MDR-TB Regimen Research Articles

A Review: Prevention, Treatment and Management of Tuberculosis through Combinational Approaches of Different Indian Systems of Medicine.

Tuberculosis (TB) is one of the oldest fatal diseases of history. Multidrugresistant tuberculosis (MDRTB) is a major public health issue in the world. In India, the incidence is getting up despite the Indian revised National Tuberculosis Control Programme. India has six recognize medicine systems in this category, namely Ayurveda, Siddha, Unani and Yoga, Naturopathy and Homoeopathy. This review study was undertaken to evaluate the efficacy of different drug treatments based on Indian Systems of Traditional Medicines to the standard MDR-TB regimen. This review mainly focuses on the combinational approaches towards treatment protocols, prevention strategies, and management of tuberculosis in different established systems of medicine in India. Along with allopathic drugs, these AYUSH based drugs work in synergistic manner. Recent research suggests that Homeopathic treatment along with the antibiotics synergise the effect of antibiotics while reaching to its site of action. Additionally in Siddha system, formulation of medicinal herbs showing significant activity against TB bacteria. Furthermore, adopting the management or principles of Unani system would be beneficial in health and disease. Similarly, Unani and Naturopathy through natural healing are equally effective. On the other hand, medicinal plants from the Ayurveda that have been successfully employed to treat TB because of less toxicity and side effect in comparison with existing antibiotics. The findings in this review have provided scientific support for anti-TB activity of different medicinal system of India via numerous underlying mechanisms.

Recent changes in guidelines on programmatic management of drug resistant tuberculosis in India 2019: a paradigm shift in tuberculosis control

The new version of guidelines of programmatic management of drug resistant tuberculosis in India 2019 by Revised National Tuberculosis Control Programme, Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare, Nirman Bhawan, New Delhi, integrates use of the shorter MDR TB regimen and all oral longer MDR TB regimen with new drugs under RNTCP with opportunity to modify the regimen based on DST results. There are mammoth and comprehensive changes in the guidelines on programmatic management of drug resistant tuberculosis in India 2019.

Urine colorimetry for levofloxacin pharmacokinetics and personalized dosing in people with drug-resistant tuberculosis.

Background:Levofloxacin is a preferred drug for multidrug-resistant (MDR)-tuberculosis (TB) with bactericidal activity that correlates with the pharmacokinetic exposures of serum peak concentration (Cmax) and total area under the concentration time curve (AUC0-24). Pharmacokinetic exposures can be measured to personalize dosing to reach targets, but this practice requires venepuncture, chromatographic or mass spectrometry equipment, and technical expertise. We sought to demonstrate the accuracy of using urine colorimetry as a more feasible estimation of levofloxacin exposure.Method:A colorimetric method using bromocresol green was tested on spiked urine samples with levofloxacin measured using a spectrophotometer. This method was tested in urine samples of healthy volunteers given one 750 mg dose of levofloxacin with urine collected at 0–4 h, 4–8 h, and 8–24 h intervals, and concomitant serum samples were collected and analyzed by high-performance liquid chromatography. Validation of this assay was done in a cohort of people living with human immunodeficiency virus (PLWH), initiating a levofloxacin containing MDR-TB regimen.Results:Urine colorimetry was reproducible in spiked samples and the calibration was curve linear for levofloxacin concentrations ranging from 7.8 μg/ml to 250 μg/ml, with r = 0.98. In healthy volunteers, correlation between urine absorbance values and serum AUC0-24 was highest in urine collected between 4 and 8 h (r = 0.91, P = 0.01), yet in PLWH, urine collected between 0 and 4 h had highest correlation (r = 0.66, P = 0.05). The area under the receiver operating characteristics curve was >0.8 in the derivation, as well as the validation cohort for the urine absorbance values identifying people with total serum exposure below target.Conclusion:Urine colorimetry was highly sensitive in predicting target serum concentrations. Colorimetric methods to determine levofloxacin in urine may improve the feasibility of therapeutic drug monitoring and personalized dose adjustment in TB endemic settings.

Economic Evaluation of New MDR TB Regimens

Economic Evaluation of New MDR TB Regimens

Treatment Outcomes and Adverse Events from a Standardized Multidrug-Resistant Tuberculosis Regimen in a Rural Setting in Angola.

Treatment for multidrug-resistant tuberculosis (MDR TB) is associated with adverse events (AE). Patients treated with an MDR TB regimen in Hospital Nossa Senhora da Paz, Cubal, Angola, were prospectively enrolled from May 2013 to July 2015. Baseline characteristics, AE, and clinical and microbiological outcomes were recorded. A total of 216 patients were treated with an MDR TB regimen and 179 (82.9%) patients developed at least one AE. The most common AE were elevation of liver enzymes (46.8% of patients), elevated creatinine (44.4% of patients), and ototoxicity (40.7% of patients). Previous TB treatment was associated with the occurrence of AE (OR 4.89, 95% CI: 2.09-11.46, P < 0.001) and months on treatment was associated to severe AE (OR 1.11 95% CI: 1.04-1.18, P = 0.001). Successful treatment was achieved in 117 (54.2%) patients. Incidence of AE was associated with an unsuccessful outcome (OR 1.23, 95% CI: 1.09-1.40, P = 0.001). Patients treated with MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. Given the high percentage of patients experiencing AE and the low treatment success rates, more effective and less toxic drugs to treat MDR TB are urgently needed.

Prevalence of isoniazid resistance-conferring mutations associated with multidrug-resistant tuberculosis in Free State Province, South Africa.

Multidrug- and extensively drug-resistant tuberculosis (MDR-TB and XDR- TB) threaten local and global control of the disease. The molecular line-probe assay (LPA) provides rapid diagnosis and early management of MDR-TB. The LPA detects mutations of katG and inhA genes associated with isoniazid (INH) resistance in Mycobacterium tuberculosis isolates. The katG and inhA genes are associated with high- and low-level INH resistance, respectively, as well as cross-resistance to ethionamide in the case of inhA gene mutations. Patients with MDR-TB due to an inhA mutation could benefit from the use of high-dose INH - instead of ethionamide - in their MDR-TB regimen. To determine the frequencies of katG and inhA mutations that conferred INH resistance among MDR-TB isolates during 2014 - 2016 in Free State (FS) Province of South Africa. We retrospectively reviewed MDR-TB isolates assayed with GenoType MTBDRplus (Hain Lifescience, Germany) (LPA) at the central TB laboratory of Universitas Academic Hospital, Bloemfontein, FS, and calculated the frequencies of katG and inhA mutations. Among 918 MDR-TB isolates, the prevalence of katG, inhA and katG plus inhA mutations was 63.9%, 13.4% and 22.7%, respectively. Approximately 60% (n=536; 58.4%) of the isolates were obtained from male patients. The patients' ages ranged from 1 to 89 (median 37) years. The Xhariep district had the highest incidence of INH resistance-conferring mutations in the province. katG-associated mutations are the predominant INH resistance-conferring mechanism among MDR-TB isolates in the FS. Patients infected with isolates that harbour the katG mutation are unlikely to benefit from high-dose INH therapy in the bedaquiline (BDQ)-containing modified short MDR-TB regimen. They may, however, benefit from the inclusion of ethionamide in the regimen. Dual katG and inhA gene mutations make these patients unlikely to respond to either high-dose INH or ethionamide and should now be considered for either the BDQ-containing long MDR-TB regimen or an individualised treatment regimen, depending on fluoroquinolone susceptibility. Clinicians should familiarise themselves with interpreting various INH resistance-conferring mutation results and their implications for management of MDR-TB treatment.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres

BackgroundThe increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015.MethodsA retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15.ResultsA total of 134 patients were selected. Median (IQR) age at admission was 33 (26–41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively).ConclusionsTailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

Once-a-week tigecycline for the treatment of drug-resistant TB.

MDR-TB and XDR-TB have poor outcomes. To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB. We performed pharmacokinetic/pharmacodynamic studies using tigecycline human-like concentration-time profiles in the hollow fibre system model of TB in five separate experiments using Mycobacterium tuberculosis in log-phase growth or as semi-dormant or intracellular bacilli, as monotherapy. We also compared efficacy with the isoniazid/rifampicin/pyrazinamide combination (standard therapy). We then applied extinction mathematics, morphisms and Latin hypercube sampling to identify duration of therapy with tigecycline monotherapy. The median tigecycline MIC for 30 M. tuberculosis clinical and laboratory isolates (67% MDR/XDR) was 2 mg/L. Tigecycline monotherapy was highly effective in killing M. tuberculosis in log-phase-growth and semi-dormant and intracellular M. tuberculosis. Once-a-week dosing had the same efficacy as daily therapy for the same cumulative dose; thus, tigecycline efficacy was linked to the AUC0-24/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC0-24/MIC ratio associated with optimal kill was 42.3. Tigecycline monotherapy had a maximum sterilizing effect (day 0 minus day 28) of 3.06 ± 0.20 log10 cfu/mL (r2 = 0.92) compared with 3.92 ± 0.45 log10 cfu/mL (r2 = 0.80) with optimized standard therapy. In our modelling, at a tigecycline monotherapy duration of 12 months, the proportion of patients with XDR-TB who reached bacterial population extinction was 64.51%. Tigecycline could cure patients with XDR-TB or MDR-TB who have failed recommended therapy. Once-a-week tigecycline could also replace second-line injectables in MDR-TB regimens.

Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF-identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012-2017: A Retrospective Province-Wide Cohort Study.

BackgroundMultidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program.Methodsof adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan–Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death.ResultsOf 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63–3.59), retreatment of TB (aOR 4.92, 95% CI 2.31–10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01–3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3–60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2–6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88–9.71).ConclusionsFavorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes.

Resistance Patterns among Multidrug-Resistant Tuberculosis Patients: A Multi-Center Study from Pakistan

Background: The high burden of multi-drug resistance tuberculosis (MDR TB) is a matter of great concern. The increasing resistance to anti tuberculosis drugs has been the area of growing concern and are posing threats to TB control. The aim of this study was to evaluate the drug resistance patterns for the first line and second line anti-Tuberculosis drugs in multiple drug resistant tuberculosis (MDR-TB) patients. Method: The study was retrospective, observational, employing purposive, non-random sampling technique for data collection conducted at the TB Clinic- of the different healthcare centers in the provinces of Pakistan Sindh and Baluchistan from December 2010 to May 2016. All bacteriologically confirmed TB patients who were found to be Rifampin Resistant (RR) on Genotypic drug susceptibility testing (GXP), or detected to be drug resistant on phenotypic Universal drug susceptibility testing were enrolled into the study. Results: Out of total 3776 patients, 96.3% were resistant to Rifampicin and 94.7% were resistant to Isoniazid. 25.5% isolates were resistant to all five first line drugs. Resistances against Pyrazinamide and Ethambutol was 54.2% and 51.6% respectively. 36.3% patients were resistant to Fluoroquinolones (FQ), 9.7% were resistant to Ethionamide (Eto) and 4.1% were resistant to both FQ and Eto. 33.5% patients were MDR plus resistant to FQ. However, the resistance to both FQ plus Aminogycosides was quite low, 2.7%. Conclusion: The drug resistance rates are quiet high in MDR-TB for both first line and second line drugs. The standardized MDR TB regimen needs to be updated, based on the prevalence of drug resistance patterns in the community for the effective management of drug resistant TB.

Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009–2013

ObjectivesTo examine treatment outcomes and factors associated with poor outcome of multidrug-resistant (MDR) tuberculosis (TB) in China. MethodsWe conducted a prospective observational cohort study including consecutive patients with MDR-TB between 2009 and 2013 in six regions of Zhejiang province. Patients were prescribed treatments by infectious disease specialists, and treatment outcomes were recorded. Sociodemographic characteristics were obtained through a structured questionnaire. The primary endpoint was poor treatment outcomes, defined as treatment failure based on microbiologic persistence, default (lost to follow-up) or death at 24 months. We assessed risk factors for poor treatment outcomes using a Cox proportional hazards model. ResultsA total of 820 MDR-TB patients were observed, and 537 with known treatment outcomes were included in our study. Overall, the treatment success rate was 40.2 per 100 years (374/537 participants, 69.6%), while treatment failure, death and default rates were 10.0 per 100 years (101 participants, 18.8%), 3.4 per 100 years (36 participants, 6.7%) and 2.7 per 100 years (26 participants, 4.8%) respectively. Independent predictors of poor treatment outcomes included age >60 years (hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2–4.2), patients registered as experiencing relapse (HR 2.2, 95% CI 1.1–4.4), patients registered as receiving treatment after failure (HR 2.4, 95% CI 1.2–4.9), use of standardized MDR-TB regimens (HR 0.6, 95% CI 0.4–1.0), cavitary disease (HR 4.9, 95% CI 2.8–8.6) and adverse events (HR 2.5, 95% CI 1.2–5.5). ConclusionsUnder well-designed treatment and management scheme, high treatment success rates were achieved in a high-MDR-TB-burden country. Antimicrobial susceptibility testing for all second-line drugs should be conducted to further assist in the treatment of MDR-TB.

Methodological considerations in clinical trials for new MDR-TB treatment regimens.

In contrast to the treatment of drug-susceptible tuberculosis (TB), the evidence base underpinning global guidelines for the treatment of multidrug-resistant (MDR) TB is very poor. This, combined with the lack of experience from previous trials and the nature of the disease, means that a number of methodological aspects are specific only to trials for new MDR-TB regimens. These aspects include the weight of evidence required to change policy and practice, the flexibility to make adaptations to an ongoing trial, the choice of patient population, the importance of internal control, the duration and frequency of follow-up, and safety monitoring of novel combinations of new and repurposed drugs.

Classifying new anti-tuberculosis drugs: rationale and future perspectives

The classification of anti-tuberculosis (TB) drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO) has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2-5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification) and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed.

Applicability of the shorter ‘Bangladesh regimen’ in high multidrug-resistant tuberculosis settings

In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as the 'Bangladesh regimen') proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. However, recent evidence from Europe and Latin America identified prevalences of resistance to the first-line drugs in this regimen (ethambutol and pyrazinamide) exceeding 60%, and of prothionamide exceeding 50%. Furthermore, the proportions of resistance to the two most important pillars of the regimen - quinolones and kanamycin - were higher than 40%. Overall, only 14 out of 348 adult patients (4.0%) were susceptible to all of the drugs composing the regimen, and were therefore potentially suitable for the 'shorter regimen'. A shorter, cheaper, and well-tolerated MDR-TB regimen is likely to impact the number of patients treated and improve adherence if prescribed to the right patients through the systematic use of rapid MTBDRsl testing.

Economic evaluation of a shortened standardised treatment regimen of antituberculosis drugs for patients with multidrug-resistant tuberculosis (STREAM): study protocol

IntroductionMultidrug-resistant tuberculosis (MDR-TB) poses a serious financial challenge to health systems and patients. The current treatment for patients with MDR-TB takes up to 24 months to complete. Evidence for a...

The WHO Shorter MDR-TB Regimen: Who Will Benefit With It?

Lung transplantation is a surgical option to replace a diseased lung with a healthy lung from a donor. This surgical process causes stop of blood flow from the point of organ retrieval or procurement followed by cold and warm storage phase (ischemia), followed by the re-instatement of blood flow with implantation (reperfusion) that occurs upon transplant. The injury incurred during ischemia (retrieval and storage) together with the injury from reperfusion (I/R injury) is considered as the main driver of onset of primary graft dysfunction (PGD). PGD is a multifactorial injury that is characterized by cellular infiltrates and severe oxidative damage; it occurs within 24 h post-transplant and is a critical factor in determining transplant outcome. PGD occurs in large part due to inflammation post-transplant when polymorphonuclear neutrophils (PMN) are recruited to and adhere to the endothelium of the lung, transmigrate and release reactive oxygen species (ROS). Recognizing the role of PMN in poor transplant outcome, the clinical strategy at present is to block PMN activation by a non-specific immunosuppression regimen administered to the transplant recipient.As immunosuppression therapy has severe side effects, alternate means of blocking and inhibiting inflammation in the lung are being considered. The binding of PMN to the endothelium is a prerequisite of inflammation; thus our research is focused on the endothelium of the donor lung so as to block endothelial signals that facilitate its bindingto PMN. Such a strategy of inhibiting the moieties on the vascular wall so that as prevent donor lung endothelial interaction with the recipient’s PMN is an early intervention and has the potential to prevent injury completely. In contrast, immunosuppression involves minimizing influx and recruitment of PMN and immune cells after the initial adherence and binding that would take place immediately upon transplant. Our extensive work on lung storage or ischemia shows that the pulmonary endothelium responds to stop of blood flow by a signaling cascade that involves K ATP channel closure, PI3Kinase activation and assembly of the enzyme NADPH oxidase 2 (NOX2) leading to the generation of ROS. We found that the ROS thus produced triggers the onset of an inflammation cascade during the storage period itself, ahead of the transplant event. Onset of inflammation causes damage to the donor lung during storage thus affecting donor lung availability; additionally it can potentially drive immune cell recruitment via inflamed lung vessel wall. Thus optimal storage conditions such as keeping the lung (organ) perfused or inhibiting ischemia induced signaling by blocking K ATP closure, PI3K activation or NOX2 assembly may potentially preserve lung viability and minimize inflammation and injury post-transplant.

Quantitative drug-susceptibility in patients treated for multidrug-resistant tuberculosis in Bangladesh: implications for regimen choice.

BackgroundMultidrug-resistant tuberculosis (MDR-TB) treatment in Bangladesh is empiric or based on qualitative drug-susceptibility testing (DST) by comparative growth in culture media with and without a single drug concentration.MethodsAdult patients were enrolled throughout Bangladesh during the period of 2011–2013 at MDR-TB treatment initiation. Quantitative DST by minimum inhibitory concentration (MIC) testing for 12 first and second-line anti-TB drugs was compared to pretreatment clinical characteristics and treatment outcomes. MIC values at or one dilution lower than the resistance breakpoint used for qualitative DST were categorized as borderline susceptible, and MIC values one or two dilutions greater as borderline resistant.ResultsSeventy-four patients were enrolled with a mean age of 35 ±15 years, and 51 (69%) were men. Of the rifampin isolates with MIC >1.0 μg/ml, 12 (19%) were fully susceptible or borderline susceptible to rifabutin (MIC ≤0.5 μg/ml). Amikacin was fully susceptible in 73 isolates (99%), but kanamycin in only 54 (75%) (p<0.001). Ofloxacin was borderline susceptible in 64%, and fully susceptible in only 14 (19%) compared to 60 (81%) of isolates fully susceptible for moxifloxacin (p<0.001). Kanamycin non-susceptibility and receipt of the WHO Category IV regimen trended with interim treatment failure: adjusted odd ratios respectively of 5.4 [95% CI 0.82–36.2] (p = 0.08) and 7.2 [0.64–80.7] (p = 0.11).ConclusionsQuantitative MIC testing could impact MDR-TB regimen choice in Bangladesh. Comparative trials of higher dose or later generation fluoroquinolone, within class change from kanamycin to amikacin, and inclusion of rifabutin appear warranted.

Successful management of multidrug-resistant tuberculosis under programme conditions in the Dominican Republic

The Dominican Republic is a high-incidence area for multidrug-resistant tuberculosis (MDR-TB; 6.6% of initial cases). Standardised treatment regimens for MDR-TB may be a potential solution. To present the effectiveness of standard regimens under routine national conditions. We reviewed all MDR-TB patients treated under routine conditions from 29 August 2006 to 30 June 2010, showing interim and final outcomes. Patients were treated with regimens that were standardised or individualised based on previously received second-line anti-tuberculosis drugs. Population description and culture conversion data are reported for the 289 MDR-TB patients. The median patient age was 31 years. Most had failed first-line treatment (72.6%). Culture negativity was obtained within 4 months (median 2 months) in 78.6%. Among the 150 patients treated between 2006 and 2008, 74% had favourable results on standardised and 66% on individualised regimens (P = 0.211). The efficacy of the standardised and individualised regimens was respectively 92.8% and 81% (P = 0.056). The relapse rate was approximately 1%. A median of five drug side effects occurred per patient. More than 2 months to culture conversion and bilateral cavitation on chest X-ray were found to be unfavourable outcome risk factors. Standardised MDR-TB regimens may be effective at the national level, even in resource-poor settings.

Moxifloxacin in multidrug-resistant tuberculosis: is there any indication for therapeutic drug monitoring?: Table 1–

To the Editors: Fluoroquinolones are rapidly emerging as important drugs in the treatment of tuberculosis (TB) worldwide [1]. In drug-susceptible TB, their use is currently under investigation and, according to the American Thoracic Society/Centers for Disease Control guidelines, fluoroquinolones are indicated only in patients receiving the conventional regimen who present severe adverse reactions [2]. However, in drug-resistant (DR) and, more specifically, in multidrug-resistant (MDR)-TB, the role of fluoroquinolones is much better established. Later-generation fluoroquinolones are included even in extensively drug resistant (XDR)-TB regimens since they may have some efficacy against ofloxacin-resistant strains [3]. The area under the concentration–time curve up to 24 h post-dosage (AUC24) is generally considered as the best predictor of fluoroquinolone efficacy [1]. Among fluoroquinolones, moxifloxacin is considered the most bactericidal, with potency comparable to that of isoniazid, and also seems to have some sterilising activity [1]. The maximal concentration (Cmax) of moxifloxacin exceeds mutant prevention concentration [1] and the currently recommended dose of 400 mg is likely to suppress the emergence of resistance in 60% of patients [4]. However, pharmacokinetic data on moxifloxacin in patients with TB are scarce, especially in the setting of an MDR-TB regimen. In this report of a pilot prospective study, we present preliminary data on pharmacokinetic parameters in patients with MDR- or XDR-TB receiving second-line treatment. Patients were receiving moxifloxacin (Avelox®; Bayer, Leverkusen, Germany) p.o. for ≥4 days, in order to achieve a steady state, as part of their anti-TB treatment, which was based on drug susceptibility test results. Quinolone resistance was determined by ofloxacin …

Linezolid in the Treatment of Multidrug‐Resistant Tuberculosis

Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB.