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Antimicrobial Agents and Chemotherapy, June 2008, p. 1912-1916, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.00193-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Bactericidal and Sterilizing Activities of Several Orally Administered Combined Regimens against Mycobacterium ulcerans in Mice

Bactériologie-Hygiène, UPMC Universite Paris 06, EA 1541, F-75005, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, F-75651, Paris, France¹

Received 11 February 2008/ Returned for modification 14 March 2008/ Accepted 24 March 2008

	ABSTRACT

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Treatment with rifampin-clarithromycin or moxifloxacin-clarithromycin for 8 weeks displayed promising bactericidal activity against Mycobacterium ulcerans in mice; none of the mice treated with rifampin-clarithromycin relapsed, whereas 59% of those treated with moxifloxacin-clarithromycin relapsed after treatment was stopped. The bactericidal and sterilizing activities of the five-times-weekly (5/7) administration of 5 mg of rifapentine/kg of body weight, either alone or in combination, were virtually identical to those of the corresponding regimens with 10 mg of rifampin/kg of body weight; however, because of the long half-life of rifapentine, accumulation of the drug after 5/7 administration is a concern. The bactericidal activity of 20 mg/kg rifapentine in monotherapy or 20 mg/kg rifapentine in combination with 150 mg/kg streptomycin or 200 mg/kg moxifloxacin administered twice weekly was as effective as the corresponding regimens containing 10 mg/kg rifampin administered 5/7, suggesting that Buruli ulcer might be treated with intermittently administered rifapentine-containing combinations.

	INTRODUCTION

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The combination of rifampin (RIF) and streptomycin (STR), currently the only drug regimen employed for treatment of Buruli ulcer (Mycobacterium ulcerans disease) in man (17), is highly effective, well tolerated, and of low cost (4, 5). This regimen represents a major breakthrough in treatment of Buruli ulcer. However, because of weak health infrastructures, ambulatory treatment requiring daily intramuscular injections of STR for 8 weeks is operationally demanding in most countries where Buruli ulcer is endemic, especially rural Africa. In addition, the administration of drugs by injection carries the risk of transmitting blood-borne viral infections. Thus, effective, patient-friendly, and orally administered combined regimens that would greatly simplify the treatment of Buruli ulcer under field conditions are urgently needed.

In earlier experiments with mice, we found that the combinations RIF-moxifloxacin (MXF), RIF-clarithromycin (CLR), and MXF-CLR were bactericidal against M. ulcerans in terms of significant reductions of the mean numbers of CFU in the inoculated footpads during treatment, as was RIF-STR, and should be considered as possible alternative, orally administered combined regimens for treatment of Buruli ulcer in humans (7, 8). However, these earlier experiments did not examine whether the combinations RIF-CLR and MXF-CLR were as capable of sterilizing the infection, i.e., killing the few, slowly metabolizing organisms that survived the initial bactericidal activity (measured by determination of the relapse rate after the completion of treatment), as were the combinations RIF-STR and RIF-MXF, which sterilized M. ulcerans infections after 8 weeks of treatment (7, 8). Therefore, we determined the relapse rates among M. ulcerans-infected mice after treatment for 8 weeks with RIF-CLR or MXF-CLR and compared these rates with those after treatment for the same duration with RIF-STR or RIF-MXF as positive controls.

None of these orally administered combined regimens was found to be more active than the combination RIF-STR (7, 8). Because the promising bactericidal activities of all RIF-containing combined regimens have been attributed mainly to their RIF component, new components that display more powerful bactericidal activity against M. ulcerans than RIF should be tested, with the aim of shortening the duration of treatment for Buruli ulcer to significantly less than 8 weeks. One such compound could be rifapentine (RFP), a semisynthetic rifamycin with a cyclopentyl substitution which differs from its parent compound by its long serum half-life, which is four to five times longer than that of RIF in both mice and humans (6, 13). Because the administration of RFP significantly increases rifamycin exposure (13, 14), on a weight-to-weight basis RFP was more bactericidal than RIF against Mycobacterium tuberculosis, and the administration of 5 mg of RFP/kg of body weight six times weekly (6/7) displayed bactericidal activity against M. tuberculosis in mice at a level similar to that of 10 mg/kg RIF administered at the same rhythm (6). Because of its long serum half-life, a RFP-containing combination was developed as a once-weekly regimen for treatment of tuberculosis. However, the rate of treatment failure or relapse after once-weekly treatment with 600 mg RFP plus 900 mg isoniazid was unacceptably high among patients with more severe pulmonary tuberculosis (16). One of the possible explanations for such disappointing results is the very high level (97% to 99%) of protein binding of RFP, which results in a low concentration of biologically active, free RFP at the site of the lesion. Because the activities of rifamycin derivatives are concentration dependent, increasing the dosage or the frequency of RFP administration would increase the concentration of free RFP and hence the antimicrobial activity. Experiments with mice have clearly demonstrated that (i) rifamycin exposure is substantially higher after 5/7 or 7/7 administration of RFP at a dosage of 7.5 to 10 mg/kg or 2/7 or 3/7 administration of RFP at a dosage of 15 to 20 mg/kg than with 5/7 administration of RIF at 10 mg/kg (13, 14); (ii) increasing the dosage of RFP from 10 to 15 or 20 mg/kg significantly increases anti-M. tuberculosis activity (10, 13); and (iii) 3/7 or 5/7 administration of RFP and MXF may shorten the current 6-month duration of treatment of tuberculosis to 3 months or less (14). We compared the bactericidal activities against M. ulcerans in mice of treatment with 5 mg/kg RFP administered 5/7 or 20 mg/kg administered 2/7, either alone or in combination, with 5/7 administration of the corresponding regimens containing RIF as a positive control. Because RIF administered either alone or in combination is less effective in both mice (6) and humans (3) when the standard dosage of 10 mg/kg (or 600 mg in humans) is administered 2/7 or 3/7 than when it is administered 6/7 or 7/7, and because immunological toxicity, including an influenza-like syndrome and other adverse effects, is more likely to occur with a 900-mg dose than with a 600-mg dose when RIF is administered intermittently in humans (12), in this study RIF was always administered 5/7 at doses of 10 mg/kg, either alone or in combination.

	MATERIALS AND METHODS

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Antimicrobial agents. RIF was purchased from Gruppo Lepetit (Anagni, Italy), STR from Panpharma (Fougères, France), MXF from Bayer Pharma (Puteaux, France), and CLR from Abbott (Rungis, France). RFP was a gift from Sanofi-Aventis (Gentilly, France).

Infection of mice with M. ulcerans. As in our earlier experiments (7, 8), the left hind footpad of each of 429 4-week-old female BALB/c mice was inoculated subcutaneously with 0.03 ml of a bacterial suspension containing 7.8 x 10⁴ CFU of M. ulcerans isolate CU001.

Treatment of mice. Seven weeks after being infected, by which time all of the mice had developed a lesion index (9) of 2 (i.e., definite inflammatory swelling limited to the inoculated footpad) or 3 (i.e., inflammatory swelling involving the entire inoculated foot), 10 mice were sacrificed for enumeration of CFU in the inoculated footpads to establish the pretreatment value. The remaining 419 mice were randomly allocated among 13 groups: one untreated control group of 9 mice and 12 treated groups of 20 to 60 mice each (Table 1) . Treatment was begun immediately after randomization. RIF, RFP, MXF, and CLR were suspended in 0.05% agar-distilled water, and STR was diluted with normal saline. All antimicrobial agents were administered by gavage, except STR, which was injected subcutaneously. For each treatment, the dosages were as follows: RIF, 10 mg/kg body weight; STR, 150 mg/kg body weight; MXF, 200 mg/kg body weight; and CLR, 100 mg/kg body weight. These dosages were identical to the dosages of the same antimicrobial agents that are effective against other mycobacterial infections in mice. The dosage for RFP was 5 mg/kg for 5/7 administration and 20 mg/kg for 2/7 administration.

Assessment of severity of infection and effectiveness of treatment. The severity of infection and effectiveness of treatment were assessed by the mean number (log₁₀) of CFU per inoculated footpad. The sterilizing activity of the treatment was assessed by measuring the relapse rate for M. ulcerans infections after treatment was stopped.

To enumerate CFU, the tissues of the footpad were removed aseptically at sacrifice and homogenized in Hanks' solution in a final volume of 2 ml. For the untreated controls, the tissue suspensions were serially diluted in 10-fold steps, and 0.1 ml of each of the three appropriate dilutions was plated in triplicate on Löwenstein-Jensen medium. For the treated mice, the entire volume (2 ml) of the undiluted tissue suspension from each footpad was plated on 10 tubes of Löwenstein-Jensen medium. Cultures were examined after 90 days of incubation at 30°C.

To monitor relapses of M. ulcerans infections during the 28-week posttreatment follow-up, the inoculated footpads were examined weekly to observe the evolution of the lesion index, which is scored from 0 to 5. The criteria for scoring the lesion index have been described elsewhere (9). If there was a rebound of the lesion index to 3 in the inoculated footpad, which suggested a possible recurrence of M. ulcerans infection, the affected mouse was sacrificed immediately, and the entire volume of the undiluted tissue suspension from the inoculated footpad was plated on 10 tubes of Löwenstein-Jensen medium for the cultivation of M. ulcerans. After 90 days of incubation at 30°C, a positive culture was taken as a relapse of M. ulcerans infection. Finally, at the end of the 28-week follow-up, all surviving mice were sacrificed for tissue cultivation by the same technique.

Statistical analysis. The results were analyzed by means of Student's t test and Fisher's exact probability calculation. Differences with a 95% confidence interval were considered significant. A regimen was considered bactericidal if the mean number of CFU per footpad in the treated group was significantly lower than the pretreatment value and was considered to have sterilized the infection if the relapse rate during the 28-week posttreatment follow-up was no greater than 5%.

	RESULTS

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Evolution of the average lesion index and mean number (log₁₀) of CFU of the inoculated footpad during treatment. Among the untreated controls at 4 weeks after the start of treatment, the inoculated footpads were invariably culture positive for M. ulcerans. Whereas the mean number (log₁₀) of CFU per footpad was similar to the pretreatment value, the average lesion index was significantly greater than its pretreatment value (P < 0.01), as shown in Table 1 and Figure 1. In stark contrast, all parameters declined progressively in all treated groups. After 4 weeks of treatment, the proportion of culture-positive mice, the mean number of CFU per inoculated footpad, and the average lesion indexes of all treated groups were significantly lower than the corresponding pretreatment values or those of the untreated controls sacrificed concomitantly (P < 0.05 or P < 0.01). After 8 weeks of treatment, all of the inoculated footpads (10 per group) of every treated group were culture negative, with the exception of the group treated with MXF-CLR: of the 10 footpads examined, two colonies were detected in one footpad and six colonies in another. The reductions of CFU and the average lesion index did not differ significantly among the three monotherapy groups (groups 2 to 4) nor among the nine groups (groups 5 to 13) treated with various combinations (P > 0.05).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Evolution of the average lesion indexes in various groups of mice during 8 weeks of treatment.

	DISCUSSION

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The results demonstrate that in terms of the reductions in culture positivity and the mean number of CFU per inoculated footpad during treatment, in the current experiment the bactericidal activities against M. ulcerans of the five positive control regimens, i.e., RIF 5/7 monotherapy (group 2), RIF-STR 5/7 (group 5), RIF-MXF 5/7 (group 8), RIF-CLR 5/7 (group 11), and MXF-CLR 5/7 (group 13), were very similar to those of the same regimens in our earlier experiments (7, 8). The experiment not only confirmed that 8 weeks of treatment with RIF-CLR displays promising bactericidal activity against M. ulcerans, but it also demonstrated that the treatment sterilized the infection with a zero relapse rate, identical to the results for treatment with the combination RIF-STR or RIF-MXF. Unlike MXF, CLR is being employed for treatment of various infectious diseases among children, who represent more than half of the patients with Buruli ulcer (4). We have launched a clinical trial with the combination of RIF and CLR for treatment of Buruli ulcer.

The combination of MXF and CLR again demonstrated promising bactericidal activity against M. ulcerans during treatment, but it is the only tested combination that failed to render all inoculated footpads culture negative after 8 weeks of treatment, a result very similar to our earlier findings (8). Although the bactericidal activity of MXF-CLR during treatment did not differ significantly from that of the other combinations, of the mice treated with MXF-CLR, 59% relapsed during the 28 weeks of posttreatment follow-up, a relapse rate significantly greater than that for mice treated with the other tested combinations, indicating that the sterilizing activity against M. ulcerans of 8 weeks of MXF-CLR was disappointing, probably because both components of the combination display only moderate bactericidal activity against M. ulcerans (7, 8). It remains unclear whether the sterilizing activity of MXF-CLR might be enhanced with a longer duration of treatment.

After 4 weeks, although more mice were converted to culture-negative status and the mean number of CFU per inoculated footpad was lower in mice treated with 5/7 administration of 5 mg/kg RFP (group 3) or 2/7 administration of 20 mg/kg RFP (group 4) than that in mice treated with 5/7 administration of 10 mg/kg RIF (group 2), the differences did not attain statistical significance (P > 0.05). After 8 weeks of treatment, all footpads in all three groups were culture negative, suggesting that the bactericidal activity against M. ulcerans of 5/7 administration of 5 mg/kg RFP or 2/7 administration of 20 mg/kg RFP was virtually the same as that of 5/7 administration of 10 mg/kg RIF. Likewise, the results of CFU enumeration and the relapse rates after 4 or 8 weeks of treatment with 5/7 administration of three different combinations containing 5 mg/kg RFP (groups 6, 9, and 12) were very similar to those for mice treated with the corresponding combinations containing 10 mg/kg RIF (groups 5, 8, and 11), indicating that the bactericidal and sterilizing activities against M. ulcerans of the 5/7 administration of combinations containing 5 mg/kg RFP were similar to but not greater than the corresponding combinations containing 10 mg/kg RIF. A recent study based on simulated steady-state pharmacodynamic curves suggested that because of the long serum half-life of RFP, there is some accumulation of free RFP in mice after the 5/7 administration of 7.5 to 10 mg/kg RFP (14). Taking into account both the effectiveness and the possible accumulation of RFP (and hence the potential adverse effects), the prospect for treating Buruli ulcer with 5/7 administration of combinations containing smaller doses of RFP is questionable.

After 8 weeks of treatment, the levels of bactericidal activity for the groups receiving 2/7 administration of 20 mg/kg RFP in combination with either STR (group 7) or MXF (group 10) did not differ significantly from those for the groups receiving 5/7 administration of RIF-STR (group 5) or RIF-MXF (group 8), suggesting that 2/7 administration of combinations containing 20 mg/kg RFP was as effective as 5/7 administration of the corresponding regimens containing 10 mg/kg RIF. These findings are encouraging, suggesting that Buruli ulcer might be treated with 2/7 intermittent therapy, thus greatly facilitating fully supervised drug administration and reducing drug costs and toxicity as well. Furthermore, most Buruli ulcer patients with small- to moderate-sized wounds often come to the clinics twice or three times weekly to have their dressings changed, thus facilitating the supervision of twice-weekly drug administration by a health worker. Of the two possible intermittent regimens, i.e., RFP-STR and RFP-MXF, the former combination is less interesting, not only because STR should be administered by injection but also because the half-life of STR is significantly shorter than that of RFP, and the pharmacokinetic mismatch may result in exposure to RFP monotherapy and the development of rifamycin resistance, similar to the occurrence of acquired rifamycin monoresistance among tuberculosis patients treated once weekly with RFP-isoniazid (16). On the other hand, the half-life of MXF is substantially longer than that of STR and similar to that of RFP; thus, 2/7 administration of RFP-MXF should be more effective in preventing the selection of rifamycin-resistant mutants. Because of limited mouse facilities, the relapse rate for M. ulcerans infections after 2/7 administration of 20 mg/kg RFP in combination with either STR or MXF was not examined in this study. Therefore, the sterilizing activity of either combination is unknown and is being determined in an ongoing experiment.

With respect to the treatment of Buruli ulcers, there are two additional justifications for treating patients with a higher dosage of RFP. First, more than half of the patients are children below the age of 15 (4); pharmacokinetic studies have indicated that larger weight-normalized dosages of RFP are likely to be required in children to achieve systemic exposures comparable to those associated with the therapeutic dosage in adults (1). Second, the bioavailability of RFP is closely associated with food intake: it decreases from 100% after a large, complex meal to 70% after an insufficient meal consisting of only one or two high-lipid biscuits and to 50% with no preceding meal (11). In the great majority of areas where Buruli ulcers are endemic, especially in rural Africa, it is virtually impossible to provide a large meal sufficient to promote good absorption of RFP while supervising the administration of the drug at the clinics; it is therefore necessary to increase the treatment dosage to achieve a reasonable drug concentration.

RFP is well tolerated when administered once weekly at dosages up to 1,200 mg and twice-weekly at dosages up to 600 mg (2, 15; Hoechst Marion Roussel, data on file). Nevertheless, the tolerability and safety of twice-weekly administration of higher dosages of RFP have not been established and should be prerequisites for launching human trials for testing 2/7 administration of regimens containing higher dosages of RFP. Preliminary studies indicate that the pharmacokinetics of RFP in healthy adolescents were similar to those observed in healthy adults, and RFP is being employed in pediatric patients over 12 years of age. However, the safety of RFP in pediatric patients under the age of 12 has not been established, because patients aged 12 or younger have been excluded from most clinical trials of RFP. There is an ongoing pharmacokinetic study with children aged 2 to 12 years; the results will become available after the end of 2008 (Didier Leboulleux, personal communication).

	ACKNOWLEDGMENTS

 
This investigation was funded by the Foundation Raoul Follereau, Paris, France, and by Université Paris 6 (EA 1541).

We thank Sanofi-Aventis for providing rifapentine.

	FOOTNOTES

 
* Corresponding author. Mailing address: Bactériologie-Hygiène, Faculté de Médecine Pierre et Marie Curie, Universite Paris 6, 91 boulevard de l'Hôpital, 75634 Paris Cedex 13, France. Phone: (331) 40 77 98 67. Fax: (331) 45 82 75 77. E-mail: baohong_ji{at}yahoo.com

Published ahead of print on 7 April 2008.

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This Article Abstract Full Text (PDF) Other Versions of this Article: AAC.00193-08v1 52/6/1912    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Ji, B. Articles by Jarlier, V. PubMed PubMed Citation Articles by Ji, B. Articles by Jarlier, V.