Table 5

In vitro or animal studies regarding impact of dosing intermittency on efficacy of tuberculosis treatment

Authors, year of publication	Measures of treatment efficacy	Source of study materials	Study design	Main findings	Likely impact of dosing intermittency on treatment efficacy of standard regimens
Weiner et al, 200551	Acquired rifamycin resistance	USA	PK-PD study involving human subjects	Lower AUC (0–24) of rifabutin and perhaps AUC (0–12) of isoniazid were associated with failure or relapse with acquired rifamycin resistance in HIV-related TB treated with twice-weekly therapy.	Negative
Weiner et al, 200357	Relapse	USA	PK study involving human subjects	Among HIV-negative patients given either H and R twice weekly or H and rifapentine once weekly in continuation phase, failure/relapse was associated with low H concentrations (AUC 0–12) rather than any rifamycin PK parameter. Dosing schedule of rifampicin appeared to be unrelated to relapse.	No
Goutelle et al, 200958	Not applicable	France	Population PK model for rifampicin	Among 34 human volunteers given 600 mg rifampicin, the proportions of subjects achieving target values for C_max/MIC ratio and AUC (0–24)/MIC ratio in epithelial lining fluid were only 35.9% and 54.5%, respectively.	Negative
Gupta et al, 200859	Not applicable	India	PK-PD studies in children	C_max, elimination half-life and clearance for pyrazinamide 15 and 25 mg/kg per day differed non-significantly. This might suggest a difference in AUC/MIC (and hence sterilizing activity) between daily and intermittent treatment regimens.	Negative with a caveat: the PAE of intermittent pyrazinamide may compensate for less sterilising activity due to lower AUC/MIC
Mitchison, 197922	Not applicable	UK	Guinea pig experiments	When the same total drug amount is given as single dose or fractionated into multiple doses of different sizes, better efficacy is observed with high doses given at long intervals, especially for rifampicin and ethambutol.	Positive
Rosenthal et al, 200852	Relapse	USA	TB mouse model	Mice with TB disease were treated daily or thrice-weekly with rifapentine, pyrazinamide, and either isoniazid or moxifloxacin. The duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampicin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.	Negative
Rosenthal et al, 200753	Relapse	USA	TB mouse model	Replacing rifampicin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. No relapse was observed after just 3 months of treatment with daily or thrice-weekly rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 months to prevent relapse.	Negative
Rosenthal et al, 200654	Relapse	USA	TB mouse model	Stable cure was achieved after 4 months of twice-weekly rifapentine (15 mg/kg or 20 mg/kg) plus isoniazid- or moxifloxacin-containing therapy, but only after 6 months of standard daily therapy (10 mg/kg). Twice-weekly rifapentine displayed more favourable pharmacodynamics than did daily rifampicin.	Negative
Veziris et al, 200555	Relapse	France	TB mouse model	Mice were treated with rifapentine, isoniazid and moxifloxacin given once a week during 5.5 months, preceded by 2 weeks of daily treatment with isoniazid, rifampicin, pyrazinamide, and moxifloxacin. When used at high dosages, such a regimen effectively achieved stable cure in mouse TB. The relapse rate increased from 0 to 11% when treatment was once-weekly throughout.	Negative
Daniel et al, 200056	Treatment failure, acquired drug resistance	France	TB mouse model	Reducing dosing frequency in the initial phase from daily to twice-weekly increased the risk of treatment failure with emergence of resistance to rifampicin or isoniazid.	Negative
Jayaram et al, 200349	Not applicable	India	PK-PD study in a murine aerosol infection model	Dose ranging and fractionation studies demonstrated that AUC (0–24)/MIC of rifampicin correlated best (r²=0.95) with a reduction in bacterial counts, followed by C_max/MIC (r²=0.86) and the time that the concentration remained above the MIC (r²=0.44).	Negative
Jayaram et al, 200460	Not applicable	India	PK-PD study in a murine aerosol infection model	Dose fractionation studies demonstrated that AUC (0–24)/MIC of isoniazid correlated best (r²=0.83) with the bactericidal efficacy, followed by C_max/MIC (r²=0.73).	Negative with a caveat: AUC/MIC of isoniazid is probably comparable for daily and intermittent regimens
Gumbo et al, 200950		USA	In vitro PK-PD study	The sterilising effect of pyrazinamide was linked to AUC (0–24) to MIC ratio (r²=0.80–0.90), with 90% of the maximal effect being achieved by a ratio of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r²=0.73–0.91).	Negative with a caveat: the PAE of intermittent pyrazinamide may compensate for less sterilising activity due to lower AUC/MIC
Gumbo et al, 200721		USA	In vitro PK-PD model	The PAE of rifampicin lasted for at least 5.2 days and closely related to free C_max to MIC ratio (r²=0.96). The microbial killing of rifampicin was linked to AUC (0–24) to MIC ratio, and suppression of resistance was associated with free C_max to MIC ratio.	Negative
Budha et al, 200961	Not applicable	USA	In vitro PK-PD study	The time-kill data suggest that AUC (0–24)/MIC is the PK/PD index most explanatory of the antimicrobial effect of isoniazid.	Negative with a caveat: AUC/MIC of isoniazid is probably comparable for daily and intermittent regimens

AUC, area under the curve; C_max, peak serum concentration; H, isoniazid; MIC, minimum inhibitory concentration; PAE, post-antibiotic effect; PK-PD, pharmacokinetics-pharmacodynamics; R, rifampicin; TB, tuberculosis.