5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

was improved by addition of BDQ to the regimen in a Phase II trial in MDR-TB.233,237

Dosing

A loading dose of 400 mg daily is administered for 2 weeks followed by a maintenance dose of 200 mg three times a week with food.

Adverse effects

BDQ at steady state prolongs the QTc interval by approximately 12 mS237 but has not been clearly associated with serious dysrhythmias. It may also be associated with gastrointestinal disturbance, arthralgia, headache, and dizziness. Phospholipidosis observed in some preclinical toxicity studies has not been observed in humans to date. The drug currently has a black box warning due to unexplained excess mortality in clinical trials.

Drug interactions

Because it is principally metabolized by CYP3A4, BDQ plasma concentrations may be significantly decreased by inducers of the enzyme (rifamycins, 75% or more for RIF and RPT)238 and increased by inhibitors (ritonavir, ketoconazole, and clarithromycin).239 BDQ should be combined with caution and appropriate monitoring with drugs that also prolong the QTc interval such as MFX and CFZ.

Special populations

No abnormalities have been observed in animal studies with BDQ but there are no relevant human and no data concerning excretion in breast milk. There are no dosing recommendations in children as yet. No dose adjustments are recommended in renal failure or liver disease but BDQ should be used with caution in severe renal or hepatic disease.

DELAMANID

O

F

O F F

N

Structure and activity

Delamanid (DLD) is a highly water-insoluble weak acid (log P 6.14, pKa 5.51, MW 534). It is the R-enantiomer of a synthetic nitro-dihydro-imidazo-oxazole derivative which is a prodrug activated by the F420 dependent nitroreductases. The mechanism of action remains uncertain but DLD inhibits mycolic acid synthesis and releases reactive oxygen species in mycobacteria.240 Wild-type MICs range from 0.001 to 0.05 µg/mL.241 The spontaneous rate of mutation conferring resistance is relatively high at approximately 2 in 105 with mutations in any of the F420 coenzymes Rv3547, FGD, FbiA, FbiB, and FbiC associated with in vitro resistance.242

Pharmacokinetics/ADME

Oral bioavailability is estimated to be 25%–47% and is increased threeto four-fold by food. The volume of distribution is 15.5– 163.2 L/kg and plasma protein binding is >99.5% to albumin and lipoproteins. The metabolism of DLD is complex. The nitro group of DLD is removed by interactions with albumin and seven other identified metabolites are believed to be subsequently formed by oxidation by CYP3A4 and possibly CYP1A1, CYP2D6,

and CYP2E1.243,244 The Cmax is 0.41 µg/mL and AUC 7.92 µg/ mL × hour with a t1/2 of 38 h in MDR-TB patients dosed at 100 mg

twice daily.245 No data are available on intrapulmonary, lesion, or CSF penetration.

Pharmacodynamics/efficacy

DLD showed modest EBA over the first 14 days (0.026 log10 CFU/ mL/day) at a dose of 100 mg twice daily246 but improved culture conversion at 2 months in MDR-TB patients by 16% compared to placebo.245 However, evidence of impact on long-term outcomes has been equivocal.

Dosing

DLD is dosed at 100 mg twice daily for 2 months and then 200 mg daily with food.

Adverse effects

DLD prolongs the QTc interval by 8–12 mS but has not been associated with serious dysrhythmias.245 Caution should be exercised in patients with hypoalbuminemia. DLD may also be associated with nausea, vomiting, tremor, anxiety, and paraesthesia.

Drug interactions

Co-administration of DLD with RIF leads to a reduction in DLD AUC of 47% whereas ritonavir increases DLD AUC by 25%.247 These results suggest that DLD will also be impacted by other inducers and inhibitors of CYP3A4. Caution should be used when combining DLD with other drugs that may prolong the QTc interval.

Special populations

The DLD parent compound did not cause teratogenicity or embryopathy in animals though studies with metabolites resulted in some fetal abnormalities. The drug is likely to be excreted in breast milk and breast feeding is not recommended. No dosing recommendations are available for children as yet. No dosage adjustments are suggested in mild–moderate renal failure but DLD is not recommended for use in severe renal failure and should be avoided in patients with moderate–severe liver impairment.

CLARITHROMYCIN

CH3

HO O

CH3

Structure and activity

Clarithromycin (CLR, 6-O-methylerythromycin) is a poorly water-soluble weak base (log P 2.69, pKa 8.9, MW 747.95). It is a semi-synthetic derivative of erythromycin, which is a natural product of Saccharopolyspora erythrea. Macrolides bind to the 50S subunit of the ribosome, preventing translocation of tRNAs from the A site to the P site by binding in the peptide exit tunnel.248 Binding of macrolides is affected by the pattern of methylation of 23S rRNA at the target site. Erythromycin ribosome methylase­ (erm) genes code for methylase enzymes that typically target residue­ A2058 but the M. tuberculosis complex has a unique gene ermMT (erm37) which also methylates additional adjacent residues, resulting in intrinsic resistance.249 MICs reported for CLR for M. tuberculosis are uniformly >8 µg/ mL.250 Among non-tuberculous mycobacteria, inducible resistance during therapy due to acquisition of erm genes has also been described in M. avium complex, Mycobacterium kansasii, M. fortuitum, and M. chelonae.251 The Mycobacterium abscessus complex typically exhibits inducible resistance due to the presence of erm41 but deletions in the gene confer uniform

susceptibility in M. massiliense and rarely in M. abscessus sub abscessus.252

Pharmacokinetics/ADME

Absolute bioavailability of CLR is 55% and is not affected by food.253 The volume of distribution is 3.5 L/kg and plasma protein binding is 80%. CLR undergoes saturable, extensive first-pass metabolism to the predominant 14-hydroxy metabolite, and also N-demethylation by CYP3A4.254 Only 18% of parent drug is eliminated in the urine and the majority of excretion is via the biliary route.255 Cmax is approximately 2.7 µg/mL, AUC 20 µg/mL × hour, and t1/2 3.6 hours after multiple doses of 500 mg.256 CLR is concentrated 5× in epithelial lining fluid and more than 90× in alveolar cells, with similar values for the 14-OH metabolite257 with concentrations in lung tissue 29× and 6× higher than that in plasma, respectively.258

Pharmacodynamics/efficacy

No studies of EBA have been carried out and observational data in treatment of MDR-TB do not support the efficacy of CLR in M. tuberculosis.250 Recent meta-analyses suggest that CLR is an unreliable agent for treatment of M. abscessus259 but improves culture conversion in treatment of M. avium complex.260

Dosing

CLR is dosed at 250–500 mg twice daily for most mycobacterial infections though doses of 1,000 mg thrice weekly have been recommended in mild M. avium lung disease.261

Adverse effects

Similar to other macrolides, the main side effects of CLR are gastrointestinal intolerance, abnormal liver enzymes, and taste disturbance. CLR prolongs the QTc interval by an average 3 mS but has been associated with torsades de pointes in post-marketing studies, particularly when combined with other QTc-prolonging drugs.262

Drug interactions

CLR is a potent mechanism-based inhibitor of CYP3A4263 and may cause serious PK interactions with numerous substrates of this enzyme including statins, midazolam, cyclosporin, tacrolimus, carbamazepine, ergot alkaloids, and omeprazole. Because it is also a substrate, plasma concentrations of CLR may also be affected by induction of CYP3A4, for example by rifamycins. CLR should be used with caution with other drugs prolonging the QT interval and in patients with additional risk factors such as electrolyte disturbance.

Special populations

CLR is embryotoxic in several animal species and very limited data are available in humans. CLR is excreted in breast milk with a

relative infant dose of 2%.264 Children are dosed at approximately 8 mg/kg. The dose should be halved in severe renal failure (CrCl <30 mL/min) and CLR is not expected to be removed by hemodialysis. The drug should be used with caution in severe liver disease but no dosage adjustment has been proposed.

THIACETAZONE

CH3

HO N

with or without STM, regimens including TCZ even in the continuation phase, were phased out in the 1990s due to inferior efficacy and safety concerns in HIV-positive patients.268 Observational data on its use in MDR-TB are sparse.

Dosing

TCZ is dosed at 150 mg daily.

Adverse effects

The most serious toxicity of TCZ is its association with severe cutaneous hypersensitivity and Stevens–Johnson syndrome in up to 20% of HIV-co-infected patients.269 Gastrointestinal intolerance, drug-induced liver injury and blood dyscrasias may also occur.

N

HS NH

NH

Structure and activity

Thiacetazone (TCZ) is a moderately water-soluble weak acid (log P 1.75, pKa 5.11–5.72, MW 262.293). It is a synthetic thiosemicarbazone. TCZ is a pro-drug, activated similar to ETM by ethA and targets mycolic acid synthesis, principally the FASII β-hydroxyacyl ACP dehydratase, encoded by the hadABC operon but also other non-essential mycolic acid-modifying enzymes, including cyclopropane mycolic acid synthases (CmaA2 and PcaA) and the mycolic acid methyltransferases (MMA) (MmaA2 and MmaA4).265 It is active only against M. tuberculosis and M. kansasii. Wild-type MIC99s range from 0.125 to 2 µg/mL.85 Spontaneous mutations in ethA or hadABC conferring resistance occur at a rate of approximately 1 in 107.

Pharmacokinetics/ADME

Absolute bioavailability of TCZ has not been determined but it is well-absorbed. Metabolism of TCZ has been incompletely studied but the primary route of elimination is believed to be hydroxylation to para-aminobenzaldehyde and para-acetylaminobenzal- dehyde with less than 25% excreted unchanged in the urine.266 Cmax is 1.6 µg/mL and t1/2 15 h after a dose of 150 mg once daily.267 No information is available about intrapulmonary or lesional distribution.

Pharmacodynamics/efficacy

EBA0–2 of TCZ is weak at 0.067 log10 CFU/mL/day.79 Originally used as a companion drug for INH at durations of 6–18 months

Structure and activity

Imipenem (IMP) and meropenem (MRP) are highly water-soluble weak acids (log P −3.9 and −4.4, pKa 3.2 and 3.47–9.39, MW 299.3 and 383.15). Both are synthetic derivatives of thienamycin, a natural product of Streptomyces cattleya. Carbapenems target multiple transpeptidases (penicillin-binding proteins) involved in bacterial cell-wall synthesis including the unique l,d-transpeptidases characteristic of mycobacteria.270 However, M. tuberculosis possesses an extended spectrum class A β-lactamase (BlaC), which must be inactivated for in vitro activity of the drugs.271 Clavulanic acid is the most potent inhibitor of BlaC among licensed β-lactamase inhibitors.272 MIC99s of meropenem–clavulanate in wild-type MDR and XDR strains range from 0.125 to 2 µg/mL.273

Pharmacokinetics/ADhME

IMP and MRP are hydrolytically unstable and can only be administered parenterally. They have similar volumes of distribution of approximately 0.2 L/kg.274 MRP has lower plasma protein binding (2%) compared to IMP (20%). Both drugs are hydrolyzed by renal dehydropeptidase-1 (DHP-1) to a microbiologically active metabolite with approximately 70% of the parent drug excreted unchanged in the urine. IMP has a higher affinity for DHP-1 than MRP and is co-administered with cilastatin, an inhibitor of the enzyme, to prolong the plasma half-life. At a dose of 1,000 mg

the Cmaxs of IMP and MRP are 35 and 49 µg/mL and the AUC 96 and 71 µg/mL × hour, respectively. The t1/2 of both drugs is about

1 hour.275 Concentrations of MRP in epithelial lining fluid and alveolar cells are 0.15 and 0.09× plasma, respectively,276 whereas penetration of ELF for IMP is 0.44×.277 No data are available on penetration of lesions. Concentrations of IMP and MRP in CSF are 10%–20% of plasma.278,279

Pharmacodynamics/efficacy

Evidence for the efficacy of carbapenem–clavulanate combinations in TB rests largely on preclinical studies.280 No comparative or controlled clinical studies have been reported though a meta-analysis of observational studies in MDR-TB observed more favorable response rates with MRP than with IMP.281

Dosing

IMP is dosed at 1,000 mg 12 hourly and MRP 1,000 mg 8 hourly intravenously. 125 mg clavulanic acid should be given orally with each dose. Because clavulanate is not currently separately formulated, this is usually given as co-amoxiclav 250/125 mg.

Adverse effects

IMP and MRP may be associated with anaphylaxis and injection site reactions. Both may cause abnormal liver enzymes and druginduced liver injury. CNS side-effects including seizures may occur in overdose in unrecognized renal failure. MRP may also cause eosinophilia and thrombocythemia.

Drug interactions

Plasma concentrations of sodium valproate are decreased by carbapenems and co-administration should be avoided if possible. Oral anticoagulants should be more frequently monitored.

Special populations

Though neither IMP nor MRP are teratogenic, the former was associated with increased fetal loss in animal studies and data in pregnancy are limited. Both drugs are excreted in breast milk but the relative infant dose is probably less than 1%.282 The recommended pediatric dose is 25 mg/kg for IMP and 20 mg/kg for MRP. The dose size and/or interval should be reduced in patients with abnormal renal function (<90 mL/min for IMP and <50 mL/min for MRP) and both drugs are removed by hemodialysis ( 50%). No dose adjustment is recommended in liver disease.

REFERENCES

1.Lei B, Wei CJ, and Tu SC. Action mechanism of antitubercular isoniazid. Activation by Mycobacterium tuberculosis KatG, isolation, and characterization of Inha inhibitor. J Biol Chem. 2000 Jan 28;275(4):2520–6.

2.Rawat R, Whitty A, and Tonge P. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance. Proc Natl Acad Sci USA 2003;100(24):13881–6.

3.Schön T et al. Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis. J Antimicrob Chemother. 2009 Oct;64(4):786–93.

4.David H. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol. 1970;20:810–4.

5.Cohen K, Bishai WR, and Pym AS. Molecular basis of drug resistance in Mycobacterium tuberculosis. In: Molecular Genetics of Mycobacteria. 2nd ed. American Society of Microbiology; 2014. 413–29.

6.Peloquin CA, Namdar R, Dodge AA, and Nix DE. Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids. Int J Tuberc Lung Dis. 1999 Aug;3(8):703–10.

7.Woo J, Cheung W, Chan R, Chan H, Cheng A, and Chan K. In vitro protein binding characteristics of isoniazid, rifampicin and pyrazinamide to whole plasma, albumin and a-1 acid glycoprotein. Clin Biochem. 1996;29(2):175–7.

8.Ellard G, and Gammon P. Pharmacokinetics of isoniazid metabolism in man. J Pharmacokinet Biopharm. 1976;4:83–113.

9.Sabbagh A, Langaney A, Darlu P, Gérard N, Krishnamoorthy R, and Poloni ES. Worldwide distribution of NAT2 diversity: Implications for NAT2 evolutionary history. BMC Genet. 2008;9:21.

10.van Oosterhout JJ et al. Pharmacokinetics of antituberculosis drugs in HIV-positive and HIV-negative adults in Malawi. Antimicrob Agents Chemother. 2015 Oct;59(10):6175–80.

11.McIlleron H, Wash P, Burger A, Norman J, Folb P, and Smith P. Determinants of rifampicin, isoniazid, pyrazinamide and ethambutol pharmacokinetics in a cohort of tuberculosis patients.

Antimicrob Agents Chemother. 2006;50(4):1170–7.

12.Conte JE Jr et al. Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid. Antimicrob Agents Chemother. 2002 Aug;46(8):2358–64.

13.Prideaux B et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. 2015 Oct;21(10):1223–7.

14.Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberc Edinb Scotl. 2010 Sep;90(5):279–92.

15.Pouplin T et al. Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infect Dis. 2016 Apr 2;16:144.

16.DonaldP,SirgelF,BothaF,SeifartH,ParkinD,andVandenplasM.The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis. Am J Respir Crit Care Med. 1997;156:895–900.

17.Donald P et al. The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid. Clin Infect Dis. 2004;39:1425–30.

18.Almeida D et al. Paradoxical effect of isoniazid on the activity of rifampin–pyrazinamide combination in a mouse model of tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4178–84.

19.Chigutsa E et al. Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):38–45.

20.Rockwood N et al. Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis. Clin Infect Dis. 2017 May 15;64(10):1350–9.

21.Sterling TR et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155–66.

22.Wang P-Y, Xie S-Y, Hao Q, Zhang C, and Jiang B-F. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: A meta-analysis. Int J Tuberc Lung Dis. 2012 May;16(5):589–95.

23.Wang F-J, Wang Y, Niu T, Lu W-X, Sandford AJ, and He J-Q. Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: Evidence from 26 studies. J Clin Pharm Ther. 2016 Jun;41(3):334–40.

24.van der Watt JJ, Harrison TB, Benatar M, and Heckmann JM. Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: A systematic review. Int J Tuberc Lung Dis. 2011 Jun;15(6):722–8.

25.van der Watt JJ, Benatar MG, Harrison TB, Carrara H, and Heckmann JM. Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy. Int J Tuberc Lung Dis. 2015 Nov;19(11):1312–9.

26.Wen X, Wang J-S, Neuvonen PJ, and Backman JT. Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes. Eur J Clin Pharmacol. 2002 Jan;57(11):799–804.

27.Court MH et al. Isoniazid mediates the CYP2B6*6 genotypedependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6.

Antimicrob Agents Chemother. 2014 Jul;58(7):4145–52.

28.Singh N, Golani A, Patel Z, and Maitra A. Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis. Br J Clin Pharmacol. 2008 Mar;65(3):418–22.

29.World Health Organisation. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. World Health Organization. 2014. Available from: http://www.who.int/tb/ publications/childtb_guidelines/en/

30.Kim YG et al. Decreased acetylation of isoniazid in chronic renal failure. Clin Pharmacol Ther. 1993 Dec;54(6):612–20.

31.Malone R, Fish D, Spiegel D, Childs J, and Peloquin C. The effect of hemodialysis on isoniazid, rifampicin, pyrazinamide and ethambutol. Am J Respir Crit Care Med. 1999;159:1580–4.

32.Campbell E et al. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001;104:901–12.

33.Peloquin C, Namdar R, Singleton M, and Nix D. Pharmacokinetics of rifampin under fasting conditions with food and with antacids. Chest 1999;115:12–8.

34.Stott KE et al. Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: A systematic review and meta-analysis. J Antimicrob Chemother. 2018 Apr 26.

35.Chigutsa E et al. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: Dosing implications. Antimicrob Agents Chemother. 2011 Sep;55(9):4122–7.

36.Sloan DJ et al. Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017;61(7).

37.Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M, and Yokoi T. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: Rifampicin, rifabutin, and rifapentine. Biochem Pharmacol. 2011 Dec 1;82(11):1747–56.

38.Martin P, Riley R, Back DJ, and Owen A. Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells. Br J Pharmacol. 2008 Feb;153(4):805–19.

39.Chirehwa MT et al. Model-based evaluation of higher doses of rifampin using a semimechanistic model incorporating autoinduction and saturation of hepatic extraction. Antimicrob Agents Chemother. 2016;60(1):487–94.

40.Svensson RJ et al. A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses. Clin Pharmacol Ther. 2018 Apr;103(4):674–83.

41.Conte JE, Golden JA, Kipps JE, Lin ET, Zurlinden E. Effect of sex and AIDS status on the plasma and intrapulmonary pharmacokinetics of rifampicin. Clin Pharmacokinet. 2004;43(6):395–404.

42.Boeree MJ et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058–65.

43.Boeree MJ et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: A multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39–49.

44.Khan FA et al. Treatment of active tuberculosis in HIV-coinfected patients: A systematic review and meta-analysis. Clin Infect Dis. 2010 May 1;50(9):1288–99.

45.Sharma SK, Sharma A, Kadhiravan T, and Tharyan P. Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. In: The Cochrane Library. John Wiley & Sons, Ltd, 2013 [cited 2018 May 8]. Available from: http://cochranelibrary-wiley.com/ doi/10.1002/14651858.CD007545.pub2/full

46.Aarnoutse RE et al. Pharmacokinetics, tolerability, and Bacteriological response of rifampin administered at 600, 900, and 1,200 milligrams daily in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017 Oct 24 [cited 2018 May 8];61(11). Available from: https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC5655063/

47.Acocella G. Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet. 1978;3:108–27.

48.Lehloenya RJ, Todd G, Badri M, and Dheda K. Outcomes of reintroducing anti-tuberculosis drugs following cutaneous adverse drug reactions. Int J Tuberc Lung Dis. 2011 Dec;15(12):1649–57.

49.Virgilio R. Rifampicin-dependent antibodies during intermittent treatment. Scand J Respir Dis Suppl. 1973;84:83–6.

50.Aquinas M et al. Adverse reactions to daily and intermittent rifampicin regimens for pulmonary tuberculosis in Hong Kong. Br Med

J.1972 Mar 25;1(5803):765–71.

51.Rae J, Johnson M, Lippmann M, and Flockhart D. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: Studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther. 2001;299(3):849–57.

52.Niemi M, Backman J, Fromm M, Neuvonen P, and Kivisto K. Pharmacokinetic interactions with rifampicin; clinical relevance. Clin Pharmacokinet. 2003;42(9):819–50.

53.Semvua HH, Kibiki GS, Kisanga ER, Boeree MJ, Burger DM, and Aarnoutse R. Pharmacological interactions between rifampicin and antiretroviral drugs: Challenges and research priorities for resource-limited settings. Ther Drug Monit. 2015 Feb;37(1):22–32.

54.Decloedt EH, Maartens G, Smith P, Merry C, Bango F, and McIlleron

H.The safety, effectiveness and concentrations of adjusted lopinavir/ ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy. PLOS ONE 2012 Mar 7 [cited 2018 May 10];7(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296695/

55.Zhang Y, and Mitchison D. The curious characteristics of pyrazinamide: A review. Int J Tuberc Lung Dis. 2003 Jan;7(1):6–21.

56.Werngren J, Sturegård E, Juréen P, Ängeby K, Hoffner S, and Schön

T.Reevaluation of the critical concentration for drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide using wild-type MIC distributions and pncA gene sequencing.

Antimicrob Agents Chemother. 2012 Mar;56(3):1253–7.

57.McGrath M et al. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother. 2014 Feb 1;69(2):292–302.

58.Peloquin CA, Bulpitt AE, Jaresko GS, Jelliffe RW, James GT, and Nix DE. Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids. Pharmacotherapy 1998 Dec;18(6):1205–11.

59.Lacroix C et al. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol. 1989;36(4):395–400.

60.Conte J, Golden J, Duncan S, McKenna E, and Zurlinden E. Intrapulmonary concentrations of pyrazinamide. Antimicrob Agents Chemother. 1999;43:1329–33.

61.Kempker RR et al. Lung tissue concentrations of pyrazinamide among patients with drug-resistant pulmonary tuberculosis.

Antimicrob Agents Chemother. 2017;61(6).

62.Via LE et al. Host-mediated bioactivation of pyrazinamide: implications for efficacy, resistance, and therapeutic alternatives. ACS Infect Dis. 2015 May 8;1(5):203–14.

63.Diacon AH et al. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med. 2015 Apr 15;191(8):943–53.

64.Fox W, Ellard GA, and Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units 1946–1986, with subsequent relevant publications. Int J Tuberc Lung Dis. 1999;3(10):S231–79.

65.Yuen CM et al. Association between regimen composition and treatment response in patients with multidrug-resistant tuberculosis: A prospective cohort study. PLoS Med. 2015 Dec;12(12):e1001932.

66.Pasipanodya JG, and Gumbo T. Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used. Antimicrob Agents Chemother. 2010 Jul;54(7):2847–54.

67.Gao XF et al. Rifampicin plus pyrazinamide versus isoniazid for treating latent tuberculosis infection: A meta-analysis. Int J Tuberc Lung Dis. 2006 Oct;10(10):1080–90.

68.Mandal AK, and Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol. 2015;77:323–45.

69.Holdiness MR. Antituberculosis drugs and breast-feeding. Arch Intern Med. 1984 Sep;144(9):1888.

70.Stamatakis G et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clin Nephrol. 1988 Oct;30(4):230–4.

71.Lacroix C et al. Haemodialysis of pyrazinamide in uraemic patients. Eur J Clin Pharmacol. 1989;37(3):309–11.

72.British Thoracic Society Standards of Care Committee and Joint Tuberculosis Committee. Milburn H et al. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 2010 Jun;65(6):557–70.

73.Peloquin CA, Bulpitt AE, Jaresko GS, Jelliffe RW, Childs JM, and Nix DE. Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids. Antimicrob Agents Chemother. 1999 Mar;43(3):568–72.

74.Alghamdi WA, Al-Shaer MH, and Peloquin CA. Protein binding of first-line antituberculous drugs. Antimicrob Agents Chemother. 2018 May 7;62.

75.Peets EA, Sweeney WM, Place VA, Buyske DA. The absorption, excretion, and metabolic fate of ethambutol in man. Am Rev Respir Dis. 1965 Jan;91:51–8.

76.Lee CS, Brater DC, Gambertoglio JG, and Benet LZ. Disposition kinetics of ethambutol in man. J Pharmacokinet Biopharm. 1980 Aug;8(4):335–46.

77.Conte JE Jr, Golden JA, Kipps J, Lin ET, and Zurlinden E. Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations. Antimicrob Agents Chemother. 2001 Oct;45(10):2891–6.

78.Zimmerman M et al. Ethambutol partitioning in tuberculous pulmonary lesions explains its clinical efficacy. Antimicrob Agents Chemother. 2017 Aug 24 [cited 2018 Apr 25];61(9). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571334/

79.Jindani A, Aber V, Edwards E, and Mitchison D. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121:939–49.

80.Chen S-C, Lin M-C, and Sheu S-J. Incidence and prognostic factor of ethambutol-related optic neuropathy: 10-year experience in southern Taiwan. Kaohsiung J Med Sci. 2015 Jul;31(7):358–62.

81.Yang HK, Park MJ, Lee J-H, Lee C-T, Park JS, and Hwang J-M. Incidence of toxic optic neuropathy with low-dose ethambutol. Int J Tuberc Lung Dis. 2016 Feb;20(2):261–4.

82.Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y Acad Sci. 1966 Apr 20;135(2):904–9.

83.Snider DE, and Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med. 1984 Mar;​144(3):589–90.

84.Varughese A, Brater DC, Benet LZ, and Lee CS. Ethambutol kinetics in patients with impaired renal function. Am Rev Respir Dis. 1986 Jul;134(1):34–8.

85.Schön T et al. Wild-type distributions of seven oral second-line drugs against Mycobacterium tuberculosis. Int J Tuberc Lung Dis. 2011 Apr;15(4):502–9.

86.Schön T et al. Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: A breakpoint artefact? J Antimicrob Chemother. 2013 Sep;68(9):2074–7.

87.Narang PK, Lewis RC, and Bianchine JR. Rifabutin absorption in humans: Relative bioavailability and food effect. Clin Pharmacol Ther. 1992 Oct;52(4):335–41.

88.Gatti G, Di Biagio A, De Pascalis CR, Guerra M, Bassetti M, and Bassetti D. Pharmacokinetics of rifabutin in HIV-infected patients with or without wasting syndrome. Br J Clin Pharmacol. 2001 Dec 24;48(5):704–11.

89.Utkin I et al. Isolation and identification of major urinary metabolites of rifabutin in rats and humans. Drug Metab Dispos Biol Fate Chem. 1997 Aug;25(8):963–9.

90.Naiker S et al. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV-infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol. 2014 Nov 19;15:61.

91.Chan SL et al. The early bactericidal activity of rifabutin measured by sputum viable counts in Hong Kong patients with ­pulmonary tuberculosis. Tuber Lung Dis. 1992 Feb;73(1):33–8.

92.Sirgel FA et al. The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: A new method of drug assessment. J Antimicrob Chemother. 1993 Dec;32(6):867–75.

93.Davies G, Cerri S, and Richeldi L. Rifabutin for treating pulmonary tuberculosis. Cochrane Database Syst Rev Online. 2007;(4):CD005159.

94.Tseng AL, and Walmsley SL. Rifabutin-associated uveitis. Ann Pharmacother. 1995 Nov;29(11):1149–55.

95.Williamson B, Dooley KE, Zhang Y, Back DJ, and Owen A. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. Antimicrob Agents Chemother. 2013 Dec;57(12):​ 6366–9.

96.Regazzi M, Carvalho AC, Villani P, and Matteelli A. Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: Focus on drug–drug interactions with rifamycins. Clin Pharmacokinet. 2014 Jun;53(6):489–507.

97.Hennig S et al. Population pharmacokinetic drug–drug interaction pooled analysis of existing data for rifabutin and HIV PIs. J Antimicrob Chemother. 2016 May;71(5):1330–40.

98.Bemer-Melchior P, Bryskier A, and Drugeon HB. Comparison of the in vitro activities of rifapentine and rifampicin against

Mycobacterium tuberculosis complex. J Antimicrob Chemother. 2000 Oct;46(4):571–6.

99.Zvada SP et al. Effect of four different meals types on the population pharmacokinetics of single dose rifapentine in healthy male volunteers. Antimicrob Agents Chemother. 2010 Jun 1 [cited 2010 Jun 15]; Available from: http://www.ncbi.nlm.nih.gov.ezproxy.liv. ac.uk/pubmed/20516273

100.Egelund EF et al. Protein binding of rifapentine and its 25-desace- tyl metabolite in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2014 Aug;58(8):4904–10.

101.Reith K, Keung A, Toren P, Cheng L, Eller M, and Weir S. Disposition and metabolism of C14-rifapentine in healthy volunteers. Drug Metab Dispos. 1998;26(8):732–8.

102.Conte JE, Golden JA, McQuitty M, Kipps J, Lin ET, and Zurlinden E. Effects of AIDS and gender on steady state plasma and intrapulmonary ethionamide concentrations. Antimicrob Agents Chemother. 2000;44(5):1337–41.

103.Sarathy JP et al. Prediction of drug penetration in tuberculosis lesions. ACS Infect Dis. 2016 Aug 12;2(8):552–63.

104.Rosenthal IM et al. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med. 2007 Dec;4(12):e344.

105.Sirgel FA et al. The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med. 2005 Jul 1;172(1):128–35.

106.Dorman SE et al. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: Study 29 of the tuberculosis trials consortium. J Infect Dis. 2012 Oct 1;206(7):1030–40.

107.Dorman SE et al. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med. 2015 Feb 1;191(3):333–43.

108.Dooley KE et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther. 2012 May;91(5):881–8.

109.Weiner M et al. Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection. J Pediatr Infect Dis Soc. 2014 Jun 1;3(2):132–45.

110.Keung AC, Eller MG, and Weir SJ. Pharmacokinetics of rifapentine in patients with varying degrees of hepatic dysfunction. J Clin Pharmacol. 1998 Jun;38(6):517–24.

111.Angeby KA et al. Wild-type MIC distributions of four fluoroquinolones active against Mycobacterium tuberculosis in relation to current critical concentrations and available pharmacokinetic and pharmacodynamic data. J Antimicrob Chemother. 2010 May;65(5):946–52.

112.Stass H, and Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother. 1999 May;43(Suppl B):83–90.

113.Lettieri J, Vargas R, Agarwal V, and Liu P. Effect of food on the pharmacokinetics of a single oral dose of moxifloxacin 400 mg in healthy male volunteers. Clin Pharmacokinet. 2001;40(Suppl 1):19–25.

114.Stass H, Dalhoff A, Kubitza D, and Schühly U. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects.

Antimicrob Agents Chemother. 1998 Aug;42(8):2060–5.

115.Soman A, Honeybourne D, Andrews J, Jevons G, and Wise R. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother. 1999 Dec;44(6):835–8.

116.Capitano B et al. Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults. Chest 2004 Mar;125(3):965–73.

117.Heinrichs MT et al. Moxifloxacin target site concentrations in patients with pulmonary TB utilizing microdialysis: A clinical pharmacokinetic study. J Antimicrob Chemother. 2018 Feb 1;73(2):477–83.

118.Alffenaar JWC et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis. 2009 Oct 1;49(7):1080–2.

119.Johnson JL et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605–12.

120.Ziganshina LE, Titarenko AF, and Davies GR. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). Cochrane Database Syst Rev. 2013;6:CD004795.

121. Gillespie SH et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1577–87.

122.Jindani A et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1599–608.

123.Falzon D et al. Resistance to fluoroquinolones and second-line injectable drugs: Impact on multidrug-resistant TB outcomes. Eur Respir J. 2013 Jul;42(1):156–68.

124.Fox GJ, Benedetti A, Mitnick CD, Pai M, and Menzies D, Collaborative Group for meta-analysis of individual patient data in MDR-TB. Propensity score-based approaches to confounding by indication in individual patient data meta-analysis: Nonstandardized treatment for multidrug resistant tuberculosis. PLOS ONE 2016;11(3):e0151724.

125.Florian JA, Tornøe CW, Brundage R, Parekh A, and Garnett CE. Population pharmacokinetic and concentration—QTc models for moxifloxacin: Pooled analysis of 20 thorough QT studies. J Clin Pharmacol. 2011 Aug;51(8):1152–62.

126.Weiner M et al. Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. Antimicrob Agents Chemother. 2007 Aug;51(8):2861–6.

127. Njiland H et al. Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin Infect Dis. 2007;45(8):1001–7.

128.Padberg S et al. Observational cohort study of pregnancy outcome after first-trimester exposure to fluoroquinolones. Antimicrob Agents Chemother. 2014 Aug;58(8):4392–8.

129.Palacios E et al. Drug-resistant tuberculosis and pregnancy: Management and treatment outcomes of 38 cases in Lima, Peru. Clin Infect Dis. 2009 May 15;48(10):1413–9.

130.Stass H, Kubitza D, Halabi A, and Delesen H. Pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone, in patients with renal dysfunction. Br J Clin Pharmacol. 2002 Mar;53(3):232–7.

131.Czock D et al. Pharmacokinetics of moxifloxacin and levofloxacin in intensive care unit patients who have acute renal failure and undergo extended daily dialysis. Clin J Am Soc Nephrol CJASN. 2006 Nov;1(6):1263–8.

132.Barth J, Jäger D, Mundkowski R, Drewelow B, Welte T, and Burkhardt O. Singleand multiple-dose pharmacokinetics of intravenous moxifloxacin in patients with severe hepatic impairment. J Antimicrob Chemother. 2008 Sep;62(3):575–8.

133.Lee LJ, Hafkin B, Lee ID, Hoh J, and Dix R. Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects. Antimicrob Agents Chemother. 1997 Oct;41(10):2196–200.

134.Fish DN, and Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet. 1997 Feb;32(2):101–19.

135.Rodvold KA, Danziger LH, and Gotfried MH. Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults. Antimicrob Agents Chemother. 2003 Aug;47(8):2450–7.

136.Conte JE, Golden JA, McIver M, and Zurlinden E. Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects. Int J Antimicrob Agents. 2006 Aug;28(2):114–21.

137.Kempker RR et al. Cavitary penetration of levofloxacin among patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2015;59(6):3149–55.

138.Prideaux B, ElNaggar MS, Zimmerman M, Wiseman JM, Li X, and Dartois V. Mass spectrometry imaging of levofloxacin distribution in TB-infected pulmonary lesions by MALDI-MSI and continuous liquid microjunction surface sampling. Int J Mass Spectrom. 2015 Feb 1;377:699–708.

139.Thwaites GE et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother. 2011 Jul;55(7):3244–53.

140.Koh W-J et al. Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2013 Oct 1;188(7):858–64.

141el-Sadr WM et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). Clin Infect Dis. 1998 May;26(5):1148–58.

142.Noel GJ, Goodman DB, Chien S, Solanki B, Padmanabhan M, and Natarajan J. Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings. J Clin Pharmacol. 2004 May;44(5):464–73.

143.Bidell MR, and Lodise TP. Fluoroquinolone-associated tendinopathy: Does levofloxacin pose the greatest risk? Pharmacotherapy 2016;36(6):679–93.

144.Zhang L, Wei M, Zhao C, and Qi H. Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes. Acta Pharmacol Sin. 2008 Dec;29(12):1507–14.

145.Cahill JB, Bailey EM, Chien S, and Johnson GM. Levofloxacin secretion in breast milk: A case report. Pharmacotherapy 2005 Jan;25(1):116–8.

146.Juréen P et al. Wild-type MIC distributions for aminoglycoside and cyclic polypeptide antibiotics used for treatment of Mycobacterium tuberculosis infections. J Clin Microbiol. 2010 May;48(5):1853–8.

147.Zhu M, Burman WJ, Jaresko GS, Berning SE, Jelliffe RW, and

Peloquin CA. Population pharmacokinetics of intravenous and intramuscular streptomycin in patients with tuberculosis. Pharmacotherapy 2001 Sep;21(9):1037–45.

148.Dijkstra JA et al. Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis. Int J Antimicrob Agents. 2015 Sep;46(3):332–7.

149.Najmeddin F et al. Evaluation of epithelial lining fluid concentration of amikacin in critically ill patients with ventilator-associated pneumonia. J Intensive Care Med. 2018 Jan 1;885066618754784.

150.Ellard GA, Humphries MJ, and Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis. 1993 Sep;148(3):650–5.

151.Donald PR et al. The early bactericidal activity of amikacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2001 Jun;5(6):533–8.

152.Donald PR et al. The early bactericidal activity of streptomycin. Int

JTuberc Lung Dis. 2002 Aug;6(8):693–8.

153.Peloquin CA et al. Aminoglycoside toxicity: Daily versus thriceweekly dosing for treatment of mycobacterial diseases. Clin Infect Dis. 2004 Jun 1;38(11):1538–44.

154.Sturdy A et al. Multidrug-resistant tuberculosis (MDR-TB) treatment in the UK: A study of injectable use and toxicity in practice. J Antimicrob Chemother. 2011 Aug;66(8):1815–20.

155.Harris T, Bardien S, Schaaf HS, Petersen L, De Jong G, and Fagan

JJ.Aminoglycoside-induced hearing loss in HIV-positive and HIVnegative multidrug-resistant tuberculosis patients. South Afr Med J Suid-Afr Tydskr Vir Geneeskd. 2012 May 8;102(6 Pt 2):363–6.

156.Kranzer K, Elamin WF, Cox H, Seddon JA, Ford N, and Drobniewski

F.A systematic review and meta-analysis of the efficacy and safety of N-acetylcysteine in preventing aminoglycoside-induced ototoxicity: Implications for the treatment of multidrug-resistant TB. Thorax 2015 Nov;70(11):1070–7.

157.Shin S et al. Hypokalemia among patients receiving treatment for multidrug-resistant tuberculosis. Chest 2004 Mar;125(3):974–80.

158. Alsultan A, and Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: An update. Drugs. 2014 Jun 1;74(8):839–54.

159.Vorherr H. Drug excretion in breast milk. Postgrad Med. 1974 Oct;56(4):97–104.

160.Armstrong DK, Hodgman T, Visconti JA, Reilley TE, Garner WL, and Dasta JF. Hemodialysis of amikacin in critically ill patients. Crit Care Med. 1988 May;16(5):517–20.

161.Eschenauer GA, Lam SW, and Mueller BA. Dose timing of aminoglycosides in hemodialysis patients: A pharmacology view. Semin Dial. 2016;29(3):204–13.

162.Heifets L, Simon J, and Pham V. Capreomycin is active against non-replicating M tuberculosis. Ann Clin Microbiol Antimicrob. 2005;4(6).

163.Black HR, Griffith RS, and Peabody AM. Absorption, excretion and metabolism of capreomycin in normal and diseased states. Ann N Y Acad Sci. 1966 Apr 20;135(2):974–82.

164.Schwartz W. Capreomycin compared with streptomycin in original treatment of pulmonary tuberculosis. XVI. A report of the Veterans Administration-Armed Forces Cooperative. Study on the Chemotherapy of Tuberculosis. Am Rev Respir Dis. 1966 Dec;94(6):858–64.

165.Aquinas M, and Citron K. Rifampicin, ethambutol and capreomycin in pulmonary tuberculosis, previously treated with first and second line drugs: Results of two years treatment. Tubercle 1972;53(153–65).

166.Lehmann CR et al. Capreomycin kinetics in renal impairment and clearance by hemodialysis. Am Rev Respir Dis. 1988 Nov;138(5):1312–3.

167.Zheng J et al. Para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem. 2013 Aug 9;288(32):23447–56.

168.Brown KA, and Ratledge C. The effect of p-aminosalicylic acid on iron transport and assimilation in mycobacteria. Biochim Biophys Acta. 1975 Apr 7;385(2):207–20.

169.Mitchison DA, and Monk M. Comparison of solid and liquid medium sensitivity tests of tubercle bacilli to para-aminosalicylic acid. J Clin Pathol. 1955 Aug;8(3):229–36.

170.Peloquin CA, Zhu M, Adam RD, Singleton MD, and Nix DE. Pharmacokinetics of para-aminosalicylic acid granules under four dosing conditions. Ann Pharmacother. 2001 Nov;35(11):1332–8.

171.Donald PR, and Diacon AH. Para-aminosalicylic acid: The return of an old friend. Lancet Infect Dis. 2015 Sep;15(9):1091–9.

172.Hughes NC et al. Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe. Pharmacogenetics. 1998 Feb;8(1):55–66.

173.Lauener H, and Favez G. The inhibition of isoniazid inactivation by means of PAS and benzoyl-PAS in man. Am Rev Respir Dis. 1959 Jul;80(1, Part 1):26–37.

174.de Kock L et al. Pharmacokinetics of para-aminosalicylic acid in HIV-uninfected and HIV-coinfected tuberculosis patients receiving antiretroviral therapy, managed for multidrug-resistant and extensively drug-resistant tuberculosis. Antimicrob Agents Chemother. 2014 Oct;58(10):6242–50.

175.Toskes PP, and Deren JJ. Selective inhibition of vitamin B 12 absorption by para-aminosalicylic acid. Gastroenterology. 1972 Jun;62(6):1232–7.

176.MacgregorAG,andSomnerAR.Theanti-thyroidactionofpara-ami- nosalicylic acid. Lancet (Lond, Engl) 1954 Nov 6;267(6845):931–6.

177.Tran JH, and Montakantikul P. The safety of antituberculosis medications during breastfeeding. J Hum Lact. 1998 Dec;14(4):337–40.

178.Held H, and Fried F. Elimination of para-aminosalicylic acid in patients with liver disease and renal insufficiency. Chemotherapy 1977;23(6):405–15.

179.Malone RS, Fish DN, Spiegel DM, Childs JM, and Peloquin CA. The effect of hemodialysis on cycloserine, ethionamide, para-ami- nosalicylate, and clofazimine. Chest 1999 Oct;116(4):984–90.

180.Hanoulle X et al. Selective intracellular accumulation of the major metabolite issued from the activation of the prodrug ethionamide in mycobacteria. J Antimicrob Chemother. 2006 Oct;58​ (4):768–72.

181.Wang F et al. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007 Jan 22;204(1):73–8.

182.Jenner PJ, Ellard GA, Gruer PJ, and Aber VR. A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man. J Antimicrob Chemother. 1984 Mar;13(3):267–77.

183.Auclair B, Nix DE, Adam RD, James GT, and Peloquin CA. Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrob Agents Chemother. 2001 Mar;45(3):810–4.

184.Zhu M et al. Population pharmacokinetics of ethionamide in patients with tuberculosis. Tuberc Edinb Scotl. 2002;82(2–3):91–6.

185.Lee HW et al. Pharmacokinetics of prothionamide in patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2009 Sep;13(9):1161–6.

186.Schwartz WS. Comparison of ethionamide with isoniazid in original treatment cases of pulmonary tuberculosis. XIV. A report of the Veterans Administration-Armed Forces cooperative study. Am Rev Respir Dis. 1966 May;93(5):685–92.

187.Comparison of the clinical usefulness of ethionamide and prothionamide in initial treatment of tuberculosis: Tenth series of controlled trials. Tubercle 1968 Sep;49(3):281–90.

188.Scardigli A, Caminero JA, Sotgiu G, Centis R, D’Ambrosio L, and Migliori GB. Efficacy and tolerability of ethionamide versus prothionamide: A systematic review. Eur Respir J. 2016;48(3):946–52.

189.Thee S, Zöllner EW, Willemse M, Hesseling AC, Magdorf K, and Schaaf HS. Abnormal thyroid function tests in children on ethionamide treatment. Int J Tuberc Lung Dis. 2011 Sep;15(9):1191–3.

190.Munivenkatappa S et al. Drug-induced hypothyroidism during anti-tuberculosis treatment of multidrug-resistant tuberculosis: Notes from the field. J Tuberc Res. 2016 Sep;4(3):105–10.

191.Bruning JB, Murillo AC, Chacon O, Barletta RG, and Sacchettini JC. Structure of the Mycobacterium tuberculosis D-alanine:D- alanine ligase, a target of the antituberculosis drug D-cycloserine.

Antimicrob Agents Chemother. 2011 Jan;55(1):291–301.

192.Nakatani Y et al. Role of alanine racemase mutations in

Mycobacterium tuberculosis D-cycloserine resistance. Antimicrob Agents Chemother. 2017 Dec;61(12).

193.Zhu M, Nix DE, Adam RD, Childs JM, and Peloquin CA. Pharmacokinetics of cycloserine under fasting conditions and with high-fat meal, orange juice, and antacids. Pharmacotherapy 2001 Aug;21(8):891–7.

194.Baron H, Epstein IG, Mulinos MG, and Nair KG. Absorption, distribution, and excretion of cycloserine in man. Antibiot Annu. 1955 1956;3:136–40.

195.Zhou H et al. Pharmacokinetic properties and tolerability of cycloserine following oral administration in healthy Chinese volunteers: A randomized, open-label, singleand multiple-dose 3-way crossover study. Clin Ther. 2015 Jun 1;37(6):1292–300.

196.Court R et al. Steady state pharmacokinetics of cycloserine in patients on terizidone for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2018 Jan 1;22(1):30–3.

197.Bignall JR. A comparison of regimens of ethionamide, pyrazinamide and cycloserine in re-treatment of patients with pulmonary tuberculosis. Bull Int Union Tuberc. 1968 Dec;41:175–7.

198.Zrilić V, Mijatović M, Mirković S, and Muzikravić T. Results of clinical trials of a new antitubercular agent, terizidone (Terivalidine). Plucne Bolesti Tuberk. 1972 Jun;24(2):89–98.

199.Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, and Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: A meta-analysis. Int J Tuberc Lung Dis. 2013 Oct;17(10):1257–66.

200.Cohen AC. Pyridoxine in the prevention and treatment of convulsions and neurotoxicity due to cycloserine. Ann N Y Acad Sci. 1969 Sep 30;166(1):346–9.

201.Ippolito JA et al. Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit. J Med Chem. 2008 Jun 26;51(12):3353–6.

202.Dookie N, Rambaran S, Padayatchi N, Mahomed S, and Naidoo K. Evolution of drug resistance in Mycobacterium tuberculosis: A review on the molecular determinants of resistance and implications for personalized care. J Antimicrob Chemother. 2018 May;73(5):1138–51.

203.Welshman IR, Sisson TA, Jungbluth GL, Stalker DJ, and Hopkins NK. Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos. 2001 Apr;22(3):91–7.

204.Stalker DJ, and Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet. 2003;42(13):1129–40.

205.McGee B et al. Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2009 Sep;53(9):3981–4.

206.Conte JE, Golden JA, Kipps J, and Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother. 2002 May;46(5):1475–80.

207.Honeybourne D, Tobin C, Jevons G, Andrews J, and Wise R. Intrapulmonary penetration of linezolid. J Antimicrob Chemother. 2003 Jun;51(6):1431–4.

208.Kempker RR et al. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J. 2018 Feb;51(2).

209.Viaggi B et al. Linezolid in the central nervous system: Comparison between cerebrospinal fluid and plasma pharmacokinetics. Scand J Infect Dis. 2011 Sep;43(9):721–7.

210.Dietze R et al. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1180–5.

211.Lee M et al. Linezolid for treatment of chronic extensively drugresistant tuberculosis. N Engl J Med. 2012 Oct 18;367(16):1508–18.

212.Millard J et al. Linezolid pharmacokinetics in MDR-TB: A systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother. 2018 Mar 23;

213.Song T et al. Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis. EBioMedicine 2015 Nov;2(11):1627–33.

214.Bolhuis MS et al. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J. 2013 Dec;42(6):1614–21.

215.Rowe HE, Felkins K, Cooper SD, and Hale TW. Transfer of linezolid into breast milk. J Hum Lact. 2014 Nov;30(4):410–2.

216.El-Assal MI, and Helmy SA. Single-dose linezolid pharmacokinetics in critically ill patients with impaired renal function especially chronic hemodialysis patients. Biopharm Drug Dispos. 2014 Oct;35(7):405–16.

217.Yano T et al. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: A pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem. 2011 Mar 25;286(12):10276–87.

218.Cholo MC et al. Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis. J Antimicrob Chemother. 2006 Jan;57(1):79–84.

219.Faouzi M, Starkus J, and Penner R. State-dependent blocking mechanism of Kv 1.3 channels by the antimycobacterial drug clofazimine. Br J Pharmacol. 2015 Nov;172(21):5161–73.

220.Cholo MC, Mothiba MT, Fourie B, and Anderson R. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline. J Antimicrob Chemother. 2017 Feb 1;72(2):338–53.

221.Nix DEDE, Adam RDRD, Auclair B, Krueger TSTS, Godo PGPG, and Peloquin CACA. Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberc Edinb Scotl. 2004;84(6):365–73.

222.Holdiness MR. Clinical pharmacokinetics of clofazimine. A review. Clin Pharmacokinet. 1989 Feb;16(2):74–85.

223.Gopal M, Padayatchi N, Metcalfe JZ, and O’Donnell MR. Systematic review of clofazimine for the treatment of drug-resis- tant tuberculosis. Int J Tuberc Lung Dis. 2013 Aug;17(8):1001–7.

224.Trébucq A et al. Treatment outcome with a short multidrug-resis- tant tuberculosis regimen in nine African countries. Int J Tuberc Lung Dis. 2018 Jan 1;22(1):17–25.

225.Hwang TJ et al. Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: Analysis of published guidance and meta-analysis of cohort studies. BMJ Open. 2014 Jan 2 [cited 2018 May 14];4(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902362/

226.Yoon H-Y, Jo K-W, Nam GB, and Shim TS. Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease. Int J Tuberc Lung Dis. 2017 Sep 1;21(9):996–1001.

227.Venkatesan K, Mathur A, Girdhar A, and Girdhar BK. Excretion of clofazimine in human milk in leprosy patients. Lepr Rev. 1997 Sep;68(3):242–6.

228.Andries K et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005 Jan 14;307(5707):223–7.

229.Torrea G et al. Bedaquiline susceptibility testing of Mycobacterium tuberculosis in an automated liquid culture system. J Antimicrob Chemother. 2015 Aug;70(8):2300–5.

230.Villellas C et al. Unexpected high prevalence of resistance-asso- ciated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline. J Antimicrob Chemother. 2017 01;72(3):684–90.

231 van Heeswijk RPG, Dannemann B, and Hoetelmans RMW. Bedaquiline: A review of human pharmacokinetics and drug–drug interactions. J Antimicrob Chemother. 2014 Sep;69(9):2310–8.

232.Liu K et al. Bedaquiline metabolism: Enzymes and novel metabolites. Drug Metab Dispos. 2014 May;42(5):863–6.

233.Diacon AH et al. The diarylquinoline TMC207 for multidrug-resis- tant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397–405.

234.Akkerman OW et al. Pharmacokinetics of bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis. Clin Infect Dis. 2016 Feb 15;62(4):523–4.

235.Rustomjee R et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008 Aug;52(8):2831–5.

236.Diacon AH et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: A randomised trial. Lancet 2012 Sep 15;380(9846):986–93.

237.Diacon AH et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21;371(8):723–32.

238.Svensson EM, Murray S, Karlsson MO, and Dooley KE. Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. J Antimicrob Chemother. 2015 Apr;70(4):1106–14.