Subject(s)
Amikacin/pharmacology , Clarithromycin/pharmacology , Erythromycin/pharmacology , Ketolides , Nocardia/drug effects , Drug Resistance, Bacterial , Erythromycin/analogs & derivatives , Humans , Microbial Sensitivity Tests , Nocardia/classification , Sampling Studies , Sensitivity and SpecificityABSTRACT
Superoxide dismutase (SOD) is a ubiquitous metalloenzyme in aerobic organisms that catalyzes the conversion of superoxide anion to hydrogen peroxide. Mycobacterium tuberculosis is unusual in that it secretes large quantities of iron-cofactored SOD. To determine the role of SOD in pathogenesis, we constructed mutants of M. tuberculosis H37Rv with reduced SOD production. Compared with controls, SOD-diminished isolates were more susceptible to killing by hydrogen peroxide. The isolates were markedly attenuated, exhibiting nearly 100,000-fold fewer bacilli than virulent control strains in the lungs and spleens of C57BL/6 mice 4 wk after intravenous inoculation. In the lung, SOD-attenuated M. tuberculosis induced robust interstitial mononuclear cell infiltration within 24 h and many cells were apoptotic by TUNEL staining, whereas virulent H37Rv exhibited minimal early inflammatory response and only rare interstitial mononuclear cell apoptosis. During prolonged infections, C57BL/6 mice tolerated SOD-attenuated M. tuberculosis better than BCG, exhibiting 68% greater weight gain, quicker eradication of bacilli from the spleen, and less alveolar lung infiltration. These results establish the importance of SOD in the pathogenesis of tuberculosis. Its effect appears to be mediated in part by inhibiting innate host immune responses, including early mononuclear cell infiltration of infected tissues and apoptosis.
Subject(s)
Mycobacterium tuberculosis/pathogenicity , Superoxide Dismutase/biosynthesis , Animals , Apoptosis , Bacterial Proteins/genetics , Female , Iron , Lung/pathology , Mice , Mice, Inbred C57BL , Mycobacterium bovis/pathogenicity , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics , Superoxide Dismutase/genetics , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , VirulenceABSTRACT
The newer rifamycin, rifalazil (RLZ) (previously known as KRM-1648), has been shown in prior experiments to be a highly potent drug against Mycobacterium tuberculosis. In this report, we studied the efficacy of RLZ in combination with pyrazinamide (PZA) and ethambutol (EMB) in a long-term in vivo experiment and compared their activity with the isoniazid (INH)-rifampin (RIF) combination which is presently used in the clinic. Combinations of RLZ with PZA alone or with both PZA and EMB were both found to have sterilizing activities comparable to that of the INH-RIF combination but significantly better activity with respect to relapse of infection. These results suggest that RLZ, or other agents with similar activity, could be combined with available agents to act as a potential alternative drug regimen to the currently used INH-RIF combination.
Subject(s)
Antitubercular Agents/therapeutic use , Rifamycins/therapeutic use , Tuberculosis/drug therapy , Animals , Colony-Forming Units Assay , Disease Models, Animal , Drug Therapy, Combination , Ethambutol/therapeutic use , Female , Isoniazid/therapeutic use , Mice , Pyrazinamide/therapeutic use , Rifampin/therapeutic useABSTRACT
ABT-773, a new ketolide antimicrobial agent, was evaluated in comparison to clarithromycin (CLA) in vitro against Mycobacterium avium complex (MAC) and in a beige mouse model of disseminated MAC infection. The MICs at which 50 and 90% of the isolates tested were inhibited were 2 and 4 microg/ml, respectively, for CLA and 8 and 16 microg/ml, respectively, for ABT-773. Eight CLA-resistant isolates were found to be resistant to ABT-773 (MICs > 64 microg/ml). In the in vivo study mice were treated with ABT-773 (50, 100, and 200 mg/kg of body weight) or CLA (200 mg/kg). Both ABT-773 (100 and 200 mg/kg) and CLA significantly decreased the viable cell counts in spleens and lungs. ABT-773 (200 mg/kg) and CLA had similar activities in lungs, but the former was more active in spleens.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Clarithromycin/therapeutic use , Erythromycin/analogs & derivatives , Ketolides , Mycobacterium avium Complex , Mycobacterium avium-intracellulare Infection/drug therapy , Animals , Cell Count , Erythromycin/pharmacology , Lung/microbiology , Mice , Microbial Sensitivity Tests , Mycobacterium avium-intracellulare Infection/microbiology , Spleen/microbiologyABSTRACT
Rifalazil (formerly known as KRM-1648) in combination with isoniazid has been found to be more active than rifampin/isoniazid. Administration of rifalazil/isoniazid for 12 weeks resulted in continued apparent sterilization of organs 6 months after cessation of therapy. In this study we evaluated the durability of rifalazil/isoniazid treatment. Female CD-1 mice were infected with Mycobacterium tuberculosis ATCC 35801 (strain Erdman). Rifalazil and isoniazid were given in combination for 6 and 12 weeks; no mycobacteria could be cultured from spleens and lungs at both the 6-week and 12-week time points. After completing treatment, groups of mice treated with rifalazil/isoniazid for 6 or 12 weeks were observed without any additional treatment. These observation groups were compared to groups of rifalazil/isoniazid-treated mice (6 and 12 weeks) given dexamethasone for 7 and 8 weeks, respectively. Modest regrowth was noted in the spleens and lungs of the group treated with rifalazil/isoniazid for 6 weeks. Regrowth in the 6-weeks group was enhanced slightly by treatment with dexamethasone. In contrast, no regrowth was noted in the 12-weeks rifalazil/isoniazid group, and treatment with dexamethasone did not result in any regrowth.
Subject(s)
Antitubercular Agents/therapeutic use , Isoniazid/therapeutic use , Mycobacterium tuberculosis/drug effects , Rifamycins/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Animals , Colony Count, Microbial , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Disease Models, Animal , Drug Therapy, Combination , Female , Glucocorticoids/administration & dosage , Glucocorticoids/pharmacology , Humans , Lung/microbiology , Mice , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/isolation & purification , Spleen/microbiology , Treatment OutcomeABSTRACT
Previous experiments with rifalazil (RLZ) (also known as KRM-1648) in combination with isoniazid (INH) demonstrated its potential for short-course treatment of Mycobacterium tuberculosis infection. In this study we investigated the minimum RLZ-INH treatment time required to eradicate M. tuberculosis in a murine model. RLZ-INH treatment for 6 weeks or longer led to a nonculturable state. Groups of mice treated in parallel were killed following an observation period to evaluate regrowth. RLZ-INH treatment for a minimum of 10 weeks was necessary to maintain a nonculturable state through the observation period. Pyrazinamide (PZA) was added to this regimen to determine whether the treatment duration could be further reduced. In this model, the addition of PZA did not shorten the duration of RLZ-INH treatment required to eradicate M. tuberculosis from mice. The addition of PZA reduced the number of mice in which regrowth occurred, although the reduction was not statistically significant.
Subject(s)
Antibiotics, Antitubercular/therapeutic use , Rifamycins/therapeutic use , Tuberculosis/drug therapy , Animals , Antibiotics, Antitubercular/pharmacology , Mice , Rifamycins/pharmacologyABSTRACT
This multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1. 5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.
Subject(s)
AIDS-Related Opportunistic Infections/drug therapy , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Mycobacterium avium-intracellulare Infection/drug therapy , AIDS-Related Opportunistic Infections/microbiology , Adult , Female , Humans , Male , Middle Aged , Mycobacterium avium , Mycobacterium avium-intracellulare Infection/blood , Mycobacterium avium-intracellulare Infection/microbiologyABSTRACT
The use of isoniazid (INH) for the treatment of INH-resistant Mycobacterium tuberculosis infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptible M. tuberculosis Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body weight) was more effective than standard-dose INH (25 mg/kg) for therapy of tuberculosis infections caused by INH-resistant mutants of M. tuberculosis Erdman. Six-week-old CD-1 mice were infected with approximately 10(7) viable mycobacteria. Early control groups of infected but untreated mice were euthanized by CO(2) inhalation 1 week later when treatment was initiated. INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week for 4 weeks. Late control groups of untreated mice and treated mice were sacrificed 2 days after the last dose of drug. Spleens and right lungs were removed aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates. In the next study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic mutant of M. tuberculosis Erdman (INH MIC, 2 microg/ml) and the parent strain. This mutant was found to have a mutation in the KatG protein (Phe to Leu at position 183). In the first study, there was no dose response with increasing doses of INH. In the second study, there was no significant difference between the reduction of viable cell counts for mice treated with INH at 100 mg/kg and that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant). These preliminary results suggest that INH may be useful in combination therapy of M. tuberculosis infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 microg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose.
Subject(s)
Antitubercular Agents/therapeutic use , Isoniazid/therapeutic use , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Tuberculosis/drug therapy , Animals , Culture Media , Dose-Response Relationship, Drug , Drug Resistance, Microbial , Female , Genes, Bacterial/genetics , Isoniazid/pharmacology , Lung/microbiology , Mice , Microbial Sensitivity Tests , Spleen/microbiology , Tuberculosis/microbiologyABSTRACT
Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.
Subject(s)
Antitubercular Agents/therapeutic use , Rifampin/analogs & derivatives , Tuberculosis/drug therapy , Animals , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Evaluation Studies as Topic , Female , Isoniazid/therapeutic use , Mice , Mycobacterium tuberculosis/drug effects , Pyrazinamide/therapeutic use , Rifampin/administration & dosage , Rifampin/therapeutic use , Rifamycins/therapeutic useABSTRACT
The activities of linezolid, eperezolid, and PNU-100480 were evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old outbred CD-1 mice. In the first study, treatment was started 1 day postinfection and was given by gavage for 4 weeks. Viable cell counts were determined from homogenates of spleens and lungs. PNU-100480 was as active as isoniazid. Linezolid was somewhat less active than PNU-100480 and isoniazid. Eperezolid had little activity in this model. In the next two studies, treatment was started 1 week postinfection. A dose-response study was performed with PNU-100480 and linezolid (both at 25, 50, and 100 mg/kg of body weight). PNU-100480 was more active than linezolid, and its efficacy increased with an escalation of the dose. Subsequently, the activity of PNU-100480 alone and in combination with rifampin or isoniazid was evaluated and was compared to that of isoniazid-rifampin. The activity of PNU-100480 was similar to that of isoniazid and/or rifampin in the various combinations tested. Further evaluation of these oxazolidinones in the murine test system would be useful prior to the development of clinical studies with humans.
Subject(s)
Acetamides/pharmacology , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Oxazoles/pharmacology , Oxazolidinones , Tuberculosis/drug therapy , Acetamides/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Antitubercular Agents/therapeutic use , Female , Linezolid , Mice , Oxazoles/therapeutic useABSTRACT
Three recently synthesized dihydrofolate reductase (DHFR) inhibitors designated SoRI 8890, 8895, and 8897 were evaluated for their in vitro activities against 25 isolates of Mycobacterium avium complex. The MICs at which 50 and 90% of isolates were inhibited were 1 and 2, 4 and 8, and 4 and 8 microgram/ml for SoRI 8890, 8895, and 8897, respectively. Although the addition of dapsone at 0.5 microgram/ml did not significantly enhance the in vitro activities of these compounds, their activities alone were comparable to, if not better than, results seen with other DHFR inhibitors, such as pyrimethamine or WR99210.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Folic Acid Antagonists/pharmacology , Mycobacterium avium Complex/drug effects , Pyrimidines/pharmacology , Microbial Sensitivity Tests , Mycobacterium avium Complex/isolation & purificationABSTRACT
5-Chloropyrazinamide and 5-chloropyrazinoic acid were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium bovis, and several nontuberculous mycobacteria by a broth dilution method. 5-Chloropyrazinamide was more active than pyrazinamide against all organisms tested. It is likely that this agent has a different mechanism of action than pyrazinamide.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium bovis/drug effects , Mycobacterium tuberculosis/drug effects , Pyrazinamide/analogs & derivatives , Pyrazinamide/pharmacology , Microbial Sensitivity TestsSubject(s)
Tinea/microbiology , Trichophyton/pathogenicity , Administration, Oral , Administration, Topical , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/therapeutic use , Erythromycin/therapeutic use , Humans , Ketoconazole/therapeutic use , Male , Middle Aged , Tinea/drug therapy , Trichophyton/isolation & purificationABSTRACT
Mycobacterium tuberculosis strains resistant to two or more of the first line antituberculosis drugs (MDR) are a serious threat to successful tuberculosis control programmes. For this retrospective study, 85 follow-up drug resistant isolates from 23 patients residing in a community with a high incidence of tuberculosis were collected and the level of in-vitro resistance to antibiotics determined quantitatively. PCR-SSCP and sequencing techniques were used to screen for gene mutations associated with resistance in 31 follow-up samples from a smaller group of eight patients. DNA fingerprint analysis was done on sequential isolates to confirm identity. Although treatment had a profound effect on changes in drug resistance patterns, the MIC for a particular agent remained constant in follow-up isolates. DNA fingerprinting and mutational analysis (14 different loci) showed that the genome of MDR strains of M. tuberculosis is relatively stable during the course of therapy. The rpoB gene was the most frequently mutated structural gene involved in drug resistance and a novel C to T mutation upstream of open reading frame (ORF)1 of the inhA operon was detected. No evidence was found of the presence of strain W (New York) in this group of MDR strains. The results stress the importance of confirming individuality of strains for the accurate calculation of frequencies of particular mutations associated with drug resistance, particularly in a high incidence area. Approximately one-half (47.8%) of the patients had isolates resistant to concentrations just above the critical concentration for isoniazid (MICs of 0.2-5 mg/L). Therefore, these patients and their contacts who develop primary drug-resistant tuberculosis may respond to higher dosages of treatment which could have a considerable impact on the cost and the ease of management of resistant tuberculosis.
Subject(s)
Antitubercular Agents/therapeutic use , Drug Resistance, Multiple/genetics , Isoniazid/therapeutic use , Mycobacterium tuberculosis/genetics , Tuberculosis, Pulmonary/drug therapy , Catalase/analysis , DNA Fingerprinting , Drug Resistance, Microbial/genetics , Follow-Up Studies , Genetic Variation , Humans , Microbial Sensitivity Tests , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Retrospective Studies , Sequence Analysis, DNA , South Africa/epidemiology , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/microbiologyABSTRACT
WR99210, a dihydrofolate reductase inhibitor, has promising in vitro activity against Mycobacterium avium complex (MAC). The in vitro activities of WR99210 alone and in combination with a fixed concentration of dapsone (0.5 microgram/ml) were evaluated against 35 clinical MAC isolates by a broth dilution method. The MIC at which 50% of isolates were inhibited (MIC50) and MIC90 of WR99210 alone were 2 and 8 micrograms/ml, respectively. The MIC50 and MIC90 of WR99210 in combination with dapsone were 0.25 and 4 micrograms/ml, respectively. Overall, 75% of the MAC isolates displayed enhanced susceptibility to the combination.
Subject(s)
Anti-Bacterial Agents/pharmacology , Dapsone/pharmacology , Mycobacterium avium Complex/drug effects , Triazines/pharmacology , Drug Synergism , Humans , Microbial Sensitivity Tests , Mycobacterium avium Complex/enzymologyABSTRACT
The in vitro activities of pyrimethamine and dapsone alone and in combination were evaluated against 23 clinical isolates of Mycobacterium avium complex. The broth dilution MICs of dapsone and pyrimethamine alone ranged from 16 to > 64 micrograms/ml. Pyrimethamine in combination with a fixed concentration of dapsone at 0.5 microgram/ml showed enhanced activity, with an MIC range of 0.5 to 16 micrograms/ml.
Subject(s)
Anti-Bacterial Agents/pharmacology , Dapsone/pharmacology , Mycobacterium avium Complex/drug effects , Pyrimethamine/pharmacology , Drug Combinations , Drug Synergism , Humans , Microbial Sensitivity Tests , Mycobacterium avium-intracellulare Infection/microbiologyABSTRACT
Substituted pyrazinoic acid esters have previously been reported to have in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as Mycobacterium tuberculosis. Modification of both the pyrazine nucleus and the ester functionality was successful in expanding the antimycobacterial activity associated with pyrazinamide to include M. avium and M. kansasii, organisms usually not susceptible to pyrazinamide. In an attempt to understand the relationship between the activity of the esters with the needed biostability, a quantitative structure-activity relationship has been developed. This derived relationship is consistent with the observation that tert-butyl 5-chloropyrazinoate (13) and 2'-(2'-methyldecyl) 5-chloropyrazinoate (25), compounds which are both 100-fold more active than pyrazinamide against M. tuberculosis and possess a serum stability 900-1000 times greater than the lead compounds in the series.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Mycobacterium/drug effects , Pyrazinamide/analogs & derivatives , Pyrazinamide/pharmacology , AIDS-Related Opportunistic Infections/microbiology , Anti-Bacterial Agents/chemical synthesis , Esters , Humans , Microbial Sensitivity Tests , Mycobacterium/isolation & purification , Mycobacterium Infections/microbiology , Mycobacterium avium/drug effects , Mycobacterium avium/isolation & purification , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/isolation & purification , Pyrazinamide/chemical synthesis , Pyrazinamide/chemistry , Structure-Activity Relationship , Tuberculosis/microbiologyABSTRACT
During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Mycobacterium avium/drug effects , Mycobacterium tuberculosis/drug effects , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Acetamides/pharmacokinetics , Animals , Anti-Bacterial Agents/pharmacokinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Oxazoles/pharmacokinetics , RatsABSTRACT
The activity of KRM-1648, alone and in combination with isoniazid, was compared with those of isoniazid, rifampin, and the combination of rifampin plus isoniazid in a murine model of tuberculosis. Four-week-old female CD-1 mice were infected intravenously with approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms. Treatment was started 1 week postinfection and was given by gavage 5 days per week. The duration of the treatment phase was 12 weeks, with groups of mice sacrificed at 2, 4, 6, 8, and 12 weeks. For the observation phase, additional groups of treated mice were sacrificed at 4, 8, 16, and 24 weeks after the cessation of treatment. Viable cell counts were determined from homogenates of the spleens and the right lungs. KRM-1648 was the most active single agent evaluated and resulted in no detectable CFUs in the spleens and lungs by the end of 6 weeks of treatment. Neither rifampin nor isoniazid reduced cell counts to undetectable levels, even after 12 weeks of treatment. The combination of KRM-1648 plus isoniazid was much more active than rifampin plus isoniazid. KRM-1648 plus isoniazid resulted in the apparent sterilization of organs at 6 months following the cessation of treatment. The promising activity of KRM-1648 may allow for ultrashort-course therapy of tuberculosis, i.e., treatment regimens of 4 months or less.
Subject(s)
Antibiotics, Antitubercular/administration & dosage , Isoniazid/administration & dosage , Mycobacterium tuberculosis/drug effects , Rifamycins/administration & dosage , Tuberculosis/drug therapy , Animals , Colony Count, Microbial , Drug Therapy, Combination , Female , Lung/microbiology , Mice , Mycobacterium tuberculosis/growth & development , Rifampin/therapeutic use , Spleen/microbiology , Time FactorsABSTRACT
The activity of pyrazinamide (PZA) against eight isolates of Mycobacterium tuberculosis in a murine infection model was evaluated. M. tuberculosis isolates with various degrees of in vitro susceptibility to PZA (MIC range, 32 to > 2,048 micrograms/ml) were used. Four-week-old female mice were infected intravenously with approximately 10(7) viable M. tuberculosis organisms. PZA at 150 mg/kg of body weight was started 1 day postinfection and given 5 days/week for 4 weeks. Infected but untreated mice were compared with PZA-treated mice. Mice were sacrificed at the completion of the treatment period, and viable cell counts were determined from homogenates of spleens and right lungs. PZA had activity in the murine test system against M. tuberculosis isolates for which the MICs were < or = 256 micrograms/ml. However, there was an inconsistent correlation between the absolute MICs and the reductions in organ viable cell counts. Studies with drug-resistant M. tuberculosis isolates with an isogenic background would improve evaluation of drug efficacy in the murine test system. Further evaluation of antimycobacterial agents against monodrug-resistant isolates will provide data that will be useful for development of algorithms for treatment of infection with drug-resistant organisms.