5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

Drug interactions

ETH is not expected to cause clinically significant drug interactions. Absorption of ETH may be impacted by antacids and should be avoided for at least 2 hours after dosing.

Special populations

ETH is teratogenic in animals at high doses and there are case reports of ophthalmic abnormalities in neonates. In practice, the drug is often prescribed for short periods in pregnant women pending confirmation of INH sensitivity. ETH is excreted in breast milk with a relative infant dose of about 5%.83 PK studies suggest that plasma concentrations in children are significantly lower than those in adults but the same mg/kg dose as for adults is usually recommended. The half-life of ETH is prolonged in renal failure84 and ETH is minimally removed by dialysis ( 1%).31 Three times weekly dosing post-dialysis is recommended with therapeutic drug monitoring to ensure 24-hour trough concentrations are less than 1 µg/mL.72 Administration during peritoneal dialysis is not recommended. There are no changes in dosing or specific cautions for patients with liver disease.

RIFABUTIN

CH3

Structure and activity

Rifabutin (RBT) is a highly lipid soluble zwitterion (log P 4.8, pKa 7.93/8.62, MW 847.005) which is a synthetic spiropiperidyl derivative of RIF. Similar to RIF, it is an inhibitor of mycobacterial DNA-dependent RNA-polymerase. In vitro MIC99s range from 0.008 to 0.064 µg/mL.85 Typical mutations in the rpoB gene associated with RIF resistance such as S531L are also associated with RBT resistance, whereas even unusual mutations such as A516V clearly raise the MIC outside the wild-type range and close to the plasma Cmax of RBT, suggesting that such strains are not likely to be more susceptible to RBT compared to RIF.86

Pharmacokinetics/ADME

Oral bioavailability of RBT is only 20% but AUC is not significantly affected by food (<5%).87 The volume of distribution is much higher than RIF at 8 L/kg with a lower protein binding of 71%.88 RBT metabolism is complex: the primary metabolite is 25-O-desacetyl-RBT but there are 20 others including several hydroxylated metabolites (30-, 31-, and 32-OH).89 Only 5%–10% of a dose is excreted unchanged in the urine. RBT t1/2 is 45 hours,

plasma Cmax is 0.3 µg/mL, and AUC 6.1 µg/mL × hour at a dose of 300 mg once daily.90 No information is available concerning ELF,

alveolar macrophage, or lesion penetration.

Pharmacodynamics/efficacy

RBT at 300 mg daily showed minimal EBA0–2 (0.014 and 0.041 log10 CFU/mL/day) in two separate studies.91,92 However, in Phase III clinical trials, RBT achieved similar rates of stable cure to RIF when substituted into first-line regimens.93

Dosing

RBT is dosed at 5 mg/kg once daily up to 300 mg daily, though doses may be adjusted upward when therapeutic drug monitoring is used.

Adverse effects

Similar to RIF, RBT may cause drug-induced liver injury. RBT may also be associated with anterior uveitis, though this sideeffect was generally observed at doses of 600–1,200 mg daily used to treat Mycobacterium avium infection in HIV-positive individuals in combination with clarithromycin which inhibits RBT metabolism.94 RBT-associated uveitis usually resolves completely within a few weeks of discontinuation of the drug. At doses of 300 mg or below, reports of uveitis have been uncommon in TB patients.93 Arthralgia, skin discoloration, and leukopenia have also been reported.

Drug interactions

RBT is a less potent inducer of CYP isoforms compared to RIF95 and though still prone to the same interactions as RIF, it is often recommended for use with drugs for which RIF would result in unmanageable interactions, particularly HIV protease inhibitors.96 However, unpredictable bidirectional effects may occur especially when boosted PIs are used, resulting in higher concentrations of RBT and/or the 25-O-desacetyl metabolite.97 A reduction of the dose of RBT to 150 mg has been suggested90 and therapeutic drug monitoring is often recommended.

Special populations

RBT is not teratogenic in animal studies but there are no adequate human data on use in pregnancy. No data are available on excretion in breast milk. Doses of 5–10 mg/kg are recommended for

children though no PK data are available. The dose of RBT should be reduced by 50% in CKD4 (CrCl <30 mL/min) and it should be used with caution in advanced liver disease.

RIFAPENTINE

Structure and activity

Rifapentine (RPT) is a highly lipid soluble zwitterionic compound (log P 5.29, pKa 7.01/7.98, MW 877.031). It is a synthetic cyclopentyl derivative of RIF. Similar to RIF, it is an inhibitor of DNA-dependent RNA-polymerase. In vitro wild-type MIC90s are lower than those for RIF, ranging from 0.06 to 0.5 µg/mL.98 The rate of spontaneous mutations resulting in resistance has not been described but is likely to be similar to RIF with a similar distribution of mutations in the rpoB gene.

Pharmacokinetics/ADME

Oral bioavailability of RPT is 70% and there is an important effect of food, with fat content influencing absorption and resulting in an increase in AUC of 30%–80%.99 The volume of distribution is 0.9 L/kg and plasma protein binding is 98%–99%.100 RPT is primarily metabolized to 25-desacetyl-RPT, which is microbiologically active, and subsequently 3-formyl and 3-formyl 25-desacetyl metabolites are formed non-enzymatically in the gut with only 1% excreted unchanged in

the urine.101 The t1/2 of RPT is 13 hours, Cmax is 15 µg/mL, and AUC is 320 µg/mL × hour at a dose of 10 mg/kg. Concentrations in ELF and

AM are 0.1–0.2× and 0.2–0.4×, respectively.102 Though no data on lesion penetration are yet available, unbound concentrations of RPT in ex vivo caseum are as low as in plasma.103

Pharmacodynamics/efficacy

Initial licensing of RPT focused on its use once weekly in the continuation phase of treatment but in recent years daily dosing has been proposed as a route to shortening of first-line therapy. In mouse models, RPT has been associated with a significant shortening of the duration of effective treatment.104 Human EBA studies did not support the improved activity over RIF that was predicted, possibly due to the high protein binding and lack of penetration of caseous lesions.105 A Phase II trial of RPT as a replacement for RIF in

the first-line regimen at a dose of 10 mg/kg suggested no benefit in terms of efficacy.106 Doses of 20 mg/kg however did appear to result in superior culture conversion,107 and Phase III trials using this dose to shorten the first-line regimen to 4 months will report in 2020.

Dosing

The currently licensed dose of RPT for treatment of active TB is 600 mg twice weekly in the intensive phase of treatment and 600 mg once weekly in the continuation phase. For treatment of LTBI, it is administered once weekly according to weight bands up to a maximum dose of 900 mg.

Adverse effects

Similar to RIF, RPT may be associated with drug-induced liver injury and with severe rifamycin hypersensitivity syndromes. Cytopenias and hypoglycemia have also been reported in 5%–10% of recipients.

Drug interactions

In vitro studies agree that RPT is a less potent inducer of CYP3A4 and ABCB1 then RIF95 but a clinical study suggested that AUC of CYP3A4 substrates may be reduced at least as much as RIF.108 For this reason, any CYP-mediated interaction relevant to RIF should be assumed applicable to RPT until further data emerge.

Special populations

RPT is associated with embryopathy in animal models and limited safety data are available from human studies. There are no data on excretion in breast milk. In a recent clinical trial, children were dosed safely at 20–30 mg/kg once weekly for treatment of LTBI.109 RPT PK have not been studied in chronic renal failure or on dialysis and no dosing adjustments for currently recommended intermittent doses have been suggested. However, for daily dosing, accumulation of the drug or its metabolites is possible in advanced renal disease. Though AUC of RPT has been reported as 19%–25% higher in the presence of liver disease, no dosage adjustment has been proposed in such patients.110

MOXIFLOXACIN

O O

F

OH

N N

O

H3C

NH

Structure and activity

Moxifloxacin (MFX) is a moderately water-soluble weak acid (log P 0.01, pKa 5.69–9.42, MW 401.43). It is a synthetic fourthgeneration fluoroquinolone with an 8-methoxy substitution. Fluoroquinolones inhibit the enzymes DNA gyrase and Topoisomerase IV (though the latter is lacking in M. tuberculosis), which are responsible for supercoiling of DNA, resulting in disruption of packing of the bacterial chromosome.5 In vitro MIC99s for wild-type organisms range from 0.03 to 0.5 µg/mL.111 Spontaneous mutation frequency (determined in Mycobacterium fortuitum) is 4 ×10−9 57 with mutations in both the gyrA (particularly codons 90 and 94) and less commonly gyrB genes conferring resistance.5

Pharmacokinetics/ADME

Oral bioavailability of MFX is greater than 90%112 and is not significantly affected by food.113 The volume of distribution is 3 L/ kg with protein binding of 48%.114 MFX does not interact with the CYP system but is a substrate of ABCB1. The major route of elimination is N-sulfoconjugation by sulfotransferase 2A1 with a smaller contribution from glucuronidation by UGT 1A1. Approximately 20% of parent drug is eliminated unchanged in the

urine.112 The t1/2 of MFX is 7 hours, Cmax ranges from 2.5 to 4.5 µg/ mL, and AUC is 25–40 µg/mL × hour at a dose of 400 mg. MFX

concentrates in epithelial lining fluid (1.5–4×) and in alveolar macrophages (9–16×).115,116 It is also concentrated in pulmonary lesions as measured by microdialysis (3.2×)117 and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) imaging (2–3×).13 CSF penetration was 71%–82% in a small series.118

Pharmacodynamics/efficacy

MFX at a dose of 400 mg daily has a moderate EBA0–2 of 0.33 log10 CFU/mL/day119 and modestly accelerated culture con-

version in several Phase IIB studies in DS-TB.120 However, it was not able to shorten first-line treatment to 4 months in two Phase III trials.121,122 In MDR-TB, meta-analyses based on individual patient data support the key role of fluoroquinolones in determining outcome.123,124

Dosing

The recommended dose of MFX is 400 mg once daily, though higher doses of up to 800 mg have been used in MDR-TB clinical trials.

Adverse effects

MFX prolongs the QTc interval by 6.4–14.9 mS at Cmax after a dose of 400 mg125 and should be used with caution in conjunction with other QTc-prolonging agents and in patients with proarrhythmic conditions. Similar to other fluoroquinolones, MFX may also be associated with psychiatric disturbances, a lower seizure threshold in epilepsy and tendinopathy. Raised transaminases and druginduced liver injury have also been described.

Drug interactions

The potential for pathway-mediated drug interactions with MFX is considered low, though two studies have shown a reduction of MFX AUC by 27%–32% when administered with RIF possibly mediated by enhancement of the sulfoconjugation pathway.126,127 However, use with anti-arrhythmics and other drugs impacting QTc is usually contraindicated due to additive prolongation, and attention should also be paid to drugs affecting potassium balance. Co-administration with compounds containing di/trivalent cations should also be avoided.

Special populations

Fluoroquinolones have been associated with cartilage defects in animal models though published human data for short-term exposures during early pregnancy are reassuring.128 However, experience with MFX and with longer exposure is relatively limited.129 Low concentrations of MFX are present in breast milk. A dose of 5 mg/kg has been suggested for children. Renal failure impacts only on clearance of the minority glucoronidated metabolite and no dosing changes are recommended.130 MFX is removed by hemodialysis ( 30%) and it should therefore be dosed after dialysis.131 PK are not significantly altered even in patients with severe hepatic impairment, who do not need dose adjustments.132

LEVOFLOXACIN

H3C

Structure and activity

Levofloxacin (LFX) is a poorly water-soluble weak acid (log P −0.02, pKa 5.45–6.2) with a MW of 361.37. It is a synthetic second­ -generation fluoroquinolone with a third morpholine ring and is the (−)-S optical isomer of ofloxacin, which is a racemic mixture. Similar to MFX, it inhibits DNA gyrase with wild-type MIC99s ranging from 0.125 to 0.5 µg/mL.111 Spontaneous mutation­ frequency (determined in M. fortuitum) is 4 ×10−9 57 with mutations in both gyrA and gyrB conferring resistance.5

Pharmacokinetics and metabolism

Oral bioavailability of LFX is 99%–100% with minimal food effect (AUC reduced <10%).133 The volume of distribution is approximately 1.5 L/kg and protein binding is 24%–38%. In total, 87% of parent drug is excreted unchanged in the urine but two metabolites, desmethyl-levofloxacin and levofloxacin N-oxide have been

identified.134 The t1/2 of LFX is 7.4 hours, Cmax is 15.5 µg/mL, and AUC is 129 µg/mL × hour at a dose of 1,000 mg. LFX concen-

trations in ELF are approximately 2–3× higher and in alveolar macrophages 4–11× higher compared to plasma.135,136 LFX accumulates in pulmonary lesions as measured by microdialysis (1.33×)137 and MALDI-ToF (2×)138). CSF penetration has been estimated to be 74%.139

Pharmacodynamics/efficacy

EBA0–2 of LFX at a dose of 1,000 mg was 0.45 log10 CFU/mL/day, slightly higher than that of MFX.119 LFX at 750 mg daily and MFX produced similar rates of culture conversion at 3 months in a randomized trial of their role in MDR-TB treatment.140 LFX did not improve culture conversion at 2 months when added to the intensive phase in DS-TB.141 Individual patient data meta-analyses support the role of fluoroquinolones in treatment of MDR-TB.

Dosing

LFX is dosed at 750–1,000 mg once daily.

Adverse effects

LFX at a dose of 1,000 mg prolongs the QTc interval by 6 mS at Cmax.142 Among the fluoroquinolones, LFX is believed to have the highest risk of tendinopathy and tendon rupture, though this probably does not exceed 0.1% of exposed patients. Patients who are elderly, have renal failure and/or are co-administered corticosteroids are at highest risk.143 LFX may also be associated with seizures, psychiatric disturbance, peripheral neuropathy, and drug-induced liver injury. It may also cause hemolytic anemia in G6PD deficiency.

Drug interactions

LFX is a weak inhibitor of CYP2C9144 with potential to affect warfarin metabolism and should be used with caution in conjunction with other drugs that prolong the QTc interval.

Special populations

LFX, similar to other fluoroquinolones, has been associated with cartilage abnormalities in animal studies. LFX is excreted in breast milk with a relative infant dose of 0.3%.145 The pediatric dose is 15 mg/kg. The t1/2 of LFX increases to 35 hours and the dose size should be reduced when creatinine clearance is less than 20 mL/min but LFX is removed by hemodialysis (20%–30%) and should be dosed after a session.131 No dosage adjustments are suggested in hepatic impairment.

AMINOGLYCOSIDES

Structure and activity

The aminoglycosides streptomycin (STM), kanamycin (KNM), and amikacin (AMK) are highly water-soluble bases (log P −7.1 to −8.6, pKa 9.75–12.1) with MWs ranging from 581.87 to 585.6. STM and KNM are natural products of Streptomyces griseus and S. kanamyceticus, respectively, whereas AMK is a semi-syn- thetic derivative of KNM. Aminoglycosides bind to A site on the 16S RNA of the 30S subunit of the prokaryotic ribosome, though the binding positions of STM and KNM/AMK are distinct­.5 Wildtype MIC99s range from 0.125 to 2 µg/mL for STM, 0.5 to 4 µg/ mL for KNM, and 0.25 to 1 µg/mL for AMK.146 In M. tuberculosis resistance is usually mediated by target modification­ of the ribosomal S12 protein (rpsL K43R or K88R associated with STM resistance) or 16S RNA (rrs A514C/A908C for STM and A1401G for KAN/AMK resistance). However, mutations in gidB may modify the methylation pattern of the 16S RNA leading to low-level resistance to STM whereas the mycobacterial eis gene codes for an aminoglycoside acetyltransferase enzyme with highest affinity for KNM which may also affect AMK.5

Pharmacokinetics/ADME

Aminoglycosides are not orally bioavailable and are administered parenterally. The volume of distribution is approximately 0.2–0.3 L/kg and protein binding is 20% or less. In total, 95% or more of the parent drug is excreted unchanged in the urine and clearance is highly dependent on renal function. The t1/2 of

all three drugs is 2–3 hours, Cmax is 35–45 µg/mL for daily dosing at 15 mg/kg and 65–80 at 25 mg/kg.147,148 Lung penetration

of aminoglycosides is generally poor and the ELF/plasma ratio in the only existing study of intrapulmonary PK of AMK was 7%–9%.149 No information on lesional concentrations is available. Studies of STM suggest the CSF penetration of 7%–21% of plasma concentrations.150

Pharmacodynamics/efficacy

STM and AMK have weak EBA by comparison with many other agents (0.043 and 0.052 log10 CFU/mL/day, respectively)151,152 but the clinical efficacy of aminoglycosides in both DS and MDR-TB is supported by meta-analyses of clinical trials and observational data showing their impact on long-term outcomes.

Dosing

A total dose of 15 mg/kg intramuscularly or intravenously is recommended for daily dosing which should not exceed 1 g for STR and 1.5 g for KNM and AMK. A dose of 25 mg/kg is recommended for intermittent dosing.

Adverse effects

Aminoglycosides are associated with nephrotoxicity and ototoxicity which is related to the duration of dosing but not to dose size or interval.153 High tone hearing loss is common in

treatment of MDR-TB154,155 and is permanent in about two-thirds of cases. A recent systematic review suggested that co-admin- istration of N-acetylcysteine may reduce the risk of ototoxicity.156 Nephrotoxicity is less common and usually reversible. Hypokalemia and hypomagnesemia due to tubular dysfunction may occur independently of changes in GFR.157 Therapeutic drug monitoring is helpful where available.158 Neuromuscular blockade is a rarer side effect, most marked in patients undergoing anesthesia or with myasthenia gravis.

Drug interactions

Though metabolic interactions are not expected, aminoglycosides should be used with caution in conjunction with other drugs that may affect renal function particularly diuretics, calcineurin inhibitors, vancomycin, and amphotericin B.

Special populations

Aminoglycosides have been associated with fetal ototoxicity in human studies. They are excreted in breast milk with a relative infant dose of 0.5% but due to minimal oral bioavailability are considered unlikely to harm the infant.159 A daily dose of 15–20 mg/kg is recommended for children. The dose of aminoglycosides must be reduced when renal function is altered either by increasing the dosing interval or reducing the dose according to established algorithms. Aminoglycosides are removed by hemodialysis (20+%) and are usually dosed after dialysis.160,161 No dose modifications are suggested in advanced liver disease though they should be used with caution in this situation.

CAPREOMYCIN

NH2

Structure and activity

Capreomycin (CPR) is a highly water-soluble base (−log P −11, pKa 10.3–10.62, MW 766.78). It is a macrocyclic polypeptide natural product derived from Streptomyces capreolus. CPR binds to a unique site on the 16S RNA and appears to block initiation rather than misreading during translation. Wild-type MIC99s range from 1 to 4 µg/mL146 and CPR has greater activity against non-replicating organisms in vitro than the aminoglycosides.162 Resistance is mediated by mutations in rrs (commonly A1401G) and by mutations in tlyA, a ribosomal methyltransferase analogous to eis.5 Hence, cross-resistance with KNM/AMK is common but not with STM.

Pharmacokinetics/ADME

CPR is not orally bioavailable and is administered parenterally. No data are available on volume of distribution or protein binding. CPR is excreted unchanged in the urine with no known metabolites. The t1/2 is 5.2 hours and Cmax is 19–44 µg/mL at a dose of 1,000 mg.163 No data are available for pulmonary, lesion, or CSF penetration.

Pharmacodynamics/efficacy

No EBA data are available for CPR. Evidence for the efficacy of CPR rests on historical clinical trials against STR when combined with PAS in new cases or in combination with RIF and ETH for retreatment.164,165

Dosing

The recommended dose is 15 mg/kg up to a maximum of 1 g daily or 15–25 mg/kg thrice weekly given intramuscularly.

Adverse effects

Nephroand oto-toxicity are the most serious side effects of CPR and similar to the aminoglycosides it may also be associated with neuromuscular blockade. Hypokalemia and hypomagnesemia are more common than with the aminoglycosides.157 Eosinophilia is described on daily dosing and leuko and thromobocytopenia and raised liver enzymes may also occur.

Drug interactions

CPR should be used with caution with drugs known to have synergistic nephroor oto-toxicity.

Special populations

CPR is teratogenic in animals and human data in pregnancy are limited. There are no data on excretion in breast milk. Children are dosed at 15–30 mg/kg daily up to a maximum of 1 g. The dose

size should be reduced at all levels of CKD and therapeutic drug monitoring is recommended. CPR is removed by dialysis and should be dosed after sessions.166 No dosing adjustment is suggested in liver disease.

pARA-AMINOSALICYLIC ACID

O OH

HO

NH2

Structure and activity

para-Aminosalicylic acid (PAS) is a poorly water-soluble weak acid (log P 0.83, pKa 2.19–3.68, MW 153.14). It is a synthetic structural analog of para-aminobenzoic acid. PAS is a prodrug activated by the hydropteroate and dihydrofolate synthases and inhibiting dihydrofolate reductase,167 though it has also been suggested that it may interfere with mycobacterial iron uptake.168 Wild-type MIC99s range from 0.12 to 4 µg/mL.169 Resistance is mediated by mutations in the thyA locus in about 30% of isolates and folC and ribD in vitro.5

Pharmacokinetics/ADME

Absolute bioavailability has not been determined but absorption is improved by food with a higher fat content (50% increase in AUC).170 The apparent volume of distribution is approximately 1 L/ kg and protein binding is 58%–73%.171 The major metabolites are N-acetyl PAS through the NAT1 pathway and p-aminosalicyluric acid which undergoes glycine conjugation. Both are excreted and secreted into the urine. The NAT1 gene is polymorphic but only one uncommon SNP (*14B) has any important impact on PAS PK.172 Inhibition of INH acetylation has been observed in patients

also taking PAS.173 The t1/2 is 3.9 hours and median Cmax is approximately 35 µg/mL at a dose of 4 g twice daily.174 No data are avail-

able for pulmonary or lesion distribution but CSF penetration is believed to be less than 50%.14

Pharmacodynamics/efficacy

PAS at a dose of 15 g once daily had an EBA0–2 of 0.26 log10 CFU/ mL/day.79 Randomized trial evidence on the efficacy of PAS in

DS-TB is sparse for historical reasons and it has not subsequently been identified in IPD meta-analyses as an independent predictor of outcome in MDR-TB.

Dosing

PAS is dosed at 8–12 g per day in 2–3 divided doses with food.

Adverse effects

Gastrointestinal tolerability is the biggest problem with PAS, despite the introduction of improved formulations and diarrhea with clinically significant malabsorption may occur. PAS also specifically reduces B12 uptake, though frank megaloblastic anemia is rare.175 PAS at high doses has been associated with hypothyroidism and goiter,176 the risk of which may be exacerbated when used with thioamides. Severe drug-induced liver injury accompanied by signs of systemic hypersensitivity and eosinophilia is also described.

Drug interactions

PAS may reduce acetylation capacity for INH resulting in higher-plasma concentrations when the drugs are used together. Efavirenz co-administration reduces PAS AUC by 30+%.174 PAS may also affect anticoagulation with vitamin K antagonists.

Special populations

PAS may cause embryopathy in animals and reliable human data are very limited. It is excreted into breast milk with a relative infant dose of 0.01%.177 The recommended dose in children is 200–300 mg/ kg in 2–4 divided doses. No dosage adjustments are suggested in renal failure but PAS is considered relatively contraindicated in severe renal disease due to possible accumulation of the N-acetyl metabolite.178 Removal of PAS by hemodialysis is only 6%.179 The drug should also be used with caution in advanced liver disease.

THIOAMIDES

N

Structure and activity

Ethionamide(ETM)andprothionamide(PTM)arewater-insoluble weak acids (log P 1.33/2.22, pKa 5–11.89/7.31, MW 166.24/180.27). ETM is a synthetic structural analog of nicotinamide and PTM is

an N-propyl derivative of ETM. Both are prodrugs activated by the mycobacterial mono-oxygenase EthA180 and target the same enoyl–acyl reductase enzyme InhA as INH, disrupting mycolic acid synthesis.181 Wild-type MIC99s range from 0.5 to 2 µg/mL for ETM and 0.25 to 1 µg/mL for PTM.85 High-level resistance is usually mediated by mutations in the ethA or inhA genes, though in vitro mshA mutations also confer resistance.5

Pharmacokinetics/ADME

Oral bioavailability is believed to be near 100%182 and is not significantly affected by food (4% change in AUC).183 The volume of distribution is 3.2 L/kg and protein binding is 10%–30%. Both drugs have a complex metabolic pathway involving sulfoxidation, desulfuration, and deamination followed by methylation, and the sulfoxide metabolites are active. Less than 1% of the drugs

are excreted unchanged in the urine. The t1/2 of ETH is 1.9 hours and predicted Cmax is 0.9 µg/mL and AUC 14.4 µg/mL × hour at

a dose of 500 mg twice daily.184 In a recent study of PTH t1/2 was 2.7 hours, Cmax is 2.2 µg/mL and AUC 11 µg/mL × hour at a dose or 250–375 mg twice daily.185 ETM is concentrated 9.7-fold in epi-

thelial lining fluid though concentrations in alveolar cells are 50% or less of plasma.102 No information is available on penetration into lesions. CSF concentrations of ETH are approximately 80% of those in plasma.14 Penetration data are not available for PTM.

Pharmacodynamics/efficacy

No EBA data are available for ETH or PTH. Evidence of efficacy is based on randomized trials in new and retreatment patients shortly before the introduction of RIF186,187 and on evidence of impact on outcomes in individual patient data meta-analyses in MDR-TB.

Dosing

ETH and PTM are dosed at 15–20 mg/kg per day up to a maximum of 1 g. To improve tolerability, the drugs are usually dosed gradually over a period of days. Once daily administration is possible but twice daily dosing is often used because individual doses of greater than 500 mg may not be tolerated.

Adverse effects

Gastrointestinal tolerability of ETH and PTH is poor, though rates of adverse events appear lower with the latter.188 Central nervous system (CNS) disturbance and peripheral neuropathy are described and may be prevented with pyridoxine prophylaxis. Abnormal thyroid function tests may occur in up to 30% of patients on ETH though the clinical significance of these findings is often unclear and resolves after discontinuation of treatment.189,190 Gynecomastia may also occur. In diabetics, ETM and PTM have been associated with hypoglycemia.

Drug interactions

Alcohol may increase the risk of psychological/psychiatric problems as may concomitant use of cycloserine.

Special populations

Thioamides are teratogenic in animal studies and few data human data exist. Concentrations in breast milk have not been studied. The recommended dose in children is 10–20 mg/kg per day in 2–3 divided doses. In severe renal impairment (CrCl <30 mL/min) the dose interval should be not more than daily. ETH is not significantly removed by dialysis (2%).179 Thioamides are contraindicated in severe liver disease.

CYCLOSERINE AND TERIZIDONE

Structure and activity

d-Cycloserine (CS) is a water-soluble weak acid (log P −2.4, pKa 4.21–8.36, MW 102.09). Terizidone (TZ) is a condensation product of two CS molecules with terephthalaldehyde, which acts as a pro-drug. CS is a natural product analog of d-alanine originating from Streptomyces garyphalus. It is a competitive inhibitor of the enzymes alanine racemase and d-alanine:d-alanine ligase, disrupting peptidoglycan synthesis.191 Wild-type MIC99s range from 8 to 32 µg/mL.85 Resistance to CS is uncommon and usually associated with mutations in the alr (alanine racemase) locus.192

Pharmacokinetics/ADME

Oral bioavailability is 65%–90% and absorption is modestly affected by food.193 The volume of distribution is 0.35 L/kg and protein binding is reported as negligible. A total of 60%–70% of parent drug is excreted unchanged in the urine and metabolites have not been characterized.194 The t1/2 of CS is approximately 13

hours, Cmax is 20 µg/mL, and AUC 264 µg/mL × hour at a dose of 250 mg.195 After a dose of 750 mg of TZ, CS median Cmax was 38 µg/mL and AUC was 319 µg/mL × hour with a t1/2 of 14.7 hours.196 No information is available on pulmonary or lesional

concentrations. CSF concentrations are 80%–100% of plasma in meningitis.14

Pharmacodynamics/efficacy

No EBA studies of CS or TZ are available. Weak evidence for their efficacy derives from combination studies in retreatment from the

1960s.197,198

Linezolid  187

Dosing

The usual starting dose of CS and TZ is 250 mg twice daily, increased after 2 weeks to a maximum of 500 mg twice daily, though once daily dosing is rational for both agents and used in some programs.

Adverse effects

The therapeutic index of CS is low with toxicity associated with a plasma concentration threshold of 30 µg/mL. Neuropsychiatric side-effects are common ( 6%) including drowsiness, anxiety, mood disturbance, psychosis, and seizures.199 Pyridoxine prophylaxis of 50–100 mg is usually suggested and higher doses (200– 300 mg) are suggested in counteracting neurotoxicity.200 Vitamin B12 and folate depletion have been reported in patients taking CS which have been associated with megaloblastic or sideroblastic anemia. Rashes due to photosensitivity or hypersensitivity are also described.

Drug interactions

Though potential for metabolic interactions is low, CS should be combined with caution with other medications that may lower seizure threshold, including fluoroquinolones.

Special populations

CS is not teratogenic in animal studies but there is limited experience in pregnancy. It is excreted in breast milk with a relative infant dose of 0.6%.159 Children are dosed at 10–20 mg/kg in two divided doses. CS is contraindicated in severe renal failure and dosing according to therapeutic drug monitoring is recommended for less severe reductions of GFR. The drug is 56% removed by hemodialysis179 so should be dosed after sessions. No dose adjustments are suggested in the presence of liver disease.

LINEZOLID

CH3

O

NH

O

N O

F

N

O

Structure and activity

Linezolid (LZD) is a water-soluble acid (log P 0.64, pKa −0.66– 14.45, MW 337.35). It is a synthetic inhibitor of ribosomal translation which binds to the 23S subunit preventing binding of formyl-methionine tRNA and therefore formation of the initiation complex.201 Wild-type MIC99s for LZD range from 0.125 to 0.5 µg/ mL.85 Resistance is associated in vitro with point mutations in the peptidyl transferase domain of the 23S rRna (rrs gene), particularly G2576T and in the gene rplC which codes for the L3 protein within the 50S subunit. The latter appears to be more clinically relevant.202

Pharmacokinetics/ADME

Oral bioavailability is approximately 100% and is not affected by food.203 The volume of distribution is 0.6 L/kg and protein binding is 31%. Biotransformation by non-enzymatic oxidation of the morpholine ring results in hydroxyethyl and aminoethoxyacetic acid metabolites which are conjugated with glycine and eliminated in the urine. A total of 30% of parent drug is eliminated unchanged

in the urine.204 The t1/2 of LZD is 2.9 hours, Cmax is 10.3 µg/mL, and AUC 66.8 µg/mL × hour at a dose of 600 mg once daily.205 LZD is

concentrated in epithelial lining fluid (4.1–8.4×) but not in alveolar cells (0.14–0.70×).206,207 Concentrations in lesions determined by ex vivo dialysis were 49% of serum.208 CSF exposure is 57% of plasma.209

Pharmacodynamics/efficacy

EBA0–2 of LZD was 0.18 and 0.26 log10 CFU/mL/day at a dose of 600 mg once and twice daily, respectively.210 LZD monotherapy

achieved 87% culture conversion at 6 months in a small trial of patients with XDR-TB.211

Dosing

LZD is usually dosed at 600 mg once daily in TB though higher doses have been used in clinical trials. Twice daily dosing at 300 mg may offer similar efficacy with fewer adverse effects212 but few comparative clinical data exist.

Adverse effects

LZD inhibits protein synthesis in human mitochondria resulting in clinically significant toxicities including myelosuppression, lactic acidosis, and peripheral and optic neuropathy. With prolonged dosing in MDR-TB more than half of patients will ultimately develop peripheral and/or optic neuropathy and 8% discontinue the drug, despite dose reduction.211 Trough concentrations of LZD correlate with mitochondrial dysfunction and risk of toxicity and therapeutic drug monitoring may be useful.213 Sideroblastic anemia has also been described. Nausea and diarrhea are also commonly reported.

Drug interactions

LZD is a weak inhibitor of monoamine oxidase and should usually not be used with MAOIs, selective serotonin reuptake inhibitors, or

triptans due to reports of serotonergic syndrome. Tyramine-rich foods (cheese and pickled fish) should also be avoided. LZD does not interact with CYPs in vitro. Unexpectedly, a recent study showed that LZD plasma exposure is increased by 44% during co-administration of clarithromycin, possibly through interactions with ABCB1214 whereas RIF co-administration also reduces LZD AUC 32%.

Special populations

LZD is embryopathic but not teratogenic in animal studies and there are no adequate human data. LZD is excreted in breast milk with a relative infant dose of 16%.215 Though not recommended by the manufacturer, children have been dosed at 10 mg/kg thrice daily. No dosage adjustment is suggested in mild-moderate renal disease but the drug should be used with caution in severe renal failure (CrCl <30 mL/min) due to accumulation of the major metabolites. LZD and its metabolites are partially removed by hemodialysis (30%–50%).216 No adjustments are specified for patients with liver disease.

CLOFAZIMINE

Cl

Structure and activity

Clofazimine (CFZ) is a highly water-insoluble cationic amphiphilic compound (log P 7.3, pKa 9.29–16.15, MW 473.40). It is a semisynthetic riminophenazine derivative of a natural product derived from the lichen Buella canescens. The mechanism of action has been postulated to be competitive inhibition of the menaquinone substrate of the NADH:quinone oxidoreductase NDH-2, disrupting electron transport and generating reactive oxygen species.217 Additional mechanisms have also been suggested including disruption of the membrane potential through inhibition of potassium uptake channels in M. tuberculosis and eukaryotic cells, which may also explain the observed anti-inflammatory effects of the drug.218,219 Wild-type MIC99s to CFZ range from 0.125 to 0.25 µg/mL.85 The spontaneous rate of mutations associated with resistance in vitro is as low as 1 in 1026 and these are invariably in the locus rv0678 which codes for a repressor protein of the membrane transporter MmpS5-MmpL5. However, these mutations have not been observed in clinical isolates to date.220

Pharmacokinetics/ADME

Oral bioavailability is 45%–62% and is increased 45% by a high-fat meal.221 The volume of distribution is greater than 12 L/kg suggesting extensive tissue distribution and binding but plasma proteinbinding data are not available. Minimal parent drug is excreted unchanged in the urine and the major metabolites are reported to be formed by hydrolytic dehalogenation and deamination, followed by glucoronidation and biliary excretion.222 After a 200 mg dose, the Cmax is 0.13–0.37 µg/mL, and AUC 3.6 µg/mL × hour.221 Though the initial t1/2 is 7.8–15.9 hours this reflects distribution, and the terminal elimination t1/2 is 70 days. No data are available on concentrations in epithelial lining fluid or alveolar cells but CFZ concentrations in the rim of lesions are 10× higher than in plasma, though similar or lower in caseum.13

Pharmacodynamics/efficacy

CFZ at a dose of 100 mg (after loading with 300 mg for 3 days) had no appreciable EBA0–2.63 Though the pooled cure rate of CFZcontaining regimens was 65% in a recent meta-analysis223 and the drug forms part of the 9-month regimen for MDR-TB,224 no comparative or controlled clinical data are currently available to support the independent efficacy of CFZ.

Dosing

CFZ is usually dosed at 100 mg daily with food, though 200 mg may be used for short periods in severe disease.

Adverse effects

CFZ crystals are deposited throughout body tissues during treatment and may be associated with side-effects. The major clinical problem is dose-related tissue, epithelial, and body fluid discoloration which may be associated with dry skin, photosensitivity, and corneal deposits. The discoloration is reversible but only after 6 months or more of treatment. Gastrointestinal discomfort is also common and gastrointestinal obstruction and bleeding have been reported. However, the estimated discontinuation rate of CFZ in a recent meta-analysis was only 0.1%.225 CFZ may also significantly prolong the QTc interval, with a mean change of 40 mS from baseline in a recent series.226

Drug interactions

Very limited clinical data exist on interactions with CFZ but major metabolic interactions are not expected. CFZ should be used with caution with other medications that prolong the QTc interval.

Special populations

CFZ is not teratogenic but has been associated with embryopathy and fetal loss in animal models. There is no reliable human data in pregnancy. The drug is excreted in breast milk with a relative infant dose of 2%.227 The drug crosses the placenta and skin discoloration has been reported in offspring of mothers taking the drug.

Children have been dosed at 1 mg/kg. No dosage modifications are suggested in renal failure or liver disease and the drug is not removed by hemodialysis.179

BEDAQUILINE

H3C

Br

Structure and activity

Bedaquiline (BDQ) is a highly water-insoluble weak base (log P 7.3, pKa 8.91–13.61, MW 555.505). It is a synthetic diarylquinoline that inhibits the mycobacterial ATP synthase.228 Wild-type MICs to BDQ range from 0.008 to 0.25 µg/mL.229 The spontaneous rate of mutations conferring resistance is approximately 1 in 10.8,57 Mutations in the atpE gene selected in vitro are clearly associated with high-level resistance whereas SNPs in the gene rv0678, a regulator of the MmpL5 efflux pump, are found in 6% of clinical MDR-TB isolates prior to treatment but are inconsistently related to changes in MIC.230

Pharmacokinetics/ADME

tion is greater than 150 L/kg and plasma protein binding is >99%. BDQ is metabolized by CYP3A4, CYP2C8, and 2C19 to N-monodesmethyl and further sequentially demethylated metabolites which are excreted in the feces.232 Less than 0.001% of the parent compound is excreted unchanged in the urine. Neither metabolite has significant activity. At steady state dosing

of 200 mg thrice weekly, the Caverage is 0.9 µg/mL with a terminal t1/2 of 20 weeks.231,233 No data on intrapulmonary or lesional con-

centrations are available. A case report suggested that CSF concentrations are undetectable.234

Pharmacodynamics/efficacy

BDQ exhibits modest EBA over the first 14 days of treatment (0.06–0.11 log10 CFU/mL/day).235,236 Culture conversion at 8 weeks