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PubMed1989

Treatment of pulmonary tuberculosis with short course chemotherapy in south India--5-year follow up.

A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1% of 126 R/5, 4.0% of 124 R/7 and 6.7% of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment.

Adolescent↗
PubMed1989

High initial drug resistance in pulmonary tuberculosis in Ghana.

Between July 1985 and March 1987, initial sensitivity to anti-tuberculosis drugs was studied in patients presenting at the Chest Clinic of Agogo Hospital in the forest area of Ghana. Culture and sensitivity test results were obtained in 99 out of 123 consecutive patients with pulmonary tuberculosis who claim not to have received previous treatment. Isoniazid resistance was alarmingly high in the isolates of M. tuberculosis: 21 out of 57 (37%), and thiacetazone resistance was very high in the M. africanum isolates: 20 out of 42 (47%). Overall resistance was high: 27% to isoniazid, 23% to streptomycin, 29% to thiacetazone, 16% to both streptomycin and isoniazid, and 5% to all of these three drugs. Only 45% of the isolates were sensitive to all three drugs. Primary drug resistance to rifampicin, pyrazinamide or ethambutol was not observed. Besides the standard treatment of isoniazid, streptomycin and thiacetazone, rifampicin and pyrazinamide were usually added for the first two months of treatment. Of 13 patients who received standard treatment only, 4 of the 5 patients with resistant organisms who could be followed up failed to respond, whereas there were no failures to respond in the 5 corresponding patients with initially sensitive organisms; 3 patients could not be assessed because they defaulted.

Antibiotics, Antitubercular↗
PubMed1992

Rapid identification of motile Aeromonas.

The clinical relevance and taxonomy of motile Aeromonas species are areas of current controversy. Strains of motile Aeromonas isolates (n = 60) from various sources were identified to species level using the following tests (all incubated at 30 degrees and 37 degrees C): esculin hydrolysis; formation of gas from glucose; production of acetoin; production of acid from mannitol and arabinose; decarboxylation of lysine and ornithine, dihydrolation of arginine; and pyrazinamide hydrolysis in a semisolid medium. The tests' results were similar at incubation temperatures of 30 degrees and 37 degrees C. Of the strains, 59 (98%) of 60 were identified to species level by the full battery of tests: 25 as A. hydrophila, 18 as A. caviae, 14 as A. sobria, one as A. veronii, and one as A. schubertii. (The only A. veronii and A. schubertii isolates identified were ATCC strains). All (25 of 25) strains of A. hydrophila and 17 (94%) of 18 of A. caviae hydrolyzed pyrazinamide in less than 24 hr, whereas all strains of A. sobria showed no pyrazinamidase activity. Absence of pyrazinamidase was, thus, a convenient phenotypic marker for A. sobria. Four additional tests (esculin hydrolysis, acetoin production, lysine decarboxylation, and gas production from glucose) identified within 24 hr all examples of the three common species of Aeromonas. Recently proposed species did not contribute to our ability to discriminate among stool, other clinical, and environmental isolates of Aeromonas spp.

Aeromonas↗
PubMed2005

Synthesis of zidovudine prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.

A series of prodrugs of zidovudine has been synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of zidovudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell-line and zidovudine ester bearing pyrazinamide acetic acid was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index (SI) of>15,723. Zidovudine prodrug bearing ciprofloxacin and norfloxacin moiety showed 100% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. The prodrugs were also found to exhibit antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterase with t1/2 ranging from 20 to 240 min.

Anti-Bacterial Agents↗
PubMed2004

Bioequivalence trials of rifampicin containing formulations: extrinsic and intrinsic factors in the absorption of rifampicin.

Rifampicin shows variable bioavailability from solid oral dosage forms and the reasons for this variable absorption reported in literature varies from extrinsic formulations factors to intrinsic variability in rifampicin absorption. Hence, we have undertaken a systematic and comprehensive evaluation of all the factors to study contribution of all the factors on rifampicin absorption. As a first step, data from eight bioequivalence studies conducted at National Institute of Pharmaceutical Education and Research (NIPER) bioavailability center was compared across the trials to understand the effect of extrinsic/intrinsic factors on the bioavailability of rifampicin, isoniazid and pyrazinamide. Out of eight fixed dose combination (FDC) formulations, six formulations were bioequivalent for rifampicin to separate formulations whereas one formulation was below and one was above the limits of bioequivalence. It was observed that more variability in rifampicin blood levels is associated with FDC formulations when compared to rifampicin-only formulations and was attributed to complexity involved in the manufacturing of FDCs. Further, one of the rifampicin-only capsule showed unexpectedly lower plasma levels indicating role of physical characteristics of rifampicin bulk material. It was also seen that rifampicin shows dose-dependent pharmacokinetics even at the modest increase in dose due to saturation of efflux system at absorption site and metabolizing enzymes for elimination. Other components of FDC formulations such as isoniazid and pyrazinamide due to high solubility and permeability have shown very less variability and were bioequivalent to separate formulations even from formulations those were failed for rifampicin. The comparison of data across the trials suggested that rifampicin bioavailability problem is more attributable to the extrinsic factors such as formulation or rifampicin bulk material rather than intrinsic variability of rifampicin absorption.

Adolescent↗
PubMed2006

Tuberculosis in children: an update.

TB is a common and serious global infection that is spread exclusively from person to person. The initial infection in most healthy people leads to LTBI 95% of the time, but untreated individuals have a 5% to 10% lifetime risk for reactivating their infection to develop highly infectious cavitary pulmonary TB or extrapulmonary disease. Following primary infection progressive disease is more likely to develop in children younger than 5 years old or those who are immunocompromised, particularly those with HIV infection. The diagnosis of TB in most of the world depends on the presence of a clinical illness typical for TB in concert with radiographic changes, the presence of AFB in sputum, or a positive TST. Newer methods of in vitro stimulation of T lymphocytes from TB-infected people to produce interferon may be more accurate than a TST but have yet to be well studied in children. Treatment of children with LTBI is generally 9 months of daily isoniazid unless the child has been in contact with an adult with known isoniazid-resistant TB. For active TB, children generally are treated for 6 months with an initial 2 months of isoniazid, rifampin, and pyrazinamide. Where exposure to an isoniazid-resistant strain is likely, ethambutol is added. After 2 months, pyrazinamide is discontinued unless the patient has been confirmed to have been infected with a resistant strain of M. tuberculosis. BCG, rarely used in the United States, is still considered important to prevent meningitis and miliary disease in very young children in areas of the world with a high prevalence of TB.

Child↗
PubMed1999

A case of classical xanthinuria (type 1) with diabetes mellitus and Hashimoto's thyroiditis.

In a 62-year-old woman with non-insulin-dependent diabetes mellitus and Hashimoto's thyroiditis, hypouricemia was detected by a routine examination. Her plasma uric acid level was markedly low and urinary excretion of uric acid was undetectable. The high plasma and urine levels of xanthine were observed, although those of hypoxanthine were within normal ranges at rest after an overnight fast. After taking diet, plasma concentration and urinary excretion of hypoxanthine were markedly increased together with those of xanthine. The xanthine oxidase activity of duodenal mucosa was below the limits of detection. Allopurinol was metabolized to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide in spite of no activity of xanthine oxidase, suggesting that aldehyde oxidase converted allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide. Based on these findings, she was diagnosed as having a subtype of classical xanthinuria type 1 with the normal plasma concentration of hypoxanthine in fast.

Diabetes Mellitus, Type 2↗
PubMed1997

Prospective randomized study of thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy.

The aim of this study is to compare the efficacy of a thrice weekly 6-month regimen, 4S3H3R3Z3/2H3R3 (which consists of an initial 4 months of streptomycin (S), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 2 months of isoniazid and rifampicin), with a thrice weekly 9-month regimen, 4S3H3R3Z3/5H3R3 (which consists of an initial 4 months of streptomycin, isoniazid, rifampicin, and pyrazinamide followed by 5 months of isoniazid and rifampicin), in the treatment of cervical tuberculous lymphadenopathy. A total of 113 patients were recruited between August 1987 and December 1993. Twenty-two patients were excluded from the analysis because of defaulting treatment or modification of regimen. Ninety-one patients were included in the analysis. Forty-three patients were given the 6-month regimen, and 48 patients were given the 9-month regimen. Two (5%) patients of the 6-month regimen and one (2%) patient of the 9-month regimen had primary failure after completion of treatment (relative risk, 2.23; 95% confidence interval, 0.21 to 23.76). Of the 88 patients who had initial clinical remission after completion of treatment, the 5-year actuarial remission rates were 89% for the 6-month regimen and 90% for the 9-month regimen (Wilcoxon, p = 0.44). There were no significant differences of both primary failure rate and 5-year actuarial remission rate of the two regimens. The 6-month regimen is recommended as the initial treatment of tuberculous lymphadenopathy.

Administration, Oral↗
PubMed1998

Regulation of renal urate excretion: a critical review.

Uric acid metabolism is reviewed as it relates mainly to kidney and electrolyte disorders, with emphasis on the difficulties in understanding urate transport because of its bidirectional transport and the species differences in which animal data may not have relevance to the human condition. A critical review of the effects of pyrazinamide and extracellular volume expansion on urate transport raises questions about the current popular teachings that pyrazinamide exclusively blocks tubule urate secretion and extracellular volume expansion has a major role in controlling urate excretion. There appears to be a renal salt-wasting syndrome with overlapping clinical features that make it indistinguishable from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), except possibly for extracellular volume depletion. Hypouricemia and the elevation in the fractional excretion of urate (%E/Furate) are extensively reviewed with a proposal to use the persistence of hypouricemia and elevated %E/Furate after the correction of hyponatremia to differentiate these patients from those with SIADH. An algorithm is proposed to differentiate one group from the other. A plasma natriuretic factor has been shown in some with probable renal salt wasting, which includes patients with AIDS, cancer, and pulmonary and intracranial diseases. The natriuretic factor may have etiologic implications and diagnostic and therapeutic applications.

Algorithms↗
PubMedDate not supplied

Spoligotyping and pncA polymorphism: a two step scenario for Mycobacterium bovis diagnosis in Portugal.

The differential diagnosis of Mycobacterium bovis is important in the control of transmission to the human population and also for treatment since M. bovis is naturally resistant to pyrazinamide. Eleven clinical isolates from the Fernando Fonseca Hospital with Spoligotypes indicative of M. bovis, through the absence of spacers 39-43 but that also counted with the absence of spacer 38, were analyzed. For the identification of these strains, the phenotypic analysis of pyrazinamide resistance and study of the polymorphisms of the pncA and gyrB genes were carried out. The study of the pncA polymorphism revealed that the strains analyzed did not contain the M. bovis specific mutation. In relation the gyrB polymorphisms, using the GenoTypeO MTBC kit, the strains were identified as belonging to the group M. tuberculosis, M. africanum subtipo II e M. canetti. The present investigation enabled us to define new genotypes on which future bacteriological studies should be based. Amongst these the study of the pncA polymorphism was considered important due to the immediate practical implications for the clinician. Evaluating transmission and defining groups of risk is an objective for which support from the veterinary services is considered relevant.

Amidohydrolases↗
PubMed2000

Activity of poloxamer CRL-1072 against drug-sensitive and resistant strains of Mycobacterium tuberculosis in macrophages and in mice.

The present experiments evaluated a new, highly refined poloxamer, CRL-1072, alone and in combination with antibiotics against drug-sensitive and -resistant organisms. In macrophage culture, CRL-1072 reduced the drug concentration inhibiting 99% of control growth of isoniazid (INH) from 10 to 0.15 mg/l (fractional inhibitory concentration=0.07) for a drug-resistant strain. CRL-1072 also increased the susceptibility of drug-resistant strains of Mycobacterium tuberculosis to INH, streptomycin, rifampicin, pyrazinamide, ethambutol, PAS, thiacetazone and ethionamide. Fractional inhibitory concentration values of <0.5 indicated significant synergistic activity. In studies of acute infection in mice, CRL-1072 was only weakly bacteriostatic when used as a single agent but increased the bactericidal activity of INH, streptomycin, rifampicin, pyrazinamide and clindamycin, but not that of ethambutol. CRL-1072 enhanced the bactericidal activity of streptomycin against a streptomycin resistant strain of M. tuberculosis in a murine infection.

Animals↗
PubMed2005

[Resistance to antituberculous drugs].

Mycobacteria responsible for tuberculosis (M. tuberculosis, M. bovis, M. africanum) are susceptible to a very small number of antibiotics. As soon as these drugs were used in humans all gave rise to the selection of resistant mycobacteria. Study of the mechanisms of acquired resistance, with the help of the genetics of mycobacteria, led to a more accurate understanding of the mode of action of antituberculous drugs. The antibiotics isoniazid, pyrazinamide, ethionamide and ethambutol are mycobacteria-specific because they inhibit the synthesis of mycolic acids, which are specific constituants of the bacterial wall. Mutations responsible for resistance to these drugs affect genes coding for activator enzymes (katg for isoniazid, pncA for pyrazinamide) or genes coding for their target (inhA for isoniazid/ethionamide, embB for ethambutol). With rifamycins, aminosides and quinolones, mechanisms of action and resistance are the same for mycobacteria as for non-mycobacterial organisms. No plasmid or resistance transposon has been described in M. tuberculosis. Currently a test for the quick detection of resistance to rifampicin is widely available but in the future DNA chips may allow the simultaneous detection of multiple resistances. Monitoring of antituberculous drugs shows that in France the prevalence of multiresistance ( resistance to both isoniazid and rifampicin) is 0.5%, primary resistance (before treatment) is 9%, and secondary resistance (after treatment) is 16%.

Antitubercular Agents↗
PubMed1991

Inter-relations between relapses, drug regimens and compliance with treatment in tuberculosis.

The inter-relationships between relapse, treatment regimen and compliance in 1009 patients treated for tuberculosis between 1978 and 1987 are reported. Multiple linear logistic regression using relapse as the dependent variable was used because of the complex relationships between treatment, compliance, age and calendar year of treatment. Compliance (P less than 0.0001) was the major determinant of relapse, but age (P = 0.047) was also significantly associated. Relapse was not related to sex, site of disease, ethnic group or the presence of multiple disease sites. Although the regimen given, the total duration of treatment and treatment with or without pyrazinamide were not statistically associated with relapse, pyrazinamide containing regimens were associated with better compliance. Compliance was best in those aged 60 years and over and worst in those aged 15-29 years. Some of the non-compliance leading to relapse was only uncovered by close Health Visitor surveillance and not by the physician supervising treatment, emphasizing the important role of field staff in patient follow-up.

Adolescent↗
PubMed2001

Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report.

BACKGROUND AND AIMS: Hepatotoxicity is a major side-effect of antitubercular drugs (ATD). As these drugs are metabolized in the liver, there is a theoretical risk of increased hepatotoxicity in patients with underlying chronic liver disease (CLD). Ofloxacin has antitubercular activity and has exclusive renal clearance. The aim was to study the efficacy and safety of an ofloxacin-based antitubercular regimen for treating tuberculosis in patients with underlying CLD. METHODS: Thirty-one cases were randomly assigned to two drug regimens using WHO dosage schedules: (i) regimen A (n = 15): isoniazid, rifampicin and ethambutol for 2 months, followed by isoniazid and rifampicin for a further 7 months; and (ii) regimen B (n = 16): isoniazid, pyrazinamide, ethambutol and ofloxacin for 2 months, followed by isoniazid, ethambutol and ofloxacin for a further 10 months. Hepatotoxicity was diagnosed if alanine aminotransferase/aspartate aminotransferase increased > fivefold from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5 mg/dL from the baseline. RESULTS: The response to ATD was achieved in all the patients who completed the therapy. Four (26.6%) patients on regimen A developed hepatotoxicity as compared to none on regimen B (P = 0.043). None of these patients could be restarted on ATD using the same regimen A because of the persistently deranged liver functions. CONCLUSIONS: In patients with tuberculosis who have underlying CLD: (i) an ofloxacin-based antitubercular regimen without rifampicin is as effective as a rifampicin-based regimen; and (ii) a combination of isoniazid with rifampicin is more hepatotoxic than a combination with ofloxacin and pyrazinamide.

Adolescent↗
PubMed2003

Treatment of latent tuberculosis infection.

Treatment of latent tuberculosis infection (LTBI) is considered an essential component of TB control programs in several industrialized countries and is being used in selected situations in developing countries. In 2000, the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC) published new recommendations on the diagnosis and treatment of LTBI. These guidelines emphasized targeted tuberculin testing as a means of diagnosis in populations at risk, and expanded the choice of drug regimens to be used for treatment. After the implementation of the recommendations, unexpected and serious hepatic injury with the use of rifampin and pyrazinamide occurred, resulting in a modification of the recommendations. This article reviews the populations who should be considered for targeted tuberculin testing, scientific rationale for the selected treatment regimens, recently completed studies related to rifampin and pyrazinamide, and the prior and updated recommendations for treatment of LTBI.

Antitubercular Agents↗
PubMed2004

Antimicrobial therapy of tuberculosis: justification for currently recommended treatment regimens.

Prevention of drug resistance became the most important aim following the first clinical trial on streptomycin with a randomized intake in 1948. The occurrence of resistance was reduced by combined therapy with streptomycin and p-aminosalicylic acid and prevented by an initial phase with three drugs. Following the Madras comparison of domiciliary and sanatorium therapy, chemotherapy for the whole world became available, but there remained the problem of compliance during 1 year of treatment. Solutions were sought by the use of intermittently supervised drug administration, and in 1970, by the inclusion of the two major sterilizing drugs rifampicin and pyrazinamide, in regimens lasting only 6 months. The next 15 years were devoted to defining modern regimens, the first with a four-drug initial phase and rifampicin throughout (2EHRZ/4RH), and the second with a continuation phase of ethambutol and isoniazid (2EHRZ/6EH). Considering individual drugs, rifampicin and pyrazinamide provide almost all of the bactericidal activity, whereas isoniazid is bactericidal only during the first 2 days and thereafter prevents the emergence of drug resistance. Although models in vitro and in the mouse suggest that drug efficacy is related to area under the concentration-time curve/minimal inhibitory concentration (AUC/MIC), clinical trials with intermittent regimens indicate that this relationship is not present during human therapy.

Journal Article↗
PubMed2002

Global drug-resistance patterns and the management of latent tuberculosis infection in immigrants to the United States.

BACKGROUND: In the United States, an increasingly disproportionate burden of tuberculosis among the foreign-born population has led to calls for improvements in the detection and treatment of latent infection in new immigrants. Current treatment guidelines do not take into account global differences in drug-resistance patterns or their implications for the treatment of immigrants. The use of multinational surveillance systems to guide the management of latent infection according to region-specific drug-resistance profiles could improve the efficiency of efforts to reduce the burden of tuberculosis in immigrants to the United States. METHODS: We constructed a decision-analysis model by using a hypothetical cohort of all documented immigrants entering the United States from developing nations. Region-specific drug-resistance profiles were derived from data on 30,388 cases of infection. The model examined the effectiveness and cost effectiveness of four strategies: no intervention or tuberculin skin testing followed by treatment with isoniazid, treatment with rifampin, or treatment with rifampin plus pyrazinamide for those with a positive test result. RESULTS: A strategy of detecting and treating latent tuberculosis infection was cost-saving among immigrants from Mexico, Haiti, sub-Saharan Africa, South Asia, and developing nations in East Asia and the Pacific. This strategy was highly cost effective among immigrants from other developing nations. Rifampin plus pyrazinamide was the preferred strategy for treating latent infection in immigrants from Vietnam, Haiti, and the Philippines. CONCLUSIONS: For new immigrants to the United States from developing nations, a strategy of detecting and treating latent tuberculosis infection would lead to substantial health and economic benefits. Because of the high prevalence of resistance to isoniazid, treatment with a rifampin-containing regimen should be strongly considered for immigrants from Vietnam, Haiti, and the Philippines.

Antitubercular Agents↗
PubMed2001

Diagnosis and treatment of isolated tuberculous mediastinal lymphadenopathy in adults.

OBJECTIVE: To evaluate the diagnostic yield of bronchoscopy and mediastinoscopy in adults with isolated mediastinal tuberculous lymphadenitis and to assess the effect of antituberculous treatment. DESIGN: Prospective longitudinal cohort study of 34 patients with mediastinal tuberculous lymphadenitis followed for 6 to 19 months after completion of treatment. SETTING: Tertiary care hospital, Kuwait. PATIENTS: 34 consecutive patients who presented with isolated mediastinal lymphadenopathy from 1996 to 1998. INTERVENTIONS: Bronchoscopy and cervical mediastinoscopy for all patients. MAIN OUTCOME MEASURES: Diagnostic yield of bronchoscopy and mediastinoscopy, and the outcome of treatment in patients with tuberculous lymphadenopathy. RESULTS: The mean age was 35 years (range 15-58). The most common symptoms were cough, fever, and weight loss. The chest radiographs and computed tomograms showed abnormal mediastinal shadows with no evidence of parenchymal disease. All patients had right sided paratracheal lymphadenopathy. Tuberculin skin test gave a weal of >15 mm in 17 patients (50%). Sputum smears and cultures failed to grow acid-fast bacilli in any patient. Seven patients had an endobronchial abnormality and samples taken at bronchoscopy gave a definite diagnosis in 3 (9%). Paratracheal lymph node biopsy and culture by mediastinoscopy diagnosed tuberculosis in all cases. All patients were treated by a six month course of rifampicin and isoniazid supplemented initially by pyrazinamide for two months. Twenty-eight patients had a good response and the remaining patients were treated for a further 3 months. CONCLUSIONS: Bronchoscopy has a low diagnostic yield in mediastinal tuberculous lymphadenopathy in the absence of a parenchymal lesion. Mediastinoscopy is a safe but invasive procedure and provides a tissue diagnosis in most cases. Six months treatment with rifampicin and isoniazid supplemented initially by pyrazinamide is adequate treatment for most adults with tuberculous mediastinal lymphadenopathy.

Adolescent↗