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PubMed1990

Microcalorimetric studies of the initial interaction between antimycobacterial drugs and Mycobacterium avium.

To further our understanding of the mechanisms by which ethambutol potentiates the effect of other antimycobacterial drugs on mycobacteria we have studied the initial physico-chemical interaction between ethambutol and the Mycobacterium avium cell envelope using batch reaction microcalorimetry. When strains of M. avium were exposed to ethambutol an immediate endothermic reaction was recorded. When the M. avium cells were pre-treated with ethambutol this strongly affected the initial interaction between streptomycin and the bacterial cell surface. When the M. avium cells were simultaneously exposed to a combination of ethambutol and streptomycin an altered initial interaction with streptomycin was seen. These data suggest that ethambutol may potentiate the effect of other antibacterial drugs on M. avium by increasing cell wall permeability.

Antitubercular Agents↗
PubMedDate not supplied

Drug-resistance of Mycobacterium tuberculosis in Patras, Greece.

BACKGROUND: The global distribution of drug resistant tuberculosis reflects the quality of tuberculosis control worldwide and is still a major public health-problem. To our knowledge, no data exists in literature about resistance to anti-tuberculosis drugs in Greece. METHODS: The aim of this study was to determine the prevalence of resistance to the main anti-tuberculosis drugs in newly and previously treated tuberculosis patients, in the region of Patras, in Greece and to evaluate the contribution of foreign-born and human immunodeficiency virus (HIV) positive cases to drug resistance. RESULTS: A total of 207 initial isolates of Mycobacterium tuberculosis were analysed. All clinical specimens submitted for cultural diagnosis were collected before chemotherapy commenced. The age of the patients varied from 16 to 78 years old. Sex distribution was 144 males (69.56%) and 63 females (30.43%). Nineteen patients (9.17%) were recent immigrants in Greece. All the patients were HIV-negative. One hundred-one initial isolates of Mycobacterium tuberculosis (48.79%) were susceptible to all first-line anti-tuberculosis drugs, isoniazid, streptomycin, ethambutol and rifampicin. The prevalence of primary mono- and poly-drug resistance was lower (isoniazid 5.79%, streptomycin 4.34%, ethambutol 1.93%, isoniazid + streptomycin 3.38%, isoniazid + ethambutol 0.9%, isoniazid + streptomycin + ethambutol 1.44%) when compared with the prevalence of secondary (acquired) mono- and poly-drug resistance (isoniazid 8.69%, streptomycin 10.14%, ethambutol 3.86%, isoniazid + streptomycin 3.86%, isoniazid + rifampicin 1.44%, isoniazid + streptomycin + ethambutol 4.83%, isoniazid + streptomycin + rifampicin 1.44%). No primary mono - resistance to rifampicin, or primary multi - drug resistance (defined here as Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin) were observed. CONCLUSIONS: According to our data, overall drug resistance was high. Fortunately, multi-drug resistance tuberculosis was not common but special efforts are needed to monitor the prevalence of drug resistance and to ensure adequate treatment in all the population.

Adolescent↗
PubMed2005

Loss of vision and renal function in a patient with miliary tuberculosis.

INTRODUCTION: Visual loss is a rare complication of tuberculosis; it can be related to anti-tuberculous drugs or to the infection itself. For the treatment of visual loss, differential diagnosis is important between infection and adverse effect of anti-tuberculous drugs. CASE: A 48-year-old male patient with a history of tuberculosis and visual loss during anti-tuberculous drug therapy was admitted to our hospital. Anti-tuberculous drugs had been stopped on the 2nd day of therapy due to development of optic neuritis secondary to ethambutol administration at another hospital. He had miliary tuberculosis, renal failure requiring dialysis and visual disturbances. Anti-tuberculous drugs, including ethambutol, were initiated at our clinic because the period between the ethambutol therapy and visual loss was too short and the dose of ethambutol was not very high. Computed brain tomography was normal. Fundoscopic examination revealed only hypertensive retinopathy. Our diagnosis was tuberculosis-related visual loss, which could be due to neuroretinitis, intraocular tuberculosis or chiasmal tuberculoma. In addition, ethambutol rarely causes visual loss during the early period or when given at lower doses. In our case no complications developed from the treatment and the patient's visual loss and renal function improved. At his last visit, 12 months later, his vision had improved and his serum creatinine was lower, at 2.2 mg/dL. CONCLUSION: With anti-tuberculous treatment, renal functions and visual disturbances were improved in a patient with miliary tuberculosis. During the anti-tuberculous therapy, visual loss can be related to ethambutol toxicity or the tuberculosis infection itself. Differential diagnosis is very important and anti-tuberculous drugs must be continued if the diagnosis is tuberculosis.

Acute Kidney Injury↗
PubMed1982

Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British Medical Research Council.

Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given 3 times a week throughout, contained isoniazid and rifampicin together with 1. streptomycin, pyrazinamide and ethambutol, 2. streptomycin and pyrazinamide, but no ethambutol, 3. streptomycin and ethambutol, but no pyrazinamide, 4. pyrazinamide and ethambutol, but no streptomycin. The fifth was a daily regimen of isoniazid, rifampicin, pyrazinamide and ethambutol. All 833 patients with drug-sensitive strains of tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rate during 18 months after stopping chemotherapy was 1% for the three-times-weekly regimens containing streptomycin and pyrazinamide in addition to isoniazid and rifampicin (regimens 1 and 2, above) and for the daily regimen, 2% for the regimen of isoniazid, rifampicin, pyrazinamide and ethambutol three times a week (regimen 4), but 8% for the only regimen which did not contain pyrazinamide (regimen 3). The results achieved by the 4 pyrazinamide regimens were practically as good for the 110 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment as they were for the patients with drug-sensitive strains.

Adolescent↗
PubMed2006

[A controlled clinical trial of long course chemotherapy regimens containing rifabutin in the treatment of multi-drug resistant pulmonary tuberculosis].

OBJECTIVE: To evaluate the curative effect and safety of a long course regimen containing Chinese-made rifabutin as compared to the regimen containing rifapentine in the treatment of multi-drug resistant pulmonary tuberculosis. METHOD: During 18 month treatment, 130 patients with multi-drug resistant pulmonary tuberculosis were divided into a treatment group (rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months), and a control group (rifapentine, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months) with proportion 1:1 random, and parallel compared method. RESULTS: After intensive phase, the sputum negative conversion rates (smear negative, culture negative) of the treatment group and the control group were 41.54% (27/65) and 35.94% (23/65), chi(2) = 2.42, P > 0.05, respectively. The remarkable effective rates in chest X-ray of the two groups were all 10.77% (7/65), chi(2) = 0.01, P > 0.05, and the effective rates were 67.69% (44/65) and 56.92% (37/65), chi(2) = 1.44, P > 0.05, respectively. At the end of the treatment, the sputum negative conversion rate (smear negative, culture negative) of the treatment group was 75.0% (48/65), and of the control group was 65.08% (41/65), chi(2) = 1.88, P > 0.05. The remarkable effective rates in chest X-ray of the two groups were 46.15% (30/65) and 44.62% (29/65), chi(2) = 0.02, P > 0.05, and the effective rates were 76.92% (50/65) and 73.85% (48/65), chi(2) = 0.19, P > 0.05, respectively. The cavity closure rates were 23.64% (13/55) and 33.33% (17/51), chi(2) = 0.00, P > 0.05, respectively. CONCLUSION: Regimens containing rifabutin or rifapentine. are very effective in sputum negative conversion rate, lesion absorption and cavity closing for the treatment of multi-drug resistant pulmonary tuberculosis, with good safety and tolerance.

Adult↗
PubMed1997

[Mycobacterium avium complex infection: a growing problem in our country].

Since the emergence of AIDS, disseminated Mycobacterium avium complex (MAC) infection has become a growing cause of morbidity and mortality in this group of patients. Our objective was to study the incidence and the clinical and microbiological features of MAC infection in HIV-positive patients as well as the response to a therapy regimen combining clarithromycin and ethambutol. At our hospital, the first patient with disseminated MAC infection was diagnosed in 1988. Since then, 54 HIV-positive patients with MAC infection have been diagnosed (30/1,000 HIV-positive patients). MAC represented 12% of recovered mycobacteria in HIV-positive patients and this percentage has increased from 3.9% in 1988 to 16.4% in 1994. All episodes of MAC infection occurred in patients with advanced HIV diseases (mean CD4: 73/microliter). MAC infection was the disease diagnosing AIDS in 23.4% of cases. The most common clinical manifestations included fever (85.7%), weight loss (55%), and pulmonary involvement (50%). A total of 55 specimens were processed for mycobacterial culture from 54 patients (mean of 10.2 specimens per patient). A total of 122 were positive (21.9%: 2.25 positive specimens per patient). The specimens with the greater percentage of positive results were bone marrow aspirates (65.3%) and blood cultures (47.7%), followed by respiratory (16.5%) and urine specimens (5.3%). Regarding therapy, sixteen of the 54 investigated patients did not receive specific drugs for MAC infection, 7 were treated with different combinations of active drugs against MAC (rifampin, clofazimine, amikacin, ethambutol, and isoniazid) and 31 received a combination of clarythromicin (1 g/12 hourly) and ethambutol (400 mg/12 hourly). Seventy-four percent of patients treated with clarythromicin and ethambutol improved clinically, and the mean survival time in these patients (253 days) was significantly longer than that in not treated patients (p < 0.05). No significant differences were noted in survival time between the group of patients treated with clarythromicin and ethambutol and that with other drug combinations. The incidence of disseminated MAC infection in our environment is increasing in patients with advanced HIV disease. The combination of clarythromicin plus ethambutol was well tolerated and efficient for the treatment of disseminated MAC infection.

AIDS-Related Opportunistic Infections↗
PubMed2002

Behavior of uptake of moisture by drugs and excipients under accelerated conditions of temperature and humidity in the absence and the presence of light. 1. Pure anti-tuberculosis drugs and their combinations.

An investigation was carried out to determine the behavior of moisture gain by four anti-tuberculosis drugs, viz. rifampicin, isoniazid, pyrazinamide and ethambutol, when exposed in pure form and in combinations to accelerated conditions of 40 degrees C and 75% RH, in the absence and the presence of light. Weight gain was seen only in those samples that contained ethambutol, and this behavior was observed both in dark and lighted chambers. There was a decrease in moisture uptake with an increase in the number of drugs in the mixture. Another observation was a higher weight gain by the mixture of ethambutol and isoniazid in a dark chamber, than either pure ethambutol or drug combinations containing ethambutol. The most interesting finding was an overall acceleration of weight gain in the presence of light as compared with dark conditions, which is a hitherto unknown phenomenon.

Adsorption↗
PubMed1987

Mycobacterium malmoense infections in Scotland: an increasing problem.

During 1982-4 20 cases of Mycobacterium malmoense infection were identified in Scotland (13 male, seven female; age 34-82, median 62 years). Features of the disease were obtained from case notes and radiographs of 19 patients and were found to be indistinguishable from those of patients with pulmonary tuberculosis. Chronic chest disease, predominantly chronic airflow obstruction, was the most frequent associated disease. The organisms showed in vitro resistance in eight patients to rifampicin, in 19 patients to isoniazid, and in all patients to pyrazinamide and p-aminosalicylic acid. Nevertheless, all patients showed an early response to standard combination chemotherapy with rifampicin, isoniazid, and ethambutol, with or without pyrazinamide. Five have been cured and none had died of the infection, although four died of unrelated disease. Of nine patients still having treatment, five had relapsed after completing a course of antituberculosis drugs. All had received ethambutol for less than five months. The response to standard drugs was more satisfactory when the course included administration of ethambutol for at least nine months. Currently one new infection with M malmoense occurs in Scotland for every 40 with tuberculosis, and the incidence appears to be rising. In view of this, it is suggested that when tuberculosis is suspected the chemotherapeutic regimen should include ethambutol until the culture results are reported. If these then show M malmoense, ethambutol should be continued in the combination for at least nine months.

Adult↗
PubMed1988

Treatment of nontuberculous mycobacterial infections in pediatric patients.

Two cases of Mycobacterium avium-intracellulare complex (MAC) infections are described, and the diagnosis, clinical features, and management of MAC infections are reviewed. In case 1, a four-year-old boy was diagnosed as having both acquired immunodeficiency syndrome (AIDS) and disseminated MAC infection. He was treated with a combination of isoniazid, ethambutol hydrochloride, rifabutin, and clofazimine. Results of susceptibility testing showed that the MAC was susceptible to rifabutin and ethambutol with intermediate susceptibility to isoniazid. The child developed severe adverse effects that necessitated the discontinuation of rifabutin therapy. Despite therapy, blood cultures remained positive for MAC. The child died of disseminated human immunodeficiency virus and MAC infection. In case 2, a 20-month-old girl was found to have a prevertebral retropharyngeal mass caused by MAC. The child did not have evidence of immunologic deficiency. She was treated with streptomycin, ethambutol, clofazimine, and rifabutin. Streptomycin was discontinued after three months. After seven months the mass decreased in size, allowing for surgical resection. Intraoperative cultures were negative for mycobacteria. Ethambutol, rifabutin, and clofazimine were continued for a total of 12 months, at which time the child was determined to be clinically and radiologically cured. Empiric multidrug antituberculous therapy should be initiated in patients with suspected disseminated nontuberculous mycobacterial infection because final isolation, identification, and susceptibility testing may take several weeks. Clofazimine and rifabutin, in combination with isoniazid and ethambutol, may be useful in the treatment of some MAC infections. At least four drugs are given, and regimens often consist of six drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1997

A controlled clinical trial of oral short-course regimens in the treatment of sputum-positive pulmonary tuberculosis. Tuberculosis Research Centre.

SETTING: The Tuberculosis Research Centre, Chennai, and its unit at Madurai, South India. OBJECTIVE: To design oral short-course regimens for the treatment of sputum-positive pulmonary tuberculosis that could be more easily implemented under field conditions. DESIGN: A total of 1203 patients was randomly allocated to one of three regimens. I (2EHRZ7/6EH7): 8-month daily regimen of ethambutol (E), isoniazid (H), rifampicin (R) and pyrazinamide (Z) for 2 months, followed by E and H for 6 months. II (2EHRZ2/4EHR2): 6-month twice-weekly regimen with the same four drugs for 2 months, followed by EHR for 4 months. III (2HRZ2/4HR2): similar to Reg. II, but without ethambutol. In Reg. I, drugs were given completely unsupervised. Regs. II and III were either completely or partially supervised. RESULTS: Drug-susceptible group: At the end of treatment, 3.6% of 305 patients in Reg. I, 0.4% of 263 in Reg. II and 9.3% of 257 in Reg. III had an unfavourable bacteriological response. By 24 months after start of treatment, 5% of 290 in Reg. I, 11% of 258 in Reg. II and 10% of 229 in Reg. III had a bacteriological relapse requiring treatment. Giving the twice-weekly regimens partly unsupervised did not influence the response to treatment, emergence of drug resistance or relapse rates. Isoniazid resistant group: Unfavourable response and relapse with Reg. I (94 patients) was 17% and 8%, with Reg. II (59 patients) 20% and 25%, and with Reg. III (74 patients) 62% and 15%, respectively. CONCLUSION: A fully unsupervised ethambutol-containing regimen given daily for 8 months (Reg. I) was found to be very effective even in the presence of isoniazid-resistant bacilli. With the ethambutol-containing twice-weekly regimen, the response at the end of treatment was near 100%, but the relapse rate was high (11%). The non-ethambutol twice-weekly regimen was not satisfactory. All three regimens failed in the presence of bacilli resistant to rifampicin and isoniazid.

Administration, Oral↗
PubMed1999

Drug tolerance in Mycobacterium tuberculosis.

Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.

Antitubercular Agents↗
PubMed2006

API TB Consensus Guidelines 2006: Management of pulmonary tuberculosis, extra-pulmonary tuberculosis and tuberculosis in special situations.

INTRODUCTION: The World Health Organization (WHO) has declared Tuberculosis (TB) a global emergency in 1993. Prevalence of TB and Human Immunodeficiency Virus (HIV) co-infection worldwide is 0.18% and about 8% TB cases have HIV infection. Effective chemotherapy has been available for treatment of TB for over 50 years now. In World Health Organization (WHO)-International Union Against Tuberculosis and Lung Disease (IUATLD) Working Group Global Anti-Tuberculosis Drug Resistance Surveillance (1994-1997), the incidence of MDR TB in Delhi was found to be 14%, of which primary multi-drug resistance was only 1.4%, indicating that most of MDR TB is acquired as a result of poor chemotherapy. DIAGNOSIS OF TB: Since TB is an infectious disease caused by Mycobacterium (M) tuberculosis the diagnosis of TB should (as far as possible) be by demonstration of M. tuberculosis on culture or acid-fast bacilli (AFB) on smear examination. The World Health Organization (WHO) has strongly recommended sputum smear examination as the preferred screening test and suggests examination of 3 deeply coughed out sputum samples - spot sample on day 1, overnight sample and a spot sample in the morning on day 2. Recently it has been shown that sputum smear positivity is greater than 90% where greater than 5 ml of sputum is used for smear diagnosis of pulmonary TB. Culture of M. tuberculosis is the gold standard for diagnosis of TB. Culture of mycobacteria is a much more sensitive test than smear examination and has been estimated to detect 10-100 viable mycobacteria per ml of sample and in case of active disease they are found to be 81% sensitive and 98.5% specific. Culture methods are also required for further drug sensitivity testing in cases of suspected drug resistant cases. Isoniazid and rifampicin resistance can be reliably measured; resistance to pyrazinamide, ethambutol, and streptomycin is more difficult due to limitations of technique. The therapeutic index for a given drug is low for certain second-line drugs such as ethionamide, cycloserine, viomycin and para amino salicylic acid (PAS) and it leads to misinterpretation of results due to failure to distinguish between sensitive and resistant strains. Misdiagnosis of MDR-TB due to laboratory related errors has been reported recently. MANAGEMENT OF TB: Chemotherapy of TB consists of prevention of infection, also called primary chemoprophylaxis, when isoniazid 5 mg/kg is given to prevent infection in newborn infants of infectious mothers till mother is sputum smear positive (2-3months). Treatment of latent tuberculosis, also called secondary chemoprophylaxis, when isoniazid 5 mg/kg is given for 6 months to prevent disease in infected persons (asymptomatic MT positive individuals) and treatment of disease with Short Course Chemotherapy (SCC), as per WHO categories. Essential anti-tuberculosis (ATT) drugs Isoniazid (H), Rifampicin (R), Ethambutol (E), Pyrazinamide (Z) and Streptomycin (S) are the essential first line anti-tuberculosis drugs. Anti TB regimen consists of two phases: an initial intensive phase (IIP) and a continuation phase (CP). Best effective SCC for treatment of TB, for adults and children, for pregnant and lactating females, for cases associated with diabetes mellitus and HIV infection, for cases with pre-existing liver diseases (but normal liver functions) and mild renal failure is 2EHRZ, 4HR given daily or thrice weekly. Higher dose SCC intermittent therapy given in thrice weekly (2E3H3R3Z3, 4H3R3) has now been advocated by WHO and implemented by the Revised National TB Control Programme. DOTS, directly observed therapy short course, where the patient takes the drugs under the direct observation (DO) of a health worker to ensure regularity of consumption of drugs. Fixed dose combinations (FDCs) drugs consisting of two or three antituberculosis medications, provide a realistic and welcome alternative to DO that minimizes the opportunity for a patient to selectively take only a single medication. MANAGEMENT OF TB IN SPECIAL SITUATIONS: Pregnancy: All drugs, that is, rifampicin, isoniazid, ethambutol, and pyrazinamide can be used during pregnancy. Streptomycin is not given due to ototoxicity to the fetus. Prophylactic pyridoxine in the dose of 10mg/day is recommended along with ATT. Diabetes mellitus: The drug regimen is same as in nondiabetic. Strict control of blood glucose is mandatory. Also, doses of oral hypoglycemic agents may have to be increased due to interaction with Rifampicin. Prophylactic pyridoxine is indicated. Renal failure: Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid. In acute renal failure, ethambutol should be given 8 hours before hemodialysis. In post renal transplant patients: Rifampicin-containing regimens are avoided as rifampicin causes increased clearance of cyclosporin. Pre-existing liver disease: In stable disease with normal liver enzymes, all anti-tuberculous drugs may be used but frequent monitoring of liver function tests is required. Treatment in unconscious patient (patients unable to swallow): If patients are fed by Ryle's tube or gastrostomy tube, usual doses and drugs may be powdered and administered avoiding feeds 2-3 hours before and after the dose. In cases where enterostomy has been performed or parenteral nutrition is being used, intramuscular streptomycin and isoniazid and intravenous quinolones may be used and switch to oral therapy once oral feed resume. Treatment of TB with HIV co-infection: In early stages the presentations of TB in TB-HIV co-infection is the same as HIV negative but in late stages extra-pulmonary and dissemination are common. The usual short course chemotherapy is indicated in HIV positive patients. The response is usually good but relapse is frequent. After initiating ATT or anti-retroviral therapy (ART) worsening of preexisting lesions or appearance of new lesions is seen, "paradoxical response" or "immune reconstitution phenomenon". Multidrug resistant TB can occur due to poor compliance to ATT due to behavioural pattern, increased incidence of side effects and malabsorption of drugs due to associated diarrhea. ART for HIV, containing protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) cannot be used along with R, as R induces metabolism of PI and reduces the efficacy. The various options are i) to postpone anti-retroviral therapy ii) to use no PI or NNRTI containing anti-retroviral combinations iii) to use certain PI/ and/or NNRTIs with modification in doses iv) Efavirenz (EFZ) or Saquinavir with Ritonavir, without the need to adjust the doses v) to use non R regimens e.g. 2SHEZ+10HE MANAGEMENT OF MDR TB: As far as possible treatment of MDR TB should be referred to specialized units with facilities for quality controlled DST and experienced in handling such cases. If such referrals are not possible, one must remember that while initiating or revising therapy for MDR-TB, drugs selection must rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence.

Algorithms↗
PubMed1981

Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis.

Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given three times a week from the start, contained isoniazid and rifampicin together with (1) streptomycin, pyrazinamide, and ethambutol, (2) streptomycin and pyrazinamide, (3) streptomycin and ethambutol, or (4) pyrazinamide and ethambutol. The fifth was daily isoniazid, rifampicin, pyrazinamide, and ethambutol. All 833 patients with drug-sensitive strains of bacilli before treatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rates during 12 months after stopping chemotherapy were 2% or less for all regimens except thrice-weekly isoniazid, rifampicin, streptomycin, and ethambutol (the only regimen without pyrazinamide), which had a relapse rate of 8%. The results were equally good for the 138 patients with bacilli resistant to isoniazid, streptomycin, or both drugs initially. The incidence of potentially serious toxicity was low. The daily regimen is relevant to programmes in which patients self-administer their drugs, and the 3 pyrazinamide-containing intermittent regimens are relevant to fully supervised outpatient programmes.

Antitubercular Agents↗
PubMed1987

Synergistic effects of antimycobacterial drug combinations on Mycobacterium avium complex determined radiometrically in liquid medium.

A technique to determine the effects of combining antimycobacterial drugs in liquid medium employing the radiometric growth readings in the Bactec system was tested using 20 Mycobacterium avium complex strains. Ten of the strains had been isolated from children with lymphadenopathy and ten from adults with pulmonary disease. All isolates were resistant to streptomycin, rifampicin, isoniazid and ethambutol when tested with a conventional resistant ratio technique on Löwenstein-Jensen medium. Synergistic interactions were shown for the two-drug combinations streptomycin + ethambutol and ethambutol + rifampicin against all 20 strains. Good efficacy was also found for all three-drug combinations containing ethambutol. Thus, although most isolates of the Mycobacterium avium complex are resistant to first-line antituberculous drugs when tested individually, they are susceptible in vitro to certain combinations of these drugs. This rapid radiometric assay is an efficient means for detecting such synergy.

Adult↗
PubMed1993

Utilization of antituberculosis drugs expressed in defined daily doses in Klenovnik Hospital in the period between 1983 and 1987.

In this paper the utilization of antituberculosis drugs was analyzed in defined daily doses per 1000 bed-days (DDD/1000 BD) in the Hospital for Pulmonary Diseases and Tuberculosis, Klenovnik, from 1983 to 1987. The utilization of these drugs increased from 894 DDD/1000 BD in 1983 to 1112 DDD/1000 BD in 1984, and then decreased to 1077 DDD/1000 BD in 1986; but in 1987 it again increased to 1270 DDD/1000 BD. During the research period the following drugs were prescribed: ethambutol, rifampin, pyrazinamide, streptomycin, isoniazid, and two combinations of drugs: a combination of isoniazid with pyridoxine and a combination of ethambutol, isoniazid and pyridoxine. For the whole of that period the use of ethambutol, isoniazid with pyridoxine and rifampin made up more than 85% of the general utilization of antituberculosis drugs, while other drugs were prescribed in lesser quantities. The data presented indicate that tuberculosis in Klenovnik hospital was in most cases treated with ethambutol, the combination of isoniazid with pyridoxine, and rifampin.

Antitubercular Agents↗
PubMed1997

Evaluation of the post-antibiotic effect of six anti-mycobacterial agents against Mycobacterium avium by the Bactec radiometric method.

We compared and evaluated the duration of the post-antibiotic effect (PAE) of six anti-mycobacterial agents (ethambutol, isoniazid, rifampicin, amikacin, ciprofloxacin and clarithromycin), alone and in combination, against ten strains of Mycobacterium avium. PAE was determined by conventional viable counting and the Bactec growth system, analysed by the T100 value (the time to produce a cumulative growth index of 100). A 2 h exposure to the drug did not induce significant killing. Thus, comparison of regrowth could be evaluated without the potential need to adjust viable counts. The correlation of duration of PAE between the viable count method and the T100 Bactec method was excellent (r = 0.94). No significant PAE (< 8 h) was induced using sub-inhibitory drug concentrations or with ethambutol or isoniazid alone. Rifampicin (20-41 h) and amikacin (8-36 h) demonstrated consistent and extended PAEs, while ciprofloxacin (1-15 h) and clarithromycin (2-10 h) displayed variable PAE activities. Different three-drug combinations (all including ethambutol) displayed variable results with a combination of ethambutol, isoniazid and rifampicin being the most effective combination for extending the PAE (> or = 8 h) which was observed in half the strains tested. It was concluded that the T100 Bactec method is highly suitable for evaluating PAE against M. avium, producing a definitive result in 5 days.

Amikacin↗
PubMed2005

Antimycobacterial agents differ with respect to their bacteriostatic versus bactericidal activities in relation to time of exposure, mycobacterial growth phase, and their use in combination.

A number of antimycobacterial agents were evaluated with respect to their bacteriostatic activity (growth inhibition) versus the bactericidal activity against a clinical isolate of Mycobacterium avium (Mycobacterium avium complex [MAC] strain 101) in relation to the time of exposure and the growth phase of the mycobacteria. In terms of growth inhibition the MAC in the active phase of growth was susceptible to clarithromycin, ethambutol, rifampin, amikacin, and the quinolones moxifloxacin, ciprofloxacin, and sparfloxacin. In terms of bactericidal activity in relation to the time of exposure these agents differed substantially with respect to the killing rate. An initial high killing capacity at low concentration was observed for amikacin, which in this respect was superior to the other agents. The bactericidal activity of clarithromycin and ethambutol was only seen at relatively high concentrations and increased with time. Killing by rifampin was concentration dependent as well as time dependent. The bactericidal activity of moxifloxacin was marginally dependent on the concentration or the time of exposure. The activity of clarithromycin in combination with ethambutol was not significantly enhanced compared to single-agent exposure. Only an additive effect was observed. The addition of rifampin or moxifloxacin as a third agent only marginally effected increased killing of MAC. However, by addition of amikacin the activity of the clarithromycin-ethambutol combination was significantly improved. The combination of amikacin and amoxicillin-clavulanic acid exhibited synergistic antimycobacterial activity. Towards MAC at low growth rates, only the quinolones exhibited a bactericidal effect.

Amikacin↗
PubMed2006

Development of a quantitative assay for mycobacterial endogenous arabinase and ensuing studies of arabinase levels and arabinan metabolism in Mycobacterium smegmatis.

Treatment of either Mycobacterium tuberculosis or M. smegmatis with ethambutol results both in inhibition of arabinan synthesis and in copious loss of previously formed arabinan from the cell wall. The loss of arabinan has been shown to be due to the action of an endogenous arabinase. To better understand this phenomenon, a quantitative assay for endogenous arabinase was developed. Using the assay it was determined that various subcellular fractions of M. smegmatis showed significant amounts of endogenous arabinase activity. Surprisingly, treatment with ethambutol yielded only minor changes in the amounts of endogenous arabinase activities. Endogenous arabinase was present in the cell wall, and consistently, incubation of the M. smegmatis cell wall in only buffer resulted in the release of arabinan, mimicking the effect of ethambutol on whole cells. To determine if cell wall arabinan is rapidly turned over, the arabinan was labeled in the early log phase of culture by feeding [(14)C]glucose, followed by a "chase" with nonradioactive glucose. Most of the labeled arabinan remained in the cell wall after the culture was grown to late log phase. Thus, there is active arabinase in the cell wall, but arabinan is not rapidly removed unless ethambutol is present. Purification of the endogenous arabinase, using the assay described, is ongoing to help further discern its biological function.

Antitubercular Agents↗