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Bactericidal activity does not predict sterilizing activity: the case of rifapentine in the murine model of Mycobacterium ulcerans disease.

Almeida DV, Converse PJ, Li SY, Tyagi S, Nuermberger EL, Grosset JH - PLoS Negl Trop Dis (2013)

Bottom Line: The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity.In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF.

Methodology/principal findings: BALB/c mice were infected with M. ulcerans in the right hind footpad and treated either daily (7/7) with STR+RIF or five days/week (5/7) with STR+RIF or STR+RPT for 4 weeks, beginning 28 days after infection when CFU counts were 4.88±0.51. The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity. All drug treatments were bactericidal. After 1 week of treatment, the decline in CFU counts was significantly greater in treated mice but not different between the three treated groups. After 2 weeks of treatment, the decline in CFU was greater in mice treated with STR+RPT 5/7 than in mice treated with STR+RIF 7/7 and STR+RIF 5/7. After 3 and 4 weeks of treatment, CFU counts were nil in mice treated with STR+RPT and reduced by more than 3 and 4 logs in mice treated with STR+RIF 5/7 and STR+RIF 7/7, respectively. In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.

Conclusions/significance: The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

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Related in: MedlinePlus

Decrease in log10 CFU counts in footpads.Decrease in the log10 CFU counts in the footpads of mice treated with, streptomycin+ rifampin for 5 days a week (STR+RIF 5/7), STR+RIF for 7 days a week (STR+RIF 7/7) and STR+ rifapentine (RPT) (STR+RPT 5/7) compared to untreated controls. The day after infection counts are shown at −25 (Mice were infected at D-26) and treatment was started after 25 days (D0).
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pntd-0002085-g001: Decrease in log10 CFU counts in footpads.Decrease in the log10 CFU counts in the footpads of mice treated with, streptomycin+ rifampin for 5 days a week (STR+RIF 5/7), STR+RIF for 7 days a week (STR+RIF 7/7) and STR+ rifapentine (RPT) (STR+RPT 5/7) compared to untreated controls. The day after infection counts are shown at −25 (Mice were infected at D-26) and treatment was started after 25 days (D0).

Mentions: The CFU counts by D-27, the day after infection, and by D0, the day on treatment initiation, and after 1, 2, 3, and 4 weeks of treatment are given in table 2 and figure 1.


Bactericidal activity does not predict sterilizing activity: the case of rifapentine in the murine model of Mycobacterium ulcerans disease.

Almeida DV, Converse PJ, Li SY, Tyagi S, Nuermberger EL, Grosset JH - PLoS Negl Trop Dis (2013)

Decrease in log10 CFU counts in footpads.Decrease in the log10 CFU counts in the footpads of mice treated with, streptomycin+ rifampin for 5 days a week (STR+RIF 5/7), STR+RIF for 7 days a week (STR+RIF 7/7) and STR+ rifapentine (RPT) (STR+RPT 5/7) compared to untreated controls. The day after infection counts are shown at −25 (Mice were infected at D-26) and treatment was started after 25 days (D0).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585034&req=5

pntd-0002085-g001: Decrease in log10 CFU counts in footpads.Decrease in the log10 CFU counts in the footpads of mice treated with, streptomycin+ rifampin for 5 days a week (STR+RIF 5/7), STR+RIF for 7 days a week (STR+RIF 7/7) and STR+ rifapentine (RPT) (STR+RPT 5/7) compared to untreated controls. The day after infection counts are shown at −25 (Mice were infected at D-26) and treatment was started after 25 days (D0).
Mentions: The CFU counts by D-27, the day after infection, and by D0, the day on treatment initiation, and after 1, 2, 3, and 4 weeks of treatment are given in table 2 and figure 1.

Bottom Line: The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity.In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF.

Methodology/principal findings: BALB/c mice were infected with M. ulcerans in the right hind footpad and treated either daily (7/7) with STR+RIF or five days/week (5/7) with STR+RIF or STR+RPT for 4 weeks, beginning 28 days after infection when CFU counts were 4.88±0.51. The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity. All drug treatments were bactericidal. After 1 week of treatment, the decline in CFU counts was significantly greater in treated mice but not different between the three treated groups. After 2 weeks of treatment, the decline in CFU was greater in mice treated with STR+RPT 5/7 than in mice treated with STR+RIF 7/7 and STR+RIF 5/7. After 3 and 4 weeks of treatment, CFU counts were nil in mice treated with STR+RPT and reduced by more than 3 and 4 logs in mice treated with STR+RIF 5/7 and STR+RIF 7/7, respectively. In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.

Conclusions/significance: The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

Show MeSH
Related in: MedlinePlus