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PubMed1994

[Endoscopic diagnosis of colonic tuberculosis].

A 67-year-old woman had developed weakness, fatigue and a 10 kg weight loss over the past year. On examination a cylindrical mass was palpated in the right middle abdominal cavity. Erythrocyte sedimentation rate was increased to 87/126 mm, there was an hypochromic anaemia (haemoglobin 9.1 mg/dl) and an hypoalbuminaemia (32 g/l) with an increase in alpha 2-globulins (9.4 g/l), Cholinesterase activity was decreased to 588 U/l. X-ray film of the abdomen revealed a calcified mesenteric lymph-node and coloscopy demonstrated polypoid tumorous changes with ulcerations, extending from the pole of the caecum to the right flexure. Histological examination showed epithelioid-cell granulomas with Langhans giant cells. Culture grew Mycobacterium tuberculosis, confirming the diagnosis of intestinal tuberculosis. She was treated with oral doses of isoniazid (300 mg daily), rifampicin (600 mg daily) and pyrazinamide (2 g daily) for 2 months, followed by isoniazid and rifampicin for a further 4 months. After this the laboratory tests were within normal limits and urine as well as stool samples contained no acid-fast bacilli. As the patient felt so well she declined another coloscopy.

Aged↗
PubMed1991

[Tuberculosis of the larynx, oral cavity and pharynx].

A 44-year-old man, a heavy smoker over many years, complained of hoarseness for 8 weeks with weight loss and dysphagia. Malignant tumour of the pharynx was suspected. Examination revealed a swelling of the right upper lip, tumorous changes in the right buccal mucosa, about 6 x 6 cm in size, as well as enlargement of the cervical lymph-nodes. Microlaryngoscopy revealed a three-level tumour of the entire side of the right larynx. Histological examination of biopsies of the right false and true vocal cords as well as the buccal mucosa demonstrated numerous, partly caseous epithelioid granulomas with Langhans giant cells. Ziehl-Neelsen staining showed acid-fast rods. Combined tuberculostatic treatment with isoniazid, rifampicin, ethambutol and pyrazinamide achieved regression of all signs and symptoms within two months. This case emphasizes the need for including laryngeal tuberculosis in the differential diagnosis of seemingly malignant laryngeal tumours.

Adult↗
PubMed1987

[Chemotherapy of pulmonary tuberculosis. Sputum culture conversion in 8 weeks in 84% of patients].

Conversion rate to negativity of sputum culture and microscopy in 50 patients, previously untreated, with open cavernous pulmonary tuberculosis was analysed. Treatment consisted of isoniazid, rifampicin and pyrazinamide for three months, followed by administration of isoniazid and rifampicin. Conversion to a negative sputum culture had occurred after four weeks in 30% of patients, after eight weeks in 84%, and after 14 weeks in all patients. In 76% of patients the cultural conversion preceded the microscopic one. Treatment was well tolerated; only one patient had side effects requiring a short interruption of drug administration. The results confirm that this regimen is effective against pulmonary tuberculosis without significant side effects.

Adolescent↗
PubMed1986

[Tuberculostatics-induced systemic lupus erythematosus].

Clinical manifestations including rheumatoid changes, lymph node swelling, fever, butterfly rash, anaemia and leukopenia had developed gradually over a period of years in a 46-year-old female patient. Due to these findings systemic lupus erythematosus (SLE) was suspected. Further diagnostic procedures revealed concomitant pulmonary tuberculosis. In the course of the tuberculostatic therapy, there occurred six episodes of marked exacerbation of drug-induced SLE signs and symptoms including fever, myalgia, swelling of joints, butterfly rash and high titers of antinuclear antibodies. These exacerbations were induced by single-agent or combination therapy with ethambutol, pyrazinamide, streptomycin and/or prothionamide and resolved readily after discontinuation of the drug(s). With concomitant use of hydroxychloroquine sulfate, a combination therapy with rifampicin and cycloserine did not give rise to further complications although the autoantibodies persisted. This treatment regimen was given until clinical cure was achieved.

Antitubercular Agents↗
PubMedDate not supplied

Chemotherapeutic efficacy of nanoparticle encapsulated antitubercular drugs.

Our objective was to evaluate the chemotherapeutic potential of oral poly lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated ethambutol in combination with PLG-nanoparticle encapsulated-(rifampicin + isoniazid + pyrazinamide) in a murine tuberculosis (TB) model. Our formulation was prepared by the multiple emulsion technique and administered orally to mice for the biodistribution, pharmacokinetic, and chemotherapeutic studies. A single oral administration of the formulation to mice could maintain sustained drug levels in the plasma for 5 days and in the organs (lungs, liver, spleen) for 7-9 days. There was a striking improvement in the pharmacokinetic parameters such as half-life and mean residence time as compared with free drugs. The relative/absolute bioavailability of the 4 antituberculosis drugs was enhanced several fold. Repeated administration of the formulation did not produce any hepatotoxicity as assessed on a biochemical basis. In M. tuberculosis H37Rv infected mice, just 3 oral doses of the 4-drug formulation administered at every 10th day resulted in undetectable bacilli in the organs replacing 28 conventional doses of free drugs. We concluded that polymeric nanoparticle based oral 4-drug combination bears significant potential to shorten the duration of TB chemotherapy, besides reducing the dosing frequency.

Animals↗
PubMed2005

Drug-drug interaction studies on first-line anti-tuberculosis drugs.

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.

Antitubercular Agents↗
PubMed1966

Microbial persistence. I. The capacity of tubercle bacilli to survive sterilization in mouse tissues.

A previously reported form of microbial persistence whereby large populations of tubercle bacilli can be made to "vanish" uniformly from the tissues of mice has been shown to occur generally throughout each group of animals subjected to the experimental procedure; it does not reflect the eradication of the bacilli in the majority of animals with their persistence and ultimate revival in only a minority. The one demonstrable alteration of the tubercle bacilli while "vanished" is that they are sterile. Thus, they are undetectable by cell-free culture, tissue culture, and blind animal passage, i.e. by any method based on microbial multiplication. Whether they have also undergone alteration in morphology and persist in some unconventional form cannot be stated. Acid-fast forms similar to tubercle bacilli can be detected in small numbers by intensified microscopic search of tissue homogenates but the relationship of these forms to the sterile bacilli that ultimately revive is unclear. Thus, the persisting tubercle bacilli are more correctly designated as being in a "sterile state" than one of true latency. The uniform induction of the sterile state is a specific phenomenon requiring the participation of both the nicotinamide derivative, pyrazinamide, and isoniazid. Once assumed, this sterile state is relatively stable and the time required for revival of the tubercle bacilli in the spleens in one-half the animals is seven months. This process can be speeded up by the administration of large doses of cortisone in the third or fourth month after sterilization but revival is not significantly affected by the administration of cortisone earlier.

Animals↗
PubMed2001

A whole blood bactericidal assay for tuberculosis.

The bactericidal activity of orally administered antituberculosis (anti-TB) drugs was determined in a whole blood culture model of intracellular infection in which microbial killing reflects the combined effects of drug and immune mechanisms. Rifampin (Rif) was the most active compound studied and reduced the number of viable bacilli by >4 logs. Isoniazid (INH), 2 quinolones, and pyrazinamide (PZA) showed intermediate levels of activity. Ethambutol exerted only a bacteristatic effect; amoxicillin/clavulanate was inactive. The combination of INH-Rif-PZA showed strong activity against 11 drug-sensitive isolates (mean, -3.8 log) but no activity against 12 multidrug-resistant (MDR) strains. The combination of levofloxacin-PZA-ethambutol had intermediate bactericidal activity against MDR isolates (mean, -1.2 log) but failed to equal that of INH-Rif-PZA against sensitive isolates (P<.001). The whole blood BACTEC method (Becton Dickinson) may be useful for the early clinical evaluation of new anti-TB drugs and in the management of individual patients.

Anti-Infective Agents↗
PubMed2003

Relative versus absolute noncontagiousness of respiratory tuberculosis on treatment.

OBJECTIVE: To assess the validity of current estimates of the noncontagiousness of sputum smear-positive respiratory tuberculosis (TB) on treatment. DESIGN: A descriptive analysis of the mycobacteriologic response to treatment. SETTING: A TB inpatient unit of a Canadian hospital. PATIENTS: Thirty-two HIV-seronegative patients with moderate to advanced sputum smear-positive respiratory TB were treated with uninterrupted, directly observed, weight-adjusted isoniazid, rifampin, and pyrazinamide. Each patient's initial isolate was drug susceptible and each patient's sputum mycobacteriology was systematically followed until 3 consecutive sputum smears were negative on 3 separate days. RESULTS: The time to smear conversion varied remarkably (range, 8 to 115 days; average, 46 days) and was influenced by sputum sampling frequency. Only 3 patients (9.4%) had smear conversions by 14 days and only 8 (25%) had smear conversions by 21 days, the average time it took for drug susceptibility test results to become available. During the first 21 days of treatment, the semiquantitative sputum smear score decreased rapidly and the time to detection of positive cultures doubled. Within the time to smear conversion, virtually all smear-positive specimens (98%) were culture positive and only 34% of the patients had culture conversions (ie, 3 consecutive negative cultures). CONCLUSION: Current estimates of the noncontagiousness of sputum smear-positive respiratory TB on treatment (for 14 days, for 21 days, or until smear conversion) are estimates of relative noncontagiousness. They do not signal absolute noncontagiousness (culture conversion). Semiquantitative smear and time-to-detection data suggest that respiratory isolation beyond 21 days of optimal treatment should be selective.

Academic Medical Centers↗
PubMed2004

Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model.

Poly (DL-lactide-co-glycolide) (PLG) nanoparticles encapsulating three front-line antitubercular drugs, i.e. rifampicin, isoniazid and pyrazinamide, were prepared by the multiple emulsion technique and administered subcutaneously to mice for pharmacokinetic/chemotherapeutic study. A single subcutaneous dose of drug-loaded PLG nanoparticles resulted in sustained therapeutic drug levels in the plasma for 32 days and in the lungs/spleen for 36 days. The mean residence time and absolute bioavailability were increased several-fold as compared with unencapsulated drugs. Further, drug-loaded PLG nanoparticles resulted in undetectable bacterial counts in the lungs and spleen of Mycobacterium tuberculosis-infected mice, thereby demonstrating a better chemotherapeutic efficacy, as compared with daily free drug treatment. Hence, injectable PLG nanoparticles hold promise for increasing drug bioavailability and reducing dosing frequency for better management of tuberculosis.

Animals↗
PubMed2005

Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution?

INTRODUCTION: It is perceived wisdom that within the host macrophage, Mycobacterium tuberculosis frequently encounters oxidative stress. Exposure of bacteria to reactive oxygen intermediates can have a mutagenic effect on the DNA. Various mutations are thought to arise as a consequence, including the oxidation of guanine residues, leading to G?C-->T?A substitution, and oxidation of cytosine resulting in a G?C-->A?T substitution. METHODS: We measured the relative contribution of oxidative stress by recording the percentage of single nucleotide substitutions reported in the genes rpoB and pncA that confer resistance to the antimicrobials rifampicin and pyrazinamide, respectively, and determined whether there is an excess of G?C-->T?A or G?C-->A?T substitutions. RESULTS: Out of 840 clinical isolates reported with single nucleotide mutations in the rpoB gene, 67% were G?C-->A?T changes, and 3% were G?C-->T?A substitutions. These figures were compared to the pncA gene, where out of 114 isolates, 30% of the single nucleotide mutations were G?C-->A?T transitions and 9% were G?C-->T?A changes. CONCLUSIONS: While there is an excess of G?C-->A?T changes in the rpoB gene, this was not the case in the pncA gene. Fifty-three percent of mutations within the rpoB gene were C-->T mutations of the type S531L. Although this mutation gives a fitness disadvantage, it is less than other common mutations, so it is more likely that that fitness is the determinant of surviving mutation rather than oxidative stress because of the small numbers of other C-->T and G-->A mutations at other sites (12%). There was no evidence of oxygen free radicals damaging the guanine bases in either gene.

Amidohydrolases↗
PubMed2000

Chromosomal aberrations and micronuclei in lymphocytes of patients before and after exposure to anti-tuberculosis drugs.

To evaluate the genetic damage induced by tuberculosis infection and also by a combination of therapeutic exposure to anti-tuberculosis (anti-TB) drugs (isoniazid + rifampicin + pyrazinamide + ethambutol or streptomycin) we have considered chromosome aberrations (CA) and micronuclei (MN) in binucleate peripheral blood lymphocytes from 36 patients diagnosed with pulmonary tuberculosis prior to receiving anti-TB drugs in the first phase and in the second phase after 6 months of therapy with anti-TB drugs. The same cytogenetic study has also been performed on 36 healthy individual controls. It was shown that the frequencies of both CA and micronucleated binucleate cells increased significantly after therapy with anti-TB drugs as compared with TB patients and controls. In addition, we observed that both cytogenetic markers (CA and MN) in patients before treatment with anti-TB drugs were significantly (P: < 0.05) higher than controls. No relationship was found between the frequency of MN and donor age. Thus, apart from drug effects, infection with tuberculosis is associated with increased CA and MN.

Adolescent↗
PubMedDate not supplied

Hyperuricosuria in the Fanconi syndrome.

A patient with asymptomatic adult Fanconi syndrome with glycosuria, amino-aciduria, hypophosphatemia, and renal tubular acidosis was found to have hypouricemia (serum uric acid, 1.5-1.8 mg/100 ml) secondary to increased renal clearance of urate (urate clearance/glomerular filtration rate, 32 per cent). Increased urate clearance in this patient with multiple reabsorptive defects probably represents diminished urate reabsorption. Consistent with this, the uricosuric response to probenecid was diminished. Reabsorption of filtered urate appeared to be intact. Inhibition of urate secretion with pyrazinamide completely suppressed the uricosuria in this patient, suggesting that increased urate clearance was due to either enhanced secretion or diminished reabsorption of secreted urate. There was no direct evidence for increased urate secretion. The response of urate excretion to pharmacologic inhibitors of tubular transport of urate differs in various clinical states associated with hyperuricosuria. The responses may reflect different mechanisms of hyperuricosuria.

Fanconi Syndrome↗
PubMed1995

Two-year follow-up of persons with HIV-1- and HIV-2-associated pulmonary tuberculosis treated with short-course chemotherapy in West Africa.

OBJECTIVE: To assess the response to therapy for tuberculosis using rifampicin-containing short-course chemotherapy, and to compare recurrence and mortality rates in seronegative persons and those with HIV-1, HIV-2, and dual serologic reactivity in West Africa. METHODS: A cohort of 835 adult patients (167 HIV-1-positive, 143 HIV-2-positive, 243 dual-reactive, 282 HIV-negative) with smear-positive pulmonary tuberculosis was followed for 2 years under programme conditions. Standard self-administered treatment was daily rifampicin and isoniazid for 6 months, and in addition pyrazinamide during the first 2 months. Outcomes evaluated were rates of completion of therapy, cure, failure of treatment, recurrence after cure, and mortality. RESULTS: HIV-positive patients had lower rates of completion of therapy (65-73%) than seronegative patients (79%), mainly because of increased mortality. Among patients completing therapy, failure of treatment was similarly low in HIV-positive (2%) and seronegative patients (1%). Recurrence rates after cure did not differ significantly in the 18 months of follow-up in the four serologic groups (3-7%). The respective mortality rates for HIV-1-positive, HIV-2-positive, and dually reactive patients were 20.3, 8.3, and 25.5 per 100 person-years (PY), compared with 2.2 per 100 PY among seronegatives. CONCLUSIONS: Rifampicin-containing short-course chemotherapy for pulmonary tuberculosis is associated with similar cure and recurrence rates in HIV-positive and HIV-negative persons completing 6 months of therapy. HIV-2 infection is associated with more favourable survival than HIV-1 infection or dual reactivity, even when AIDS-defining illness is already present. However, mortality is significantly increased in all seropositive groups compared with HIV-negative tuberculosis patients; thus, establishing the causes of this increased mortality is a priority.

AIDS-Related Opportunistic Infections↗
PubMed1999

Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa.

OBJECTIVE: To determine the effectiveness of twice-weekly directly observed therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients, irrespective of their previous treatment history. Also to determine the predictive value of 2-3 month smears on treatment outcome. METHODS: Four hundred and sixteen new and 113 previously treated adults with culture positive pulmonary TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa. Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice a week to 6 months in the community. RESULTS: Outcomes at 6 months among the 416 new patients were: transferred out 2%; interrupted treatment 17%; completed treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%; 95% CI 92-99%) new patients. Outcomes were similar among previously treated and new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2 months did not predict the final outcome. CONCLUSION: A twice-weekly rifampicin-containing drug regimen given under DOT cures most adherent patients irrespective of HIV status and previous treatment history. The 2 month smear may be safely omitted. Relapse rates need to be determined, and an improved system of keeping treatment interrupters on therapy is needed. Simplified TB treatment may aid implementation of the DOTS strategy in settings with high TB caseloads secondary to the HIV epidemic.

AIDS-Related Opportunistic Infections↗
PubMed1999

Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons.

OBJECTIVE: To determine the rate of tuberculosis relapse among HIV-seropositive and -seronegative persons treated for active tuberculosis with short-course (6-month) therapy. DESIGN: Consecutive cohort study. SETTING: City of Baltimore tuberculosis clinic. PATIENTS: Tuberculosis patients treated between 1 January 1993 and 31 December 1996. INTERVENTION: Patients received 2 months of isoniazid, rifampin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampin. MAIN OUTCOME MEASURE: Passive follow-up for tuberculosis relapse was performed through September 30, 1998. RESULTS: There were 423 cases of tuberculosis during the study period; 280 patients completed a 6-month course of therapy. Therapy was directly-observed for 94% of patients. Of those who completed therapy, 47 (17%) were HIV-seropositive, 127 (45%) were HIV-seronegative, and 106 (38%) had unknown HIV status. HIV-infected patients required more time to complete therapy (median 225 versus 205 days; P = 0.04) but converted sputum culture to negative within the same time period (median 77 versus 72 days; P = 0.43) as HIV-seronegative or unknown patients. Relapse occurred in three out of 47 (6.4%) HIV-infected patients compared to seven out of 127 (5.5%) HIV-seronegative patients (P = 1.0). Relapse rates also did not differ when HIV-seropositive patients were compared with HIV-seronegative and patients with unknown HIV status (6.4% versus 3.0%; P = 0.38). Of the 10 patients with tuberculosis relapse, restriction fragment length polymorphism data were available for five; all five relapse isolates matched the initial isolate. CONCLUSIONS: These results support current recommendations to treat tuberculosis in HIV-infected patients with short-course (6-month) therapy.

AIDS-Related Opportunistic Infections↗
PubMed2001

Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults.

OBJECTIVE: To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression. METHODS: In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years). RESULTS: There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006). CONCLUSIONS: Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT.

AIDS-Related Opportunistic Infections↗
PubMed1990

A randomized trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis.

Fully intermittent short course chemotherapy regimens have been used successfully in adults but not in children. We report the results on 76 children with tuberculosis, excluding central nervous system tuberculosis and primary pulmonary complex. Isoniazid, rifampin and pyrazinamide were used for treatment. They were randomly allocated to Regimen A (52 doses) and Regimen B (94 doses). Overall efficacy of both schedules was greater than 95% in 27 children with lymphatic, 43 with pulmonary and 6 with disseminated tuberculosis. Compliance in 10 children after 2 to 4 months of therapy was poor because rapid improvement was mistaken by parents for cure. Two children died, probably of underlying lung disease. Follow-up for up to 2 years did not reveal any case of relapse or recurrence of the disease. Therapy for 6 months involving administration of only 52 or 94 doses of drugs was found to be economical, effective and safe for treating children with tuberculosis.

Adolescent↗