Reviews in Health Care 2012; 3(1): 17-31

Drugs

Narrative review

Role of fluoroquinolones in the treatment of tuberculosis

Suhail Ahmad 1, Eiman Mokaddas 1

1 Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait

Abstract

Introduction: The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis is hampering efforts to control the global tuberculosis (TB) epidemic. Although treatment of drug-susceptible TB is possible in ≥ 95% of disease cases, long (≥ 6 months) duration of supervised combination therapy is challenging. Non-adherence to treatment often results in much lower cure rates. Treatment of MDR-TB and XDR-TB is far less effective. The aim of this review is to summarize the current status of fluoroquinolones in shortening the duration of drug-susceptible pulmonary TB and in improving the outcome of MDR-TB/XDR-TB.

Methods: All the relevant articles were identified through a search of PubMed and Scopus databases by using search terms like tuberculosis (or M. tuberculosis), fluoroquinolones, drug-susceptible TB, MDR-TB, XDR-TB, combination therapy, treatment regimens, treatment duration, drug target and drug resistance. The current literature on the role of fluoroquinolones in the treatment of TB was reviewed.

Results: The fluoroquinolones, particularly newer compounds such as levofloxacin, moxifloxacin and gatifloxacin, have bactericidal activity against M. tuberculosis, excellent oral bioavailability, favorable safety profile and no cross-resistance with other first-line anti-TB drugs. Data from phase II trials of fluoroquinolones-containing regimens for shortening the duration of treatment for pulmonary TB are encouraging and phase III trials are currently underway. The fluoroquinolones are also effective as substitute agents for those individuals who are intolerant to first-line drugs. Several studies and clinical trials have also supported the use of fluoroquinolones in patients with MDR-TB/XDR-TB.

Discussion: The fluoroquinolones-containing regimens are being tested to shorten the duration of treatment for pulmonary TB to 4 months. They are also regarded as one of the two cornerstone drugs for the treatment of MDR-TB/XDR-TB. However, they are also among the commonly prescribed antibiotics for lower respiratory tract infections and are becoming increasingly associated with delayed treatment and resistance in TB. If these trends are not reversed soon, we may lose fluoroquinolones as effective anti-TB agents very rapidly.

Keywords

Fluoroquinolones; Drug-susceptible tuberculosis; Multidrug-resistant tuberculosis; Resistance

Corresponding author

Suhail Ahmad

Department of Microbiology

Faculty of Medicine, AMAR Health Sciences Center

Kuwait University, PO box 24923, Safat 13110 – Kuwait

Email: suhail_ah@hsc.edu.kw; suhail_ah2000@yahoo.com

Tel: 00965-2498-6503; Fax: 00965-2531-8454

Disclosure

The authors declare that they have no financial competing interests

Introduction

Despite concerted worldwide efforts, tuberculosis (TB) continues to remain a major public health issue of our times as it contributes considerably to illness and death around the world. Active TB disease is caused primarily by the obligate human pathogen Mycobacterium tuberculosis. Currently, the TB epidemic is being sustained and fuelled by two major factors: global human immunodeficiency virus (HIV) infection and its association with active TB disease and increasing resistance of M. tuberculosis strains to the most effective (first-line) anti-TB drugs [1,2]. Other factors contributing to the resurgence of active TB disease include inadequate TB control and prevention programs as well as poor case detection/cure rates in endemic countries, and disease association with other underlying conditions including diabetes [1-3].

Close contact with sputum-positive pulmonary TB patients is mainly responsible for new infections in a community. Incidentally, primary infection with M. tuberculosis leads to clinical disease in only ~10% of exposed individuals while initial growth and multiplication of M. tuberculosis is arrested by the protective immune response in the remaining cases. However, pathogen clearance occurs in ~10% people while the remaining ~90% individuals succeed in containment of infection only as some bacilli escape killing and remain in non-replicating (latent) state in granulomatous lesions [4]. The dormant bacilli can resuscitate and cause active TB in the event of disruption of host’s immune response [5]. The World Health Organization (WHO) has estimated that 2.2 billion people worldwide are now latently infected with M. tuberculosis and 5-10% of the infected individuals will eventually develop active TB disease during their life time [5,6]. However, the annual risk of active TB is 5-15% and the lifetime risk is ~50% in HIV-seropositive individuals [1,7].

Epidemiology of TB and drug-resistant TB

The current estimates of global burden of TB are based on the results of yearly surveys conducted by the WHO for the prevalence of infection. In 2009, 9.4 million incident cases of active TB disease and 1.68 million deaths occurred worldwide [1]. Most of the estimated TB cases in 2009 occurred in Asia (55%) followed by Africa (30%) while smaller proportions of cases occurred in Eastern Mediterranean region (7%), European region (4%) and the region of the Americas (3%). The highest incidence rate (340 per 100,000 population) was recorded for the African region, mainly due to higher prevalence of concomitant HIV infection [1]. Pulmonary TB accounted for > 85% of active TB cases in high TB incidence countries while extrapulmonary TB was more common in low TB incidence countries [1,8,9].

The WHO has also performed surveys for estimating drug susceptibility testing (DST) data for first-line drugs: isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and streptomycin (SM) [2]. Resistance to at least one anti-TB drug (defined as “any resistance”) among previously treated TB patients (25.1%) was higher than in new TB cases (11.1%). The worldwide average for multidrug-resistance (MDR) (defined as infection with M. tuberculosis strains resistant at least to INH and RMP) was also higher in previously treated TB cases compared to new cases (11.7% versus 1.6%, respectively). Monoresistance to RMP occurs rarely except in individuals co-infected with HIV or with other underlying conditions and resistance to RMP is considered a good surrogate marker for infection with MDR strains of M. tuberculosis (MDR-TB) [2,10,11]. The highest percentage of MDR-TB cases have been estimated for Eastern European countries (19.2%) followed by Western Pacific region (7%) and Southeast Asia (4.3%). Overall, ~440,000 cases of MDR-TB occurred in 2008, resulting in 150,000 deaths [12].

The MDR-TB is a major threat to global public health as it is more difficult to treat than drug-susceptible TB and often results in relapse or treatment failure [13-16]. It is also a risk factor for the emergence of extensively drug-resistant (XDR) TB (defined as infection with MDR-TB strains additionally resistant to a fluoroquinolone and an injectable anti-TB agent such as kanamycin, amikacin, capreomycin or viomycin) [12,17]. The XDR-TB is more difficult to treat than MDR-TB even in developed countries and is virtually an untreatable disease in much of the developing world [18-22]. By 2009, the presence of XDR-TB has been documented in 58 countries. Nearly 5.4% of all MDR-TB cases were found to have XDR-TB in 46 countries while eight countries reported XDR-TB in > 10% of all MDR-TB cases. No information on the incidence of XDR-TB is available for several other countries that have a high incidence of MDR-TB and many of these countries have reported a high incidence of fluoroquinolone resistance among MDR-TB strains, indicating that the worldwide incidence of XDR-TB is likely to climb further [12].

Fluoroquinolones as anti-TB drugs

Fluoroquinolones (FQs) are broad-spectrum bactericidal antimicrobial agents that are currently being used for a variety of bacterial infections including respiratory infections other than TB [23-27]. The older FQs, such as ciprofloxacin (CFX) and ofloxacin (OFX), are synthetic derivatives of nalidixic acid and are highly effective as antibacterial agents. New generation FQs such as levofloxacin (LFX), two 8-methoxy-fluoroquinolones (mFQs), moxifloxacin (MFX) and gatifloxacin (GFX), are more potent antibacterial agents. These drugs are a relatively recent addition to the armamentarium against M. tuberculosis [28-31]. The minimum inhibitory concentration (MIC), recommended daily oral dose, early bactericidal activity (EBA, a measure of reduction in viable colony forming units during the first few days of therapy), pharmacokinetic and other properties of different FQs are summarized in Table I.

Higher daily oral doses of CFX (1500 mg), OFX (800 mg) and LFX (1000 mg) have also been used safely in TB patients with normal renal functions [28,30]. The MIC values for mFQs (MFX and GFX) are lower than for other FQs and are comparable to the range of MIC values of first-line anti-TB drugs:

• INH = 0.02-0.04 mg/l;
• RMP = 0.2-0.4 mg/l;
• EMB = 0.5-2.0 mg/l;
• SM = 0.5-2.0 mg/l.

The EBA (0-2 days) of MFX and GFX and high dose LFX (and to a lesser extent high dose OFX) is close to or equal to that of INH (recorded as 0.5-0.6 at oral dose of 300 mg), which is regarded as the most effective anti-TB drug in the intensive phase of chemotherapy [32-36]. The CFX is the least effective FQ against M. tuberculosis as the EBA of even high dose CFX is quite low (Table I). Thus, high dose LFX and normal dose GFX and MFX are bactericidal while even high dose CFX is bacteriostatic for M. tuberculosis.

The potent EBA of MFX and GFX, against M. tuberculosis and once daily oral dosing make these drugs highly desirable agents for combination therapy of fully susceptible pulmonary TB (Table II) [34-39]. Since RMP was inducted in combination therapy more than forty years ago, these drugs are the first new antibiotic class to be considered as first-line agents against active TB disease and are currently being evaluated for shortening the treatment duration of fully susceptible pulmonary TB. The FQs (MFX and GFX as well as high dose OFX and LFX) with the exception of CFX are also useful as second-line agents for the treatment of TB patients who are intolerant to some of the first-line drugs as well as for the treatment of drug-resistant TB [30,31,37]. Although early studies used OFX for the treatment of drug-resistant TB and MDR-TB, more recent studies in developed countries have mainly used high dose LFX (even though it is more expensive than OFX), due to bactericidal and better pharmacokinetic properties, in therapy regimens for the treatment of MDR-TB patients [30-32,37]. However, due to lower cost, OFX is still being used for the treatment of MDR-TB patients in developing countries.

Early studies carried out in murine models of TB suggested that replacement of EMB or INH with MFX in first-line treatment for TB has the potential to improve outcome and to shorten therapy to four months from the current standard of six months [40,41]. The maximum treatment benefit was noted when MFX was used in place of INH in the murine model of TB [40]. The effect of replacement of EMB with standard dose of MFX or GFX (each at 400 mg) was evaluated in three separate phase II clinical trials in the intensive phase of treatment of sputum smear-positive pulmonary TB patients which yielded variable results. The first of these studies, carried out by the TB Trials Consortium, reported higher rates of sputum culture conversion at 4 and 6 weeks of therapy but not at week 8 in MFX-containing regimen [42]. Another study conducted in Rio de Janeiro, Brazil, also reported higher rates of sputum culture conversion beginning at 2 weeks and persisting till week 8 of therapy in MFX-containing regimen [43]. The third study carried out in Durban, South Africa (OFLUTUB Consortium study) also evaluated the replacement of EMB by MFX or GFX (or by OFX at 800 mg) in the intensive phase of standard WHO recommended 6-month regimen. This study reported rapid elimination of viable bacteria from sputum of pulmonary TB patients when MFX or GFX was substituted for EMB while no measurable improvement was noted when EMB was replaced by OFX [44].

The effect of replacement of INH with MFX was also evaluated in a phase II double blind, randomized controlled trial in the intensive phase of treatment of sputum smear-positive pulmonary TB patients. The conversion from positive sputum cultures at initiation of therapy to negative cultures from sputum specimens after 8 weeks of therapy occurred in 99 (60.4%) of 164 participants in MFX group versus 90 (54.9%) of 164 participants in the INH group. The data showed a slight but statistically insignificant (p = 0.37) increase in sputum conversion rate in MFX-containing regimen [45]. The FQs (particularly older FQs) have generally been regarded as relatively safer drugs that are well tolerated by most individuals [27,30,46]. During clinical trials of TB patients, nearly similar number of adverse drug events (AEDs) have been recorded in the FQ arm compared to the control arms [30,32]. In the clinical trial involving replacement of INH with MFX, serious adverse events were recorded in 9 of 214 TB patients in the MFX arm compared to 8 of 205 TB patients in the control arm. Serious adverse events related to therapy were recorded in 3 TB patients in the MFX arm and in 2 TB patients in the control arm [45]. Thus, unlike some FQs (such as grepafloxacin and sparfloxacin) which were withdrawn from the market due to QTc interval prolongation, the recommended daily dose (400 mg) of MFX appears to be safe in most TB patients. However, FQs (including MFX and GFX) are known to produce cardiac QTc interval prolongation in some patients which limits the recommended daily dose (400 mg) of these two compounds that can be safely administered during anti-TB treatment [47]. Furthermore, GFX is contraindicated in some TB patients as it can cause dysglycemic events, which seem to occur more frequently in elderly and/or diabetic subjects [48].

The results of the four phase II trials involving MFX and GFX have shown that replacement of either MFX or GFX with EMB or replacement of MFX with INH is at least as efficacious as the standard intensive phase of therapy and may even contribute towards more rapid clearing of the infected lungs by rapidly dividing tubercle bacilli [42-45]. Both mFQs are now in two separate phase III clinical trials for the treatment of adult patients newly diagnosed with drug sensitive, pulmonary TB for investigation of whether treatment duration can be effectively shortened to 4 months by substitution of GFX for EMB or MFX for either EMB or INH [49,50]. The results of these trials will be compared with the WHO therapy regimen of 6 months duration with four standard first-line drugs. The advantages of an efficacious four-month treatment regimen are obvious. They will greatly reduce the economic burden of delivering TB treatment in impoverished countries and improve treatment-completion rates. The evolution and spreading of drug resistant and MDR strains of M. tuberculosis will also be reduced considerably.

The FQs, particularly new generation FQs such as LFX, MFX and GFX due to their potent bactericidal activity and lack of cross-resistance with existing anti-TB drugs, have also been used extensively for the treatment of drug-resistant TB and are now regarded as one of the two most important second-line agents for the treatment of MDR-TB [22,28,31,36,51,52]. Several studies have shown that inclusion of a FQ (particularly mFQs) and an injectable aminoglycoside (kanamycin or amikacin) or cyclic peptide (capreomycin and viomycin) in multidrug treatment regimens has the maximum effect for a more favorable outcome in the treatment of MDR-TB [12-14,51-54]. This is also apparent from the fact that development of resistance of MDR-TB strains to FQs is associated with poor treatment outcome. Additional development of resistance of MDR-TB strains to FQs is also one of two key defining conditions of XDR-TB [12-14,53-55]. Although initial studies were carried out with OFX-containing regimens, some studies and clinical trials involving MDR-TB patients in developed countries have also used LFX in treatment regimens. This is due to the fact that high dose LFX is bactericidal while OFX is bacteriostatic. More recently, MFX which is also bactericidal at the daily recommended oral dose, has also been used for the treatment of MDR-TB patients. A phase III clinical trial to compare the effectiveness of LFX and MFX on the culture conversion after three months of treatment among MDR-TB patients is currently underway [56]. However, OFX continues to be used for the treatment of MDR-TB patients due to its lower cost compared to the other two FQs.

The FQs have also been useful for the treatment of central nervous system infections as favorable drug concentrations were achieved in cerebrospinal fluid (CSF) at daily recommended dose (for GFX and MFX) or high-dose (for LFX) administration of these agents in several studies [57-59]. Thus, addition of a FQ early in the course of therapy is likely to improve outcome in the treatment of tuberculous meningitis, particularly when MDR-TB is suspected or confirmed [60,61]. A phase II clinical trial is currently underway to evaluate the pharmacokinetics, pharmacodynamics and tolerability of MFX in intensive treatment regimens for TB meningitis [62]. The current clinical development status of important FQs in the treatment of drug-susceptible pulmonary TB and MDR-TB is summarized in Table II. While more potent FQs (MFX and GFX) are being evaluated for shortening the duration of treatment of fully susceptible pulmonary TB, OFX and LFX are being used mainly for the treatment of MDR-TB patients. Although FQs, particularly new generation mFQs like MFX and GFX, have the potential to contribute to chemotherapy of TB, resistance of M. tuberculosis strains to FQs has also been detected in nearly all the countries of the world that are endemic for TB [12].

Mechanism of action and resistance of fluoroquinolones in M. tuberculosis

Resistance of M. tuberculosis to anti-TB (both, first-line and second-line) drugs is caused exclusively by chromosomal mutations occurring at a predictable rate in genes encoding drug targets that reduce the susceptibility of M. tuberculosis to specific anti-TB drugs [16,63]. Thus, mutations in target genes, rpoB, katG, inhA, embB, rpsL, rrs and pncA are the major mechanisms conferring resistance of clinical M. tuberculosis strains to first-line anti-TB drugs RMP, INH, INH, EMB, SM, SM and PZA, respectively [16,64-79]. The cellular target of FQs in M. tuberculosis is DNA gyrase, a type II topoisomerase that controls negative supercoiling in bacterial DNA. Only one type II topoisomerase activity is present in M. tuberculosis, which is also the main target for FQ activity in this organism. The active enzyme is a tetramer, consisting of two A and two B subunits that are encoded by gyrA and gyrB genes, respectively. Studies have shown that inhibition of DNA gyrase activity by FQs results in inhibition of DNA replication, transcription and repair, causing cell death [37,80-82]. Clinical M. tuberculosis isolates with wild-type gyrA and gyrB gene sequences are highly susceptible to FQs while chromosomal mutations in clinical M. tuberculosis strains in gyrA and gyrB genes usually confer moderate to high-level resistance to FQs [37,65,83-85]. In some M. tuberculosis strains, changes in the drug efflux pump systems may also result in low-level resistance to FQs [86].

Early in vitro studies, performed with laboratory strains of virulent M. tuberculosis and Mycobacterium smegmatis (a non-pathogenic species) showed that resistance to FQs results from missense mutations causing amino acid alterations in the conserved and putative FQ binding region in gyrA or gyrB genes [85,87]. The presence of missense mutations in the so-called quinolone resistance-determining region (QRDR) of gyrA or gyrB genes conferring resistance to FQs was subsequently confirmed by using clinical M. tuberculosis isolates in multiple studies [83-85,87-97]. The presence of S95 or T95 at gyrA codon 95 is a naturally occurring polymorphism that is not associated with resistance of M. tuberculosis isolates to FQs. However, this polymorphism together with katG codon 463 polymorphism (R463 or L463), is used to define the three principal genetic groups of worldwide collection of M. tuberculosis strains [98-100]. The FQ-resistant clinical M. tuberculosis isolates more frequently contain mutations in gyrA gene, particularly at codon 90 (A90) or codon 94 (D94) but also occasionally at codon 74 (A74), codon 88 (G88) and codon 91 (S91) while mutations in few codons of the gyrB gene occur in a small minority of clinical strains [83,89-91]. Surprisingly, some M. tuberculosis isolates have also been described that are hypersusceptible to FQs due to mutations at gyrA codon 80 (T80), particularly in association with other FQ resistance-associated mutations [83]. Recent studies have shown that the vast majority (~90%) of FQ-resistant M. tuberculosis strains can be accurately detected by analysis of QRDR of gyrA gene alone since additional targeting of gyrB gene did not enhance the sensitivity significantly [91,93-95]. Attempts have also been made to correlate the nature and kind of gyrA mutations with the level of resistance to FQs in M. tuberculosis strains with conflicting results. Some studies have reported that M. tuberculosis strains containing D94G mutation in the gyrA gene exhibit high-level resistance to FQs while those with D94A mutation have lower MIC for LFX [93,96,97]. On the contrary, other reports have not found an association of different mutation patterns in gyrA or gyrB genes with the level of FQ resistance in M. tuberculosis isolates [89,94].

Several genotypic tests have recently been developed (Table III) for rapid (within 1-2 days) detection of vast majority of FQ-resistant clinical M. tuberculosis isolates [95]. Although some of these assays target both gyrA and gyrB genes, the majority of genotypic tests target only QRDR of gyrA gene for simplicity and acceptable levels of sensitivity. The genotypic tests that have been developed include PCR-DNA sequencing [83-85], PCR-single strand conformation polymorphism [101], temperature-mediated heteroduplex analysis by using denaturing high-pressure liquid chromatography (HPLC) [102], pyrosequencing [103], microchip array [104], locked nucleic acid probe real-time PCR [105], multiplex PCR amplimer conformation analysis [89] and both, in-house developed as well as commercially available line probe assays [92,96,97].

The FQs are an important component of the therapy regimens for patients with MDR-TB or XDR-TB since their inclusion greatly improves treatment outcome. Furthermore, resistance of MDR-TB or XDR-TB strains to FQs has been shown to increase the risk of treatment failure and death [15,18,53,55,106]. Although all FQs share the same drug targets (gyrA and gyrB) and cross-resistance between different FQs is generally assumed, there are some reports contrary to these generalizations. A study from Hong Kong showed that LFX was effective against some OFX-resistant M. tuberculosis strains [107]. Furthermore, one M. tuberculosis strain resistant to both MFX and GFX with mutation at gyrB codon 533 (N533T) has also been isolated recently that exhibited in vitro susceptibility to OFX [91]. These findings suggest that cross-resistance between different FQs is not always complete. Nonetheless, resistance of M. tuberculosis strains to FQs, including third-generation compounds (MFX and GFX), has been described from several countries worldwide [2,12,84]. Recent WHO reports suggest that nearly 25% of MDR-TB strains from China and India, the two countries accounting for nearly 35% of all estimated active TB disease cases and 50% of estimated MDR-TB cases worldwide, are likely to be resistant to FQs [1,12]. Several other high TB incidence countries are also predicted to have a high prevalence of FQ resistance among MDR-TB strains [12]. Furthermore, the incidence of resistance of M. tuberculosis strains to FQs also appears to be increasing in several developing countries [108-111].

How we are creating FQ-resistant TB

The history of treatment of active TB disease during early days of chemotherapy has shown that resistance to anti-TB drugs develops soon after they are introduced into therapy regimens. This is exemplified by development of resistance of M. tuberculosis to SM which developed soon after the drug was used as monotherapy in the 1940s [112]. Although para-aminosalicylic acid (PAS) and INH were subsequently introduced into combination therapy to suppress the development of resistance to SM, resistance to both SM and INH soon became widespread and a challenge to combination therapy. It was only when RMP and pyrazinamide (PZA) were introduced into combination therapy and the duration was reduced to six months that the problem of drug resistance was brought under control [113,114]. However, widespread use and misuse (due to poor quality of medications, non-adherence of TB patients to treatment, etc.) of short-course regimens have also resulted in the emergence and spreading of MDR-TB strains in the 1980s.

Today, a major impediment in the effective use of FQs in the treatment of both drug-susceptible TB and MDR-TB is rapidly emerging due to pre-existing and/or increasing levels of FQ resistance among M. tuberculosis strains in several countries. Although FQ-resistant TB is mainly generated by the use of these drugs in anti-TB treatment regimens, these agents are also being used widely in the treatment of other infections including acute lower respiratory tract infections. This is further complicated by easy, uncontrolled access of these drugs in many developing countries. Furthermore, the published expert recommendations and clinical guidelines in some countries have promoted widespread use of FQs for common infections such as pneumonia and sinusitis. For example, the consensus guidelines of the Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) have recommended empiric therapy with a FQ for the management of community-acquired pneumonia as a first-line selection in several clinical situations, including those with comorbid conditions like renal disease, diabetes or immunosuppression [115]. Incidentally, most of these conditions also increase the risk of developing active TB disease in an individual. Thus, such clinical practices are likely to contribute to the emergence of FQ resistance in M. tuberculosis. The same conclusions were also advocated by a recent study from the United States. This study showed that the risk of FQ-resistant TB was higher in patients who had received FQs for more than 10 days for lower respiratory tract infections, particularly if the drug was prescribed 60 days or earlier but before the diagnosis of active TB disease [116]. A more recent systematic review and meta-analysis has also shown that empirical treatment of pneumonia with FQs was associated with longer delays in diagnosis and treatment of pulmonary TB and a higher risk of developing FQ-resistant TB [117]. The empirical FQ prescriptions are certainly more problematic in developing countries with a high TB incidence since patients diagnosed with lower respiratory tract infections in such settings may, in fact, have a much higher chance of active TB disease than in low TB incidence developed countries and the diagnosis of their active disease may be substantially delayed by monotherapy with FQs. Thus, if we plan to protect FQs for the treatment of TB, great caution is warranted while considering the use of FQs in the community setting and to limit/avoid the use of prolonged or repeated courses of FQs in patients who may be at higher risk of having active TB disease.

References

1. World Health Organization. Global tuberculosis control: WHO report 2010. WHO/HTM/TB/2010.7. Geneva, Switzerland: WHO, 2010
2. World Health Organization. Anti-tuberculosis drug resistance in the world: fourth Global report. WHO/HTM/TB/2008.394. Geneva, Switzerland: WHO, 2008
3. Dooley K, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 2009; 9: 737-46
4. Ahmad S. New approaches in the diagnosis and treatment of latent tuberculosis infection. Resp Res 2010; 11: 169
5. Ahmad S. Pathogenesis, immunology and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol 2011; 2011: Article ID 814943 (17 pages)
6. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999; 282: 677-86
7. Sonnenberg P, Glynn JR, Fielding K, Murray J, Godfrey-Faussett P, Shearer S. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis 2005; 191: 150-8
8. Cailhol J, Decludt, Che D. Sociodemographic factors that contribute to the development of extrapulmonary tuberculosis were identified. J Clin Epidemiol 2005; 58: 1066-71
9. Mokaddas E, Ahmad S, Samir I. Secular trends in susceptibility patterns of Mycobacterium tuberculosis isolates in Kuwait, 1996-2005. Int J Tuberc Lung Dis 2008; 12: 319-25
10. Sandman L, Schluger NW, Davidow AL, Bank S. Risk factors for rifampin-monoresistant tuberculosis: a case-control study. Am J Respir Crit Care Med 1999; 159: 468-72
11. Mokaddas E, Ahmad S, Abal AT, Al-Shami AS. Molecular fingerprinting reveals familial transmission of rifampin-resistant tuberculosis in Kuwait. Ann Saudi Med 2005; 25: 150-3
12. World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. WHO/HTM/TB/2010.3, Geneva, Switzerland: WHO, 2010
13. Lew W, Pai M, Oxlade O, Martin D, Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med 2008; 149: 123-34
14. Mitnick CD, Appleton SC, Shin SS. Epidemiology and treatment of multidrug-resistant tuberculosis. Semin Respir Crit Care Med 2008; 29: 499-524
15. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009; 9: 153-61
16. Ahmad S, Mokaddas E. Recent advances in the diagnosis and treatment of multidrug-resistant tuberculosis. Resp Med 2009; 103: 1777-90
17. Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide, 2000-2004. Mor Mort Weekly Rep 2006; 55: 301-5
18. Mitnick CD, Shin SS, Seung KJ, Rich ML, Atwood SS, Furin JJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563-74
19. LoBue P. Extensively drug-resistant tuberculosis. Curr Opin Infect Dis 2009; 22: 167-73
20. Dheda K, Warren RM, Zumla A, Grobusch MP. Extensively drug-resistant tuberculosis: epidemiology and management challenges. Infect Dis Clin N Am 2010; 24: 705-25
21. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 2010; 51: 6-14
22. Gillespie SH, Singh K. XDR-TB, what is it; how it is treated; and why is therapeutic failure so high? Recent Pat Antiinfect Drug Discov 2011; 6: 77-83
23. Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001; 61: 9-18
24. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Crit Care Med 2001; 163: 1730-54
25. Bolon MK. The newer fluoroquinolones. Infect Dis Clin North Am 2009; 23: 1027-51
26. Wispelwey B, Schafer KR. Fluoroquinolones in the management of community-acquired pneumonia in primary care. Expert Rev Anti Infect Ther 2010; 8: 1259-71
27. Rotschafer JC, Ullman MA, Sullivan CJ. Optimal use of fluoroquinolones in the intensive care unit setting. Crit Care Clin 2011; 27: 95-106
28. Gillespie SH, Kennedy N. Fluoroquinolones: a new treatment for tuberculosis? Int J Tuberc Lung Dis 1998; 2: 265-71
29. Sulochana S, Rahman F, Pramasivan CN. In vitro activity of fluoroquinolones against Mycobacterium tuberculosis. J Chemother 2005; 17: 169-73
30. Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR, Marra F. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs 2007; 67: 2077-99
31. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167: 603-62
32. Donald PR, Diacon AH. The early bactericidal activities of anti-tuberculosis drugs: a literature review. Tuberculosis 2008; 88 (Suppl. 1): S75-S83
33. Rodriguez JC, Ruiz M, Climent A, Royo G. In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis. Int J Antimicrob Agents 2001; 17: 229-31
34. Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168: 1342-5
35. Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10: 605-12
36. Rieder HL. Fourth-generation fluoroquinolones against tuberculosis. Lancet 2009; 373: 1148-9
37. Ginsburg AS, Grosset JH, Bishai WR. Fluoroquinolones, tuberculosis, and resistance. Lancet Infect Dis 2003; 3: 432-42
38. Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J. In vitro and in vivo activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 783-5
39. Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective randomized study. Antimicrob Agents Chemother 2004; 48: 780-2
40. Nuernberger EL, Yoshimatsu T, Tyagi S, O’Brien RJ, Vernon AN, Chaisson RE, et al. Moxifloxacin-containing regimens greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 2004; 169: 421-6
41. Nuernberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O’Brien RJ, et al. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med 2004; 170: 1131-4
42. Burman WJ, Goldberg S, Johnson JL, Williams K, Rosenthal I, O‘Brien RJ, et al. Moxifloxacin versus ethambutol in the first two months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174: 331-8
43. Conde MB, Efron A, Loredo C, Muzanye G, Engle M, Mosher AW, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomized, controlled phase II trial. Lancet 2009; 373: 1183-9
44. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A phase II study of the sterilizing activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2008; 12: 128-38
45. Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2009; 180: 273-80
46. Gonzales MA, Uribe F, Duran Moisen S, Pichardo Fuster A, Selen A, Welling PG, et al. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1984; 26: 741-4
47. Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents 2007; 29: 374-9
48. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 2006; 354: 1352-61
49. ClinicalTrials.gov. A controlled trial of a 4-month quinolone-containing regimen for the treatment of pulmonary tuberculosis. Trial Identifier: NCT00216385
50. ClinicalTrials.gov. Controlled comparison of two moxifloxacin-containing treatment shortening regimens in pulmonary tuberculosis. Trial Identifier: NCT00864383
51. Yew WW, Chan CK, Chau CH, Tam CM, Leung CC, Wong PC, et al. Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens. Chest 2000; 117: 744-51
52. Veziris N, Truffot-Pernot C, Aubry A, Jarlier V, Lounis N. Fluoroquinolone-containing third-line regimen against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother 2003; 47: 3117-22
53. Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007; 4: article no. e292
54. Ahmad S, Mokaddas E. New challenges in the treatment of tuberculosis in the 21st century. Treat Strat Resp 2011; 1: 100-10
55. Kliman K, Altraja A. Predictors of poor treatment outcome in multi and extensively drug-resistant pulmonary TB. Eur Respir J 2009; 33: 1085-94
56. ClinicalTrials.gov. A comparison of the effect between levofloxacin and moxifloxacin among MDR-TB patients. Trial Identifier: NCT01055145
57. Pea F, Pavan F, Nascimben E, Benetton C, Scotton PG, Vaglia A, et al. Levofloxacin disposition in cerebrospinal fluid in patients with external ventriculostomy. Antimicrob Agents Chemother 2003; 47: 3104-8
58. Alffenaar JWC, van Altena R, Bokkerink HJ, Luijckx GJ, van Soolingen D, Arnoutse RE, et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis 2009; 49: 1080-2
59. Donald PR. Cerebrospinal fluid concentrations of antituberculous agents in adults and children. Tuberculosis 2010; 90: 279-92
60. Thwaites GE, Bhavani SM, Chau TTH, Hammel JP, Torok ME, Van Wart SA, et al. Randomized pharmacokinetic and pharmacodynamics comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother 2011; 55: 3244-53
61. Donald PR. The chemotherapy of tuberculous meningitis in children and adults. Tuberculosis 2010; 90: 375-92
62. ClinicalTrials.gov. A comparison of intensive treatment regimens and standard treatment regimens for tuberculous meningitis: pharmacokinetic, pharmacodynamics and tolerability study. Trial Identifier: NCT01158755
63. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009; 13: 1320-30
64. Telenti A, Imboden P, Marchesi F, Lowrie D, Cole S, Colston MJ, et al. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 1993; 341: 647-50
65. Ramaswamy S, Musser JM. Molecular genetics basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuberc Lung Dis 1998; 79: 3-29
66. Ahmad S, Mokaddas E, Fares E. Characterization of rpoB mutations in rifampin-resistant clinical Mycobacterium tuberculosis isolates from Kuwait and Dubai. Diagn Microbiol Infect Dis 2002; 44: 245-52
67. Ahmad S, Mokaddas E. The occurrence of rare rpoB mutations in rifampicin-resistant Mycobacterium tuberculosis isolates from Kuwait. Int J Antimicrob Agents 2005; 26: 205-12
68. Zhang Y, Heym B, Allen B, Young D, Cole ST. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992; 358: 591-3
69. Abal AT, Ahmad S, Mokaddas E. Variations in the occurrence of the S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Kuwait. Microb Drug Resist 2002; 8: 99-105
70. Ahmad S, Fares E, Araj GF, Chugh TD, Mustafa AS. Prevalence of S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Dubai and Beirut. Int J Tuberc Lung Dis 2002; 6: 920-6
71. Ramaswamy S, Reich R, Dou S, Jasperse L, Pan X, Wanger A, et al. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 1241-50
72. Ahmad S, Mokaddas E. Contribution of AGC to ACC and other mutations at codon 315 of the katG gene in isoniazid-resistant Mycobacterium tuberculosis isolates from the Middle East. Int J Antimicrob Agents 2004; 23: 473-9
73. Telenti A, Philipp WJ, Sreevatsan S, Bernasconi C, Stockbauer KE, Wieles B, et al. The emb operon, a unique gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 1997; 3: 567-70
74. Ramaswamy S, Amin AG, Koksel S, Stager CE, Dou SJ, El Sahly H, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2000; 44: 326-36
75. Ahmad S, Jaber AA, Mokaddas E. Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait. Tuberculosis 2007; 87: 123-9
76. Ahmad S, Itani LY, Fares E, Araj GF. Varying prevalence of embB codon 306 mutations in ethambutol-resistant clinical Mycobacterium tuberculosis isolates from Beirut and Dubai. J Chemother 2009; 20: 285-7
77. Sreevatsan S, Pan X, Stockbauer KE, Williams DL, Kreisworth BN, Musser JM. Characterization of rpsL and rrs mutations in streptomycin-resistant Mycobacterium tuberculosis isolates from diverse geographic locations. Antimicrob Agents Chemother 1996; 40: 1024-6
78. Cooksey RC, Morlock GP, McQueen A, Glickman SE, Crawford JT. Characterization of streptomycin resistance mechanisms among Mycobacterium tuberculosis isolates from patients in New York City. Antimicrob Agents Chemother 1996; 40: 1186-8
79. Scorpio A, Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidedase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nature Med 1996; 2: 662-7
80. Wang JC. DNA topoisomerases. Annu Rev Biochem 1996; 65: 635-92
81. Aubry, A, Pan XS, Fisher LM, Jarlier V, Cambau E. Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrob Agents Chemother 2004; 48: 1281-8
82. Piton J, Petrella S, Delarune M, Andre-Leroux G, Jarlier V, Aubry A, et al. Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase. PLoS One 2010; 5: e12245
83. Aubry A, Veziris N, Cambau E, Truffot-Pernot C, Jarlier V, Fisher M. Novel gyrase mutations in quinolone-resistant and hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother 2006; 50: 104-12
84. Wang JY, Lee LN, Lai HC, Wang SK, Jan IS, Yu CJ, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis isolates: associated genetic mutations and relationship to antimicrobial exposure. J Antimicrob Chemother 2007; 59: 860-5
85. Takiff HE, Salazar L, Guerrero C, Philipp W, Huang WM, Kreiswirth B, et al. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 1994; 38: 773-80
86. Escribano I, Rodriguez JC, Llorca B, Garcia-Pachon E, Ruiz M, Royo G. Importance of the efflux pump systems in the resistance of Mycobacterium tuberculosis to fluoroquinolones and linezolid. Chemotherapy 2007; 53: 397-401
87. Xu C, Kriesworth BN, Sreevatsan S, Musser JM, Drlica K. Fluoroquinolone resistance associated mutations in clinical isolates of multidrug-resistant Mycobacterium tuberculosis. J Infect Dis 1996; 174: 1127-30
88. Al-Mutairi NM, Ahmad S, Mokaddas E. First report of molecular detection of fluoroquinolone resistance-associated gyrA mutations in multidrug-resistant clinical Mycobacterium tuberculosis isolates in Kuwait. BMC Res Notes 2011; 4: 123
89. Cheng AF, Yew WW, Chan EW, Chin ML, Hui MM, Chan RC. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2004; 48: 596-601
90. Sun Z, Zhang J, Zhang X, Wang S, Zhang Y, Li C. Comparison of gyrA gene mutations between laboratory-selected ofloxacin-resistant Mycobacterium tuberculosis strains and clinical isolates. Int J Antimicrob Agents 2008; 31: 115-21
91. Von Groll A, Martin A, Jureen P, Hoffner S, Vandamme P, Portaels F, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis and mutations in gyrA and gyrB. Antimicrob Agents Chemother 2009; 53: 4498-500
92. Hillemann D, Rusch-Gerdes S, Richter E. Feasibility of the GenoType MTBDRsl assay for fluoroquinolone, amikacin-capreomycin and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol 2009; 47: 1767-72
93. Yin X, Yu Z. Mutation characterization in gyrA and gyrB genes in levofloxacin-resistant Mycobacterium tuberculosis clinical isolates from Guangdong Province in China. J Infect 2010; 61: 150-4
94. Cui Z, Wang J, Lu J, Huang X, Hu Z. Association of mutation patterns in gyrA/B genes and ofloxacin resistance levels in Mycobacterium tuberculosis isolates from East China in 2009. BMC Infect Dis 2011; 11: 78
95. Chang KC, Yew WW, Chan RCY. Rapid assays for fluoroquinolone resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother 2010; 65: 1551-61
96. Giannoni F, Iona E, Sementilli F, Brunori L, Pardini M, Migliori GB, et al. Evaluation of a line probe assay for the rapid identification of gyrA mutations in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49: 2928-33
97. Ando H, Mitarai S, Kondo Y, Suetake T, Kato S, Mori T, et al. Evaluation of a line probe assay for the rapid detection of gyrA mutations associated with fluoroquinolone resistance in multidrug-resistant Mycobacterium tuberculosis. J Med Microbiol 2011; 60: 184-8
98. Sreevatsan S, Pan X, Stockbauer KE, Connell ND, Kreiswirth BN, Whittam TS, et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 1997; 94: 9869-74
99. Ahmad S, Abal AT, Mokaddas E, Araj GF, Fares E, Mustafa AS. Genetic polymorphism at codon 463 in the katG gene in isoniazid sensitive and resistant isolates of Mycobacterium tuberculosis. Med Princ Pract 2001; 10: 129-34
100. Al-Mutairi N, Ahmad S, Mokaddas E. Performance comparison of four methods for rapid detection of multidrug-resistant Mycobacterium tuberculosis strains. Int J Tuberc Lung Dis 2011; 15: 110-5
101. Sougakoff W, Lemaitre N, Combau E, Szpytma M, Revel V, Jarlier V. Nonradioactive single strand conformation polymorphism analysis for detection of fluoroquinolone resistance in mycobacteria. Eur J Clin Microbiol Infect Dis 1997; 16: 395-8
102. Shi R, Zhang J, Li C, Kazumi Y, Sugawara I. Emergence of ofloxacin resistance in Mycobacterium tuberculosis clinical isolates from China as determined by gyrA mutation analysis using denaturing high-pressure liquid chromatography and DNA sequencing. J Clin Microbiol 2006; 44: 4566-8
103. Bravo LT, Tuchy MJ, Ang C, Destura RV, Mendoza M, Procop GW, et al. Pyrosequencing for rapid detection of Mycobacterium tuberculosis resistance to rifampin, isoniazid and fluoroquinolones. J Clin Microbiol 2009; 47: 3985-90
104. Antonova OV, Gryadunov DA, Lapa SA, Kuzmin AV, Larionova EE, Smirnova TG, et al. Detection of mutations in Mycobacterium tuberculosis genome determining resistance to fluoroquinolones by hybridization on biological microchip. Bull Exp Biol Med 2008; 145: 108-13
105. van Doorn HR, An DD, de Jang MD, Lan NT, Hoa DV, Quy HT, et al. Fluoroquinolone resistance detection in Mycobacterium tuberculosis with locked nucleic acid probe real-time PCR. Int J Tuberc Lung Dis 2008; 12: 736-42
106. Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug resistant tuberculosis. Lancet Infect Dis 2010; 10: 621-9
107. Yew WW, Chan CK, Leung CC, Chau CH, Tam CM, Wong PC, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest 2003; 124: 1476-81
108. Agrawal D, Udwadia ZF, Rodriguez C, Mehta A. Increasing incidence of fluoroquinolone-resistant Mycobacterium tuberculosis in Mumbai, India. Int J Tuberc Lung Dis 2009; 13: 79-83
109. Jabeen K, Shakoor S, Chisti S, Ayaz A, Hasan R. Fluoroquinolone-resistant Mycobacterium tuberculosis, Pakistan, 2005-2009. Emerg Infect Dis 2011; 17: 564-6
110. Grimaldo ER, Tupasi TE, Rivera AB, Quelapio MI, Cardano RC, Derilo JO, et al. 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 2001; 5: 546-50
111. Xu P, Li X, Zhao M, Gui X, DeRiemer K, Gagneux S, et al. Prevalence of fluoroquinolone resistance among tuberculosis patients in Shanghai, China. Antimicrob Agents Chemother 2009; 53: 3170-2
112. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council Investigation. Brit Med J 1948; 4582: 769-82
113. Mitchison DA. The action of antituberculosis drugs in short-course chemotherapy. Tubercle 1985; 66: 219-25
114. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med 2005; 171: 699-706
115. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44: S27-S72
116. Devasia RA, Blackman A, Gebretsadik T, Griffin M, Shintani A, May C, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis: the effect of duration and timing of fluoroquinolone exposure. Am J Respir Crit Care Med 2009; 180: 365-70
117. Chen TC, Lu PL, Lin CY, Lin WR, Chen YH. Fluoroquinolones are associated with delayed treatment and resistance in tuberculosis: a systematic review and meta-analysis. Int J Infect Dis 2011; 15: e211-e216