Different macrophage polarization between drug-susceptible and multidrug-resistant pulmonary tuberculosis.

BACKGROUND: Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used. METHODS: iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated. RESULTS: The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6 weeks than in those who received anti-TB drugs not containing pyrazinamide. CONCLUSIONS: The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.

Development and evaluation of Chitosan nanoparticles based dry powder inhalation formulations of Prothionamide.

Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent administration limit its use. An alternate approach was thought of administering PTH through pulmonary route in a form of nanoparticles, which can sustain the release for several hours in lungs. Chitosan, a bio-degradable polymer was used to coat PTH and further freeze dried to prepare dry powder inhaler (DPI) with aerodynamic particle size of 1.76µm. In vitro release study showed initial burst release followed by sustained release up to 96.91% in 24h. In vitro release further correlated with in vivo study. Prepared DPI maintained the PTH concentration above MIC for more than 12h after single dose administration and increased the PTH residency in the lungs tissue more than 24h. Animal study also revealed the reduction of dose in pulmonary administration, which will improve the management of tuberculosis.

Dosis de protionamida y PAS. Corrección al «Documento de Consenso sobre diagnóstico, tratamiento y prevención de la tuberculosis» / Prothionamide and PAS doses. Correction to «Consensus document on the diagnosis, treatment and prevention of tuberculosis»

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A review of the use of ethionamide and prothionamide in childhood tuberculosis.

Ethionamide (ETH) and prothionamide (PTH), both thioamides, have proven efficacy in clinical studies and form important components for multidrug-resistant tuberculosis treatment regimens and for treatment of tuberculous meningitis in adults and children. ETH and PTH are pro-drugs that, following enzymatic activation by mycobacterial EthA inhibit InhA, a target shared with isoniazid (INH), and subsequently inhibit mycolic acid synthesis of Mycobacterium tuberculosis. Co-resistance to INH and ETH is conferred by mutations in the mycobacterial inhA promoter region; mutations in the ethA gene often underlie ETH and PTH monoresistance. An oral daily dose of ETH or PTH of 15-20 mg/kg with a maximum daily dose of 1000 mg is recommended in children to achieve adult-equivalent serum concentrations shown to be efficacious in adults, although information on optimal pharmacodynamic targets is still lacking. Gastrointestinal disturbances, and hypothyroidism during long-term therapy, are frequent adverse effects observed in adults and children, but are rarely life-threatening and seldom necessitate cessation of ETH therapy. More thorough investigation of the therapeutic effects and toxicity of ETH and PTH is needed in childhood TB while child-friendly formulations are needed to appropriately dose children.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.).

Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial.

BACKGROUND: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection. METHODS/DESIGN: STREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites. DISCUSSION: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB. TRIAL REGISTRATION: This trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010.

Hepatitis associated with prothionamide for treatment of multidrug-resistant tuberculosis.

Timely and intensive monitoring for, and management of, adverse effects caused by anti-tuberculosis drugs are essential components of control programs for multidrug-resistant tuberculosis (MDR-TB). This retrospective case series was conducted in northern Taiwan from January 2007 to December 2008 at Taipei Medical University-Wan Fang Hospital, a 750-bed tertiary-care center and MDR-TB referral center. Hepatitis associated with prothionamide was defined as the recurrence of hepatitis after a second prothionamide treatment re-challenge. In total, 47 patients with MDR-TB enrolled in the Directly Observed Therapy, Short Course-Plus Program were identified during the study period, and 44 (93.6%) were treated with prothionamide. Seven of these 44 patients (15.9%) developed hepatitis after being treated with prothionamide concurrent with other anti-tuberculosis agents. Hepatitis associated with prothionamide occurred in three of these seven patients (6.8%). In these three patients, hepatitis developed following treatment with prothionamide for 28 days, 39 days or 45 days. Hepatitis developed rapidly after re-challenge with prothionamide at 4 days, 4 days and 3 days, respectively. Liver function returned to the normal range after cessation of prothionamide treatment for 19 days, 27 days or 28 days. Close monitoring of liver function was necessary in MDR-TB patients who received prothionamide treatment.

Pharmacokinetics of prothionamide in patients with multidrug-resistant tuberculosis.

SETTING: National Masan Tuberculosis Hospital, Masan, South Korea. OBJECTIVE: To evaluate the pharmacokinetics of prothionamide (PTH) in South Korean patients with multidrug-resistant tuberculosis (MDR-TB) and to investigate whether differences in body mass index (BMI) could explain observed differences in PTH disposition. DESIGN: Seventeen patients participated in the study; all had MDR-TB and had received combination anti-tuberculosis treatment, including PTH, cycloserine, ofloxacin, para-aminosalicylic acid and streptomycin or kanamycin, for at least 2 weeks. The patients were divided into two groups based on BMI: Group A (18.5 < or = BMI<23), and Group B (BMI<18.5). Serum samples were collected over 24 h, and the plasma PTH concentration was determined by a validated high-performance liquid chromatography assay. RESULTS: After steady-state administration of PTH, the mean area under the plasma concentration-time curve from time 0 to 12 h (AUC(0-12h)) was 11.0 +/- 3.7 microg h/ml. The mean T(max) and t(1/2) were respectively 3.6 h and 2.7 h. No significant difference in PTH disposition was observed between groups A and B, except for ke and t(1/2). CONCLUSION: In the pharmacokinetic parameter estimates for PTH in MDR-TB patients during routine treatment, the pharmacokinetics of PTH did not appear to correlate with extent of emaciation in MDR-TB patients.

[Optimization of chemotherapy regimens in children with primary pulmonary tuberculosis].

The efficiency of treatment was analyzed in 142 children aged 3-14 years who had local forms of primary pulmonary tuberculosis. Therapy was performed according to regimens 3 and 1, by using individual dosage regimens depending on the extent and severity of a specific process, the presence of complications, and age-related features. In minor tuberculosis, solitary calcifications being detected without signs of the activity of tuberculous infection, the basic course of therapy was 6-8 months; it was performed using 2 drugs in individual cases. In disseminated and complicated processes, eliminated intoxication and visible X-ray inflammatory changes were observed in 58.8-61.7% of children by months 3-4 of treatment, which required a longer intensive phase, by administering 3 drugs in the continuation phase till 6-9 months.

Can leprosy be eradicated with chemotherapy? An evaluation of the Malta Leprosy Eradication Project.

The Malta Leprosy Eradication Project (MLEP) was proposed in 1971 by Freerksen with the aim of eradicating leprosy in Malta. The project involved re-treatment of all known cases in Malta as of 1972 and all new cases thereafter with a regimen consisting of Isoprodian (a combination of dapsone, prothionamide and isoniazid) and rifampicin for varying intervals depending on the severity of their disease and their response to treatment. Overall the response to therapy was excellent with an extremely low relapse rate. During the 30 years of the project the incidence of leprosy steadily decreased continuing a decline that had started at least two decades earlier and Freerksen declared the disease eradicated from Malta in 2001. Although given the long incubation period of leprosy cases may still be occasionally detected in the future, the disease has been basically eradicated at this time and there are no patients currently receiving treatment. This work was done at the leprosy clinic, Boffa Hospital, Floriana, Malta.

Self-administered, standardized regimens for multidrug-resistant tuberculosis in South Korea.

SETTING: National Masan Tuberculosis Hospital, Masan, South Korea, a 430-bed tertiary referral hospital specializing in tuberculosis. OBJECTIVE: To evaluate the treatment outcomes of standardized, empiric regimens for multidrug-resistant tuberculosis (MDR-TB). DESIGN: A retrospective analysis of the hospital records of 142 patients with MDR-TB who had failed short-course chemotherapy. Between 1 January 1998 and 30 June 2000, patients were started on one of two standardized, empiric regimens based on previous treatment history. Drug susceptibility testing of the infecting strain was not used to modify the treatment regimen. Treatment was continued for at least 18 months after conversion to a negative culture. RESULTS: Sixty-three patients (44.1%) were cured and discharged from treatment after at least 18 months of negative cultures; 18 (12.7%) failed treatment, 41 (28.9%) defaulted, four died (2.8%), and 15 (10.6%) were transferred to another institution. One patient is still on treatment. Resistance to ofloxacin was the only risk factor related to poor outcome (death or failure) in univariate or multiple logistic regression analysis. CONCLUSIONS: High levels of resistance to second-line drugs are likely a cause of poor outcome of MDR-TB therapy in Korea. Directly observed therapy and other methods to increase patient compliance should be considered nationwide, as they may improve MDR-TB treatment outcomes.

[Chemotherapy-induced erythema nodosum leprosum: successful treatment with thalidomide]. / Erythema nodosum leprosum unter Chemotherapie. Erfolgreiche Behandlung mit Thalidomid.

The severity and outcome of a chronic granulomatous infection caused by M. leprae depend on the cell-mediated immunity towards the pathogen. The disease classification is based on the host's response to M. leprae ranging from high to low resistance (polar tuberculoid leprosy to polar lepromatous leprosy). The host's position in the spectrum is not stable; leprosy reactions reflecting changed immune status may occur spontaneously or during chemotherapy. The type II reaction or erythema nodosum leprosum can most often be seen in patients with lepromatous leprosy, a multiorgan disease characterized by an unrestricted bacillary replication. Clinically, this reaction is characterized by crops of painful bright pink, dermal and subcutaneous nodules arising in clinically normal skin, in association with fever, malaise, glomerulonephritis and arthralgias. Therefore, prompt institution of immunosuppressive therapy with corticosteroids or thalidomide is recommended. This case report describes the development of erythema nodosum leprosum during chemotherapy treated successfully with thalidomide. Furthermore, immunologic effects and potential side effects of this drug are discussed.

[Analysis of causes of drug resistance and therapeutic effects on 27 multi-drug resistant pulmonary tuberculosis patients].

OBJECTIVE: To analyse the causes of multi-drug resistant tuberculosis (MDR-TB) and to evaluate the effects of chemotherapy with ofloxacin and other antituberculosis drugs. METHOD: 27 cases with MDR-TB were treated with the regimen of 3KPTHOX/PTHOX. Changes of sputum convesion, X-ray manifestations and side effects after the treatment were also evaluated. RESULTS: 67% of the MDR-TB patients were due to irregular treatment, and 18% were caused by improper treatment. The sputum culture conversion rate at end of treatment was 89%. The bacteriological relapse rate of converted cases during 2 year follow-up was 8%. CONCLUSIONS: MDR-TB might be prevented by a combination of health education and rational use of short-course chemotherapy. Ofloxacin and other second-line anti-tuberculosis drugs are effective and were tolerated in treating patients with MDR-TB.

[Ofloxacin-cycloserine-protionamide-INH combination against treatment refractory lung tuberculosis]. / Ofloxacin-Cycloserin-Protionamid-INH-Kombination gegen therapieresistente Lungentuberkulose.

Multiresistant tuberculoses are on the increase. The conversion rates in "additional" therapy are only modest. 17 multiresistant patients and 6 treatment-refractory tuberculoses were treated by us with ofloxacin-cycloserin-protionamide-INH. 16 of these patients were HIV positive. 21 patients converted after 3 months of treatment by the latest. 3 patients died of HIV syndrome. There was otherwise no difference between HIV positive and HIV negative patients. As a rule, the combination was well tolerated. In multiresistant tuberculosis, it is mandatory to administer at least 3 drugs to which there is no resistance.

Does isoniazid increase the hepatotoxicity of the combination prothionamide-dapsone? Isoprodian Study Group.

In order to assess the potential additive liver toxicity of isoniazid to that of a thioamide-containing treatment, a prospective, randomized, double-blind trial of 24 weeks' duration involving 772 adult patients was conducted in four leprosy centers--two in India, one in Madagascar, and one in the Ivory Coast. Patients with multibacillary leprosy were given daily 100 mg dapsone (DDS) and 350 mg prothionamide (PTH) plus monthly 600 mg rifampin (RMP) in combination either with 350 mg isoniazid (INH) or with a placebo. After clinical and laboratory (including HBs-Ag testing) examinations on admission, the side effects (especially gastrointestinal disturbances and liver toxicity) were assessed at regular intervals during treatment by laboratory testing (aminotransferases, bilirubin, alkaline phosphatase) and by recording spontaneous complaints. Analysis of the frequency and seriousness of the side effects was made before breaking the code (with or without INH). Although 10% of the patients had liver toxicity leading to stopping treatment, no significant difference in the occurrence of side effects was observed between patients treated with or without INH. Most (75%) of the observed side effects occurred during the first 4 weeks of treatment, and the time of their onset was not related to INH. Body weight and age were factors related to the frequency of side effects [the higher the body weight, the lesser the rate of side effects (p = 0.03)] and the rate of serious side effects increased with age (p = 0.02). But, again, the frequency of the side effects was not related to INH administration. Therefore, from the present study it can be concluded that INH does not increase the toxicity of the thioamide-containing treatment.

Treatment of paucibacillary leprosy with a regimen containing rifampicin, dapsone and prothionamide.

Ninety paucibacillary leprosy patients having indeterminate (I), tuberculoid (TT) and borderline tuberculoid (BT) type of leprosy with bacterial index (BI) of less than two on the Ridley scale were treated with rifampicin (RFM) 600 mg once a month, dapsone (DDS) 100 mg daily and prothionamide (PTH) 250 mg daily. Treatment was stopped at the end of six months. The patients tolerated the drugs fairly well and in only two patients the drugs had to be stopped (in one due to jaundice and in the other due to gastric intolerance). About 6% of patients had early reactions which subsided with additional steroid therapy. The inactivity rate was 60% at six months and this improved to 96% at 12 months. No cases of late reactions and relapses were encountered in the limited follow-up period of six months; and a longer follow-up is necessary for ascertaining the relapse rates. The preliminary results however suggest that the addition of prothionamide to the standard WHO paucibacillary regimen is well-tolerated with increased inactivity rate and fewer instances of late reactions.

[Leprosy in Africa. Current status and epidemiological significance]. / Lepra in Afrika. Aktueller Stand und epidemiologische Bedeutung.

The introduction briefly describes the pathogenesis, classification, diagnosis and modern treatment possibilities. In Africa leprosy is considered endemic. The World Health Organization estimates the total number of cases at 3.5 million. Over the last 20 years, however, the recorded number of cases has decreased dramatically. Increasing mobility on the part of the population, relocation from countryside to the cities, and a tendency towards urbanization are introducing a new dimension to leprosy distribution and the fight against the disease in Africa. Despite the not-inconsiderable financial, material and human resources that have so far been made available--mostly from outside the country--only a small percentage of the presumptive number of leprosy sufferers are receiving an adequate, modern combination therapy. This means that leprosy continues to represent a serious public and individual health problem in Africa.

[Short- and long-term results of tuberculosis therapy with a fixed combination of isoniazide, prothionamide and diaminodiphenylsulfone combined with rifampicin]. / Kurz- und Langzeitergebnisse der Tuberkulosetherapie mit einer fixen Kombination aus Isoniazid, Prothionamid und Diaphenylsulfon (IPD) in Verbindung mit Rifampicin.

This is a report on 912 patients treated during 1973 to 1979 for pulmonary tuberculosis and/or extrapulmonary organ involvement. These patients had been treated with a fixed tablet combination of isoniacide, prothionamide and diaphenyl sulfone in association with rifampicin and partly other substances. It was the aim of our study to examine this form of therapy in respect of side effects and effectivity. 535 of these 912 patients were followed up for as long as 13 years (maximum follow-up period). According to the criteria of the American Tuberculosis and Respiratory Diseases Association the patients were suffering from 182 cases of pulmonary tuberculosis of only slight extension, 490 of moderate extension and 130 of large extension, as well as 55 cases of pleuritis, 67 extrapulmonary organ tuberculoses and 1 tuberculosis of the bronchial mucosa. Allergic skin reactions occurred in 0.7% of the cases, and in 0.9% there were neurological disturbances such as vertigo, paroxysms and polyneuropathies. In 7.4% of the patients there was an increase in serum enzyme activities of SGOT, SGPT, Y-GT as a sign of hepatotoxicity. In 5.5% of the patients there were several gastrointestinal concomitant phenomena such as sensation of fullness, nausea, and vomiting. Under IPD therapy the hemoglobin valuedropped on the average by 12% up to the 5th or 6th week of treatment and rose subsequently to almost normal levels. No permanent damage was seen in any of the patients under observation. In the moderately extended tuberculosis cases disinfection occurred on the average between the 6th and 8th week of treatment, in the greatly extended cases on the average in the 9th to 13th week.(ABSTRACT TRUNCATED AT 250 WORDS)

Random variation in tuberculin sensitivity in schoolchildren. Serial skin testing before and after preventive treatment for tuberculosis.

Schoolchildren were Mantoux-tested with 2 TU freeze-dried PPD RT23, and the strong reactors with indurations of 14.0 mm or more were selected for treatment with one of three different fixed drug combinations containing isoniazid or with placebo for 2 to 6 months. The initial tuberculin test was repeated after 8, 14, and 27 months. Of the 8,934 black schoolchildren initially tested, 5,165 did not react to the skin test, 2,898 had indurations up to 14.0 mm, and 871 reacted strongly. Of these strong reactors, 808 were allocated to four preventive treatment groups. On completion of treatment, the mean tuberculin reaction for all groups was significantly decreased. Because the placebo group showed changes similar to those seen in the other treatment groups, the tuberculin skin test is probably not suitable for monitoring the success of preventive therapy. Differences between skin test results before and after treatment when retesting only strong reactors are caused by a combination of effects that are difficult to distinguish. Assuming random variation in tuberculin sensitivity, the decrease can be explained as a combined effect of regression to the mean and some boosting. The increased reaction sizes in the subsequent Mantoux tests are explained by the booster phenomenon and possibly by reinfection. When using a cutting point for deriving a positive reactor, the chance of being selected for preventive treatment may depend primarily on the moment in time when the test is done. Thus, all reactors with no recent BCG vaccination should equally be considered for treatment.