Significant myoglobin removal during continuous veno-venous haemofiltration using F80 membrane

The combination of clarithromycin and pyrazinamide was found to be synergistic against Mycobacterium tuberculosis in human macrophages. MICs were four- to eightfold lower for this combination than they were for either drug alone. Clarithromycin and rifampin, however, had only an additive effect.     

Determination of iron by the Ferrochem II: interference by tuberculostatics

Iron levels in samples from certain treated tuberculous patients are underestimated by the Ferrochem II analyser. Of the tuberculostatic drugs examined for a possible interference, isoniazid, ethambutol, rifampicin, pyrazinamide and Rifater (a mixture of rifampicin, isoniazid and pyrazinamide), only pyrazinamide and Rifater (due to its pyrazinamide content) were associated with iron levels differing significantly (p < 0.001) from those of controls, with means of -317.2 and -185.6 mumol l-1 for pyrazinamide and Rifater respectively as against 9.91 mumol l-1 for the controls. The negative interference (I) due to pyrazinamide was independent of iron level in the samples but dependent on pyrazinamide concentration in the same (P) (r = 0.9993), I = -0.4380P-0.4276.     

In vitro oxidation of pyrazinamide and allopurinol by rat liver aldehyde oxidase

Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with M(r) of 2.7 x 10(5) on polyacrylamide gel electrophoresis (PAGE) and M(r) of 1.35 x 10(5) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, pyrazinamide and pyrazinoic acid was investigated. Allopurinol and pyrazinamide were oxidized to oxypurinol and 5-hydroxy-pyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for pyrazinamide was 160 microM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of pyrazinamide to 5-hydroxypyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrazinamide.     

Efficacy of serial electrical cardioversion therapy in patients with chronic atrial fibrillation after valve replacement and implications for surgery to cure atrial fibrillation

In April 1993, a 51-year-old woman had a fever, and an infiltrative shadow was seen in the left upper lobe on a chest X-ray film. Repeated sputum cultures were positive for Mycobacterium avium complex. She underwent antituberculosis therapy consisting of pyrazinamide, ofloxacin, and streptomycin. Her symptom disappeared and the abnormal shadow resolved. In January 1994, she was admitted to the hospital because of bloody sputum and abnormal chest X-ray findings consisting of a left hilar mass and atelectasis of the left upper lobe. Bronchoscopy revealed multiple polypoid lesions without necrosis in the left upper-lobe bronchus. Histological examination showed that the tumor consisted of an aggregation of lymphocytes and plasma cells, and was positive for Ziehl-Neelsen stain. The acid-fast bacillus was identified as Mycobacterium avium by the DNA probe method. Anti-tuberculosis treatment was given: rifampicin, isoniazid, sparfloxacin, and clarithromycin. Three months later, the atelectasis and the polypoid mass in the left upper-lobe bronchus had disappeared. We believe that the polypoid lesions in the left upper-lobe bronchus were due to infection by Mycobacterium avium. The patient was HIV-negative and immunocompetent. Such endobronchial lesions caused by Mycobacterium avium are rare in HIV-negative hosts.     

Does AIDS impair the absorption of antituberculosis agents?

SETTING: Case reports of low serum concentrations of antituberculosis drugs, with resultant treatment failure and emergence of drug-resistant organisms in patients with the acquired immune-deficiency syndrome (AIDS), have prompted suggestions that therapeutic drug monitoring (TDM) may be indicated in patients co-infected with the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. OBJECTIVE: To test whether the bioavailability of antituberculosis drugs is altered in HIV-infected patients with tuberculosis. METHOD: Twenty-seven hospitalized tuberculosis patients (13 with AIDS, 14 HIV-negative) were entered into a pharmacokinetic trial. Following the supervised administration of standardized doses of isoniazid, rifampicin and pyrazinamide, the plasma concentrations of the drugs were measured repeatedly over 12 hours and the following parameters were derived for each agent: maximum measured drug concentration (Cmax), time-to-maximum measured drug concentration (Tmax) and area-under-the-concentration-time curve to 12 hours (AUC). RESULTS: No significant differences emerged between the two groups in Cmax, Tmax, and AUC for isoniazid and pyrazinamide. For rifampicin the AIDS patients showed a greater AUC (P < 0.01) than the controls, but there were no significant differences in Cmax and Tmax. CONCLUSION: There was no evidence that HIV infection reduced the plasma concentrations of antituberculosis drugs.     

Priming of human neutrophils by peroxynitrite: potential role in enhancement of the local inflammatory response

The antimicrobial activity of a new super-oxidized water, Sterilox, has been tested against Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Mycobacterium chelonae, Escherichia coli (including type O157), Enterococcus faecalis, Pseudomonas aeruginosa, Bacillus subtilis var niger spores, methicillin-resistant Staphylococcus aureus, Candida albicans, poliovirus type 2 and human immunodeficiency virus HIV-1. Under clean conditions, freshly generated Sterilox was found to be highly active against all these micro-organisms giving a 5 log10 (99.999%) or greater reduction in two minutes or less.     

Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus

Naturally pyrazinamide (PZA)-resistant Mycobacterium bovis and acquired PZA-resistant M. tuberculosis strains lose pyrazinamidase (PZase). To investigate the molecular mechanism of PZA resistance, we have cloned the gene (pncA) encoding M. tuberculosis PZase. Mutations in pncA were identified in both types of PZA-resistant strains, and transformation of these strains with a functional pncA gene restored PZase activity and PZA susceptibility. These findings, besides providing the basis for understanding how PZA works, should have implications for rapid detection of PZA-resistant clinical isolates of M. tuberculosis and also for rapid differentiation of M. bovis from M. tuberculosis strains.     

Cerebral tuberculosis presenting as complex febrile convulsions

Complex febrile convulsions were the initial clinical manifestation of miliary tuberculosis in a 4-year-old immigrant girl. The cerebral lesions were visible only after contrast-enhanced cranial computed tomography (CT) while native CT scan as well as cell count and glucose concentration in the cerebrospinal fluid were normal. Mycobacterium tuberculosis was cultured from gastric aspirate and liver biopsy tissue. Treatment with isoniazid and rifampin for 12 months, pyrazinamide for 9 months, and ethambutol for the initial 6 weeks resulted in resolution of the cerebral lesions but a retinal scar after granuloma formation in the right eye caused reduced visus. This case demonstrates the importance of thorough search for tuberculosis even in the absence of overt clinical pulmonary signs especially in high-risk individuals such as immigrants.     

Purification, gene cloning, targeted knockout, overexpression, and biochemical characterization of the major pyrazinamidase from Mycobacterium smegmatis

The pyrazinamidase from Mycobacterium smegmatis was purified to homogeneity to yield a product of approximately 50 kDa. The deduced amino-terminal amino acid sequence of this polypeptide was used to design an oligonucleotide probe for screening a DNA library of M. smegmatis. An open reading frame, designated pzaA, which encodes a polypeptide of 49.3 kDa containing motifs conserved in several amidases was identified. Targeted knockout of the pzaA gene by homologous recombination yielded a mutant, pzaA::aph, with a more-than-threefold-reduced level of pyrazinamidase activity, suggesting that this gene encodes the major pyrazinamidase of M. smegmatis. Recombinant forms of the M. smegmatis PzaA and the Mycobacterium tuberculosis pyrazinamidase/nicotinamidase (PncA) were produced in Escherichia coli and were partially purified and compared in terms of their kinetics of nicotinamidase and pyrazinamidase activity. The comparable Km values obtained from this study suggested that the unique specificity of pyrazinamide (PZA) for M. tuberculosis was not based on an unusually high PZA-specific activity of the PncA protein. Overexpression of pzaA conferred PZA susceptibility on M. smegmatis by reducing the MIC of this drug to 150 micrograms/ml.     

Removal of a torn Racz catheter from lumbar epidural space

A 45-year-old man with the acquired immune deficiency syndrome (AIDS) developed disseminated Mycobacterium tuberculosis infection and was started on isoniazid, rifampin, pyrazinamide and ethambutol. The treatment was interrupted because of side effects. On resumption of treatment be developed a rapidly progressive neurological illness characterized by left hemiparesis, right gaze preference, convulsions, coma, evidence of cerebral edema on computed tomography scan and death 9 days later. Autopsy showed the presence of miliary tuberculosis affecting the lungs, liver, spleen, lymph nodes and bone marrow. The brain showed evidence of acute hemorrhagic leukoencephalitis (AHL)-the first such case in a patient with AIDS. We speculate that treatment-induced lysis of mycobacteria with concomitant release of mycobacterial lipoproteins may have activated T-lymphocytes to cause AHL in this patient.     

Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis

The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.     

Lomefloxacin in complex treatment of acute progressive form of pulmonary tuberculosis

The effect of lomefloxacin in combination with isoniazid, pyrazinamide, streptomycin or ethambutol on the process of tuberculosis and concomitant nonspecific pathological processes in the lungs was investigated in the treatment of 69 patients with newly diagnosticated acute progressive destructive tuberculosis of the lungs and isolation of Mycobacterium tuberculosis. It was shown that lomefloxacin provided rapid disappearance of the disease clinical signs and bacillus isolation in the patients with tuberculosis due to the tubercle bacilli susceptible or resistant to the main antituberculosis drugs, acceleration of the resolution of the infiltrates and caseous lesions in the lungs and elimination of the pathological processes in the bronchi. The tolerance of lomefloxacin was satisfactory and it did not affect the tolerance of the other antituberculosis drugs.     

Genitourinary tuberculosis

Genitourinary tuberculosis, once the most prevailed disease, has become very rare. Urinary frequency, pain on urination and aseptic pyuria are the key symptoms of urinary tuberculosis. At least three consecutive urine cultures for Mycobacterium tuberculosis are necessary. Renal calcification in KUB film, distortion, obliteration and destruction of single or more calices in excretory urography may lead to proper diagnosis. Induration and swelling of the globus minor of epididymis adhering to the skin or with cutaneous fistula are suggestive of genital tuberculosis. It is of extreme importance to suspect the tuberculosis in such patients especially when the symptoms are not relieved by antibiotic treatment. Current short-term chemotherapy using pyrazinamide, isonizid and rifampicin with a help of surgery is successful in most of the patients with genitourinary tuberculosis.     

Quantitative bacillary response to treatment in HIV-associated pulmonary tuberculosis

A group of 122 patients with culture-proven pulmonary tuberculosis were recruited to examine the concentrations of Mycobacterium tuberculosis in sputum and the relationship to HIV-1 antibody status. They were followed for up to 28 days from the start of antituberculous chemotherapy to assess the early bacillary response to two chemotherapeutic regimens. Of 67 treated with streptomycin, thiacetazone, and isoniazid 17 were HIV positive, and subsequently 55, of whom 20 were HIV positive, were treated with streptomycin, rifampin, isoniazid, and pyrazinamide. The mean initial concentration of M. tuberculosis in the sputum of the HIV-negative patients was significantly higher than in HIV-positive patients (6.95 and 6.34 log colony-forming units respectively; p = 0.019). The HIV-positive patients had less radiologic evidence of disease and significantly fewer zones of lung affected with cavities. The response to treatment was similar, but with HIV-positive patients more likely to become culture negative by 28 days. The differences that exist between HIV-positive and HIV-negative patients are minor, and standard regimens are at least as effective in HIV-positive patients in the first month of treatment.     

Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic Mycobacterium tuberculosis strains

The pyrrole derivative BM212 [1, 5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)methyl-pyrrole] was shown to possess strong inhibitory activity against both Mycobacterium tuberculosis and some nontuberculosis mycobacteria. BM212 was inhibitory to drug-resistant mycobacteria and also exerted bactericidal activity against intracellular bacilli residing in the U937 human histiocytic lymphoma cell line.     

Stability of bethanechol chloride, pyrazinamide, quinidine sulfate, rifampin, and tetracycline hydrochloride in extemporaneously compounded oral liquids

The stability of five drugs commonly prescribed for use in oral liquids but not commercially available as such was studied. Bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, quinidine sulfate 10 mg/mL, rifampin 25 mg/mL, and tetracycline hydrochloride 25 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 90% of the initial drug concentration was retained for 60 days in the liquids containing bethanechol chloride, pyrazinamide, or quinidine sulfate and for 28 days in the rifampin-containing liquids and the mixture of tetracycline hydrochloride and Ora-Sweet-Ora-Plus at both 5 and 25 degrees C. Tetracycline hydrochloride concentrations of 90% or more of the initial concentration were retained in the liquids prepared with Ora-Sweet SF-Ora-Plus for 10 days at 5 degrees C and 7 days at 25 degrees C and in those prepared with cherry syrup for 7 days at 5 degrees C and 2 days at 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. At 5 and 25 degrees C, bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, and quinidine sulfate 10 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days and rifampin 25 mg/mL was stable for 28 days. The stability of tetracycline hydrochloride 25 mg/mL varied with the vehicle.     

The adverse reactions of anti-tuberculosis drugs and its management

This paper reviews adverse reactions to anti-tuberculous drugs. Hepatotoxicity occur with isoniazid, rifampicin, pyrazinamide and ethionamide. Risk factors include high age, malnutrition and high alcohol consumption. Liver function should be followed every two weeks to prevent serious hepatotoxicity. If this occurs drugs should be stopped until improvement of liver functions. Fulminant hepatitis has poorer prognosis in regimen with pyrazinamide than without. The Combination of pyrazinamide and ethionamide is frequently hepatotoxic and should be avoided. Gastric reactions occur frequently. Elderly persons are highly intolerant to rifampicin. Peripheral neuritis is reported with isoniazid, ethambutol and ethionamide, but effectively prevented with pyridoxine. Allergic reaction including fever or rash occur with many anti-tuberculosis drugs. If necessary desensitization to re-introduce the drugs. Ocular toxicity due to ethambutol occur infrequently with a dose of 15 mg/kg. Drug interactions are frequent in tuberculosis treatment. Rifampicin reduce serum the concentration of such drugs as Methadone, Corticosteroid, and Theophylline.     

Comparative activity of azithromycin against clinical isolates of mycobacteria

Azithromycin exhibited in-vitro activity against 20 clinical isolates of Mycobacterium avium complex for which the MIC90 was 32 mg/L and 22 clinical isolates of other mycobacteria but showed no activity against 20 isolates of Mycobacterium tuberculosis (MIC90 > 128 mg/L) nor against the single isolate of Mycobacterium marinum tested (MIC 128 mg/L). These results suggest that the drug may prove useful for the prophylaxis and treatment of infections due to non-tuberculous mycobacteria, including M. avium complex in patients with AIDS.     

Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children

BACKGROUND: This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children. METHODS: A total of 114 children ages 6 months to 15 years (4.5 +/- 3.4 years) with diagnosed pulmonary tuberculosis from 1985 to 1995 entered the trial. A 2-month regimen of isoniazid, rifampin and pyrazinamide, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to all children. Clinical adverse effects specifically investigated were gastrointestinal disturbances, rash, signs of hepatotoxicity and arthralgias. Laboratory toxicity data (number of leukocytes, erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and serum uric acid) were collected before treatment and 1, 3 and 5 months after the beginning of chemotherapy. RESULTS: Clinical adverse effects were mild in all cases. Three children (2.6%) had fever and 5 (4.4%) had gastrointestinal disturbances. Aspartate aminotransferase and alanine aminotransferase mean values showed no differences along time and no patients had clinical signs of hepatotoxicity. Only 11 children (19.6%) showed a slight increase in alanine aminotransferase (< 194 units/l). Serum uric acid increased in 92.2% of the children compared with pretreatment values. This increase remained within the normal range in all but 9.8% of patients. There was a significant increase in uric acid mean concentrations after 1 month of therapy (from 3.7 +/- 0.7 mg/dl to 5.7 +/- 1.6 mg/dl, P < 0.05), which fell again (4.0 +/- 1.1) 1 month after pyrazinamide was stopped. There were no signs of gout or arthralgias. In no case was the treatment interrupted. CONCLUSION: The addition of pyrazinamide in chemotherapy for pulmonary tuberculosis in children was found to be safe. The slight increase in uric acid concentration during its administration had no recognized adverse consequences.     

Chronic recurrent multifocal osteomyelitis

On the basis of a preliminary study of antimycobacterial activity of thiobenzanilides a series of eight thiosalicylanilides have been prepared. Synthetized compounds have been examined in vitro against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium and Mycobacterium fortuitum. All compounds have been found very active. The values of minimal inhibitory concentrations are summarized in Table 1. 3',4'-Salicylanilide was selected for the following research. The compound have been found inactive in vivo (on experimental murine tuberculosis).