatr Infect Dis J2003;22(suppl),S186-S192
 
Narita, M, Tsuji, BT, Yu, VL Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome.Pharmacotherapy2007;27,1189-1197
 
Tahaoglu, K, Torun, T, Sevim, T, et al The treatment of multidrug-resistant tuberculosis in Turkey.N Engl J Med2001;345,170-174
 
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