Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.

BACKGROUND: Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. METHODS: Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens. RESULTS: Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis. CONCLUSIONS: Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome.

Ameliorative potential of Adhatoda vasica against anti-tubercular drugs induced hepatic impairments in female Wistar rats in relation to oxidative stress and xeno-metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Adhatoda vasica Nees is widely used herb of indigenous system to treat various ailments especially upper respiratory tract infections. Not only, anti-tubercular efficacy of crude extract and phytoconstituents of A. vasica has been documented but its hepatoprotective role against various drugs mediated hepatic alterations in different animal models has also been observed. BACKGROUND AND PURPOSE: Isoniazid, rifampicin and pyrazinamide (H-R-Z) are anti-tubercular drugs normally prescribed by health professionals for the treatment of tuberculosis, however along with their medical effectiveness these drugs also exhibit hepatotoxicity among TB patients. Unexpectedly, substantial toxicological data on the metabolism of anti-TB drugs are available but the mystery behind these xenobiotics is too complex and partly implicit. In this study, we further explored the hepatotoxic effects of these xeno-metabolic products and their amelioration by Adhatoda vasica Nees by elucidating its mechanistic action. METHODS: We generated a hepatotoxic rodent model by oral administration of H, R and Z (30.85, 61.7 and 132.65 mg/kg body weight) drugs for 25 days in Wistar rats. Additionally, to achieve hepatoprotection two different doses of Adhatoda vasica Nees ethanolic leaf extract (200 and 300 mg/kg body weight) were used along with H-R-Z dosage, orally and once daily for 25 days and tried to ascertain their mechanistic action. For this, initially phytoconstituents of the extract were evaluated followed by extract standardization using RP-HPLC and FTIR methods. Furthermore, antioxidant activity of the extract was analyzed by DPPH assay. Finally, different treated groups were analyzed for hepatic oxidative stress markers, antioxidant markers, histopathological changes and gene expression study including CYP2E1, CYP7A1, NAT, NR1I2 and UGT1A1 genes involved in phase I and phase II xeno-metabolism. RESULTS: Estimated content of vasicine in RP-HPLC method and free-radical scavenging activity in DPPH assay was found to be 134.519 ± 0.00269µg/10mg of leaf extract and 47.81 µg/mL respectively. In H-R-Z treated group, a significant increase in the levels of thiobarbituric acid, significant reduction in the levels of GSH, and enzymatic markers and marked changes in hepatic histological architecture were observed. In addition, there was significance up-regulation of CYP7A and NAT genes, down-regulation of CYP2E1 gene and insignificant expression levels of NR1I2 and UGT1A1 genes were observed in H-R-Z group. Conversely, high dose of A. vasica extract effectively diminished these alterations by declining oxidative stress and boosting of antioxidant levels. In addition, it acted as bi-functional inducer of both phase I (CYP2E1) and phase II (NAT and UGT1A1) enzyme systems. CONCLUSION: Hence, we concluded that anti-TB drugs exposure has potential to generate reactive metabolites that eventually cause hepatotoxicity by altering oxidant-antioxidant levels and their own metabolism. This study not only emphasized on xeno-metabolism mediated hepatic alterations but also explore the benefit of A. vasica on these toxic insults.

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China.

BACKGROUND: Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrug-resistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations. METHODS: MDR-TB isolates from the 2007 national drug resistance survey of China were sub-cultured and examined for pyrazinamide susceptibility by BACTEC MGIT 960 method. pncA mutations were identified by sequencing. Characteristics associated with pyrazinamide resistance were analyzed using univariable and multivariable log-binominal regression. RESULTS: Of 401 MDR-TB isolates, 324 were successfully sub-cultured and underwent drug susceptibility testing. Pyrazinamide resistance was prevalent in 40.7% of samples, similarly among new and previously treated MDR-TB patients. Pyrazinamide resistance in MDR-TB patients was associated with lower age (adjusted OR 0.54; 95% CI, 0.34-0.87 for those aged ≧60 years compared to < 40 years). Pyrazinamide resistance was not associated with gender, residential area, previous treatment history and Beijing genotype. Of 132 patients with pyrazinamide resistant MDR-TB, 97 (73.5%) had a mutation in the pncA gene; with 61 different point mutations causing amino acid change, and 11 frameshifts in the pncA gene. The mutations were scattered throughout the whole pncA gene and no hot spot region was identified. CONCLUSIONS: Pyrazinamide resistance among MDR-TB patients in China is common, although less so in elderly patients. Therefore, pyrazinamide should only be used for treatment of RR/MDR-TB in China if susceptibility is confirmed. Molecular testing for detection of pyrazinamide resistance only based on pncA mutations has certain value for the rapid detection of pyrazinamide resistance in MDR-TB strains but other gene mutations conferring to pyrazinamide resistance still need to be explored to increase its predictive ability .

Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!

Background: One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity. Methods: We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients. Results: The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log10 CFU/mL/day, respectively. The high-dose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log10 CFU/mL/day and 0.72 (95% CI, .56-.79) log10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05). Conclusions: The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.

[Optochiasmatic tuberculomas as a paradoxical reaction to treatment for meningeal tuberculosis]. / Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

TITLE: Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

Gitelman-like Syndrome with Kanamycin Toxicity.

A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.

Prevalence and transmission of pyrazinamide resistant Mycobacterium tuberculosis in China.

Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, however, there are relatively few available data on PZA resistant (PZA-R) rate in China. From June 2009 to June 2012, we selected 493 isolates from five field settings in China to investigate PZA-R by pncA gene sequencing. The result showed that PZA-R rate was 1.0% (2/196) among pan-susceptible isolates, 3.1% (4/130) among isoniazid (INH) mono-resistant isolates, 14.0% (6/43) among rifampin (RIF) mono-resistant isolates and 43.5% (54/124) among multidrug resistant (MDR) isolates. MDR tuberculosis (TB), RIF mono-resistance, and retreatment were found to be risk factors for PZA-R. Newly diagnosed PZA-R TB patients and clustered isolates with identical pncA mutations indicate that transmission of PZA-R isolates plays an important role in emergence of PZA-R TB. The results suggest that, it is necessary to conduct PZA susceptibility test among MDR isolates and modify the treatment regimens accordingly.

PA-824 , moxifloxacin and pyrazinamide combination therapy for tuberculosis.

INTRODUCTION: New treatment regimens are urgently required for tuberculosis (TB). The existing four-drug regimen for TB is > 20 years old, with multidrug resistant (MDR) and extensively drug-resistant (XDR) TB on the increase. AREAS COVERED: Recently, the first novel potential combination TB treatment regimen for both drug-sensitive and MDR TB incorporating a new nitroimidazole compound, PA-824 , was investigated in a Phase II proof-of-concept clinical trial. This article reviews the rationale for this novel study, discusses the development strategy for PA-824 and highlights the study findings and its implications for future development of this regimen. EXPERT OPINION: Expert opinion will be offered on the utility of this new multicomponent treatment regimen. We will highlight how this study informs the development pathway for future novel TB regimens and explore the PA-824, moxifloxacin (MOX) and pyrazinamide combination as a first step towards developing a single treatment regimen for both drug-sensitive and drug-resistant diseases.

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil.

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Desfechos clínicos do tratamento de tuberculose utilizando o esquema básico recomendado pelo Ministério da Saúde do Brasil com comprimidos em dose fixa combinada na região metropolitana de Goiânia / Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil

OBJETIVO: Descrever as taxas de cura, falência e abandono do tratamento da tuberculose com o esquema básico preconizado pelo Ministério da Saúde (tratamento com rifampicina, isoniazida, pirazinamida e etambutol por dois meses seguido de isoniazida e rifampicina por quatro meses) utilizando comprimidos em dose fixa combinada em regime autoadministrado e descrever os eventos adversos e seus possíveis impactos nos desfechos do tratamento. MÉTODOS: Estudo descritivo utilizando dados coletados prospectivamente dos prontuários médicos de pacientes com tuberculose (idade > 18 anos) tratados com o esquema básico em duas unidades básicas de saúde da região metropolitana de Goiânia, GO. RESULTADOS: A amostra foi composta por 40 pacientes com tuberculose. A taxa de cura foi de 67,5%, a taxa de abandono foi de 17,5%, e não ocorreram casos de falência. Nessa amostra, 19 pacientes (47%) relataram reações adversas aos medicamentos. Essas foram leves e moderadas, respectivamente, em 87% e 13% dos casos. Em nenhum caso houve necessidade de mudança do esquema ou suspensão do tratamento. CONCLUSÕES: A taxa de cura do esquema básico com o uso de comprimidos em dose fixa combinada sob regime autoadministrado foi semelhante às taxas históricas do esquema anterior. A taxa de abandono, na amostra estudada, foi muito acima da taxa preconizada como adequada (até 5%).

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.

BACKGROUND: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING: The Global Alliance for TB Drug Development (TB Alliance).

Protective effect of curcumin, silymarin and N-acetylcysteine on antitubercular drug-induced hepatotoxicity assessed in an in vitro model.

Tuberculosis (TB) is highly endemic in India. The first-line anti-TB therapy (ATT) involving isoniazid (INH), rifampicin and pyrazinamide causes hepatotoxicity in approximately 11.5% of Indian patients. Studies have shown that ATT-induced hepatotoxicity is primarily due to oxidative stress caused by the drugs and metabolites. Herbal drugs with antioxidative properties have been tested in animal studies and clinical trials for the management of hepatotoxicity. The objective of this study was to investigate the role of curcumin (CUR), silymarin (SILY) and N-acetylcysteine (N-ACET) on hepatotoxicity by ATT drugs using an in vitro model of human hepatocellular carcinoma cell line (HepG2). HepG2 cells were treated with ATT drugs alone or along with CUR, SILY or N-ACET for a 48-h duration. The cells were monitored for viability, morphology, respiring mitochondria and cell cycle. Our results suggest that the presence of hepatoprotective drugs during treatment of HepG2 cells with ATT drugs lowers the hepatotoxic effect of the latter. This is observed in terms of (a) increased cell viability, (b) healthy-looking cell morphology as revealed by phase contrast microscopy, (c) active respiring cells as observed with confocal microscopy upon staining with a mitochondrial membrane-specific dye, MitoTracker(®) Red, and reduction in the sub-G(1) peak in cell cycle analysis by flow cytometry. Our results suggest that these hepatoprotective drugs need to be further explored as potential adjuvant therapy along with ATT drugs.

Assessment of protective role of polyherbal preparation, Livina, against anti-tubercular drug induced liver dysfunction.

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post-ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+AITT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Prevention of hepatotoxicity due to anti tuberculosis treatment: a novel integrative approach.

AIM: To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity. METHODS: Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation. Isoniazid, rifampicin, pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment. Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant. Hemogram, bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result. RESULTS: Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316, P<0.0001). Mean aspartate transaminase (AST) (195.93+/-108.74 vs 85+/-4.24, P<0.0001), alanine transaminase (ALT) (75.74+/-26.54 vs 41+/-1.41, P<0.0001) and serum bilirubin (5.4+/-3.38 vs 1.5+/-0.42, P<0.0001). A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137, P=0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278, P=0.0037) was observed. Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P<0.0001). CONCLUSION: The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

Successful treatment of multidrug-resistant tuberculosis following drug-induced hepatic necrosis requiring liver transplant.

A 28-year-old female developed multidrug-resistant (MDR) tuberculous lymphadenitis following a trip to India. She was initially treated with a four-drug regimen of first-line anti-tuberculosis medications, but when sensitivities indicated resistance to isoniazid and rifampin, her regimen was altered to ciprofloxacin (CFX), pyrazinamide (PZA) and ethambutol. She subsequently developed a rash, flu-like symptoms and fever, which progressed to acute hepatic necrosis despite discontinuation of medication. The clinical presentation and subsequent investigations suggested a hypersensitivity reaction, possibly related to the quinolone. The patient subsequently had an orthoptic liver transplant; second-line anti-tuberculosis medications were restarted to which she responded clinically and radiologically. Our findings raise the possibility that the CFX and PZA combination was responsible for the hepatic necrosis. The patient also illustrates that active, even MDR tuberculosis is not a contraindication to hepatic transplant.

Adverse drug reactions observed during DOTS.

A total of 8.37% of the 1195 patients treated at NDTB Centre with DOTS under RNTCP between January 2002 to June 2003 presented with adverse drug reactions. Patients showing any sort of adverse reactions were studied in detail by personal interviews and a semi-structured questionnaire. The profile of patients presenting with adverse reactions showed that majority of the patients (53%) had gastrointestinal reactions, the commonest presenting complaint being nausea and vomiting. General aches and pains were complained by about 35% and giddiness was the presenting complaint in 27% irrespective of the use of streptomycin, although giddiness was observed more often in Category II patients (59%). Skin rash and itching was complained by about 17% of patients and 11% complained of arthralgia, while only 1% had hepatotoxicity during treatment. Majority of the adverse reactions (67%) were observed within the first four weeks of treatment and only 0.25% of patients treated with DOTS had interruption of treatment for short periods.

Chemoprophylaxis of multidrug-resistant tuberculous infection in HIV-uninfected individuals using ciprofloxacin and pyrazinamide. A decision analysis.

STUDY OBJECTIVE: To evaluate the use of ciprofloxacin and pyrazinamide for the prophylaxis of individuals infected with multiply drug-resistant strains of Mycobacterium tuberculosis. DESIGN: Decision analysis, using software (SMLTREE). Probabilities based on published studies, with sensitivity analysis for each probability. SETTING: Health-care workers infected with multidrug-resistant strains of M tuberculosis. INTERVENTIONS: Prophylaxis with ciprofloxacin and pyrazinamide. MEASUREMENTS AND RESULTS: We calculated the utilities of taking or not taking prophylaxis with ciprofloxacin and pyrazinamide. The decision analysis favored the use of ciprofloxacin-pyrazinamide prophylaxis by a small margin. CONCLUSION: Ciprofloxacin-pyrazinamide prophylaxis should be considered for health-care workers infected with multiply drug-resistant M tuberculosis.

Cerebellar syndrome caused by isoniazid.

Treatment of tuberculosis in a hemodialysis patient with isoniazid, rifampin, and pyrazinamide resulted in the development of acute cerebellar dysfunction. This resolved rapidly following the discontinuation of isoniazid and pyrazinamide, reinstitution of isoniazid at a lower dose, and addition of pyridoxine. We discuss why we believe this syndrome was caused by isoniazid. Patients with renal failure who undergo antituberculous therapy with isoniazid should receive supplemental pyridoxine to reduce the likelihood of isoniazid-related neurotoxicity.