Activities of Several Novel Oxazolidinones againstMycobacterium tuberculosis in a Murine Model

ABSTRACT The activities of linezolid, eperezolid, and PNU-100480 were evaluated in a murine model of tuberculosis. Approximately 107 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.

Download Full-text

Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.14 ◽

1996 ◽

Vol 40 (1) ◽

pp. 14-16 ◽

Cited By ~ 16

Author(s):

S P Klemens ◽

C A Sharpe ◽

M H Cynamon

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Efficacy ◽

Viable Cell ◽

Test System ◽

Infection Model ◽

Drug Resistant ◽

In Vitro Susceptibility ◽

Cell Counts ◽

Treatment Of Infection

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.

Download Full-text

Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.2.298 ◽

1996 ◽

Vol 40 (2) ◽

pp. 298-301 ◽

Cited By ~ 20

Author(s):

S P Klemens ◽

M H Cynamon

Keyword(s):

Mycobacterium Tuberculosis ◽

Murine Model ◽

Single Agent ◽

Treatment Phase ◽

Viable Cell ◽

Observation Phase ◽

Treatment Regimens ◽

Cell Counts ◽

The Right ◽

Cessation Of Treatment

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.

Download Full-text

High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine Mycobacterium tuberculosis Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.12.2922 ◽

1999 ◽

Vol 43 (12) ◽

pp. 2922-2924 ◽

Cited By ~ 33

Author(s):

M. H. Cynamon ◽

Y. Zhang ◽

T. Harpster ◽

S. Cheng ◽

M. S. DeStefano

Keyword(s):

Mycobacterium Tuberculosis ◽

Dose Response ◽

Standard Dose ◽

Resistant Mutant ◽

Viable Cell ◽

High Dose ◽

Control Groups ◽

Mycobacterium Tuberculosis Infection ◽

Cell Counts ◽

Significant Difference

ABSTRACT The use of isoniazid (INH) for the treatment of INH-resistantMycobacterium tuberculosis infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptibleM. 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. tuberculosisErdman. Six-week-old CD-1 mice were infected with approximately 107 viable mycobacteria. Early control groups of infected but untreated mice were euthanized by CO2 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 μg/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 μg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose.

Download Full-text

Effective Treatment of Acute and Chronic Murine Tuberculosis with Liposome-Encapsulated Clofazimine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.7.1638 ◽

1999 ◽

Vol 43 (7) ◽

pp. 1638-1643 ◽

Cited By ~ 43

Author(s):

Linda B. Adams ◽

Indu Sinha ◽

Scott G. Franzblau ◽

James L. Krahenbuhl ◽

Reeta T. Mehta

Keyword(s):

Body Weight ◽

Mycobacterium Tuberculosis ◽

Effective Treatment ◽

Dose Response ◽

Therapeutic Efficacy ◽

Chronic Infection ◽

Maximum Tolerated Dose ◽

Toxic Effects ◽

Unit Reduction ◽

Higher Doses

ABSTRACT The therapeutic efficacy of liposomal clofazimine (L-CLF) was studied in mice infected with Mycobacterium tuberculosisErdman. Groups of mice were treated with either free clofazimine (F-CLF), L-CLF, or empty liposomes twice a week for five treatments beginning on day 1 (acute), day 21 (established), or day 90 (chronic) postinfection. One day after the last treatment, the numbers of CFU ofM. tuberculosis in the spleen, liver, and lungs were determined. F-CLF at the maximum tolerated dose of 5 mg/kg of body weight was ineffective; however, 10-fold-higher doses of L-CLF demonstrated a dose response with significant CFU reduction in all tissues without any toxic effects. In acutely infected mice, 50 mg of L-CLF/kg reduced CFU 2 to 3 log units in all three organs. In established or chronic infection, treated mice showed no detectable CFU in the spleen or liver and 1- to 2-log-unit reduction in the lungs. A second series of L-CLF treatments cleared M. tuberculosisin all three tissues. L-CLF appears to be bactericidal in the liver and spleen, which remained negative for M. tuberculosis growth for 2 months. Thus, L-CLF could be useful in the treatment of tuberculosis.

Download Full-text

PSII-18 Greater feed amounts during late gestation do not improve piglets birth weight: a dose-response study performed in gilts

Journal of Animal Science ◽

10.1093/jas/skz122.405 ◽

2019 ◽

Vol 97 (Supplement_2) ◽

pp. 230-231

Author(s):

Andre L Mallmann ◽

Elisar Camilotti ◽

Deivison Fagundes ◽

Carlos Vier ◽

Ana Paula Mellagi ◽

...

Keyword(s):

Body Weight ◽

Birth Weight ◽

Dose Response ◽

Feed Intake ◽

Feeding Strategy ◽

The Body ◽

Late Gestation ◽

Average Birth Weight ◽

Feeding Level ◽

Dose Response Study

Abstract In breeding farms, pork producers commonly use “bump feeding” as a feeding strategy. This technique consists of increasing daily feed amount on late gestation to improve piglets birth weight. A dose-response arrangement with 4 treatments (1.8, 2.3, 2.8, and 3.3 kg/d) was used to evaluate the effects on female reproductive performance and piglet birth weight. A total of 977 gilts were fed based on a corn-soybean meal diet from day 90 of gestation until farrowing. Gilts were weighed on days 90 and 112 of gestation and at weaning. Born alive and stillborn piglets were weighed within 12 h of birth. Colostrum yield and lactation feed intake were measured in a randomly selected sub-sample of 245 gilts. As expected, body weight gains were different at day 112 (P < 0.001) with the highest values observed in 3.3 kg/d treatment. As the feed amount increased during late gestation, greater were the body losses between d 112 and weaning (P < 0.001). Statistical tendencies for a quadratic effect of feeding level were observed for piglets born alive (P = 0.079), average birth weight of piglets (P = 0.083), and litter weight (P = 0.059). However, there were no differences among treatments on total born and mummified fetuses (P > 0.05). Gilts fed with lower feed amounts during late gestation had reduced stillborn percentages compared to those gilts fed with greater amounts. Colostrum yield and voluntary feed intake decreased linearly (P < 0.05) as the feed amount performed during late gestation increased. In conclusion, increasing the feed intake from day 90 of gestation until farrowing increased gilts body weight and stillborn rate, but reduced the colostrum yield and the lactation feed intake. In addition, there were no effects of the feeding level in late gestation on piglets birth weight.

Download Full-text

Efficient Intermittent Rifapentine-Moxifloxacin-Containing Short-Course Regimen for Treatment of Tuberculosis in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4015-4019.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4015-4019 ◽

Cited By ~ 15

Author(s):

N. Veziris ◽

N. Lounis ◽

A. Chauffour ◽

C. Truffot-Pernot ◽

V. Jarlier

Keyword(s):

Body Weight ◽

Mycobacterium Tuberculosis ◽

Relapse Rate ◽

Murine Model ◽

Half Life ◽

Antituberculous Treatment ◽

Short Course ◽

Control Regimen ◽

Intermittent Regimen

ABSTRACT Long-half-life drugs raise the hope of once-a-week administration of antituberculous treatment. In a previous study with the murine model of tuberculosis, the most active intermittent regimen which contained rifapentine (RFP), isoniazid (INH), and moxifloxacin (MXF) given once a week during 5.5 months, preceded by 2 weeks of daily treatment with INH, rifampin (RIF), pyrazinamide (PZA), and MXF, was less active than the standard 6-month daily RIF-INH-PZA regimen. We evaluated with the same model similar regimens in which we increased the dosing of rifapentine from 10 to 15 mg/kg of body weight and of moxifloxacin from 100 to 400 mg/kg. Mice infected intravenously by 6.2 ×106 CFU of Mycobacterium tuberculosis H37Rv were treated 2 weeks later when infection was established. After 6 months of treatment, all mice had negative lung culture. After 3 months of follow-up, no relapse occurred in the two groups that received moxifloxacin at 400 mg/kg, whatever the dosage of RFP, and in the group receiving the standard RIF-INH-PZA control regimen. In contrast, in the two groups receiving moxifloxacin at a lower dosage, the relapse rate was significantly higher (13% in mice receiving RFP at 15 mg/kg and 27% in those receiving RFP at 10 mg/kg). Finally, the fully intermittent once-a-week regimen (26 drug ingestions) of INH, RFP (15 mg/kg), and MXF (400 mg/kg) led to a relapse rate of 11%. In conclusion, when used at high dosage, rifapentine and moxifloxacin are very efficient when combined with isoniazid in a once-a-week treatment in mouse tuberculosis.

Download Full-text

Activity of ABT-773 against Mycobacterium avium Complex in the Beige Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.10.2895-2896.2000 ◽

2000 ◽

Vol 44 (10) ◽

pp. 2895-2896 ◽

Cited By ~ 8

Author(s):

M. H. Cynamon ◽

J. L. Carter ◽

C. M. Shoen

Keyword(s):

Body Weight ◽

Mouse Model ◽

Antimicrobial Agent ◽

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Viable Cell ◽

Beige Mouse ◽

Cell Counts

ABSTRACT 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 μg/ml, respectively, for CLA and 8 and 16 μg/ml, respectively, for ABT-773. Eight CLA-resistant isolates were found to be resistant to ABT-773 (MICs > 64 μg/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.

Download Full-text