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PubMed1989

1,25(OH)2-vitamin D3 synergizes with pyrazinamide to kill tubercle bacilli in cultured human macrophages.

Pyrazinamide (PZA) is believed to be mycobactericidal in vivo. Because it is ineffective at neutral pH in vitro, it is thought to owe its in vivo activity at least partly to acting upon tubercle bacilli (TB) in the helpfully low pH of macrophage (MP) phagolysosomes. However, when it was tested in TB-infected cultured human MP, it was not bactericidal and was able only to slow intra-MP bacillary growth. Recent evidence has suggested that human MP need hormonal support from certain vitamin D metabolites to resist TB. This support was not provided in the culture medium of the earlier experiments in which the PZA was relatively ineffective. Here, PZA has been retested in MP cultured in medium supplemented with the hormonally active metabolite of vitamin D, 1,25(OH)2-vitamin D3 (1,25D3). The MP were infected with virulent TB and incubated in various concentrations of PZA. 1,25D3 was added to postinfection medium at 4 micrograms/ml. Inhibition or killing of intracellular TB was quantitated by counts of culturable TB from samples of lysed MP taken at zero, 4, and 7 days after MP infection. Previous evidence for the protectiveness of 1,25D3 alone for human MP against TB was confirmed. The weak inhibition of TB in MP by PZA alone also was confirmed. The two used together synergized to decrease concentrations of PZA which were inhibitory and to switch the action of PZA from weakly inhibitory to bacteriostatic or mildly bactericidal. 1,25D3 had no direct anti-TB effect, and it did not synergize with PZA in the absence of MP, as determined with acidified bacteriologic culture medium in the BACTEC radiometric system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide.

In a first experiment, the efficacy of a 6-month course of isoniazid (INH) alone in comparison with 2-month courses of rifampin (RMP) alone, RMP + pyrazinamide (PZA), or RMP + PZA + INH as preventive therapy of tuberculosis was evaluated in the mouse. To simulate the infected, non-diseased state of humans, a nonreplicating bacillary population of limited size was developed in the mouse. Mice were vaccinated intravenously with 2.74 log10 M. bovis BCG and infected a month later with 3.38 log10 M. tuberculosis. Treatment began 2 wk after infection when the mean size of the M. tuberculosis population was 4.98 +/- 0.26 log10 cfu in the spleen. After 2 months of therapy, the proportion of mice with positive spleen cultures was 100%, 50%, 0%, and 20% in those animals treated, respectively, with INH alone, RMP alone, RMP + PZA, or RMP + PZA + INH. After 6 months of therapy with INH alone, the proportion of mice with positive spleen cultures was 38%. In order to confirm the extreme activity of the combination RMP + PZA and to assess the value of 3 months of therapy with RMP, a second experiment was performed following similar procedures. On completion of treatment, the proportion of mice with positive spleen cultures was 100%, 20%, 0%, and 80% in those animals treated, respectively, for 6 months with INH alone, 3 months with RMP alone, or 2 months with RMP + PZA, or RMP + PZA + INH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Is pyrazinamide bactericidal against Mycobacterium tuberculosis?

Bactericidal activity of pyrazinamide (PZA) was tested at pH 5.6 in 7H12 broth against drug-susceptible M. tuberculosis strains. The highest tested concentrations of PZA, 500 and 1,000 micrograms/ml, killed no more than 76% of the bacterial population. These concentrations are more than 32 times greater than the minimal inhibitory concentration (MIC) and the achievable in vivo concentrations. Despite high clinical efficacy of PZA and its so-called sterilizing activity in mouse experiments, this drug is much less bactericidal in vitro than any other known antituberculosis drug.

Dose-Response Relationship, Drug↗

PubMed1977

Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months.

A comparison was made between 6-month and 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily, 3 times a week, or twice a week in the treatment of newly diagnosed, smear-positive pulmonary tuberculosis in Chinese patients. At 6 months, the twice-weekly regimen was marginally inferior; treatment failed for 5 (4 per cent) of 126 patients with drug-susceptible strains before treatment compared with 2 (1 per cent) of 141 on the 3-times-weekly regimen and none of 137 on the daily regimen. The results for patients with pretreatment strains resistant to isoniazid, to streptomycin, or to both drugs were not as good, treatment failing for 10 (30 per cent) of 33 on the daily regimen, 15 (37 per cent) of 41 on the 3-times-weekly regimen, and 14 (39 per cent) of 36 on the twice-weekly regimen. In contrast, the relapse rates after chemotherapy were similar for patients with drug-susceptible and drug-resistance strains before treatment and for patients on the daily and intermittent regimens. By 30 months, 35 (21 per cent) of 167 patients with susceptible strains who were treated for 6 months and 10 (6 per cent) of 179 treated for 9 months had relapsed, all with strains still susceptible to isoniazid and streptomycin. The relapse rates for patients with resistant strains were 7 (24 per cent) of 29 and 1 (4 per cent) of 26, respectively. Drug toxicity was not a special problem.

Adolescent↗

PubMed1977

Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis.

Log-phase cultures of Mycobacterium tuberculosis in Tween-albumin medium were exposed to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide in concentrations in the range likely to be present in serum during treatment of patients. The bactericidal activity of the drugs was measured as the decrease in viable counts at 4 and 7 days. The activity of single drugs was highest for streptomycin and next highest for rifampin and isoniazid, but ethambutol only started to kill after 4 days. When exposed to 2 drugs, bactericidal synergism was found with streptomycin/isoniazid and isoniazid/ethambutol; additivity, with streptomycin/rifampin; indifference, with isoniazid rifampin and streptomycin/ethambutol; and antagonism, with rifampin/ethambutol and isoniazid/pyrazinamide. When cultures were exposed to the 3 drugs, isoniazid, rifampin, and ethambutol, marked antagonism was found between isoniazid and rifampin, whereas the addition of isoniazid or an increase in its concentration increased the bactericidal activity.

Drug Interactions↗

PubMed1984

Supervised six-months treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with and without streptomycin.

In a previous study, we have shown that a 6-month regimen consisting of 2 months of isoniazid, rifampin, pyrazinamide, and streptomycin administered daily (2IRSZ) followed by 4 months of isoniazid and rifampin administered twice weekly (4I2R2) yielded no relapses after 30 months of follow-up. In order to assess the contribution of streptomycin to this treatment regimen, 213 patients with newly detected smear-positive pulmonary tuberculosis were randomly assigned to the following two 6-month treatment regimens: 2IRZ/4I2R2 and 2IRSZ/4I2R2. One hundred seventy-two of the 213 patients (81%) completed therapy, i.e., 116 of 135 patients (86%) treated with 2IRZ/4I2R2 and 56 of 78 patients (72%) treated with 2IRSZ/4I2R2. Adverse reactions requiring withdrawal of drugs for 7 days or longer were observed in 4.2% of patients (3.7% receiving the 2IRZ/4I2R2 regimen and 5.1% receiving the 2IRSZ/4I2R2 regimen). At the end of treatment, all patients in the 2IRZ/I2R2 series had negative smears and cultures. Two of the 116 patients (1.7%) in the 2IRZ/I2R2 series developed isoniazid resistance in the fourth month of treatment and remained sputum positive at the end of treatment. In the follow-up period, 4 patients (3.4%) treated with 2IRZ/4I2R2 relapsed and 1 (1.8%) treated with 2IRSZ/4I2R2 relapsed. The only significant difference between the 2 regimens was the higher dropout rate among those assigned to the 2IRSZ/4I2R2 regimen.

Adolescent↗

PubMed1985

The penetration of rifampicin, pyrazinamide, and pyrazinoic acid into mouse macrophages.

The degree of penetration of rifampicin, pyrazinamide, and its metabolite pyrazinoic acid in mouse macrophages was evaluated over a period of 24 h. Cell cultures were exposed to 14C-labeled drugs at concentrations corresponding to peak, trough, and intermediate serum concentrations observed in humans after administration of therapeutic doses. The study was carried out with dead, resident, and stimulated peritoneal macrophages. The results indicated that the 3 compounds penetrate macrophages rapidly. At the lower concentrations, uptake of the 3 drugs is practically complete. With increasing concentrations, the absolute amount in the intracellular compartment increased. Comparison of the degree of penetration of the 3 drugs into dead, resident, and stimulated macrophages seems to suggest that the process of transfer through the macrophage wall is of a passive nature and not related to the metabolic state of the cells. Analysis of the binding of the 3 drugs to intracellular proteins indicated that more binding sites are probably available for rifampicin than for the other 2 drugs.

Animals↗

PubMed1985

Killing of macrophage-ingested mycobacteria by rifampicin, pyrazinamide, and pyrazinoic acid alone and in combination.

A study was undertaken with the aim of assessing the killing capacity of rifampicin, pyrazinamide, and pyrazinoic acid on macrophage-ingested, live Mycobacterium tuberculosis. The 3 drugs were used at concentrations corresponding to the average peak levels observed in humans after administration of therapeutic doses that had been found to penetrate into macrophages in a previous study. The degree of killing was studied after exposure of the cell cultures to the individual drugs and their combinations for 3, 18, 24, 48, and 72 h. Comparing the degree of killing in the control, drug-free cultures with that observed in the drug-containing systems, over a period of 3 to 24 h, indicated that in these a greater, more rapid, although not statistically significant, killing of intracellular mycobacteria took place. At 48 h the degree of killing was similar in the control and in the drug-containing cell cultures. Between 48 and 72 h, however, a marked growth of intracellular mycobacteria was observed in the control cultures. This phenomenon was much less evident in the drug-containing cultures. No major increase in the killing effect with respect to that observed with the individual drugs was found after exposure of the macrophages to all possible combinations of the 3 drugs.

Animals↗

PubMed1986

Inhibition by pyrazinamide of tubercle bacilli within cultured human macrophages.

Pyrazinamide (PZA) is a unique antituberculosis drug because it is effective in vivo but not in mediums commonly used to culture tubercle bacilli. Consequently, it was employed to test the validity of an in vitro macrophage model of human tuberculosis for value as a correlate of clinical events. The drug was as active in the macrophage model as it was clinically, inhibiting virulent tubercle bacilli at concentrations at 20 micrograms/ml or higher. By contrast, it was ineffective in 7H9 bacteriologic culture medium, even at concentrations as high as 2,560 micrograms/ml. It could be either bacteriostatic or bactericidal against intramacrophage tubercle bacilli, depending on its concentration, the donor of the macrophages, and the length of exposure of the infected macrophages to the drug. The data presented suggest that the clinical effectiveness of PZA is determined by a complicated self-modulating sequence of interactions between it, tubercle bacilli, and host macrophages. Specific evidence was found that tubercle bacilli may replicate within human macrophages in non-acid-fast form, thus indicating that colony-forming unit counts are inherently more accurate than acid-fast bacilli counts in these experiments, and also suggesting that important changes in bacillary cell wall composition may occur among tubercle bacilli within infected human macrophages.

Adult↗

PubMed1986

Pyrazinamide is not active in vitro against Mycobacterium avium complex.

Strains of M. tuberculosis that elaborate pyrazinamidase are typically susceptible in vitro and in vivo to pyrazinamide (PZA). However, we found that 33 strains of M. avium complex (MAC), all of which were pyrazinamidase-positive, were resistant in vitro to a high concentration (100 micrograms/ml) of PZA when tested at low pH in 7H12 broth by radiometric (BACTEC) method. The drug was equally ineffective against these bacteria within cultured normal human macrophages. We conclude that the pyrazinamidase test is not suitable for susceptibility studies against M. avium complex. On the basis of our in vitro studies, which support earlier data, we believe that PZA is not appropriate for therapy of MAC disease.

Amidohydrolases↗

PubMed2002

Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis.

An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0-8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0-11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.

Adolescent↗

PubMed2001

The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis.

Multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have emerged worldwide. In many countries and regions, these resistant strains constitute a serious threat to the efficacy of tuberculosis control programs. An important element in gaining control of this epidemic is developing an understanding of the molecular basis of resistance to the most important antituberculosis drugs: isoniazid, rifampin, and pyrazinamide. On the basis of this information, more exacting laboratory testing, and ultimately more appropriate and timely treatment regimens, can be developed.

Antibiotics, Antitubercular↗

PubMed2006

Terminalia chebula (fruit) prevents liver toxicity caused by sub-chronic administration of rifampicin, isoniazid and pyrazinamide in combination.

Terminalia chebula Gertn. (Combetraceae) is an important herbal drug in Ayurvedic pharmacopea. In the present study, a 95% ethanolic extract of T. chebula (fruit) (TC extract), which was chemically characterized on the basis of chebuloside II as a marker, was investigated for hepatoprotective activity against anti-tuberculosis (anti-TB) drug-induced toxicity. TC extract was found to prevent the hepatotoxicity caused by the administration of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (in combination) in a sub-chronic mode (12 weeks). The hepatoprotective effect of TC extract could be attributed to its prominent anti-oxidative and membrane stabilizing activities. The changes in biochemical observations were supported by histological profile.

Animals↗

PubMed1997

Effects of dietary pyrazinamide on the metabolism of tryptophan to niacin in streptozotocin-diabetic rats.

We investigated the effects of feeding with a diet containing pyrazinamide (PYR) on the metabolism of L-tryptophan (Trp) to nicotinamide in streptozotocin (STZ)-diabetic rats and whether the diabetic action of STZ is prevented by feeding with the PYR diet, which is known as an inhibitor of aminocarboxymuconate-semialdehyde decarboxylase and poly(ADP)ribose synthetase and therefore, significantly increases the formation of nicotinamide from Trp in normal rats. As was expected, feeding with the PYR diet to the STZ-injected rats caused a significantly increased excretion of nicotinamide and its metabolites like that in normal rats. The body weight increased in the STZ-injected rats fed with the PYR diet, while it was lost in the STZ-injected rats fed with the non-PYR diet. However, the blood glucose level and the urinary excretion of glucose were not improved even when the rats were fed with the PYR diet. Therefore, it was suggested that chronically increasing the formation of nicotinamide from Trp could not completely prevent the STZ-diabetic action.

Animals↗

PubMed2002

Growth-promoting activity of pyrazinoic acid, a putative active compound of antituberculosis drug pyrazinamide, in niacin-deficient rats through the inhibition of ACMSD activity.

We have recently reported that the antituberculosis drug, pyrazinamide (PZA), caused a significant increase in the conversion ratio of tryptophan to niacin in rats. In the present work, we investigated whether or not pyrazinoic acid (POA), a putative metabolite of PZA, increased the conversion ratio of tryptophan to niacin. Weaning rats were fed with a niacin-free and tryptophan-limited diet (negative control diet), or with the negative control diet supplemented with 0.003% nicotinic acid (positive control diet) or 1% POA (test diet) for 27 days. The growth rate was almost same between the groups fed on the positive control diet and the test diet. Dietary POA significantly increased the conversion ratio of tryptophan to niacin. Although POA did not directly inhibit the activity of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), the rate-limiting enzyme in the tryptophan-niacin pathway, liver ACMSD activity was only not detected in the test diet group. These results suggest that a derivative of POA metabolized by rats inhibited the ACMSD activity.

Animals↗

PubMed2001

Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates.

STUDY OBJECTIVES: To determine whether short-course treatment of latent tuberculosis infection (LTBI) with 2 months of rifampin and pyrazinamide (2RZ) is well tolerated and leads to increased treatment completion among jail inmates, a group who may benefit from targeted testing and treatment for LTBI but for whom completion of > or = 6 months of isoniazid treatment is difficult because of the short duration of incarceration. DESIGN: Prospective cohort. SETTING: Large, urban county jail. PATIENTS: All inmates admitted to the Fulton County Jail who had positive tuberculin skin test results, normal findings on chest radiography, and expected duration of incarceration of at least 60 days. INTERVENTION: Inmates were offered 2RZ via daily directly observed therapy for 60 doses as an alternative to isoniazid therapy. MEASUREMENTS AND RESULTS: We measured the completion of 2RZ treatment and toxicity due to 2RZ treatment during incarceration. From December 14, 1998, through December 13, 1999, 1,360 new inmates had positive tuberculin skin test results and normal findings on chest radiography, and 168 new inmates had an expected duration of incarceration of > or = 60 days. One hundred sixty-six inmates (> 99%) were HIV-negative. Eighty-one inmates (48%) completed 60 doses of 2RZ treatment while incarcerated. Seventy-four inmates (44%) were released before completion. Treatment was stopped in 1 inmate (< 1%) for asymptomatic elevation of asparginine aminotransferase (> or = 10 times normal) and in 12 inmates (7%) for minor complaints. Twenty-one inmates had completed isoniazid treatment in the year before the availability of 2RZ, and 9 inmates completed isoniazid treatment in the year during the availability of 2RZ. CONCLUSIONS: 2RZ was acceptable to and well tolerated by inmates, and led to a marked increase in the number of inmates completing treatment of LTBI during incarceration.

Adult↗

PubMed2002

Death associated with rifampin and pyrazinamide 2-month treatment of latent mycobacterium tuberculosis.

We present the case of an elderly patient who died of fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin for his latent tuberculosis. This 2-month course of treatment for latent tuberculosis is one of four options recently recommended by the Centers for Disease Control and Prevention. We discuss the safety of using this two-drug regimen to treat latent tuberculosis in stable elderly patients.

Aged↗

PubMed2002

Short-course rifamycin and pyrazinamide treatment for latent tuberculosis infection in patients with HIV infection: the 2-year experience of a comprehensive community-based program in Broward County, Florida.

OBJECTIVES: To determine the completion rate and tolerability of short-course rifamycin and pyrazinamide treatment of latent tuberculosis infection (LTBI) in HIV-infected patients through a comprehensive community-based program. DESIGN: Prospective cohort, with comparison to a historical control group. PATIENTS: Of 3,118 patients with HIV infection screened for LTBI between February 1999 and March 2001, 135 patients were placed on rifamycin/pyrazinamide for 2 months under directly observed therapy and were compared to a historical group comprised of 93 HIV-infected patients who were placed on self-administered treatment of isoniazid for 12 months between 1996 and 1998. RESULTS: Of 135 patients receiving rifamycin/pyrazinamide, 124 patients (92%) completed treatment; 5 patients had to discontinue treatment due to side effects (allergic skin reactions [n = 4], hepatitis [n = 1]). The completion rate of the historical group who received isoniazid therapy was 61% (57 of 93 patients; p < 0.001); none of those who received isoniazid experienced significant side effects. CONCLUSION: In our experience, a comprehensive, community-based program of rifamycin/pyrazinamide for LTBI achieved significantly higher adherence than that of traditional isoniazid therapy, and thus may provide improved tuberculosis prevention in a community with high prevalence of HIV-infected patients.

AIDS-Related Opportunistic Infections↗