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Population pharmacokinetics of antituberculous drugs and treatment of Mycobacterium bovis infection in bongo antelope (Tragelaphus eurycerus isaaci).

After clinical illness, treatment, and death of a captive male bongo antelope (Tragelaphus eurycerus isaaci) caused by tuberculosis involving Mycobacterium bovis, four tuberculin test reactive captive bongos were treated for 6 mo with isoniazid (INH) and rifampin (RIF) and intermittent single doses of other medications before being euthanized. In all cases, postmortem examination indicated no evidence of active disease and cultures of multiple organs were negative. We present detailed pharmacokinetic (PK) data for amikacin (AMK), ethambutol (EMB), INH, pyrazinamide (PZA), RIF, and levofloxacin in four female bongos. Adequate absorption and serum levels were obtained after parenteral administration of AMK, EMB, and INH and after oral administration of INH and PZA. Parenterally administered drugs were well described by a one-compartment PK model with first-order absorption and elimination processes. Treatment with INH and RIF over a 6-mo period did not result in demonstrable adverse effects. Starting doses of 10-15 mg/kg, i.m., or 30 mg/kg, p.o., of INH, 50 mg/kg, p.o., of EMB, and 25 mg/kg, i.m., s.i.d., of AMK are recommended. The treatment is continued with at least two drugs to which the organism is susceptible for a total treatment length of 6-12 mo. Treatment may be an option to eradicate M. bovis from suspect animals, with carefully administered and monitored drug treatment.

Amikacin↗

Renal handling of urate in a patient with familial juvenile gouty nephropathy.

We encountered a case of familial juvenile gouty nephropathy (FJGN) with an autosomal dominant transmission pattern. Hyperuricemia in the propositus was caused by renal underexcretion of urate although his erythrocyte purine enzyme was normal. A renal biopsy specimen from the propositus showed interstitial fibrosis with tubular atrophy. On pyrazinamide and probenecid tests, the tubular secretion of urate selectively decreased without changes in either presecretory or postsecretory reabsorption of urate when his renal function was normal. Probenecid increased the urinary urate excretion and Cur/Ccr. The serum urate concentration was poorly controlled by allopurinol. When his renal function deteriorated, the uricosuric effects of both probenecid and benzbromarone were attenuated. However, the combined administration of probenecid with allopurinol decreased the serum urate concentration. These data suggest that the tubular secretion of urate is selectively impaired in FJGN and at the stage of renal failure, the combination of an uricosuric agent with allopurinol might be effective in treating hyperuricemia in FJGN.

Adolescent↗

Esophagomediastinal fistula as a complication of tuberculous mediastinal lymphadenitis.

In a 44-year-old female esophagomediastinal fistula was found secondary to tuberculous mediastinal lymphadenitis. Chest computed tomography revealed amorphous air collection in the subcarinal region of the mediastinum with mediastinal lymphadenopathy. Esophagography with gastrografin confirmed esophagomediastinal fistula. The patient was treated with antituberculous therapy with rifampicin, isoniazid, pyrazinamide and ethambutol, resulting in resolution of the esophagomediastinal fistula and mediastinal lymphadenopathy.

Adult↗

Two cases of renal hypouricemia with nephrolithiasis.

We treated two cases of renal hypouricemia with nephrolithiasis. The serum uric acid level of the first patient was 1.5 mg/dl, and the ratio of uric acid clearance to creatinine clearance (CUA/Ccr) was 75.7%. In the benzbromarone (BZB) suppression test, CUA/Ccr was increased from 60.4% to 130.0%, but was not decreased in response to the pyrazinamide (PZA) suppression test. This patient was considered to have a presecretory reabsorptive urate transportation defect. His condition was also associated with IgA nephropathy. The serum uric acid level in the second patient was 1.0 mg/dl and CUA/Ccr was 56.0%. Neither PZA nor BZB had a significant effect on CUA/Ccr. He was considered to have a subtotal uric acid transportation defect. Both patients were incidentally found to have nephrolithiasis. The second patient had abnormal maximum tubular secretory capacity for para-aminohippurate (PAH) (TmPAH), and was found to have two kinds of proximal tubular abnormalities related to uric acid and PAH.

Adult↗

Appearance of tuberculoma during treatment of tuberculous meningitis.

Case histories of two young Indian female patients are described who, during the course of regular chemotherapy for tuberculous meningitis, developed tuberculoma as suggested by CT-scan. Such lesions were not seen at the start of treatment. Twelve similar cases are collected from literature. Most of the patients developed new symptoms and/or signs having initially shown good response to drugs. The pathogenetic mechanisms for such an evolution of lesions are not known but possibly include immunological modulations. This development should not lead to excessive anxiety for treating physician. Surgery is not needed and a patient follow up is well rewarded. Pyrazinamide has emerged as a useful drug.

Adult↗

Initial screening for antituberculous drug resistance at an inpatient facility in Leon, Nicaragua.

Antituberculous (anti-TB) drug resistance has become a major tuberculosis control issue in the United States, where this situation has closely paralleled the current acquired immunodeficiency syndrome epidemic associated with human immunodeficiency virus type-1 (HIV-1) infections. In less developed countries, especially those like Nicaragua with an apparently low prevalence of known HIV-1 infections, less is known about the epidemiology of antituberculous drug resistance. To understand the potential extent of this problem in Nicaragua, we conducted a cross-sectional prevalence study at Nicaragua's only inpatient tuberculosis treatment facility, located in Leon, Nicaragua. A radiometric method was used during recovery, purification, and drug susceptibility testing of clinical Mycobacterium tuberculosis isolates. Resistance to at least one of the major anti-TB medications was found in 15 (40.5%) of 37 sputum isolates, of which seven (19%) were resistant to either isoniazid alone, or to isoniazid plus another agent other than rifampin. Five were resistant to at least isoniazid and rifampin (i.e., 13.5% demonstrated multidrug resistance). Two isolates were resistant to pyrazinamide alone, and one was resistant to streptomycin alone. These initial results suggest that anti-TB drug resistance is a defined problem for tuberculosis control programs in Nicaragua, a problem that is largely related to individual noncompliance, lack of extensive drug susceptibility testing facilities, and a general unavailability of expensive anti-TB medications for re-treatment. Ongoing surveillance for drug resistance, using the methodology presented here, might assist Nicaraguan public health officials in their tuberculosis control programs.

Adult↗

Fixed-dose combinations of antituberculous medications to prevent drug resistance.

The treatment of tuberculosis requires at least two drugs to retard the development of drug resistance. Unfortunately, patients may take only one drug (monotherapy) when more than one is prescribed. Fixed-dose combinations with two or more antituberculous drugs in one capsule or tablet are available to prevent this. In the United States, these drugs are Rifamate (Marion Merrell Dow), which contains isoniazid plus rifampin, and Rifater (Marion Merrell Dow), which contains isoniazid plus rifampin and pyrazinamide. Because these preparations make monotherapy impossible, they are clearly preferable to individual drugs. In the United States in 1993, however, only 15% to 18% of rifampin was sold in the form of fixed-dose combinations. To correct this deficiency, fixed-dose combinations should be widely promoted and accepted as a primary way to prevent drug-resistant tuberculosis. There are two caveats regarding these preparations. First, many fixed-dose combinations, especially those in developing countries, achieve inadequate blood levels of one or more of the component drugs, especially rifampin. Our recommendations apply only to preparations with proven bioavailability. Second, because the name Rifamate is similar to the name rifampin, mistakes in prescribing and dispensing can result in the patient receiving rifampin alone when Rifamate is intended. A name change from Rifamate to a highly distinctive name such as Rif-Isoniazid is needed to prevent such occurrences.

Antitubercular Agents↗

USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results.

STUDY OBJECTIVE: To determine the effectiveness, toxicity, and acceptability of a 6-month antituberculous regimen compared with a 9-month regimen. DESIGN: A nonblinded, unbalanced, randomized, multicenter clinical trial. SETTING: Twenty-two tuberculosis clinics in public health departments and hospitals in the United States. PATIENTS: Patients were eligible if Mycobacterium tuberculosis, isolated from sputum cultures, was susceptible to study drugs. Of 1451 patients enrolled, 75% (617 of 823) assigned to the 6-month regimen and 71% (445 of 628) assigned to the 9-month regimen were eligible. INTERVENTIONS: Patients took self-administered isoniazid and rifampin daily for 24 weeks (6-month regimen) or 36 weeks (9-month regimen). In addition, patients assigned to the 6-month regimen took self-administered pyrazinamide daily during the first 8 weeks. RESULTS: Patients on the 6-month regimen converted more rapidly than patients on the 9-month regimen (94.6% compared with 89.9% after 16 weeks of therapy, with a difference of 4.7% [95% CI, 0.7% to 8.7%]); had similar rates of adverse drug reactions (7.7% compared with 6.4%, with a difference of 1.3% [95% CI, 0.0% to 4.6%]); had lower noncompliance rates (16.8% compared with 29.2%, with a difference of 12.4% [95% CI, 6.8% to 18.0%]); and had similar relapse rates 96 weeks after completing therapy (3.5% compared with 2.8%, with a difference of 0.7% [95% CI, 0.0% to 3.9%]). A significantly greater proportion of patients assigned to the 6-month regimen successfully completed therapy (61.4% compared with 50.6%; chi 2 = 11.976). CONCLUSIONS: Our results suggest that this 6-month regimen is similar in effectiveness, toxicity, and acceptability to the 9-month regimen for treating pulmonary tuberculosis.

Adult↗

Ascorbic acid-induced uricosuria. A consequency of megavitamin therapy.

The effect of ascorbic acid on the serum and urinary uric acid was studied in 14 subjects. Two to 6 h after the ingestion of 4.0 g of ascorbic acid, the fractional clearance of uric acid increased to 202% +/- 41% of the control value. This uricosuria was inhibited by pyrazinamide and by low-dose acetylsalicylic acid, but was not accompanied by an increase of the creatinine clearnace. Ascorbic acid did not diminish protein-bound uric acid. In 3 subjects who ingested 8.0 g of ascorbic acid for 3 to 7 days the serum uric acid decreased by 1.2 to 3.1 mg/dl as a result of a sustained uricosuria. These results suggest that ascorbic acid could invalidate studies involving the measurement of uric acid and obscure the diagnosis of gout in some cases. Theoretically it could precipitate attacks of gouty arthritis or renal calculi in predisposed persons. These observations show a pharmacologic effect of megadoses of a simple vitamin.

Ascorbic Acid↗

The natural history of urate overproduction in sickle cell anemia.

Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 +/- 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.

Adolescent↗

[Profile of the patients lost to treatment in the National Anti-Tuberculosis Program in Madagascar].

A national anti-tuberculosis program has been in operation in Madagascar since 1991. Despite the significant efforts made in the management, education and surveillance of patients, the number of patients lost to treatment remains high (18.8%). Noncompliance with treatment is the principal cause of treatment failure and of the development of resistance to tuberculosis drugs. This study investigated the profile of the patients who discontinue treatment. The study population consisted of the patients withdrawing from a clinical trial carried out between August 1994 and September 1996. The aim of the trial was to compare several treatments in routine practice conditions in Madagascar. The treatments tested were streptomycin (S) or ethambutol (E) associated with isoniazid (H), rifampicin (R) or pyrazinamide (Z) for the first two months, followed by 6 months of treatment H and thiacetazone (T). The trial involved four public and three private diagnosis and treatment centers in Antananarivo, Fianarantsoa and Mahajanga. A total of 1, 023 patients were included in the trial and 192 (18.8%) withdrew during the eight-month treatment period. We tracked down 109 of these patients (56.8%) and 19 patients came back to the treatment center on their own initiative for a checkup. The rate of response to a recall letter sent by mail was low. The 106 patients interviewed mostly gave professional, financial or family reasons for discontinuing treatment. Many patients stopped the treatment as soon as they began to feel better. To reduce the number of patients discontinuing treatment, the National Anti-Tuberculosis Program should improve the education of patients and their families.

Adolescent↗

Tuberculosis chemotherapy and sputum conversion among HIV-seropositive and HIV-seronegative patients in south-eastern Uganda.

OBJECTIVE: To investigate if there is a difference in response to tuberculosis treatment between HIV seronegative and HIV seropositive patients following two months of intensive phase tuberculosis treatment. DESIGN: Prospective cohort study. SETTING: St. Francis Leprosy Centre, south-east Uganda. SUBJECTS: Four hundred fifty seven patients with never previously treated sputum smear-positive tuberculosis admitted during a two-year period in 1991/1993. INTERVENTION: Intensive phase treatment with streptomycin, isoniazid, rifampicin and pyrazinamide. MAIN OUTCOME MEASURES: Sputum conversion from a positive to a negative smear at eight weeks of treatment. RESULTS: HIV seropositivity prevalence was 28%. Among HIV seronegative patients, conversion to a negative smear status occurred in 76% persons compared to 78% in HIV seropositive patients. This difference was not statistically significant (OR = 0.9; 95% CI, 0.6-1.5). HIV seropositive patients, however, were more likely to die (p = 0.017). A high prevalence of resistance to isoniazid and streptomycin was found. Isoniazid resistance was more likely in HIV seronegative patients with M. tuberculosis strains compared to HIV seropositive persons (p < 0.005). Initial resistance to antituberculosis drugs did not have a significant effect on smear conversion. CONCLUSION: This study demonstrates that HIV-seropositive status is not a principal factor in delaying sputum conversion among patients receiving intensive phase tuberculosis treatment.

AIDS-Related Opportunistic Infections↗

Exercise-induced acute renal failure in a patient with renal hypouricemia.

We describe a case of exercise-induced acute renal failure (ARF) in a patient with hypouricemia. Following recovery from ARF, the patient's serum urate concentration was 0.6-0.9 mg/dl, and the ratio of urate clearance to creatinine clearance (Cua/Ccr) was 41.9%-56.6%. There was no change in the Cua/Ccr following the administration of pyrazinamide or probenecid, suggesting defects of tubular urate/anion exchangers. Because the renal biopsy revealed acute tubular necrosis without uric acid crystals, the ARF of this patient might be due to oxygen free radicals resulting from exercise stress and hypouricemia.

Acute Kidney Injury↗

Role of individual drugs in the chemotherapy of tuberculosis.

During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of treatment. Its bactericidal role is then replaced by rifampicin and pyrazinamide during the intensive phase. In the continuation phase with an isoniazid/rifampicin regimen, rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially isoniazid-resistant or sensitive strains. If the continuation phase regimen does not contain rifampicin but does contain isoniazid, the dominant bactericidal drug is isoniazid. In this case, the response of patients with initial isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials of a continuation phase of rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically resistant to rifampicin.

Antibiotics, Antitubercular↗

Treatment of tuberculosis: a well-standardised protocol.

(1) The recommended treatment protocol for the vast majority of cases of tuberculosis is a 6-month course of isoniazid and rifampicin, plus pyrazinamide and ethambutol for the first two months. (2) This protocol is recommended for both adults and children, and for both pulmonary and extra-pulmonary disease (except for central nervous system involvement). (3) Good adherence to this protocol induces relapse-free recovery in more than 97% of patients with tuberculosis due to non resistant strains.

Adult↗

[Early anterolateral surgery for tuberculosis of the lower cervical spine with neurological complications in adult. Our experience in Gabon].

OBJECTIVE: To report our therapeutic experience with tuberculosis of the lower cervical spine with neurological complications in 9 adults in Gabon. PATIENTS AND METHODS: A retrospective study of these 9 adults treated for progressive Pott's tetraplegia or paraplegia from 1982 to 1998 was conducted. The medical treatment consisted of the early administration in the first 3 patients of rifampin, isoniazid and ethambutol for 18 months; and, in the remaining 6 patients, of rifampin, isoniazid, ethambutol and pyrazinamide for 6 months. This medical treatment was systematically started 3 weeks before surgery in 7 patients, once the disease had been diagnosed radiologically. Two patients with an acute onset of paraplegia underwent surgery on an emergency basis. The standard anterior approach was used: debridement was done in 3 cases, to establish the diagnosis; 6 patients underwent radical surgery for severe neurological deficit and spinal instability. Average follow-up time was 40.6 months. RESULTS: Three patients were found to be functionally and neurologically normal at follow-up examinations. Eight of the nine patients recovered sufficiently to walk unaided. One patient was able to get about on crutches. After 3-4 months, a satisfactory consolidation was already observed, with reduction of kyphosis in 4 cases. All patients were considered medically cured by the Antituberculous Center. CONCLUSION: Early radical surgery, as primary procedure, in conjunction with a six-month chemotherapeutic regimen (four drugs) seems to be adequate for the management of tuberculosis of the lower cervical spine with neurological complications and spinal instability, in our setting.

Adult↗

Osteoarticular tuberculosis: current diagnosis and treatment.

Tuberculous synovitis frequently presents as a monoarthritis of weight-bearing joints such as the hip, knee, or ankle. Owing to its low incidence in developed countries, the diagnosis is often delayed for months to years. Early diagnosis with a synovial biopsy permits prompt antituberculous therapy and substantially improves the prospect of preservation of joint structure and function. Initial treatment typically includes combination therapy with four drugs (isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol) because of the frequency of isoniazid resistance. Antimicrobial therapy should be of at least 9 months' duration, longer in immunocompromised hosts. Partial synovectomy and other surgical procedures should be restricted to joints with severe cartilage destruction, large abscesses, joint deformity, multiple drug resistance, or atypical mycobacteria.

Adult↗

[Controlled clinical trial on efficacy of 5-month regimens and whole course intermittent 6-month regimens in treating bacillary pulmonary tuberculosis].

OBJECTIVE: To assess the therapeutic efficacy of rifapentine (L), to reduce the duration of treatment and the frequency of drug administration, and to observe the influence on efficacy and adverse reactions of using pyrazinamide (Z) through whole-course. METHOD: Two 5-month regimens respectively including rifampin (R) and L and two whole course intermittent regimens were designed as following: I: 2SHRZ/3R2H2Z2; II: 2SHRZ/3L1H2Z2; III: 2S3H3R3Z3/4L1H2Z2; IV: 2S3H3R3Z3/4L1H2E2. A total of 366 newly-diagnosed bacillary pulmonary tuberculosis patients were admitted and randomly allocated. RESULTS: 339 cases completed the prescribed short course chemotherapy. The sputum conversion rates at the end of the treatment of groups I, II, III and IV were 97.0%, 94.1%, 100.0% and 97.2% respectively. X-ray resolution rates were 96.0%, 97.6%, 100.0% and 94.4% respectively. Cavity-close rates of the 5-month regimens and the 6-month regimens were 77% and 76%. Comparing the results among groups, there were no statistically significant differences (P > 0.05), and no obvious side-effect was found. 305 patients have been followed up for 3 years since completion of the chemotherapy. The bacteriological relapse and bacteriological relapse with deterioration on chest X-ray in groups I, II, III and IV were seen in 2,3,6 and 3 cases respectively. CONCLUSION: Domestic-made rifapentine is a long-acting, highly effective antituberculosis drug. It is unnecessary to use Z in continuation phase, and it is possible to shorten the duration to 5 months with the appropriate combination of essential drugs, which is worthwhile for further study.

Antitubercular Agents↗