JAC Advance Access originally published online on April 5, 2007
Journal of Antimicrobial Chemotherapy 2007 59(5):860-865; doi:10.1093/jac/dkm061
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Fluoroquinolone resistance in Mycobacterium tuberculosis isolates: associated genetic mutations and relationship to antimicrobial exposure
1 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
* Corresponding author. Tel: +886-2-23123456 ext. 5355; Fax: +886-2-23224263; E-mail: hsporen{at}ha.mc.ntu.edu.tw
Received 30 November 2006; returned 20 December 2006; revised 31 January 2007; accepted 5 February 2007
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
Objectives: We assessed the fluoroquinolone (FQ) susceptibility of clinical isolates of Mycobacterium tuberculosis in an endemic area. The genetic mutations responsible for FQ resistance were also evaluated.
Methods: A total of 420 M. tuberculosis isolates during January 2004 to December 2005 were randomly selected. Data on the clinical characteristics of the patients were obtained from medical records. The MICs of ofloxacin, ciprofloxacin, levofloxacin and moxifloxacin were determined. Spoligotyping and sequencing of the gyrA and gyrB genes were performed for all isolates resistant to any tested FQ.
Results: Of the 420 isolates, 52 (12.4%), 26 (6.2%), 26 (6.2%) and 30 (7.1%) were resistant to isoniazid, rifampicin, ethambutol and streptomycin, respectively. Multidrug resistance was found in 5.0% of isolates. For all tested FQs, the susceptibility rate was higher than 97%. Resistance to any first-line drug and isolation from a patient with prior anti-tuberculous treatment were correlated with FQ resistance. Multidrug resistance had the strongest correlation with FQ resistance (19% of isolates). Neither the previous use of FQs nor the duration of FQ exposure was correlated with the FQ susceptibility. Of the 14 FQ-resistant isolates, five (35.7%) had gyrA mutations (four D94G and one A90V) and another one (7.1%) had a gyrB mutation (N538D).
Conclusions: This study found FQ resistance in 3.3% of all clinical isolates of M. tuberculosis. FQ resistance was correlated with first-line drug resistance and prior anti-tuberculous treatment, suggesting the need for routine FQ susceptibility testing in patients with these characteristics.
Keywords: M. tuberculosis , TB, multidrug resistance , gyrA , gyrB
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
The fluoroquinolones (FQs) were introduced into clinical practice in Taiwan in 1986. FQs have broad-spectrum antimicrobial activity and so are widely used for the treatment of bacterial infections of the respiratory, gastrointestinal and urinary tracts, as well as sexually transmitted diseases and chronic osteomyelitis.1,2 In contrast to many other antibiotics used to treat bacterial infections, the FQs have excellent in vitro and in vivo activity against Mycobacterium tuberculosis.3–5 FQs are recommended for use as prophylactic treatment of patients exposed to multidrug-resistant tuberculosis (MDR-TB, defined as simultaneously resistant to at least isoniazid and rifampicin), for treatment of proven MDR-TB, for empirical treatment of TB disease in settings with high rates of MDR-TB and for patients with severe adverse reaction to first-line agents.6–8 Recent studies showed that previous FQ use and MDR-TB were associated with FQ resistance in M. tuberculosis isolates,9,10 therefore it is crucial to maintain information about the FQ susceptibility in different patient populations to guide selection of the most appropriate treatment. This is especially important for those patients with recurrent TB after treatment, those with MDR-TB as well as those who have previously received FQ therapy. This study was conducted to assess the FQ susceptibility of M. tuberculosis isolates from patients in a medical centre in Taiwan. In our hospital, isepamicin was a recently available aminoglycoside with a low level of toxicity to the kidney and inner ear,11 clarithromycin was the most commonly used macrolide in treating mycobacterial disease and linezolid was the only available oxazolidinone, and so these were also included in the survey.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
M. tuberculosis isolates
This study was conducted in northern Taiwan at a tertiary-care referral centre with 2000 beds. From January 2004 to December 2005, M. tuberculosis was isolated from 2984 clinical specimens, including 2780 respiratory and 204 non-respiratory specimens. Of them, a total of 2778 isolates were preserved, including 2592 (93.2%) from respiratory specimens and 186 (91.2%) from non-respiratory specimens. Preserved isolates were frozen at –80°C in Dubos liquid medium prior to being subcultured on Lowestein–Jensen medium and incubated at 37°C in an aerobic atmosphere with 5–10% CO2.12 Of the 2778 preserved isolates, 420, from 420 patients, were randomly selected. Susceptibility to isoniazid, rifampicin, ethambutol and streptomycin was tested using the modified proportion disc elution method on 7H10 agar (BBL, Becton Dickson, Franklin Lakes, NJ, USA) as described previously.12
The range of concentrations tested for ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, linezolid and isepamicin was 0.06–128 mg/L. Except for isepamicin, which was tested against 117 M. tuberculosis isolates, all drugs were tested against all 420 isolates. The MICs were determined by serial dilution on agar plates as described previously.13 Resistance was defined as an MIC of >2 mg/L for ciprofloxacin and ofloxacin, >1 mg/L for levofloxacin and >0.5 mg/L for moxifloxacin.9,14
Clinical evaluation of patients
The medical records (including pharmacy records and the interview records from TB case managers), as well as the registered information on the National Surveillance Network of Communicable Disease (Center for Disease Control, Taiwan) of the selected patients were reviewed to identify prior FQ exposure, prior history of TB and anti-tuberculous treatment prior to collection of the clinical specimens.
Spoligotyping and sequencing of the quinolone resistance-determining regions (QRDRs)
Isolates resistant to any tested FQ were selected. Isolation of mycobacterial DNA and spoligotyping were performed as previously described.15,16 Amplification of the QRDRs of the gyrA and gyrB genes of M. tuberculosis was carried out with primers GYRA-1 (5'-CAGCTACATCGACTATGCG) and GYRA-2 (5'-GGGCTTCGGTGTGTACCTCAT) for the gyrA gene,17 and with primers GYRB-1 (5'-CCACCGACATCGGTGGATT) and GYRB-2 (5'-CTGCCAClTGAGTTTlGTACA) for the gyrB gene.18 Briefly, the PCR mixture (100 µL) contained 
1 ng of DNA template, final concentrations of 1.0 µM of each set of primers, 200 µM deoxynucleoside triphosphate (dATP, dCTP, dGTP and dTTP; Pharmacia, Uppsala, Sweden) and 10 µL Taq buffer and 5.0 U/µL Taq polymerase (Gibco-Bethesda Research Laboratories). Amplification was performed for 40 cycles (1 min at 94°C, 1 min at 52°C and 2 min at 72°C). The QRDRs of each isolate were amplified in two independent reactions. The PCR products were purified and sequenced in both directions by an automated sequencer.10
Analysis of the association of factors with FQ resistance was performed using the 
2 test.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
In 2003, the incidence and mortality of TB in Taiwan was 62.4 and 5.8 per 100 000, respectively. Among all TB patients, 7.5% were infected by MDR-TB.19 Of the 420 isolates, 52 (12.4%), 26 (6.2%), 26 (6.2%) and 30 (7.1%) were resistant to isoniazid, rifampicin, ethambutol and streptomycin, respectively. The overall rate of resistance to any one drug was 17.1%, and the MDR rate was 5.0%. The MIC distributions of the seven tested drugs are shown in Table 1. The mean age of the 420 TB patients was 58.0 years (range: 4 months–94 years). A total of 176 (41.9%) patients had underlying disease, the most common being diabetes mellitus (81 patients, 19.3%) and malignancy (71 patients, 16.9%). Serostatus of HIV was tested in 307 (73.1%) patients and was positive in 10 (2.4%). Of the 113 patients with unknown HIV serostatus, all were free of other AIDS-defining illnesses before 30 June 2006. Of the 22 patients receiving immunosuppressant treatment, 11 were post-transplant patients, 8 had autoimmune disease and the remaining 2 had interstitial lung disease. The clinical characteristics of the patients are summarized in Table 2.
|
|
The rates of susceptibility to ofloxacin, ciprofloxacin, levofloxacin and moxifloxacin were 98.3%, 98.6%, 98.6% and 97.6%, respectively. Except for streptomycin resistance, first-line drug resistances were correlated with any FQ resistance (Table 3). This correlation was strongest for MDR isolates. Of the 420 isolates, 108 were isolated from clinical specimens collected after FQ exposure. The median duration of FQ exposure was 7 days (25th percentile: 2; 75th percentile: 15). Four (8.9%) of the 45 patients with previous FQ exposure >1 week and 5 (7.9%) of the 63 with previous FQ exposure
1 week had cavitation on chest images, compared with 50 (16.0%) of the 312 patients without FQ exposure (P = 0.047). Neither the previous exposure to FQs nor the duration of FQ exposure was correlated with the FQ susceptibility of M. tuberculosis isolates (Table 3).
|
Among the 420 M. tuberculosis isolates, 63 were isolated from clinical specimens in patients who had received prior anti-tuberculous treatment. Of them, 19 patients had a prior history of TB post complete treatment and 44 were currently receiving anti-tuberculous treatment. The regimens used were isoniazid + ethambutol + rifampicin + pyrazinamide in 35 patients, isoniazid + ethambutol + rifampicin in 4, isoniazid + rifampicin + pyrazinamide in 2 and FQ-containing anti-tuberculous regimens in the remaining 3. Prior anti-tuberculous treatment was correlated with FQ resistance (Table 3).
A total of 14 isolates were resistant to at least one of the tested FQs. Of them, six belonged to the Beijing family (strains that only hybridized to the last nine spacer oligonucleotides).20 All of the eight non-Beijing strains had unique patterns. Sequencing of the QRDRs was performed for the 14 FQ-resistant isolates and another 28 FQ-susceptible isolates. Of them, 41 isolates had gyrA 95T while only one strain had a gyrA 95S allele. As shown in Table 4, five (35.7%) FQ-resistant isolates had a point mutation in gyrA (four D94G and one A90V). Another one (7.1%) FQ-resistant isolate had a point mutation in gyrB (N538D). No mutations in gyrA and gyrB were found in the remaining 8 FQ-resistant isolates and the 28 FQ-susceptible isolates.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
This study found that clinical isolates of M. tuberculosis had an overall FQ resistance of 3.3% and MDR isolates had a resistance rate of 19%. These rates were lower than those found in previous studies from southern Taiwan (6.2% in general and 22.2% for MDR-TB)10 and the Philippines (35.3% in general and 51.4% in MDR-TB),21 but higher than those found in previous studies conducted from other countries (1.8% in general and 4.1% in MDR-TB in the United States and Canada;3 4.3% in MDR-TB in Russia22). Since the study was performed in a tertiary-care centre, our results could probably be biased towards drug-resistant isolates. However, because several studies demonstrated an association of prior FQ use with the emergence of FQ-resistant M. tuberculosis,9,23 the high FQ resistance rate in the Philippines and Taiwan may reflect the poor control of FQ use in these countries, where all FQs are available without a prescription in local drug stores.21 In our hospital, FQs were prescribed for a total of 7482 and 7987 patient-episodes in 2004 and 2005, respectively, more than 60% being used for respiratory infections. Our further analysis revealed no correlation between previous exposure of FQs and FQ susceptibility of M. tuberculosis isolates. A longer duration of FQ exposure (>1 week versus
1 week) was also not associated with a higher resistance rate (Table 3). Given the previously reported natural prevalence of spontaneous FQ-resistant mutants of M. tuberculosis was 2 x 10–6 to 1 x 10–8 per replicating organism,17 and the large burden of organisms in the pulmonary cavity (1 x 108 cfu/mL on average),24 the significantly lower rate of pulmonary cavitation in patients with previous FQ exposure than in those without (8.3% versus 16.0%, P = 0.047) in this study might explain the reduced in vivo selection of FQ-resistant mutants. The lack of available data on previous medication history outside our hospital, which may have led to failure to consider FQ use prior to the hospital visit, is another possible explanation for these discrepant findings. In addition, the number of isolates in this study may not have been large enough to demonstrate significant differences in FQ susceptibility. The similar proportion of Beijing family (42.9%) among FQ-resistant isolates to that (44.4%) in the general TB population in Taiwan20 and the unique spoligotypes of all of the non-Beijing isolates in this study did not support the clonal spreading of an FQ-resistant strain. Similar to previous studies,10,25 mutation in the QRDR of gyrA was the most common cause of FQ resistance. Other mechanisms, such as mutations in areas of gyrA or gyrB outside of the QRDR, decreased cell-wall permeability to the drug, an active drug efflux pump, sequestration of drug or drug inactivation, probably accounted for the FQ resistance in other FQ-resistant isolates, as well as FQ-resistant isolate 1 and isolate 13 (Table 4).26,27
Although a previous study showed that there was no cross-resistance between FQs and other anti-tuberculous agents,28 the selection of an FQ-resistant subpopulation of M. tuberculosis requires an actively multiplying bacillary population large enough to contain spontaneous drug-resistant mutants.14 Therefore, FQ resistance is primarily seen in patients with drug-resistant TB, especially MDR-TB, treated with an FQ as the only active agent.3,10,14 Our finding that M. tuberculosis isolates resistant to any first-line anti-tuberculous drug (isoniazid, rifampicin and ethambutol) were more likely to have FQ resistance was consistent with these previous studies (Table 3). This association was strongest in MDR isolates. Because of their potent in vitro and in vivo activity,3,4,29 as well as excellent safety record in long-term therapy,30,31 FQs continue to be used for the treatment of TB primarily in cases involving resistance or intolerance to first-line anti-tuberculous drugs. They are also candidates for use as new first-line drugs.31 Therefore we recommend that in Taiwan or other areas with a high FQ resistance rate, FQ susceptibility should be routinely assessed for clinical isolates of M. tuberculosis, especially for drug-resistant isolates, and when patients have a prior history of TB or prior use of anti-tuberculous drugs.
Because MDR-TB has emerged as a threat to TB control worldwide,32 new anti-tuberculous agents with bactericidal mechanisms different from those of available first-line drugs are urgently needed. In addition to FQs, other classes of antimicrobial agents that display various degrees of in vitro and/or in vivo activities against M. tuberculosis include aminoglycosides,33,34 macrolides35 and oxazolidinones.36 Our results showed that 17.6%, 96.0% and 82.9% of the tested M. tuberculosis isolates were susceptible to clarithromycin, linezolid and isepamicin, respectively, if resistance was defined as an MIC of >2 mg/L for clarithromycin35 and >1 mg/L for linezolid36 and isepamicin.34
In conclusion, our study demonstrated that overall clinical isolates were very susceptible to FQs, with a resistance rate of 3.3%. First-line drug resistance, especially MDR, and prior anti-tuberculous treatment were significantly associated with FQ resistance, implying that FQ susceptibility should be routinely assessed in these special situations. Mutations in the QRDR of gyrA (35.7%) and gyrB (7.1%) were the major causes of FQ resistance.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
None to declare.
|
Acknowledgements |
|---|
This study was supported by the Institute for Biotechnology and Medicine Industry, Taiwan.
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionTransparency declarationsReferences |
|---|
1 Bartlett JG, Dowell SF, Mandell LA, et al. (2000) Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 31:347–82.[CrossRef][Medline]
2
Huang ES and Stafford RS. (2002) National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med 162:41–7.
3 Bozeman L, Burman W, Metchock B, et al. (2005) Fluoroquinolone susceptibility among Mycobacterium tuberculosis isolates from the United States and Canada. Clin Infect Dis 40:386–91.[CrossRef][Web of Science][Medline]
4
Gillespie SH and Billington O. (1999) Activity of moxifloxacin against mycobacteria. J Antimicrob Chemother 44:393–5.
5
Wang JY, Hsueh PR, Jan IS, et al. (2006) Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas. Thorax 61:903–8.
6 Yew WW, Chau CH, Wong PC, et al. (1995) Ciprofloxacin in the management of pulmonary tuberculosis in the face of hepatic dysfunction. Drugs Exp Clin Res 21:79–83.[Web of Science][Medline]
7 Gillespie SH and Kennedy N. (1998) Fluoroquinolones: a new treatment for tuberculosis? Int J Tuberc Lung Dis 2:265–71.[Web of Science][Medline]
8 Berning SE. (2001) The role of fluoroquinolones in tuberculosis today. Drugs 61:9–18.[CrossRef][Web of Science][Medline]
9 Ginsburg AS, Hooper N, Parrish N, et al. (2003) Fluoroquinolone resistance in patients with newly diagnosed tuberculosis. Clin Infect Dis 37:1448–52.[CrossRef][Web of Science][Medline]
10
Huang TS, Kunin CM, Shin-Jung Lee S, et al. (2005) Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995–2003. J Antimicrob Chemother 56:1058–62.
11 Jones RN. (1995) Isepamicin (SCH 21420, 1-N-HAPA gentamicin B): microbiological characteristics including antimicrobial potency of spectrum of activity. J Chemother 7:Suppl 2, 7–16.[Medline]
12 Wang JY, Lee LN, Hsueh PR, et al. (2003) Tuberculous myositis: a rare but existing clinical entity. Rheumatology (Oxford) 42:836–40.[Medline]
13 National Committee for Clinical Laboratory Standards. (2003) Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes: Approved Standard(NCCLS, Wayne, PA, USA).
14 Ginsburg AS, Grosset JH, Bishai WR. (2003) Fluoroquinolones, tuberculosis, and resistance. Lancet Infect Dis 3:432–42.[CrossRef][Web of Science][Medline]
15
Plikaytis BB, Crawford JT, Shinnick TM. (1998) IS1549 from Mycobacterium smegmatis forms long direct repeats upon insertion. J Bacteriol 180:1037–43.
16 Kamerbeek J, Schouls L, Kolk A, et al. (1997) Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 35:907–14.[Abstract]
17 Alangaden GJ, Manavathu EK, Vakulenko SB, et al. (1995) Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. Antimicrob Agents Chemother 39:1700–3.[Abstract]
18
Takiff HE, Salazar L, Guerrero C, et al. (1994) Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 38:773–80.
19 Center for Disease Control. (2004) Statistics of Communicable Diseases and Surveillance Report in Taiwan Area, 2003, Taipei, Taiwan Center for Disease Control.
20
Jou R, Chiang CY, Huang WL. (2005) Distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan. J Clin Microbiol 43:95–100.
21 Grimaldo ER, Tupasi TE, Rivera AB, et al. (2001) Increased resistance to ciprofloxacin and ofloxacin in multidrug-resistant Mycobacterium tuberculosis isolates from patients seen at a tertiary hospital in the Philippines. Int J Tuberc Lung Dis 5:546–50.[Web of Science][Medline]
22 Balabanova Y, Ruddy M, Hubb J, et al. (2005) Multidrug-resistant tuberculosis in Russia: clinical characteristics, analysis of second-line drug resistance and development of standardized therapy. Eur J Clin Microbiol Infect Dis 24:136–9.[CrossRef][Web of Science][Medline]
23
Ginsburg AS, Woolwine SC, Hooper N, et al. (2003) The rapid development of fluoroquinolone resistance in M. tuberculosis. N Engl J Med 349:1977–8.
24 Canetti G. (1965) Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 92:687–703.[Web of Science][Medline]
25 Yew WW, Chan E, Chan CY, et al. (2002) Genotypic and phenotypic resistance of Mycobacterium tuberculosis to rifamycins and fluoroquinolones. Int J Tuberc Lung Dis 6:936–7.[Web of Science][Medline]
26
Takiff HE, Cimino M, Musso MC, et al. (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc Nat Acad Sci USA 93:362–6.
27 Jarlier V and Nikaido H. (1994) Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 123:11–8.[CrossRef][Web of Science][Medline]
28
Collins CH and Uttley AH. (1985) In-vitro susceptibility of mycobacteria to ciprofloxacin. J Antimicrob Chemother 16:575–80.
29
Miyazaki E, Miyazaki M, Chen JM, et al. (1999) Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob Agents Chemother 43:85–9.
30 Richeldi L, Covi M, Ferrara G, et al. (2002) Clinical use of levofloxacin in the long-term treatment of drug resistant tuberculosis. Monaldi Arch Chest Dis 57:39–43.[Medline]
31
Burman WJ, Goldberg S, Johnson JL, et al. (2006) Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 174:331–8.
32 World Health Organization/International Union Against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance. (2004) Anti-tuberculosis Drug Resistance in the World: Report No. 3.(WHO, Geneva, Switzerland).
33
Medical Research Council Investigation. (1950) Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid; a Medical Research Council investigation. Brit Med J 2:1073–85.
34 Lounis N, Ji B, Truffot-Pernot C, et al. (1997) Which aminoglycoside or fluoroquinolone is more active against Mycobacterium tuberculosis in mice? Antimicrob Agents Chemother 41:607–10.[Abstract]
35 Doucet-Populaire F, Buriankova K, Weiser J, et al. (2002) Natural and acquired macrolide resistance in mycobacteria. Current Drug Targets 2:355–70.
36
Rusch-Gerdes S, Pfyffer GE, Casal M, et al. (2006) Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second-line drugs and newer antimicrobials. J Clin Microbiol 44:688–92.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Devasia, A. Blackman, T. Gebretsadik, M. Griffin, A. Shintani, C. May, T. Smith, N. Hooper, F. Maruri, J. Warkentin, et al. Fluoroquinolone Resistance in Mycobacterium tuberculosis: The Effect of Duration and Timing of Fluoroquinolone Exposure Am. J. Respir. Crit. Care Med., August 15, 2009; 180(4): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Feuerriegel, H. S. Cox, N. Zarkua, H. A. Karimovich, K. Braker, S. Rusch-Gerdes, and S. Niemann Sequence Analyses of Just Four Genes To Detect Extensively Drug-Resistant Mycobacterium tuberculosis Strains in Multidrug-Resistant Tuberculosis Patients Undergoing Treatment Antimicrob. Agents Chemother., August 1, 2009; 53(8): 3353 - 3356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Xu, X. Li, M. Zhao, X. Gui, K. DeRiemer, S. Gagneux, J. Mei, and Q. Gao Prevalence of Fluoroquinolone Resistance among Tuberculosis Patients in Shanghai, China Antimicrob. Agents Chemother., July 1, 2009; 53(7): 3170 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Coban, K. Bilgin, M. Uzun, A. Akgunes, A. Yusof, and B. Durupinar Comparative Study for Determination of Mycobacterium tuberculosis Susceptibility to First- and Second-Line Antituberculosis Drugs by the Etest Using 7H11, Blood, and Chocolate Agar J. Clin. Microbiol., December 1, 2008; 46(12): 4095 - 4098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Mitnick, S. S. Shin, K. J. Seung, M. L. Rich, S. S. Atwood, J. J. Furin, G. M. Fitzmaurice, F. A. Alcantara Viru, S. C. Appleton, J. N. Bayona, et al. Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis N. Engl. J. Med., August 7, 2008; 359(6): 563 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Mokrousov, T. Otten, O. Manicheva, Y. Potapova, B. Vishnevsky, O. Narvskaya, and N. Rastogi Molecular Characterization of Ofloxacin-Resistant Mycobacterium tuberculosis Strains from Russia Antimicrob. Agents Chemother., August 1, 2008; 52(8): 2937 - 2939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. W. Yew and C. C. Leung Update in Tuberculosis 2007 Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 479 - 485. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||