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PubMed1992

Intensive short course chemotherapy for treatment of Greek children with tuberculosis.

This prospective study with an 18-month posttreatment follow-up evaluated the efficacy of intensive short course chemotherapy in Greek children with pulmonary or extrapulmonary tuberculosis. Between November, 1988, and March 1991 a 2-month regimen of rifampin, 10 to 12 mg/kg/day, isoniazid, 10 to 12 mg/kg/day, and pyrazinamide, 30 to 35 mg/kg/day, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to 36 children with tuberculosis. Twenty-three boys and 13 girls ages 8 months to 12 years (mean, 5 1/2 years) were enrolled in the study. The diagnostic criteria for establishing tuberculosis were tuberculin skin test reactivity, radiographic findings compatible with tuberculosis, epidemiological data and clinical and laboratory findings. Four children had extrapulmonary and 32 had pulmonary tuberculosis; 9 of the latter were asymptomatic. Among the pulmonary cases there were 2 children with pleural effusion. Clinical response to therapy was apparent within 7 to 14 days; the pleural effusions resolved in 2 to 6 weeks and the pulmonary infiltrates cleared in 2 to 6 months. Hilar adenopathy regressed within 18 months or longer. No serious problems with drug tolerance or toxicity were noted during the treatment period. Temporary hyperuricemia and transient elevation in serum transaminases were observed in 11 patients but no drug modification was required. There were no posttreatment relapses. These findings suggest that intensive short course chemotherapy for the treatment of Greek children with pulmonary or extrapulmonary tuberculosis appears to be effective, safe, of good patient compliance and comparable to the longer treatment regimens.

Anti-Bacterial Agents↗
PubMed1996

Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment.

We studied human immunodeficiency virus (HIV)-seroprevalence among children with clinically diagnosed tuberculosis (TB) and compared the clinical features and response to short-term anti-TB therapy of children with and without HIV infection in Santo Domingo, Dominican Republic. Children aged 18-59 months with new-onset, clinically diagnosed TB were tested for HIV antibodies, their clinical features were recorded and their response to a standard 6-month regimen of daily isoniazid and rifampicin with daily streptomycin and pyrazinamide for the first 2 months was assessed. To increase the number of HIV-infected children with TB available for study, we also included children previously known to be HIV infected who developed new-onset TB. Eleven (5.8%) of 189 consecutively enrolled children with clinically diagnosed TB were HIV infected. Fifteen other children with previously documented HIV infection and new-onset TB were available for study, yielding 26 HIV-positive and 178 HIV-negative children with TB. Of these 204 children with clinically diagnosed TB, 25 HIV-positive and 156 HIV-negative children were successfully followed for 6 months or until death. The proportion of HIV-positive children who failed treatment was 6 (29%) of 21 as compared with only 5 (3%) of 156 HIV-negative children [relative risk = 8.9; 95% confidence interval (CI) 2.9, 26.6; p = 0.0004]. HIV-infected children with clinically diagnosed TB are substantially more likely to fail standard treatment for TB than are HIV-uninfected children. If standard treatment regimens are used in such children, response to treatment must be monitored very closely and appropriate changes in the regimen must be made expeditiously.

AIDS Serodiagnosis↗
PubMed1997

Mycobacterium hassiacum sp. nov., a new rapidly growing thermophilic mycobacterium.

A new rapidly growing, scotochromogenic mycobacterium was isolated from urine. This strain is thermophilic (it grows at 65 degrees C), tolerates 5% NaCl, and was unable to utilize any of the sugars tested or citrate or to take up iron. The isolate splits benzamide, urea, nicotinamide, and pyrazinamide and is sensitive to streptomycin, ethambutol, cycloserine, ciprofloxacin, and chlarithromycin but resistant to isoniazid, rifampin, and prothionamide. These characteristics clearly place this organism in a new mycobacterial species, which was confirmed by the unique 16S rRNA nucleotide sequence. The high level of similarity between this rapid grower and Mycobacterium xenopi is surprising. For this new rapidly growing scotochromogenic and thermophilic mycobacterium we propose the name Mycobacterium hassiacum sp. nov.

Bacteriological Techniques↗
PubMed2002

Biochemical and genetic evidence for the transfer of Mycobacterium tuberculosis subsp. caprae Aranaz et al. 1999 to the species Mycobacterium bovis Karlson and Lessel 1970 (approved lists 1980) as Mycobacterium bovis subsp. caprae comb. nov.

We propose to replace the species designation Mycobacterium tuberculosis subsp. caprae (Aranaz et al. 1999) by Mycobacterium bovis subsp. caprae comb. nov., since isolates of this subspecies share their main growth, biochemical and genetic characteristics with M. bovis and not with M. tuberculosis. These include negative biochemical test results for niacin accumulation and nitrate reduction as well as genetic features like the presence of an M. bovis-specific mutation in the oxyR locus, absence of the mtp40 sequence and a specific mutation in the gyrB gene, all of which have been described as characteristics for the differentiation of M. bovis. The only obvious biochemical character that differentiates the caprae subtype from other M. bovis isolates is susceptibility to pyrazinamide (PZA), which is due to the lack of a single point mutation in the pncA gene. However, susceptibility to PZA among clinical isolates of M. bovis isolates has been reported previously and, thus, may now been explained by a PZA-susceptible subspecies of M. bovis. We conclude that the species designation M. tuberculosis subsp. caprae is misleading and not correct in light of the biochemical and genetic characteristics and propose that the accurate designation of isolates of this subtype is M. bovis subsp. caprae.

Amidohydrolases↗
PubMed2000

Simultaneous identification and typing of multi-drug-resistant Mycobacterium tuberculosis isolates by analysis of pncA and rpoB.

In Mycobacterium tuberculosis there is a strong correlation between in-vitro resistance to rifampicin (RIF) and pyrazinamide (PZA) and mutations in rpoB and pncA, respectively. Approximately 50 mutations associated with resistance have been reported for rpoB and 70 for pncA, and, theoretically, many more are possible. Therefore, the identification of rpoB and pncA mutations in M. tuberculosis might be used for the simultaneous determination of resistance and for typing multi-drug-resistant (MDR) strains during possible outbreaks. The present study examined four sensitive and six MDR isolates of M. tuberculosis from Turkey and eight isolates from a nosocomial MDR tuberculosis (TB) outbreak in the UK. Gene mutations were identified by the Innogenetics LiPA rpoB assay or automated sequencing, or both. All the sensitive isolates had rpoB and pncA wild-type genotypes, whereas all the RIF- and PZA-resistant isolates had rpoB and pncA mutations. All four mutations seen in rpoB, but none of the six in pncA, had been reported previously. The rpoB and pncA mutations seen in the Turkish isolates defined six distinct genotypes amongst the six MDR isolates, while standard IS6110 typing discriminated only four. All isolates from the single strain MDR-TB outbreak had identical genotypes. Rapid genotyping was performed on the sputum from a patient who presented 2 years after the initial MDR-TB outbreak and this showed rpoB and pncA genotypes identical to the other outbreak isolates. This result was available within 36 h. The analysis of rpoB and pncA is a rapid and practical means of simultaneously identifying and typing MDR isolates of M. tuberculosis.

Amidohydrolases↗
PubMed1991

Comparative efficacy of drug regimens in skin tuberculosis.

Three antituberculous drug regimens have been employed to study the therapeutic response in 90 patients with any one of the commonly encountered paucibacillary forms of skin tuberculosis, namely lupus vulgaris, tuberculosis verrucosa cutis and scrofuloderma. The first two regimens contained rifampicin, isoniazid and either pyrazinamide or thiacetazone, and the third regimen had rifampicin and isoniazid only. The disease was clinically defined as localized when confined to one area and widespread when the lesions were disseminated. The observations revealed that the response of lupus vulgaris and tuberculosis verrucosa cutis was alike in all the three regimens, with the localized lesions subsiding completely after 4 months of therapy and the more extensive forms taking 5 months. Patients with scrofuloderma responded similarly to both the triple drug regimens. The discharge, sinuses and ulcers cleared in 6 months but the lymph nodes took longer to regress, up to 7 months in localized and 9 months in more widespread scrofuloderma. To obtain the same results with rifampicin and isoniazid, all patients with widespread scrofuloderma and one-third of those with localized forms had to be treated for 10 and 9 months, respectively. No serious drug side-effects, apart from giddiness with rifampicin and acneiform eruptions with thiacetazone, were encountered. No instances of relapse were noted in the 50% of patients who were followed-up for 3 1/2 years after therapy. Single-drug therapy with isoniazid for lupus vulgaris, as given in the past, is to be discouraged as it may promote the emergence of drug-resistant bacilli in those with an undetected focus of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2006

Antituberculosis drugs and hepatotoxicity.

Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.

Antitubercular Agents↗
PubMed1979

Familial renal hypouricaemia: two additional cases with uric acid lithiasis.

Two families are reported affected with hereditary renal hypouricaemia associated with uric acid lithiasis. The propositi of both families were found also to have hyperabsorptive hypercalciuria. Based on the study of the effect of pyrazinamide and probenecid on uric acid excretion in both propositi, it is suggested that the defect in uric acid reabsorption is most probably at the pre-secretory site.

Adult↗
PubMed1984

The management of urinary tuberculosis--a logical approach.

The chemotherapy of urinary tuberculosis is controversial as far as choice of drug regimen and duration of treatment are concerned. We propose a course of treatment that is tailored to the pathological state of infection and the type of surgical procedure performed. One hundred and ten patients with tuberculous infection were divided into three groups. Group I comprised 27 patients in whom surgery was not necessary; Group II contained 48 patients where ablative surgery was carried out; Group III consisted of 35 patients who underwent reconstructive surgery. Anti-tuberculous drugs (rifampicin, pyrazinamide, isoniazid and ethambutol) were given according to this tailored regimen. Patient compliance and results of treatment were excellent.

Adult↗
PubMed2005

Melatonin prevents the free radical and MADD metabolic profiles induced by antituberculosis drugs in an animal model.

The objective was to determine the effect of combined antituberculosis (anti-TB) drug therapy and an antioxidant, melatonin, on the free radical and organic acid profiles in an experimental rat model. A combined anti-TB drug, Rifater, consisting of 12.0 mg rifampicin, 0.8 mg isoniazid, and 23.0 mg pyrazinamide and 18.56 microg melatonin/kg body weight per day (corresponding to average physiological human intake) were orally administered to Sprague-Dawley rats. Hydroxyl radical production was monitored by quantifying 2,3-dihydroxybenzoic acid produced after intraperitonial sodium salicylate injections. Organic acid extractions and gas chromatography-coupled mass spectrometry analyses were performed on collected urine samples. The results show hydroxyl radicals (P = 0.0019) and organic acids (P-value range: 0.037 to <0.001), characteristic of a multiple acyl-CoA dehydrogenase defect (MADD), were elevated with Rifater treatment and these elevations were significantly lowered with melatonin pretreatment (P-value range: 0.031 to <0.001), probably because of its inherent antioxidant activity. We conclude that hydroxyl radical production and an increased organic acid profile induced by anti-TB medication indicates inhibition of the electron transport chain. We also conclude that free radicals leading to clinical symptoms associated with an MADD metabolic profile induced by anti-TB treatment could be alleviated by melatonin intervention.

Animals↗
PubMed2006

Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.

The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

Animals↗
PubMed2006

Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration.

The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case.

Animals↗
PubMed1980

Isoniazid interaction with tyrosine as a possible mode of action of the drug in mycobacteria.

The antitubercular drug isoniazid (INH) was hown by radio-chromatographic studies to react with tyrosine in growth medium. Exogenous tyrosine added to the growth medium interfered with the inhibitory action of INH on Mycobacterium phlei. These observations were confirmed by difference spectra studies which showed that tyrosine would react with INH as long as the tyrosine phenolic hydroxyl group was not blocked. These results led to the hypothesis that INH could exert its influence by interfering with tyrosine residues in mycobacterial proteins. N-acetylimidazole, a tyrosine-acetylating agent, mimicked the action of INH on the reduced nicotinamide adenine dinucleotide oxidase and dehydrogenase activity in electron transport particles from wild-type and INH-resistant M. phlei. Pyrazinamide, a drug structurally related to INH, also mimicked its effect on electron transport particles. To confirm that INH could react with tyrosine in proteins, purified enzymes with known tyrosine positions were tested. Bovine carboxypeptidase A with tyrosine at the active site was inhibited by INH and N-acetylimidazole, whereas the controls, yeast alcohol dehydrogenase and ribonuclease A, were not. It is therefore proposed that tyrosine residues in proteins may serve as the target for INH action in mycobacteria.

Culture Media↗
PubMed1999

Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice.

Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.

Animals↗
PubMed2000

Evaluation of rifalazil in a combination treatment regimen as an alternative to isoniazid-rifampin therapy in a mouse tuberculosis model.

The newer rifamycin, rifalazil (RLZ) (previously known as KRM-1648), has been shown in prior experiments to be a highly potent drug against Mycobacterium tuberculosis. In this report, we studied the efficacy of RLZ in combination with pyrazinamide (PZA) and ethambutol (EMB) in a long-term in vivo experiment and compared their activity with the isoniazid (INH)-rifampin (RIF) combination which is presently used in the clinic. Combinations of RLZ with PZA alone or with both PZA and EMB were both found to have sterilizing activities comparable to that of the INH-RIF combination but significantly better activity with respect to relapse of infection. These results suggest that RLZ, or other agents with similar activity, could be combined with available agents to act as a potential alternative drug regimen to the currently used INH-RIF combination.

Animals↗
PubMed2000

Phenotypic characterization of pncA mutants of Mycobacterium tuberculosis.

We examined the correlation of mutations in the pyrazinamidase (PZase) gene (pncA) with the pyrazinamide (PZA) resistance phenotype with 60 Mycobacterium tuberculosis isolates. PZase activity was determined by the method of Wayne (L. G. Wayne, Am. Rev. Respir. Dis. 109:147-151, 1974), and the entire pncA nucleotide sequence, including the 74 bp upstream of the start codon, was determined. PZA susceptibility testing was performed by the method of proportions on modified Middlebrook and Cohn 7H10 medium. The PZA MICs were > or =100 microg/ml for 37 isolates, 34 of which had alterations in the pncA gene. These mutations included missense substitutions for 24 isolates, nonsense substitutions for 3 isolates, frameshifts by deletion for 4 isolates, a three-codon insertion for 1 isolate, and putative regulatory mutations for 2 isolates. Among 21 isolates for which PZA MICs were <100 microg/ml, 3 had the same mutation (Thr47-->Ala) and 18 had the wild-type sequence. For the three Thr47-->Ala mutants PZA MICs were 12.5 microg/ml by the method of proportions on 7H10 agar; two of these were resistant to 100 microg of PZA per ml and the third was resistant to 800 microg of PZA per ml by the BACTEC method. In all, 30 different pncA mutations were found among the 37 pncA mutants. No PZase activity was detected in 35 of 37 strains that were resistant to > or =100 microg of PZA per ml or in 34 of 37 pncA mutants. Reduced PZase activity was found in the three mutants with the Thr47-->Ala mutation. This study demonstrates that mutations in the pncA gene may serve as a reliable indicator of resistance to > or =100 microg of PZA per ml.

Amidohydrolases↗
PubMed2002

Simple fibroblast-based assay for screening of new antimicrobial drugs against Mycobacterium tuberculosis.

In this study, we propose a simple and reproducible host-cell-based assay for the screening of antimycobacterial drugs that is suitable for drug discovery. The method evaluates both antimycobacterial activity of the drugs and their cytotoxicity to host cells. The basis of this simple fibroblast-based assay (SFA) is that cells of human lung fibroblast cell line MRC-5, which are highly sensitive to mycobacterial cytotoxicity, are killed by virulent Mycobacterium tuberculosis strain H(37)Rv bacilli in response to the viability of bacilli. Clinically used antimycobacterial drugs inhibited the mycobacterial cytotoxicity to MRC-5 cells in a dose-dependent manner. MICs of isoniazid, streptomycin, rifampin, and ethambutol determined by this SFA (0.428, 1.816, 0.013, and 3.465 microg/ml, respectively) were within 1 log of MICs determined by the broth dilution test (BDT) using Middlebrook 7H9 medium. The MIC of pyrazinamide, which exhibits bactericidal activity only at a high dose by BDT (1,231 microg/ml at pH 6.6 and 492 microg/ml at pH 5.8), was 3.847 microg/ml in the modified method of SFA. On the other hand, sodium azide, a toxic agent for both mammalian cells and bacteria, exhibited cytotoxicity to fibroblasts at a dose lower than that required to inhibit mycobacterial growth. Thus, this fibroblast-based method enabled us to evaluate both antibacterial activity of drugs and their cytotoxicity to human cells within a short period of time.

Antitubercular Agents↗
PubMed2004

Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease.

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.

Acetylation↗