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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

Time to footpad swelling.Post infection time to foot pad swelling in mice treated with either rifampin (RIF) or rifapentine (RPT) containing regimens for one week, two weeks, three weeks or four weeks. Untreated controls are shown in black squares, streptomycin (STR) + rifampin (RIF) for 5 days a week (5/7) in blue circles, STR+RIF for 7 days a week (7/7) in green triangles and STR+ rifapentine (RPT) (5/7) is in red asterisk.
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pntd-0002085-g002: Time to footpad swelling.Post infection time to foot pad swelling in mice treated with either rifampin (RIF) or rifapentine (RPT) containing regimens for one week, two weeks, three weeks or four weeks. Untreated controls are shown in black squares, streptomycin (STR) + rifampin (RIF) for 5 days a week (5/7) in blue circles, STR+RIF for 7 days a week (7/7) in green triangles and STR+ rifapentine (RPT) (5/7) is in red asterisk.

Mentions: The time to foot pad swelling after cessation of treatment with each of the different regimens given for 1, 2, 3, and 4 weeks is depicted in figure 2. This figure illustrates several important and rather unexpected findings. First, more than 50% (median) of untreated control mice exhibited foot pad swelling by week 6 after infection, providing the reference to which median time to swelling in treated mice were compared. Second, in all treated mice whatever the drug regimen and the duration of treatment, the median time to foot pad swelling was considerably delayed, by at least 12 weeks, compared to that in the untreated controls This finding reflects the potent bactericidal activity and/or the post-antibiotic effect of the tested drug regimens, even when they were administered for one week only. Third, as shown in figure 2, the longer the duration of treatment, the longer the time to swelling and the lower the proportion of mice that developed swelling during the 40 weeks of the experiment. The median times to swelling in mice treated for one and two weeks were 18 weeks and 20–22 weeks, respectively, indicating that a 2-week course of treatment was insufficient to prevent reactivation of the disease after treatment cessation. However, only 30 to 40% of mice treated for 3 weeks exhibited foot pad swelling at week 40, indicating that a treatment of 3 weeks duration was enough to cure more than half of the infected mice. Only a few mice treated for 4 weeks whatever the drug regimens exhibited foot pad swelling between weeks 25 to 30, suggesting that a treatment of 4 weeks duration is able to cure close to 100% of mice. Finally, and most surprisingly, none of the drug regimens tested over a period of 1 to 4 weeks was significantly better than the others in preventing foot pad swelling, e.g. reactivation of the disease. In other words, in the current experimental conditions, the RPT-containing regimen did not result in a higher rate of relapse-free cure than the RIF-containing regimens despite its much better bactericidal activity. It should also be noticed that the relapse-free cure rate was not better in mice receiving the STR+RIF regimen given 7/7 than in mice receiving the same regimen given 5/7.


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)

Time to footpad swelling.Post infection time to foot pad swelling in mice treated with either rifampin (RIF) or rifapentine (RPT) containing regimens for one week, two weeks, three weeks or four weeks. Untreated controls are shown in black squares, streptomycin (STR) + rifampin (RIF) for 5 days a week (5/7) in blue circles, STR+RIF for 7 days a week (7/7) in green triangles and STR+ rifapentine (RPT) (5/7) is in red asterisk.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0002085-g002: Time to footpad swelling.Post infection time to foot pad swelling in mice treated with either rifampin (RIF) or rifapentine (RPT) containing regimens for one week, two weeks, three weeks or four weeks. Untreated controls are shown in black squares, streptomycin (STR) + rifampin (RIF) for 5 days a week (5/7) in blue circles, STR+RIF for 7 days a week (7/7) in green triangles and STR+ rifapentine (RPT) (5/7) is in red asterisk.
Mentions: The time to foot pad swelling after cessation of treatment with each of the different regimens given for 1, 2, 3, and 4 weeks is depicted in figure 2. This figure illustrates several important and rather unexpected findings. First, more than 50% (median) of untreated control mice exhibited foot pad swelling by week 6 after infection, providing the reference to which median time to swelling in treated mice were compared. Second, in all treated mice whatever the drug regimen and the duration of treatment, the median time to foot pad swelling was considerably delayed, by at least 12 weeks, compared to that in the untreated controls This finding reflects the potent bactericidal activity and/or the post-antibiotic effect of the tested drug regimens, even when they were administered for one week only. Third, as shown in figure 2, the longer the duration of treatment, the longer the time to swelling and the lower the proportion of mice that developed swelling during the 40 weeks of the experiment. The median times to swelling in mice treated for one and two weeks were 18 weeks and 20–22 weeks, respectively, indicating that a 2-week course of treatment was insufficient to prevent reactivation of the disease after treatment cessation. However, only 30 to 40% of mice treated for 3 weeks exhibited foot pad swelling at week 40, indicating that a treatment of 3 weeks duration was enough to cure more than half of the infected mice. Only a few mice treated for 4 weeks whatever the drug regimens exhibited foot pad swelling between weeks 25 to 30, suggesting that a treatment of 4 weeks duration is able to cure close to 100% of mice. Finally, and most surprisingly, none of the drug regimens tested over a period of 1 to 4 weeks was significantly better than the others in preventing foot pad swelling, e.g. reactivation of the disease. In other words, in the current experimental conditions, the RPT-containing regimen did not result in a higher rate of relapse-free cure than the RIF-containing regimens despite its much better bactericidal activity. It should also be noticed that the relapse-free cure rate was not better in mice receiving the STR+RIF regimen given 7/7 than in mice receiving the same regimen given 5/7.

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