Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis

Ian M Rosenthal, Rokeya Tasneen, Charles A Peloquin, Ming Zhang, Deepak Almeida, Khisimuzi E Mdluli, Petros C Karakousis, Jacques H Grosset, Eric L Nuermberger, Ian M Rosenthal, Rokeya Tasneen, Charles A Peloquin, Ming Zhang, Deepak Almeida, Khisimuzi E Mdluli, Petros C Karakousis, Jacques H Grosset, Eric L Nuermberger

Abstract

In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.

Figures

Fig 1
Fig 1
Mean (± SD) serum drug concentrations of rifampin (a) and rifapentine (b) after 2 weeks of daily dosing (5 days per week). Sampling was performed after the 10th (R10), 11th (P10 and P20), or 13th (R20, R40, and P5) dose.
Fig 2
Fig 2
Mean (± SD) lung log10 CFU counts at treatment initiation (D0) and after 2 weeks (a), 4 weeks (b), 8 weeks (c), or 10 weeks (d) in experiment 1.
Fig 3
Fig 3
Mean (± SD) lung log10 CFU counts in BALB/c (a and b) or C3HeB/FeJ (c and d) mice at treatment initiation (D0) and after 4 weeks (a and c) or 8 weeks (b and d) in experiment 2.
Fig 4
Fig 4
(a and b) Histopathology of a necrotic granuloma (a) in untreated mouse lung 3.5 months after low-dose challenge with M. tuberculosis, demonstrating central caseation with abundant extracellular acid-fast bacilli (b). Magnification, ×20 (a) or ×500 (b, inset). (c, inset) Large numbers of extracellular bacilli were also found at the transition zone between the central necrosis and the cellular cuff, where evidence of more recent cellular necrosis was observed. Magnification, ×500. (d, inset) Intracellular bacilli were found in smaller concentrations at the outer margin of the cellular cuff. Magnification, ×200.
Fig 5
Fig 5
Histopathology of nonnecrotic lung foci in infected BALB/c (a and b) and C3HeB/FeJ (c and d) mice, demonstrating chronic inflammation with foamy macrophages containing acid-fast bacilli (arrows). Magnification, ×500.

References

    1. Almeida D, et al. 2009. Paradoxical effect of isoniazid on the activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis. Antimicrob.Agents Chemother. 53:4178–4184
    1. Blumberg HM, et al. 2003. American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America: treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 167:603–662
    1. British Thoracic and Tuberculosis Association 1975. Short-course chemotherapy in pulmonary tuberculosis. Lancet i:119–124
    1. British Thoracic and Tuberculosis Association 1976. Short-course chemotherapy in pulmonary tuberculosis. Lancet ii:1102–1104
    1. Burman WJ, Gallicano K, Peloquin C. 2001. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin. Pharmacokinet. 40:327–341
    1. Davies GR. 2010. Early clinical development of anti-tuberculosis drugs: science, statistics and sterilizing activity. Tuberculosis (Edinb.) 90:171–176
    1. Davis SL, et al. 2009. Noninvasive pulmonary [18F]-2-fluoro-deoxy-D-glucose positron emission tomography correlates with bactericidal activity of tuberculosis drug treatment. Antimicrob. Agents Chemother. 53:4879–4884
    1. Diacon AH, et al. 2007. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob. Agents Chemother. 51:2994–2996
    1. Dooley KE, et al. 2012. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin. Pharmacol. Ther. doi:
    1. Dorman S, et al. 2011. A phase II study of a rifapentine-containing regimen for intensive phase treatment of pulmonary tuberculosis: preliminary results for Tuberculosis Trials Consortium Study 29. Am. J. Respir. Crit. Care Med. 183:A6413
    1. Dutta NK, et al. 30 April 2012, posting date Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs. Antimicrob. Agents Chemother. doi:
    1. East and Central African and British Medical Research Councils 1986. Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis: final report. Tubercle 67:5–15
    1. East and Central African and British Medical Research Councils 1973. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet i:1331–1338
    1. Gagneux S, et al. 2006. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–1946
    1. Grosset J. 2003. Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Antimicrob. Agents Chemother. 47:833–836
    1. Grosset J, et al. 1998. Once-weekly rifapentine-containing regimens for treatment of tuberculosis in mice. Am. J. Respir. Crit. Care Med. 157:1436–1440
    1. Grosset JH, Rosenthal I, Zhang M, Williams K, Nuermberger EL. 2008. Low doses of rifapentine versus high doses of rifampin in the mouse model of tuberculosis. Int. J. Tuberc. Lung Dis. 12(11 Suppl. 2):S63
    1. Grosset JHE, Rosenthal IM, Zhang M, Nuermberger EL. 2008. Dose-ranging comparison of rifampin and rifapentine in combination with isoniazid and pyrazinamide in the mouse model of tuberculosis, abstr. A-1825. Abstr. 48th Annu. Intersci. Conf. Antimicrob. Agents Chemother. (ICAAC)-Infect. Dis. Soc. Am. (IDSA) 46th Annu. Meet American Society for Microbiology and Infectious Diseases Society of America, Washington, DC
    1. Gumbo T, et al. 2007. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob. Agents Chemother. 51:3781–3788
    1. Harper J, et al. 2012. Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J. Infect. Dis. 205:595–602
    1. Hunter RL, Jagannath C, Actor JK. 2007. Pathology of postprimary tuberculosis in humans and mice: contradiction of long-held beliefs. Tuberculosis (Edinb.) 87:267–278
    1. Jayaram R, et al. 2003. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob. Agents Chemother. 47:2118–2124
    1. Jindani A, Aber VR, Edwards EA, Mitchison DA. 1980. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am. Rev. Respir. Dis. 121:939–949
    1. Kenny MT, Strates B. 1981. Metabolism and pharmacokinetics of the antibiotic rifampin. Drug Metab. Rev. 12:159–218
    1. Keung A, Eller MG, McKenzie KA, Weir SJ. 1999. Single and multiple dose pharmacokinetics of rifapentine in man: part II. Int. J. Tuberc. Lung Dis. 3:437–444
    1. Keung A, et al. 1999. Enzyme induction observed in healthy volunteers after repeated administration of rifapentine and its lack of effect on steady-state rifapentine pharmacokinetics: part I. Int. J. Tuberc. Lung Dis. 3:426–436
    1. Kjellsson MC, et al. 2012. Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions. Antimicrob. Agents Chemother. 56:446–457
    1. Kochar DK, et al. 2006. A double blind, randomised placebo controlled trial of rifampicin with omeprazole in the treatment of human cutaneous leishmaniasis. J. Vector Borne. Dis. 43:161–167
    1. Lenaerts AM, Chase SE, Chmielewski AJ, Cynamon MH. 1999. Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice. Antimicrob. Agents Chemother. 43:2356–2360
    1. Mor N, Simon B, Mezo N, Heifets L. 1995. Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages. Antimicrob. Agents Chemother. 39:2073–2077
    1. Nuermberger E. 2008. Using animal models to develop new treatments for tuberculosis. Semin. Respir. Crit. Care Med. 29:542–551
    1. Nuermberger E, et al. 2006. Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis. Antimicrob. Agents Chemother. 50:2621–2625
    1. Nuermberger EL, et al. 2004. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am. J. Respir. Crit. Care Med. 170:1131–1134
    1. Pan H, et al. 2005. Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767–772
    1. Peloquin C. 2003. What is the ‘right’ dose of rifampin? Int. J. Tuberc. Lung Dis. 7:3–5
    1. Peloquin CA, et al. 1997. Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrob. Agents Chemother. 41:2670–2679
    1. Peloquin CA, Namdar R, Singleton MD, Nix DE. 1999. Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest 115:12–18
    1. Rosenthal IM, Zhang M, Grosset JH, Nuermberger EL. 2008. Rifapentine-containing regimens cure murine tuberculosis in weeks rather than months. Am. J. Respir. Crit. Care Med. 177:A789
    1. Rosenthal IM, et al. 2006. Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am. J. Respir. Crit. Care Med. 174:94–101
    1. Rosenthal IM, Zhang M, Almeida D, Grosset JH, Nuermberger EL. 2008. Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis? Am. J. Respir. Crit. Care Med. 178:989–993
    1. Rosenthal IM, et al. 2007. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med. 4:e344 doi:
    1. Ruslami R, et al. 2007. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob. Agents Chemother. 51:2546–2551
    1. Singapore Tuberculosis Service and British Medical Research Council 1981. Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: the results up to 30 months. Tubercle 62:95–102
    1. Solera J, et al. 1995. Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. The GECMEI Group. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas. Antimicrob. Agents Chemother. 39:2061–2067
    1. Steingart KR, et al. 2011. Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review. Int. J. Tuberc. Lung Dis. 15:305–316
    1. Tasneen R, et al. 2011. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob. Agents Chemother. 55:5485–5492
    1. Tasneen R, Peloquin C, Nuermberger E. 2011. Dose-ranging activity of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis, abstr. O_15. Progr. Abstr. Fourth Int. Workshop Clin. Pharmacol. Tuberc. Drugs, Chicago, IL Virology Education B.V., Utrecht, The Netherlands
    1. Telenti A, et al. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647–650
    1. Verbist L. 1969. Rifampicin activity “in vitro” and in established tuberculosis in mice. Acta Tuberc. Pneumol. Belg. 60:397–412
    1. Verbist L. 1971. Pharmacological study of rifampicin after repeated high dosage during intermittent combined therapy. I. Variation of the rifampicin serum levels (947 determinations). Respiration 28(Suppl.):7–16
    1. Weiner M, et al. 2010. Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob. Agents Chemother. 54:4192–4200
    1. Weiner M, et al. 2011. Rifapentine exposure in a trial of daily rifapentine compared to rifampin during the intensive phase of TB treatment. Am. J. Respir. Crit. Care Med. 183:A6341
    1. Wilkins JJ, et al. 2008. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob. Agents Chemother. 52:2138–2148
    1. Williams KN, et al. 2009. Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis. Am. J. Respir. Crit. Care Med. 180:371–376
    1. Zhang M, et al. 2011. Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice. Am. J. Respir. Crit. Care Med. 183:1254–1261
    1. Zhang T, Li SY, Williams KN, Andries K, Nuermberger EL. 2011. Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. Am. J. Respir. Crit. Care Med. 184:732–737

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