5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

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\144.\ Pantaleo G, and Harari A. Functional signatures in antiviral T-cell immunity for monitoring virus-associated diseases. Nat Rev Immunol. 2006;6(5):417–23.

\145.\ Casey R et al. Enumeration of functional T-cell subsets by fluo- rescence-immunospot defines signatures of pathogen burden in tuberculosis. PLOS ONE 2010;5(12):e15619.

\146.\ Day CL et al. Functional capacity of Mycobacterium tuberculosis- specific T cell responses in humans is associated with mycobacterial load. J Immunol. 2011;187(5):2222–32.

\147.\ Harari A et al. Dominant TNF-α+ Mycobacterium tuberculosis- specific CD4+T cell responses discriminate between latent infection and active disease. Nat Med. 2011;17(3):372–6.

\148.\ Sester U et al. Whole-blood flow-cytometric analysis of antigenspecific CD4 T-cell cytokine profiles distinguishes active tuberculosis from non-active states. PLOS ONE 2011;6(3):2–8.

\149.\ Lalvani A, and Millington KA. T-cell interferon-γ release assays: Can we do better? Eur Respir J. 2008;32(6):1428–30.

\150.\ Taub DD et al. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med. 1993;177:1809–14.

\151.\ Ruhwald M, Aabye MG, and Ravn P. IP-10 release assays in the diagnosis of tuberculosis infection: Current status and future directions. Expert Rev Mol Diagn. 2012;12(2):175–87.

\152.\ Tebruegge M et al. Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis. Am J Respir Crit Care Med. 2015;192(4):485–99.

\153.\ Naranbhai V et al. Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy. J Infect Dis. 2014;209(4):500–9.

\154.\ Naranbhai V et al. The association between the ratio of monocytes: Lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life. BMC Med. 2014;12:120.

\155.\ Rakotosamimanana N et al. Biomarkers for risk of developing active tuberculosis in contacts of TB patients: A prospective cohort study. Eur Respir J. 2015;46:1095–103.

\156.\ Harada N et al. Comparison of the sensitivity and specificity of two whole blood interferon-gamma assays for M. tuberculosis infection. J Infect. 2008;56(5):348–53.

\157.\ Arend SM, and Uzorka JW. New developments on interferon-γ release assays for tuberculosis diagnosis. Lancet Infect Dis. 2019;19(2):121–2.

\158.\ Menozzi FD et al. Identification of a heparin-binding hemagglutinin present in mycobacteria. J Exp Med. 1996;184:993–1001.

\159.\ Zheng Q et al. Heparin-binding hemagglutinin of Mycobacterium tuberculosis is an inhibitor of autophagy. Front Cell Infect Microbiol. 2017;7(33):1–11.

\160.\ Pethe K et al. The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature. 2001;412:190–4.

\161.\ Meier NR, Jacobsen M, Ottenhoff THM, and Ritz N. A systematic review on novel Mycobacterium tuberculosis antigens and their discriminatory potential for the diagnosis of latent and active tuberculosis. Front Immunol. 2018;9(2476). doi: 10.3389/fimmu.2018.02476.

\162.\ Loxton AG, Black GF, Stanley K, and Walzl G. Heparin-binding hemagglutinin induces IFN-γ+IL-2+IL-17+ multifunctional CD4+ T cells during latent but not active tuberculosis disease. Clin Vaccine Immunol. 2012;19(5):746–51.

\163.\ Hougardy JM et al. Heparin-binding-hemagglutinin-induced IFN-γ release as a diagnostic tool for latent tuberculosis. PLOS ONE 2007;2(10):e926.

\164.\ DeloguGetal.MethylatedHBHAproducedinM.smegmatisdiscriminates between active and non-active tuberculosis disease among RD1responders. PLOS ONE 2011;21. doi: 10.1371/journal.pone.0018315.

\165.\ Wyndham-Thomas C et al. Key role of effector memory CD4+T lymphocytes in a short-incubation heparin-binding hemagglutinin gamma interferon release assay for the detection of latent tuberculosis. Clin Vaccine Immunol. 2014;21:321–8.

\166.\ Chiacchio T et al. Immune characterization of the HBHA-specific response in Mycobacterium tuberculosis-infected patients with or without HIV infection. PLOS ONE 2017;12:e0183846.

\ 167.\ Goletti D et al. Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection. Eur Respir J. 2010;36(1):135–42.

\168.\ Nonghanphithak D, Reechaipichitkul W, Namwat W, Naranbhai V, and Faksri K. Chemokines additional to IFN-γ can be used to differentiate among Mycobacterium tuberculosis infection possibilities and provide evidence of an early clearance phenotype. Tuberculosis 2017;105:28–34.

\169.\ Chegou NN et al. Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting. BMC Infect Dis. 2012;12. doi: 10.1186/1471-2334-12-10.

\170.\ Chegou NN et al. Potential of host markers produced by infection phase-dependent antigen-stimulated cells for the diagnosis of tuberculosis in a highly endemic area. PLOS ONE 2012;7. doi: 10.1371/journal.pone.0038501.

\171.\ Commandeur S et al. Doubleand monofunctional CD4+ and CD8+T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals. Eur J Immunol. 2011;41. doi: 10.1002/eji.201141602.

\172.\ Arroyo L, Marín D, Franken KLMC, Ottenhoff THM, and Barrera LF. Potential of DosR and Rpf antigens from Mycobacterium tuberculosis to discriminate between latent and active tuberculosis in a tuberculosis endemic population of Medellin Colombia. BMC Infect Dis. 2018;18(1):1–9.

\173.\ Alvarez-Corrales N et al. Differential cellular recognition pattern to M. tuberculosis targets defined by IFN-γ and IL-17 production in blood from TB+ patients from Honduras as compared to health care workers: TB and immune responses in patients from Honduras. BMC Infect Dis. 201313;. doi: 10.1186/1471-2334-13-125.

\174.\ Winje BA et al. Stratification by interferon-γ 3 release assay level predicts risk of incident TB. Thorax 2018;73(7):652–61.

\175.\ Gupta RK et al. Quantitative interferon gamma release assays and tuberculin skin test to predict incident tuberculosis: Data from the UK PREDICT Cohort Study. Am J Respir Crit Care Med. 2020;201:984–91.

\176.\ Arroyo L, Rojas M, Franken KLMC, Ottenhoff THM, and Barrera LF. Multifunctional T cell response to DosR and Rpf antigens is associated with protection in long-term Mycobacterium tubercu- losis-infected individuals in Colombia. Clin Vaccine Immunol. 2016;23:813–24

\177.\ De Araujo LS, Da Silva NDBM, Da Silva RJ, Leung JAM, Mello

FCQ, and Saad MHF. Profile of interferon-gamma response to latency-associated and novel in vivo expressed antigens in a cohort of subjects recently exposed to Mycobacterium tuberculosis. Tuberculosis 2015;95:751–7.

\ 178.\ Bai XJ et al. Potential novel markers to discriminate between active and latent tuberculosis infection in Chinese individuals. Comp Immunol Microbiol Infect Dis. 2016;44:8–13.

179.Hozumi H et al. Immunogenicity of dormancy-related antigens in individuals infected with Mycobacterium tuberculosis in Japan. Int J Tuberc Lung Dis. 2013;17:818–24.

180.Belay M et al. Proand anti-inflammatory cytokines against Rv2031 are elevated during latent tuberculosis: A study in cohorts of tuberculosis patients, household contacts and community controls in an endemic setting. PLOS ONE 2015;10. doi: 10.1371/jour- nal.pone.0124134.

181.Delogu G et al. Lack of response to HBHA in HIV-infected patients with latent tuberculosis infection. Scand J Immunol. 2016;84:344–52.

182.Dreesman A et al. Age-stratified T cell responses in children infected with Mycobacterium tuberculosis. Front Immunol. 2017;8. doi: 10.3389/fimmu.2017.01059.

183.Wyndham-Thomas C et al. Contribution of a heparin-binding haemagglutinin interferon-gamma release assay to the detection of Mycobacterium tuberculosis infection in HIV-infected patients: Comparison with the tuberculin skin test and the QuantiFERON®-TB Gold In-tube. BMC Infect Dis. 2015;15(59). doi: 10.1186/s12879-015-0796-0.

184.Schwander SK et al. Pulmonary mononuclear cell responses to antigens of Mycobacterium tuberculosis in healthy household contacts of patients with active tuberculosis and healthy controls from the community. J Immunol. 2000;165:1479–85.

185.Li G et al. Evaluation of a new IFN-γ release assay for rapid diagnosis of active tuberculosis in a high-incidence setting. Front Cell Infect Microbiol. 2017;7(April):1–9.

186.Wilkinson KA, and Wilkinson RJ. Polyfunctional T cells in human tuberculosis. Eur J Immunol. 2010;40(8):2139–42.

187.Fletcher HA et al. T-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun. 2016;7(May). doi: 10.1038/ ncomms11290.

188.Tameris MD et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: A randomised, placebo-controlled phase 2b trial. Lancet 2013;381:1021–8. doi: 10.1016/S0140-6736(13)60177-4.

189.Petruccioli E et al. Assessment of CD27 expression as a tool for active and latent tuberculosis diagnosis. J Infect. 2015;71(526–533). doi: 10.1016/j.jinf.2015.07.009.

190.Portevin D et al. Assessment of the novel T-cell activation markertuberculosis assay for diagnosis of active tuberculosis in children: A prospective proof-of-concept study. Lancet Infect Dis. 2014;14:931–8.

191.Goletti D, Petruccioli E, Joosten SA, and Ottenhoff THM. Tuberculosis biomarkers: From diagnosis to protection. Infect Dis Rep. 2016;8:6568.

192.Schuetz A et al. Monitoring CD27 expression to evaluate Mycobacterium tuberculosis activity in HIV-1 infected individuals in vivo. PLOS ONE 2011;6(11):1–6.

193.Pollock KM et al. T-cell immunophenotyping distinguishes active from latent tuberculosis. J Infect Dis. 2013;208(6):952–68.

194.Riou C, Berkowitz N, Goliath R, Burgers WA, and Wilkinson RJ. Analysis of the phenotype of Mycobacterium tuberculosis-specific CD+ T cells to discriminate latent from active tuberculosis in HIV-uninfected and HIV-infected individuals. Front Immunol. 2017;10(8):968.

195.Parekh MJ, and Schluger NW. Treatment of latent tuberculosis infection. Ther Adv Respir Dis. 2013;7(6):351–6.

196.Landry J, and Menzies D. Preventive chemotherapy. Where has it got us? Where to go next? Int J Tuberc Lung Dis. 2008;12(12):1352–64.

197.Halliday A et al. Stratification of latent Mycobacterium tuberculosis infection by cellular immune profiling. J Infect Dis. 2017;215(9):1480–7.

198.Mistry R et al. Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. J Infect Dis. 2007;195(3):357–65.

199.Agranoff D et al. Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum. Lancet 2006;368:1012–21.

200.Zak DED et al. A blood RNA signature for tuberculosis disease risk: A prospective cohort study. Lancet 2016;387(10035):2312–22.

201.Suliman S et al. Four-gene pan-African blood signature predicts progression to tuberculosis. Am J Respir Crit Care Med. 2018;197(9):1–4.

202.Mahomed H et al. Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa. Int J Tuberc Lung Dis. 2011;15(3):331–6.

203.Singhania A et al. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. Nat Commun. 2018;9(2308):1–17.

204.Dupnik KM et al. Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum. Int J Tuberc Lung Dis. 2018;22(8):950–8.

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206.Sweeney TE, Braviak L, Tato CM, and Khatri P. Genome-wide expression for diagnosis of pulmonary tuberculosis: A multicohort analysis. Lancet Respir Med. 2016;4(3):213–24.

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209.Saunders MJ et al. A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: A prospective derivation and external validation cohort study. Lancet Infect Dis. 2017;17(11):1190–9.

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Introduction Isoniazid Rifampicin Pyrazinamide Ethambutol Rifabutin Rifapentine Moxifloxacin Levofloxacin Aminoglycosides Capreomycin

para-Aminosalicylic acid Thioamides

Cycloserine and terizidone Linezolid

Clofazimine

Bedaquiline

Delamanid Clarithromycin Thiacetazone Carbapenems References

Key sources not specifically cited

INTRODUCTION

Treatment of active and latent tuberculosis (TB) has evolved steadily over the 70 years since the dawn of the antibiotic era with 25 drugs from many distinct classes now in common use in different clinical situations. This diversity is compounded by the need for combination therapy to avoid the emergence of resistance and to shorten the duration of treatment. Although latent infection can be successfully eradicated with monotherapy, treatment of drug-sensitive disease is typically initiated with four drugs and

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up to seven drugs may be used together in multidrug-resistant TB. This complexity is almost unique in the treatment of infectious diseases and poses significant problems in the interpretation of efficacy, toxicity, and drug–drug interaction datawithin and between combination regimens. The ability to co-formulate several agents with differing physico-chemical properties has at times proved challenging and fixed-dose combinations are only available for first-line regimens. Finally, the prevalence of human immunodeficiency virus (HIV) co-infection in people with TB and the need for antiretroviral therapy as early as possible mandates consideration of the mutual impact of treatment for each

disease on the other, particularly the potential for overlapping toxicities, immune reconstitution inflammatory syndrome, and poorer virological efficacy.

Though a considerable body of evidence from randomizedclinical trials has accumulated over the decades in latent infection and drug-sensitive disease, in multidrug-resistant disease such trials are a recent innovation. Similarly, although millions of patients have been treated with first-line regimens, high-quality observational pharmacovigilance data on the toxicity of these regimens are relatively scarce. After a hiatus of 30 years, the recent resumption of drug development efforts in TB and attempts to reexamine and re-purpose the existing drugs has drawn attention to many gaps in fundamental knowledge about the clinical pharmacology of older agents which are gradually being addressed retrospectively by new studies. This chapter attempts to summarize the current state of knowledge about all the drugs that physicians treating TB may be called upon to prescribe for their patients and to point out how the use of some of them may change in the near future as our understanding of their pharmacokinetics (PK) and pharmacodynamics advances.

ISONIAZID

NH2

O NH

single-nucleotide polymorphisms (SNPs) in the gene resulting in decreased activity.9 These mutations result in highly variable rates of acetylation and distinct “fast,” “intermediate,” and “slow” phenotypes, which vary significantly worldwide. Acetylisoniazid undergoes further modification to acetyland diacetylhydrazines. However, 40% of each dose is excreted unchanged in the urine. The t1/2 ranges from 1 to 3.5 hours, plasma Cmax ranges from 3 to 5 µg/mL, and area under the curve (AUC) from 15 to 35 µg/ mL × hour depending on acetylator status.10,11 INH accumulates in epithelial lining fluid (1.2–3.2×) and in alveolar macrophages (2.1×)12 whereas concentrations in pulmonary lesions are similar to plasma.13 Concentrations in cerebrospinal fluid (CSF) are similar to those in plasma.14,15

Pharmacodynamics and efficacy

In monotherapy studies of early bactericidal activity (EBA), INH is the most active anti-TB drug so far evaluated with an EBA0–2 of 0.5 log10 CFU/mL/day which is both dose and exposure dependent.16,17 Dose-titration studies suggest that maximal activity is achieved at a dose of approximately 5 mg/kg. In early Phase III clinical trials of INH monotherapy, cure was achieved in 30% after 6 months but the development of resistance was common. Some recent and conflicting data suggest that INH may be antagonistic to the activity of other agents in the first-line regimen but the impact of these findings on long-term treatment outcomes remains unclear.18–20

N

Structure and activity

Isoniazid (INH) is a synthetic analog of nicotinamide. It is a highly water-soluble weak acid (log P −0.6, pKa 1.8/3.5/9.5, MW 137.14). INH is a pro-drug which is activated by the mycobacterial catalase-peroxidase enzyme KatG1 and targets InhA, an NADHdependent enoyl–acyl carrier protein reductase involved in mycolic acid synthesis.2 In vitro minimum inhibitory concentration (MIC99) for wild-type strains is 0.03–0.25 µg/mL.3 The spontaneous rate of mutations resulting in resistance is approximately 1 in 108.4 Resistance is conferred by mutations in katG (high-level) and/or inhA (low-level).5

Pharmacokinetics/ADME

INH has greater than 90% oral bioavailability and absorption is affected by food which may reduce drug exposure by 12%, but not by antacids.6 The volume of distribution is typically 0.85–1.2 L/kg and plasma protein binding is 20%.7 The primary route of metabolism is N-acetylation to the major metabolite acetylisoniazid through the highly polymorphic NAT2 pathway,8 with numerous

Dosing

The recommended daily dose of INH is 300 mg daily, administered on an empty stomach. For intermittent administration, doses of 15 mg/kg are recommended. Higher doses of up to 20 mg/kg have also been advocated for patients with neurological TB, with inhA mutations and in shorter course regimens for MDR-TB.

Adverse effects

Serious drug-induced liver injury occurs in 2% of people taking INH monotherapy for chemoprophylaxis at standard doses21 and has been associated in meta-analyses with NAT2 polymorphisms predicting slow/intermediate acetylator phenotype.22 The acetylhydrazine metabolite has been identified as a candidate toxigen which may generate additional hepatotoxins through the CYP2E1 pathway. Meta-analyses in predominantly Asian populations suggest that polymorphisms in this pathway may be associated with a higher risk of hepatotoxicity.23 Neurotoxicity of INH is believed to be related to the formation of hydrazones which inhibit enzymes requiring pyridoxal phosphate as a co-factor. The most common manifestation is sensory peripheral neuropathy, which was observed in 2%–12% of patients in early studies and is more common with higher doses, HIV co-infection, and slow acetylator status.24,25 It is reliably prevented by prophylaxis with small doses of pyridoxine (10–50 mg daily). More serious neurological side effects including encephalopathy may occur in overdose and may be counteracted by much higher doses of pyridoxine­ . In addition,

INH is structurally related to iproniazid, one of the first monoamine oxidase inhibitors and can rarely be associated with mood disturbance. INH is also a rare cause of drug-induced systemic lupus erythematosus and of sideroblastic anemia.

Drug interactions

INH is a weak or moderate inhibitor of some CYP isoforms in vitro (CYP1A2, CYP2A6, CYP3A4, and CYP2C19)26 though few confirmed clinically relevant DDIs consistent with these findings have been reported. CYP2B6 slow metabolizers may have clinically important rises in efavirenz plasma concentrations due to INH inhibition of CYP2A6, which is a key accessory metabolic route for these individuals.27 Drugs that are substrates for CYP3A4 or CYP2C19 including anticonvulsants, coumarins, citalopram, diazepam, and theophylline may have reduced clearance and higherplasma concentrations. There may also be potential for enhanced hepatotoxicity of paracetamol through undefined mechanisms.

Special populations

INH is not teratogenic but has been associated with embryocidal effects in animal studies and there are no high-quality human data. However, these risks are balanced by long clinical experience with the drug and in practice INH is routinely prescribed for pregnant women with active TB, though delaying chemoprophylaxis is an option in latent tuberculosis infection (LTBI). The relative infant dose during breastfeeding is approximately 1%, though pyridoxine supplementation for the infant is recommended.28 PK studies in children have resulted in World Health Organization (WHO) recommending that children receive a higher dose of INH (10 mg/kg) to maintain plasma concentrations comparable to adults.29 In chronic renal failure, changes in dosing are not usually recommended but the half-life may be very variable, possibly due to changes in N-acetylation capacity rather than renal function.30 Less than 10% of the drug is removed by hemodialysis31 but INH is usually dosed after a dialysis session. INH should be used with caution and frequent monitoring in patients with liver disease.

RIFAMPICIN

Structure and activity

Rifampicin (RIF) is a semi-synthetic derivative of Rifamycin SV, a natural product of Amycolatopsis mediterranei. It is a moderately lipid-soluble and zwitterionic compound (log P 3.719, pKa 1.7/7.9, MW 822.94). RIF binds to the beta subunit of the mycobacterial DNA-dependent RNA polymerase enzyme, efficiently inhibiting transcription.32 In vitro MIC99 for wild-type strains ranges from 0.03 to 0.5 µg/mL.3 The spontaneous rate of mutation conferring resistance is approximately 1 in 1010.4 Resistance is conferred by mutations clustered in an 81-bp region of the rpoB gene.5

Pharmacokinetics/ADME

RIF has approximately 70% oral bioavailability and absorption is modestly affected by food which may reduce AUC by up to 6%, but not by antacids.33 The volume of distribution is typically 0.5 L/kg and protein binding is 80%.7 At steady state, the t1/2 of RIF is 2 hours, plasma Cmax is approximately 6 µg/mL, and AUC 39 µg/mL × hour.34 RIF is a substrate for the hepatic organic anion transporter SLCO1B1 but there are conflicting reports on the clinical significance of polymorphisms in this gene on bioavailability.35,36 RIF is metabolized by hepatic esterases, possibly arylacetamide deacetylase(AADAC), to the primary metabolites 25-O-desacetyl-rifampicin and 3-formyl-rifampicin.37 These and many other metabolic pathways including multiple CYP isoforms (CYP3A4) are induced by activation by RIF of several orphan nuclear receptors.38 Induction appears to be maximal at a dose of approximately 450 mg and 90% complete after 2 weeks of dosing with AUC decreasing by 45% at steady state at doses of 10 mg/kg daily.39 Non-linear increases in AUC are observed at doses up to 40 mg/kg.40 RIF and its metabolites are excreted in the bile and may undergo enterohepatic recirculation with only approximately 20% of each dose excreted unchanged in the urine.

RIF concentrations are lower than plasma in epithelial lining fluid (0.2×) but RIF accumulates modestly in alveolar macrophages (1.2×).41 Penetration into pulmonary lesions is initially only 0.4 × plasma but accumulates with repeated dosing to greater than 9× in caseum which may explain its unique sterilizing activity.13 Concentrations in CSF at doses of 10 mg/kg are very low, typically failing to exceed wild-type MICs.14,15

Pharmacodynamics/efficacy

In EBA studies, activity appears to increase linearly with no maximum effect identified up to doses of 50 mg/kg42 and doses of up to 35 mg/kg result in more rapid culture conversion.43 RIF has been identified in meta-analyses of Phase III trials as a key determinant of stable cure, particularly when used throughout the regimen and is largely responsible for the shorter duration of modern regimens.44

Dosing

RIF is dosed orally according to weight bands with 600 mg for patients above 50 kg and 450 mg for those below, without food.

The same dose sizes are usually given for intermittent therapy. Higher doses of up to 35 mg/kg have been explored in clinical trials in pulmonary and neurological TB but are not routinely recommended.43

Adverse effects

Hepatotoxicity is not common with RIF monotherapy45 and does not appear to be dose-dependent46 though transient rises in bilirubin and/or transaminases due to hepatic adaptation may occur in the first 2 weeks of treatment.47 RIF may be the most common cause of cutaneous hypersensitivity among first-line drugs.48 Serious hypersensitivity reactions associated with generation of anti-rifamycin antibodies49 have usually been observed during intermittent dosing and appear to be related to the dosing interval rather than the dose size, generating systemic inflammatory responses resulting in a non-specific flu-like syndrome or rarely respiratory distress.50 Similar to other rifamycins, hematological toxicities may occur including hemolytic anemia, leukopenia, and severe thrombocytopenia, the last of which mandates permanent discontinuation of the drug.

Drug–drug interactions

RIF is a strong inducer of multiple CYP isoforms including CYP3A4, CYP2A6, CYP2B6, CYP2C9, and CYP2C19 but not CYP2D6 in vitro.51 Induction of metabolism due to RIF therefore results in numerous DDIs because the majority of prescription drugs are metabolized by one or more of these isoforms. Of particular note, efficacy of oral and injectable contraception is impaired and plasma concentrations of azole antifungals, corticosteroids, immunosuppressants such as cyclosporin and tacrolimus, and opiates will be reduced which may impact their efficacy. In HIVpositive people, doses of non-nucleoside reverse transcriptase and integrase-inhibitors may require adjustment whereas most protease inhibitors, boosted or unboosted by ritonavir, are incompatible with RIF therapy.52,53 Increased doses of PIs have also been associated with unexpectedly high rates of drug-induced liver injury in healthy volunteers, though double doses of lopinavir/ ritonavir achieve acceptable plasma concentrations and appear safe in TB patients.54

Special populations

RIF is teratogenic in animal models at high doses and there is little reliable human data. In practice however the benefits of RIF in treatment of pregnant patients are usually considered to ­outweigh these risks. RIF is excreted in breast milk but the relative infant dose has not been defined. RIF treatment may be associated with neonatal hemorrhage due to hypovitaminosis K. The pediatric dose of RIF has recently been adjusted by the WHO to 15 mg/kg to ensure comparable plasma concentrations with adults.29 No dose adjustments are recommended in renal failure at doses up to 600 mg but saturation of hepatic metabolic pathways at higher doses may lead to accumulation and empirical adjustments may be required. Only 4% of parent drug is ­dialyzed but RIF is generally

dosed after hemodialysis.31 Caution is necessary when prescribing in those with hepatic disease which may disturb metabolic processing and biliary secretion of the drug.

PYRAZINAMIDE

N

H2N

N

O

Structure and activity

Pyrazinamide (PZA) is a synthetic nicotinamide analog which is a pro-drug activated by human and mycobacterial amidases to form pyrazinoic acid (POA). It is a highly water-soluble weak acid (log P −1.88, pKa 0.5, MW 123.11). The mechanism of action remains disputed but it appears that accumulation of protonated POA due to defective efflux mechanisms specific to Mycobacterium tuberculosis damages many important cellular processes including fatty acid synthesis, trans-translation, and energy metabolism.55 In vitro MIC99s for wild-type strains range from <8 to 64 µg/mL.56 The spontaneous rate of mutations conferring resistance is approximately 1 in 105.57 Resistance is associated with mutations in the pncA gene and less commonly in the rpsA gene encoding the ribosomal S1 protein.5

Pharmacokinetics/ADME

Oral bioavailability of PZA in humans has not been determined but it is well-absorbed and not affected by food or antacids.58 The volume of distribution is 0.7 L/kg and protein binding is 40%.7 PZA is metabolized by hepatic microsomal deamidase to POA and subsequently to 5-hydroxy-pyrazinoic acid by xanthine oxidase.59 Only 3% of parent drug is excreted unchanged in the urine. PZA t1/2 is 6–7 hours, plasma Cmax is approximately 35–52 µg/mL, and AUC is 288–386 µg/mL × hour.10,11 PZA accumulates strongly in epithelial lining fluid (20×) but not in alveolar macrophages (0.8×)60 whereas penetration into pulmonary lesions of PZA is approximately 0.7 ×plasma concentrations.13,61 In animal models, relative penetration of POA into lesions appears 2–3-fold higher than that of PZA.62 Concentrations in CSF are similar to those in plasma.14,15

Pharmacodynamics/efficacy

The EBA of PZA over the first 14 days of treatment is 0.036 log10 CFU/mL/day.63 PZA shortened treatment for DS-TB where its maximum impact appeared to occur within the first 2 months64 whereas in MDR-TB resistance to PZA is associated with worse outcomes.65

Dosing

25 mg/kg once daily or 50–70 mg/kg three times per week. Higher daily doses of 35 mg/kg were also used safely in historical studies.

Adverse effects

In early studies of PZA monotherapy with doses of 50 mg/kg or greater, hepatotoxicity occurred in approximately 6% of patients and available data suggest similar rates at lower doses during combination therapy.66 However, 2RZ regimens for LTBI with PZA given intermittently at doses of up to 50 mg/kg were associated with discontinuation rates due to drug-induced liver injury of more than 8%, leading to the removal of the regimen from guidelines.67 Though it can be difficult to judge which individual drug is culpable in combination regimens, current guidelines do not recommend reintroducing PZA after a severe episode of DILI. POA is a high-affinity substrate of the renal organic anion transporter URAT1 (SLC22A12) which stimulates reabsorption of uric acid from the proximal tubule.68 Increased plasma uric acid concentrations may be associated with arthralgia and pruritis which appears to be dose-related66 but very rarely results in clinical gout. PZA may also be associated with significant gastrointestinal intolerance.

Drug interactions

PZA is not expected to cause clinically significant drug interactions but should be used with caution with other potentially hepatotoxic drugs and drugs acting on uric acid metabolism.

Special populations

No relevant animal toxicology data or adequate studies of PZA in pregnancy have been conducted but the drug is routinely prescribed for pregnant women with active TB. PZA is excreted in breast milk with an estimated relative infant dose of approximately 1%.69 Dosing of PZA in children is identical to adults. In chronic kidney disease (CKD) Stage 4, PZA should be dosed thrice weekly to avoid accumulation of POA and uric acid.70 PZA is significantly removed by hemodialysis (45%)31,71 and should be dosed after hemodialysis sessions.72 PZA should be used with caution­ and enhanced liver enzyme monitoring in patients with liver disease.

ETHAMBUTOL

Structure and activity

Ethambutol (ETH) is a water-soluble weak acid (log P −0.14, pKa 6.35/9.35, MW 204.31). The d-isomer is an inhibitor of mycobacterial cell wall arabinotransylferases leading to depletion of arabinogalactan and lipoarabinomannan. In vitro MIC99 for wildtype strains ranges from 0.5 to 4 µg/mL.3 The spontaneous rate of mutations conferring resistance is 1 in 107.4 Resistance is most commonly associated with mutations in the embB gene which codes for the major arabinosyltransferase enzyme and also embR and ubiA which modulate the activity of the arabinosyltransferase pathway.5

Pharmacokinetics/ADME

Oral bioavailability is approximately 80% with minimal effect of food or antacids, reducing AUC by 4% and 10%, respectively.73 The volume of distribution is 0.5–7/kg and protein binding is 12%.74 ETH undergoes hepatic metabolism to 2,2′-ethylene- diamino-dibutyric acid but 70% is excreted unchanged in the urine and elimination is related to renal function.75,76 ETH t1/2

is 2–3 hours, plasma Cmax ranges from 2 to 6 µg/mL, and AUC from 20 to 40 µg/mL × hour. ETH does not accumulate in

epithelial lining fluid but concentrates 26× in alveolar macrophages.77 ETH is also strongly concentrated in pulmonary lesions ( 9–12×).78 Concentrations in CSF are typically 50% or less than those in plasma and frequently below the wild-type MIC.14

Pharmacodynamics/efficacy

The EBA0–2 of ETH is 0.25 log10 CFU/mL/day and 0.177 log10 CFU/ mL/day over the first 14 days of treatment.79 ETH was used as a companion drug for INH and in retreatment regimens for INHresistant disease until the mid-1970s. Its addition to the current first-line regimen is intended to prevent emergence of resistance. However, evidence of its independent efficacy is weak and its contribution to outcomes has not been apparent in meta-analyses in MDR-TB.

Dosing

ETH is dosed at 15–25 mg/kg daily or 50 mg/kg thrice weekly.

Adverse effects

The most serious toxicity of ETH is optic neuritis, which occurs in 0.7%–1.2% of adult patients80,81 and is dose-related.82 Visual loss is permanent in 50% of patients. Screening of acuity and color vision prior to treatment is therefore essential and the drug should be discontinued as soon as this complication is suspected. ETH may also cause disturbance of liver enzymes, pruritis, arthralgia, gastrointestinal disturbance, headache, and confusion.