C H A P T E R

30
Drugs Used in Tuberculosis and Leprosy
C. Padmapriyadarsini1, M.S. Jawahar
Department of Clinical Research, National Institute for Research in Tuberculosis [ICMR], Mayor Sathiyamoorthy road,
Chetput, Chennai
1Corresponding author: E-mail: padmapriyadarsinic@nirt.res.in

TOLERANCE OF HIGH DOSE RIFAMPICIN

Rifampicin (RMP) is the cornerstone of multidrug therapy for Tuberculosis (TB). Its ability to kill both rapidly
metabolizing Mycobacterium tuberculosis as well as those with a limited period of metabolism, the dormant state,
has earned it a unique position in the armamentarium against TB [1E]. RMP is currently being used in the standard
dose of 10 mg/kg or a maximum of 600 mg for a single daily dose as the minimum effective dose in ‘short-course’
combination therapy for active TB in both adults and children. Pharmacokinetic, toxicity and cost arguments are
the three main reasons that led to the 600-mg daily dosing of RMP that eventually made its way into TB treatment
guidelines [2R]. Although termed ‘short-course’ therapy, combination therapy with RMP still requires that TB drugs
be taken for a minimum of 6 months. This becomes burdensome to patients once they become asymptomatic, result-
ing in non-adherence to treatment, drug resistance and treatment failure [3R, 4M].
Recently, there has been an interest in the efficacy of using higher doses of RMP in the combination therapy for TB
with a view to reduce the duration of TB treatment. Evidence from animal experiments has demonstrated enhanced
sterilising activity, increased bacterial killing and decrease in treatment duration with increasing doses of RMP from
10 to 15, 20 or 40 mg/kg [5E, 6E]. Higher doses of RMP (900–1200 mg) have been used in other diseases, including
brucellosis, leishmaniasis and legionnaires disease, without significant tolerability problems [7C, 8C]. However, the
safety of using a higher-than standard dose of RMP for pulmonary TB has to be considered. This is especially true
given the extended duration for which the agent must be given to achieve treatment success.
Flu-like syndrome: In a clinical trial of newly diagnosed smear-positive pulmonary TB, 481 adult Chinese, Malays
and Indians were allocated at random to four regimens of intermittent RMP plus isoniazid (INH). After the initial
2 weeks of daily intensive phase, patients were randomised to twice-weekly INH 15 mg/kg plus RMP 900 or 600 mg,
or once-weekly INH 15 mg/kg plus RMP 900 or 600 mg. Adverse reactions to intermittent RMP occurred in 25% of
patients given once-weekly RMP, but on the other three regimens their incidence was low. Flu-like syndrome was
the most frequently observed adverse event. Its occurrence was associated with both the interval between doses
and RMP dose size during intermittent administration, occurring in 6% of patients on twice-weekly RMP and 16%
of patients on once-weekly RMP (P < 0.001), and in 15% of patients given RMP 900 mg and 7% of those given RMP
600 mg (P < 0.01). Flu-like syndrome was not reported in patients taking daily RMP [9c].
Intermittent high doses of RMP (1200 mg twice weekly with 900 mg of INH) led to RMP sensitisation and antibody
formation; in one study, 11 (22%) of the 49 patients discontinued treatment after developing mostly fever, thrombo-
cytopaenia or renal failure, which is designated as the ‘flu-like syndrome’ [10c].
Hepatotoxicity: The link between RMP and hepatotoxicity has been long known. Further, when used in combina-
tion with other hepatotoxic agents, such as INH, these effects appear to be magnified. Studies have demonstrated
that in addition to the inherent risk of hepatotoxicity with RMP, its dosing scheme may be important to minimising
these risks. This effect was demonstrated in a trial of 822 newly diagnosed pulmonary TB patients who were assigned
randomly to one of three daily RMP–INH regimens: 450, 600 or 750 mg of RIF in combination with 300 mg of INH for
5 months followed by 300 mg of INH and 15 mg of ethambutol (Emb)/kg of body weight for either 12 or 18 months.

Side Effects of Drugs Annual, Volume 36

ISSN: 0378-6080 445
http://dx.doi.org/10.1016/B978-0-444-63407-8.00030-7 © 2014 Elsevier B.V. All rights reserved.
446 30.  DRUGS USED IN TUBERCULOSIS AND LEPROSY

The incidence of adverse reactions requiring the discontinuation of the RMP–INH therapy was quite low ­(3.3 ­percent).
A large proportion of patients (44%) developed increased concentrations of transaminase during therapy with RMP–
INH. These abnormalities were usually transient and, in most cases, of no clinical significance. The incidence of
adverse events requiring treatment interruption or termination with RMP dose of 750 mg was 3.3% overall [11C].
Similarly, Kreis et al., investigating 1200 mg of RMP, found high sputum culture negativity (>93%) by 2 months,
but no adverse events were reported [12c]. A systemic review of 14 randomised controlled trials (4256 participants)
evaluated a range of RMP doses, including doses higher than standard (>10 mg/kg or >600 mg), used as part of com-
bination drug therapies for pulmonary TB [13M]. Hepatotoxicity was rarely observed, and no trend in the occurrence
of hepatotoxicity with RMP dose was evident in these trials.
However, the use of the two-drug combination of RMP (at the normal dose of 10 mg/kg daily) and PZA (at
≤20 mg/kg daily) has resulted in high rates of hepatotoxicity in the treatment of latent TB infection, particularly
among older patients [14c]. Similarly, a combination of daily INH 20 mg/kg with RMP 12 mg/kg was associated with
unacceptable levels of hepatotoxicity in children with tuberculous meningitis [15c]. A recent study has also suggested
an increased incidence of mild (grade 1 or 2) hepatotoxicity with a higher RMP dosing of 600 mg daily in adult TB
patients (46% vs. 20%, P = 0.054), but no patient developed severe hepatotoxicity [16c]. The rhythm of administration
of RMP appears to play a role, as regimens containing daily RMP carry a greater risk of hepatic toxicity than does the
regimen where it is given intermittently.
Others: Most of the other adverse effects, other than gastrointestinal, are thought to be idiosyncratic rather than
dose dependent [17H].
Rifapentine: Rifapentine (RPT) is a semisynthetic rifamycin derivative related to RMP. In a prospective, ran-
domised, double-blind trial of RPT at three doses (600, 900 and 1200 mg) plus INH 15 mg/kg once weekly in the con-
tinuation phase of culture-positive TB among 150 adults, treatment discontinuation was seen in three of 52 (6%), two
of 51 (4%) and three of 47 (6%) in the RPT 600-, 900- and 1200-mg treatment arms, respectively. Only one discontinua-
tion, in the RPT 1200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend
towards more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 10.051). RPT
900 mg, once-weekly dosing appears to be safe and well tolerated [18C]. A Pharmacokinetics study of 35 TB patients
using RPT once-weekly in the continuation phase at 600, 900 and 1200 mg showed infrequent serious adverse effects
of therapy (1 of 35 cases; 3%) and was not linked with a higher RPT area under curve or peak concentration [19c].
In general, higher doses of rifamycins may be better tolerated if administered daily or given 5 days per week. The
Pan African Consortium for the Evaluation of Anti-TB Antibiotics has a sub-consortia HIGHRIF, that is trying to
answer the question ‘What is the right dose of RMP?’ through a series of three clinical trials. One is a maximum toler-
ability study where the RMP dose will be increased step by step and group by group, with and without concurrent
anti-TB drugs (ATDs), in consecutive small groups of 15 TB patients, with the aim of trying to find the maximal toler-
able dose in terms of safety and tolerability. The other is a proof-of-concept Phase II double-blind, placebo-controlled
randomised clinical trial in groups of 50 patients receiving, respectively, 10, 15 or 20 mg/kg of RMP in combination
with standard ATDs to look at safety, tolerability, pharmacokinetic and dynamic parameters. Finally, a larger multi-
centric Phase IIB study will be performed with the maximal tolerable dose [20r].
Adverse reactions to anti-TB drugs occur in about 5% of treatment patients and can be responsible for cessation
or switching the therapy. Major adverse drug reactions (ADRs) are more frequent in subjects being treated with
second-line regimens (16%) compared to in those treated with first-line regimens (2.5%). In a multivariate analysis
of an ongoing natural history cohort study of ADRs, infection with multi-resistant or extensively drug-resistant dis-
ease and a previous history of anti-TB treatment were risk factors for major ADRs with adjusted hazard ratios of 2.2
(p = 0.02) and 1.6 (P = 0.04), respectively [21C].
Liver: A significant number of adult patients on first-line treatment experience hepatotoxicity. In a retrospective
review of 926 pulmonary TB adults identified and followed for 4122.9 person-months (pm), 111 (12.0%) developed
hepatotoxicity after a median 38.0 days from the start of the treatment. Around 3.5% had severe hepatotoxicity. The
most common symptoms were general malaise and poor appetite. The incidence rate of hepatotoxicity was 0.59, 0.69
and 3.71/100 pm for INH, RMP and pyrazinamide (PZA), respectively. Old age, female sex, autoimmune disease,
alcohol intake, human immunodeficiency virus infection, more days with PZA in the past 8–14 days and fewer days
with RMP in the past 15–21 days before hepatotoxicity were independent risk factors for hepatotoxicity during treat-
ment [22C]. A comprehensive database search of the Chinese literature of 21,789 patients has shown tuberculostatics
to be the most common aetiology for drug-induced liver injury (DILI) in China. In western populations, non-steroidal
anti-inflammatory drugs are the most common cause of DILI [23M]. While using second-line ATDs for the treat-
ment of multidrug-resistant TB (MDR-TB), baseline factors associated with hepatotoxicity included elevated alanine
aminotransferase/aspartate aminotransferase (AST)/bilirubin (odds ratio [OR] 53.9, 95%CI [confidence interval]
 Tolerance of high dose Rifampicin 447
6.30–438.7) and renal insufficiency (OR 19.6, 95%CI 2.71–141.6). However, patients treated for MDR-TB who devel-
oped hepatotoxicity during therapy did not have a statistically significant increase in poor outcomes [24c].
Genetic susceptibility: Genetic predisposition may play an important role in increased incidence of ATD-induced
hepatotoxicity (ATDH). A candidate gene-based association study, among 100 unrelated Japanese patients with new
onset pulmonary TB treated with a regimen including INH (400 mg/day) and RMP (450 mg/day) for 6–9 months,
investigated the association between single nucleotide polymorphisms in 10 genes in the antioxidant pathway and
ATDH susceptibility. Eighteen patients in the study developed ATDH. A C/C genotype at rs11080344 in NOS2A, a
C/C genotype at rs2070401 in BACH1 and a G/A or A/A genotype at rs4720833 in MAFK independently conferred
ATDH susceptibility with the last two showing a high statistical significance (P = 0.0006) with an OR of 9.730 [25c].
Thus, a combination of BACH1 and MAFK polymorphisms may be considered as biomarkers to identify high-risk
TB patients for ATDH. Also, there may be an increased risk of ATDH in individuals with null genotypes of glutathi-
one S ­ -transferase mu 1 (GSTM1) polymorphism, especially in East Asians and patients receiving HRZE or HRZES.
­However, polymorphisms of glutathione S-transferase theta 1 (GSTT1) null genotype may have no association with
susceptibility to ATDH, except for patients receiving HRZ [26M].
In a study to investigate the impact of the interaction between environmental risk factors and pharmacogenetic
polymorphisms in four common drug-metabolizing enzymes – N-acetyltransferase 2 [NAT2], GSTT1, GSTM1 and
cytochrome P450 2E1 [CYP2E1], patients carrying multiple, but not single polymorphisms in the NAT2, GSTM1,
GSTT1 and CYP2E1 genes were found to have an increased risk of ADRs, as revealed by a gene–gene interaction
analysis [27c]. Another study, to evaluate the relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms to
mild elevation of liver enzymes (MILE) on 59 TB patients and 40 controls, showed that patients carrying NAT2*5/*5
genotype had an increased susceptibility to MILE (OR: 9.00, 95%CI: 1.46-55.48, p = 0.018). CYP2E1*5B allele (*1A/*5B
plus *5B/*5B genotypes) carriers had a trend for a reduced risk for MILE (OR: 0.34, 95%CI: 0.11–1.03, p = 0.056)
that was confirmed by lower levels of liver markers than CYP2E1*1A/*1A carriers after treatment (p < 0.05). Also,
increased posttreatment Alanine Aminotransferase (ALT), AST and total bilirubin were associated with GSTM1*1/
GSTT1*1 genotypes (p < 0.05) [28c]. Similarly, CYP2E1 c1/c1 genotype was associated with an increased DILI risk
compared to variant genotypes (OR 1.36, 95%CI 1.09–1.69), particularly among the Chinese and Korean population
[29M]. The risk increased from 1.88 (95%CI 1.14–3.09) for CYP2E1 c1/c1 with rapid/intermediate acetylators to 6.44
(95%CI 3.47–11.97) for CYP2E1 c1/c1 with slow acetylators. Compound UGT1A1*27 and UGT1A1* 28 are also asso-
ciated with an increased risk for developing DILI after adjusting for age (OR 13.86; 95%CI 1.08–177.06) [30c].
A randomised controlled clinical trial of 172 Japanese pulmonary TB patients to study the influence of NAT2 geno-
type-guided dosing of INH in a 6-month four-drug standard anti-TB regimen showed that the NAT2 genotype-guided
regimen resulted in a much lower incidence of INH-induced liver injury in the first 8 weeks of therapy – 8% of slow acety-
lators in the standard treatment vs. none of the slow acetylators in the NAT2 genotype-guided treatment developed liver
injury [31C]. There appears to be a potential for the NAT2 genotype-guided dosing stratification of INH in chemotherapy
for TB. NAT2 acetylator status (slow acetylators have a higher risk of DILI) along with gender and ethnicity can also be
regarded as an important risk factor for developing hepatotoxicity [32c]. Liver function testing at 2 weeks is useful for the
prompt identification of a subgroup that develops early DILI and may offer better specificity in ruling out late DILI [33H].
Skin: ATD-induced cutaneous leukocytoclastic vasculitis is very rare but should be considered in the differential
diagnosis of annular non-blanchable macules and papules [34A].
  

• A
 62-year-old Thai man presented with a generalised exanthematous rash on his trunk and
extremities two weeks after Anti-TB therapy (ATT) of INH 300 mg, RMP 450 mg and Emb 800 mg daily was
administered. ATDs were withheld, the exanthematous rashes resolved only to recur a day later as multiple,
­erythematosus-to-purplish, non-blanchable macules and papules with an annular arrangement on his
extremities. The histopathology of the purpuric skin lesion was consistent with leukocytoclastic vasculitis.
The skin lesion improved after the discontinuation of the ATDs and treatment with oral antihistamine and
topical corticosteroid drugs. Streptomycin, Emb and ofloxacin were administered as second-line ATT
during the patient’s hospitalisation. No adverse reactions were observed.
  

ATD-induced hypersensitivity syndrome (HSS) is a serious adverse reaction to ATDs. In a study comparing ATD-
induced HSS in 14 Korean subjects with ATD-tolerant controls and general population, a strong association was
found between ATD-induced HSS with human leukocyte antigen. The frequency of Cw*0401 was much higher in
the cases (50.0%) compared with in ATD-tolerant controls (12.7%, Pc = 0.0204, OR = 6.90) and the general population
(12.8%, Pc = 0.0132, OR = 6.82) [35c]. This suggests that ATD is an important causative agent inducing HSS with dis-
tinct clinical features. The strong association of Cw*0401 with the risk for ATD-induced HSS suggests immunological
involvement in the development of this syndrome.
448 30.  DRUGS USED IN TUBERCULOSIS AND LEPROSY

Haematology: DNA damage in peripheral blood mononuclear cells and total hydrophilic antioxidant capacity in
the plasma from 19 TB patients and healthy tuberculin test-positive controls were evaluated by single-cell gel elec-
trophoresis and inducible isoform Nitric Oxide Synthase (iNOS) expression measured by quantitative polymerase
chain reaction (qPCR). Compared to controls, pulmonary TB patients under treatment presented with increased
DNA damage and increased antioxidant capacity, which diminished during treatment. TB patients showed lower
iNOS expression, but expression tended to increase during treatment [36c].
DRESS syndrome: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse reaction
with a high mortality rate and can occur with ATDs [37A].
  

 41-year-old woman developed florid non-pruritic maculopapular rash all over her body, fever >38∘C, myalgia,
• A
lethargy, mild liver dysfunction, eosinophilia and atypical monocytosis 21 days after the initiation of ATT
with INH, RMP, Emb and PZA for TB cervical lymphadenitis. HHV-7 DNA was detected in her blood by PCR
suggesting infection with or more likely reactivation of HHV-7 as a contributing factor or consequence of this
serious ADR. All four ATDs were stopped on day 24. Within 48 h of the peak abnormality in the blood tests,
her C-reactive protein and liver function tests started to improve. Thirty-five days after all medications were
stopped, a stepwise reintroduction ATT was attempted. However, within 5 h of taking the first dose, the fever
and rash recrudesced. The patient stopped taking the medication, and the symptoms settled within 3 days.
Sequential reintroduction of INH, Emb and rifabutin (RFB; rather than rifampin to try and reduce any cross-
reactivity) was reattempted, but each drug on each occasion led to the rapid occurrence of high fever and rash
requiring cessation of the drug.
  

Developing DRESS leads to significant interruptions in TB treatment and a dilemma as to which ATD can be given
next. If DRESS had developed due to the combination of ATD, reintroduction of any one of the four medications can
cause a re-emergence of symptoms. In such cases, an alternative anti-TB regimen will need to be started.
  

• I n a series of 11 cases of anti-TB DRESS syndrome, all patients had rash and toxic hepatitis. Following
interruption of treatment, systemic corticosteroids were started. TB did not progress under corticosteroid
treatment. The drug most frequently involved was RMP, and re-treatment scheme included levofloxacin, Emb,
streptomycin and cycloserine [38c].
  

Endocrine: Hypothyroidism, previously believed to be rare in MDR-TB treatment, has been reported in 51% of
patients (36% requiring laevothyroxine therapy) on MDR-TB treatment [39R]. The incidence may be higher in a com-
bination regimen that includes both ethionamide and Para-Aminosalicylate Sodium (PAS) as they have an additive
effect in causing hypothyroidism. Also, measuring thyroid-stimulating hormone (TSH) only in symptomatic patients
will miss subclinical cases.
  

• I n a retrospective study of 212 MDR-TB patients who initiated treatment, 186 patients were screened of whom
129 (69%) had hypothyroidism, defined as at least one documented TSH result>10.0 mIU/l; 100 (54%) patients
had a maximum TSH > 20.0 mIU/l. At 93 days after starting MDR-TB treatment, half of the patients had
developed hypothyroidism [40c].
  
Screening all patients, even those without symptoms, for hypothyroidism within 2–3 months of starting MDR-TB
treatment with ethionamide and/or PAS should be considered until prospective studies can inform screening guidelines.
Anaphylaxis: Anaphylaxis to streptomycin (12/284) and to INH (1/284) was reported from a retrospective chart
review of patients managed for spinal TB in southwest China [41c]. Multiple drug hypersensitivity (MDH) has been
observed to both first- and second-line ATDs. Itch, oedema, eosinophilia and fever are the most common features of
MDH. Streptomycin and ofloxacin are associated with the most serious reactions [42c].

ISONIAZID

Isoniazid is relatively safe, with determinants of adverse events being relatively predictable and addressable. In
a study on 11,963 patients to evaluate the feasibility, treatment completion and adverse events of INH preventive
therapy, age was identified as the main determinant of transaminase increase (OR 1.03, 95%CI 1.03–1.04), as were
adverse events of the gastrointestinal (OR 1.02, 95%CI 1.02–1.03), central nervous (OR 1.02, 95%CI 1.02–1.05) and
peripheral nervous systems (OR 1.04, 95%CI 1.02–1.05) [43c].
Endocrine – Administration of INH to patients receiving glimepiride may increase the risk of hypoglycemia
owing to interaction between glimepiride and INH [44A].
  
 Isoniazid 449
• A
 76-year-old woman, with well-controlled type 2 diabetes mellitus treated for a period of 8 years with 4 mg
glimepiride, presented with a positive tuberculin skin test (30 mm) and sputum smear and cultures negative for
mycobacteria. She was diagnosed with latent TB and was started on INH tablets for 9 months. One month after
the initiation of INH, she was admitted because of hypoglycemia, cold sweating, palpitations and lethargy with
serum glucose 1.4 mmol/l (reference values 3.9–5.9 mmol/l), insulin 37.17 μIU/ml (reference values 4–16 μIU/ml).
An oral glucose tolerance test revealed high serum insulin and C peptide, suggesting hyperinsulinaemia. After
INH withdrawal, hypoglycaemia regressed, and glimepiride was reinitiated. Insulin and C peptide elevation
was attributed to the interaction between the two drugs.
  

Hepatotoxicity – A high association has been found between slow acetylators and hepatotoxicity, particu-
larly with regard to allele 5. Therefore, large-scale screening for NAT2 and CYP2E1 genotypes can prove to be
useful in predicting the risk of INH-induced hepatotoxicity [45c]. In a study on 270 Brazilian TB patients on the
role of NAT2 and CYP2E1 on development of hepatotoxicity in patients treated with INH, 18 (6.7%) developed
drug-related hepatotoxicity. The adjusted risk of developing hepatotoxicity was significant in individuals car-
rying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07–8.64). Joint evaluation of the genes revealed a
high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI
1.47–12.37, P = 0.008).
Neurotoxicity – Serotonin toxicity is a rare clinical state, which may be serious and life threatening, and occurs
due to a combination of one serotonergic agent and one monoamine oxidase (MAO) inhibitor. INH is a weak MAO
inhibitor and may interact with serotonergic agents like escistalopram [46A].
  

• A
 43-year-old female on corticosteroids for Takayasu arteritis, INH for suspicious positive tuberculin skin test for
past three months and escistalopram 20 mg/day for past month, developed acute onset of fever and confusion.
Neurological examination revealed fever, rigidity, clonus, bilateral positive Babinsky and Hoffman signs
and hyperactive deep tendon reflexes. Nerve conduction studies were normal, but needle electromyography
demonstrated spontaneous neurogenic changes (fibrillation and positive waves) in her extensor digitorum
brevis, tibialis anterior and gastrocnemius muscles. With the help of this medical history, she was diagnosed as
suffering from serotonergic toxicity, and escistalopram was stopped. In her follow-up, she started to get better
on the third day of drug-free period. After one week, she completely improved. No rigidity, clonus or pyramidal
signs were detected. The repeated electromyography was completely normal.
  

Psychiatry – INH-induced common psychiatric conditions include psychosis, obsessive-compulsive disorders

and mood alterations. INH-induced delirium (with all clinical features of delirium according to Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV) criteria) has been reported recently [47A].
  

• A
 56-year-old homeless man with fever and cough of a 20-day duration, hepatic cirrhosis and abdominal-free
fluid on ultrasonogram abdomen and computed tomography (CT) scan showing left pleural effusion with
thickened parietal pleura was started on INH, RMP and Emb therapy. Over the following days, the patient
developed psychomotor agitation, flapping tremors and became confused, disoriented and hallucinated. A
psychiatric evaluation diagnosed delirium, attributed at first to hepatic insufficiency. Hypertonic glucose
solutions together with lactulose orally and by enemas, and with delorazepam 1 mg tid were given to treat the
agitation, but his state of consciousness did not ameliorate. CT scan of the brain, cerebrospinal fluid examination
and electroencephalogram were normal. Finally, a toxic aetiology of the delirium and psychosis was considered,
and INH therapy was stopped and substituted with moxifloxacin; sedative therapy was also progressively
reduced to haloperidol 1 mg and delorazepam 1 mg once every 2 days. Over the next few days, a rapid and
progressive improvement of the state of consciousness was observed. The hallucinations and delusions
disappeared. His health condition steadily improved, and he was discharged.
  

INH-associated psychosis or delirium may be due to INH acting as an MAO inhibitor, thus preventing the
degradations of catecholamine and serotonin and ultimately leading to an increased concentration of these
neurotransmitters.
Musculoskeletal: INH-induced interstitial pneumonia can occur during the course of anti-TB chemoprophylaxis
in patients with rheumatoid arthritis who are at an increased risk for TB during the TNF-blocker treatment.
  

• A
 56-year-old patient with rheumatoid arthritis, who was started on INH chemoprophylaxis for a positive
tuberculin skin test, developed interstitial pneumonia 2 weeks after the start of INH. The result of Drug
Lymphocyte Stimulation Test (DLST) for INH was positive with the peripheral blood lymphocytes (stimulation
index 208%). Trans-Bronchial Lung Biopsy specimens showed cellular no specific interstitial pneumonia pattern
450 30.  DRUGS USED IN TUBERCULOSIS AND LEPROSY

with alveolitis with moderate inflammatory cell infiltrates including lymphocytes and monocytes. Bacterial
cultures of specimens from venous blood and sputum revealed were negative. Interstitial pneumonia improved
after stopping INH and with corticosteroid treatment [48A].
  

Interstitial pneumonia is usually caused by a mechanism related to hypersensitivity to INH. Its diagnosis is mainly
based on the medication history, lung pathology consistent with drug-induced interstitial pneumonia and the posi-
tive result of the DLST.

RIFAMYCINS

Rifampicin
Nephrotoxicity – RMP is one of the most effective ATDs, but it can rarely lead to adverse reactions of an immuno-
logic nature such as acute renal failure [49A].
  

• A
 57-year-old healthy man on treatment for pulmonary TB presented with haemolysis and severe acute renal
failure. His kidney biopsy showed acute tubulointersitital nephritis with no evidence of granulomas. RMP was
discontinued, and he was treated with fluid repletion, iv furosemide and dialysis therapy. Patient significantly
improved and discharged subsequently.
  

RMP-induced acute tubulointersitital nephritis and/or acute tubular necrosis can occur irrespective of intermit-
tent or continuous RMP therapy [50A].
  

• A
 50-year-old Caucasian male undergoing continuous therapy with RMP for culture confirmed pulmonary
TB developed progressive deterioration of his renal function after 6 weeks of treatment. His serum creatinine
levels rose from 38.9 to 318.2 μmol/L and urine volume also progressively increased to polyuria (8–10 L of
urine/day). Renal biopsy showed focal segmental glomerulosclerosis associated with acute tubulointersitital
nephritis. RMP was discontinued following which his renal function improved and serum creatinine values
returned to normal.
  

A high index of suspicion for RMP-associated acute renal failure should be maintained in patients with pulmo-
nary TB who develop a progressive deterioration of renal function during treatment with RMP.
Anaphylaxis – Clinical manifestations of RMP allergy typically occur as serum sickness and mild cutaneous reac-
tions in 0.5–5% of patients. Severe anaphylactic reaction, though rare, may occur and should be distinguished from
flushing due to PZA [51A]. Prompt diagnosis and treatment by clinicians are vital and can be life saving.
  

• A
 47-year-old Turkish female patient diagnosed with TB of the sacro-iliac joints and terminal ileum was
started on first-line ATT consisting of INH, RMP, PZA and Emb [52S, 53S]. However, she developed severe
ADRs within 5 min of ingestion – in the form of pruritic rash, angioedema localised to the tongue and throat
with increasing difficulty in breathing, resulting in emergency admission. Soon she developed an audible
wheeze in addition to vomiting, abdominal and throat pain, decrease in blood pressure and fever with violent
rigours. ATT was discontinued. Clinical manifestations were swiftly treated with oral prednisolone (30 mg),
cetirizine (10 mg), nebulised salbutamol (2.5 mg), Cyclizine (50 mg) and paracetamol (1 g). The patient was
discharged the same day after resolution of the symptoms. Confirmation of immediate hypersensitivity to
RMP resulted in a change of the treatment regimen to streptomycin, INH, Emb and PZA for 2 months and
INH and Emb for 12 months.
  

RMP can also result in serious drug–drug interactions. Profound hypotension has been reported in a patient who
was treated with two 600-mg doses of rifampin for prophylaxis of infection before surgery [54A]. A significant and
profound drop in arterial blood pressure can occur when patients on RMP receive propofol. However, this phenom-
enon is not seen with thiopental.

Rifabutin
RFB is a semisynthetic derivative of rifampin that is effective for the prophylaxis and treatment of Mycobacterium
avium complex (MAC) infection as well as M. tuberculosis [55S]. Anterior uveitis and hypopyon are well-recognised
and frequently reported complications of RFB treatment; however, posterior involvement is relatively rare. Severe
cases may develop dense vitritis with large yellow–white opacities or panuveitis resembling endophthalmitis [56A].
  
 Ethambutol 451
• A
 17-year-old Eritrean girl with a history of acute myeloid leukaemia, presented with a 5-day history of redness,
tearing and photophobia, which started in her right eye and then involved her left eye. She was diagnosed with
panuveitis. She was on Emb, clarithromycin and RFB for recurrent MAC. RFB dosing was twice as high (300 mg
thrice weekly), and she was no longer on systemic immunosuppressive agents. (She had also received the same
treatment for MAC two years back along with immunosuppressive agents for graft versus host disease.) After
RFB-associated uveitis was diagnosed, her medication was switched over from RFB to moxifloxacin. Topical
corticosteroids were administered every 2 h, and the hypopyon resolved 5 days later.
  

RFB-associated uveitis was initially described in HIV-positive patients, but it may also occur in patients who are
immunocompetent. They may present with uveitis several months after the start of RFB and respond quickly to topi-
cal corticosteroids and discontinuation of RFB. Due to the possible association with low body weight, weight-based
dosing has been suggested as a strategy to prevent uveitic complications.
RFB can rarely cause drug-induced lupus, resembling idiopathic systemic lupus erythromatosis, and may require
a high degree of suspicion by the treating physician [57M].
  

• A
 55-year-old woman with HIV infection, on treatment for TB meningitis, presented with severe generalised
arthralgia of knees, ankles, wrists and recurrent oral ulcers after 5 weeks of ATT. She had no associated fever
or rash. Her antinuclear antibody was a 1:1280 homogeneous pattern, antidouble stranded DNA was negative,
antihistone antibody was strongly positive, anti-Smith and antiribonucleoprotein were negative. Her symptoms
and antinuclear antibody (ANA) resolved within 2 months of stopping RFB while continuing other ATD.

ETHAMBUTOL

Emb is a bacteriostatic antimycobacterial agent associated with ocular toxicity due to optic neuropathies. CMT2A2
is part of the group of genetic disorders (mutation in the mitofusin two gene) that encodes a protein involved in the
process of mitochondrial fusion.
Visual Impairment – A meta-analysis of original studies that prospectively followed all patients treated with an
Emb-containing regimen for active TB has reported a cumulative incidence of any visual impairment in all patients to be
22.5/1000 persons receiving Emb at standard doses for up to 9 months (95%CI 10.2–35), and permanent impairment to
be 2.3/1000 (95%CI 0.3–9.0) [58M]. In reversible cases, resolution of impairment can occur after an average of 3 months.
Genetic predisposition – Emb-induced optic neuropathy occurs in patients with mutations in a related fusion
gene, OPA1, which is responsible for autosomal dominant optic atrophy [59A].
  

• A
 69-year-old lady, with a known history of Charcot–Marie–Tooth disease (CMT2), which is a group of
hereditary sensory and motor peripheral neuropathy, was started on Emb 1200 mg daily, RFB and zithromax.
Three months into the therapy, she complained of acceleration in the progression of her baseline weakness and
functional decline in strength, as she lost the ability to ambulate and became wheelchair dependent within
12 months. Associated with this rapid decline was new onset hoarseness that progressed to vocal cord paralysis,
hypophonia and dyspnoea with rapidly progressive restrictive thoracic dysfunction on pulmonary function
testing. Within 12 months of initiation of Emb, she developed visual loss, which progressed over the subsequent
12–14 months, to near complete bitemporal hemianopsia. Emb was discontinued following which her visual
field defects improved. However, she did not improve with respect to weakness, hoarseness or dyspnoea. As
part of her workup for subacute worsening, genetic testing was performed, which confirmed her diagnosis of
CMT2A2.
  

This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely
susceptible to Emb-induced neurotoxicity. Older age, hypertension (adjusted OR = 1.62, 95%CI 1.16–2.26) and renal
diseases (without end-stage renal disease, adjusted OR = 2.11, 95%CI 1.02 to 4.35; with end-stage renal diseases,
adjusted OR = 3.73, 95%CI 1.79–7.74) are factors associated with increased risk of Emb–induced optic neuropathy.
Patients whose average daily dose was >1200 mg or duration of Emb >3 months were not at elevated risk compared
with those whose prescription was <3 months (OR = 1.35, 95%CI 0.99 to 1.83, adjusted for age, sex, hypertension and
renal diseases) [60C].
Hypersensitivity reactions – Reactions as rash (0.5%) and drug fever (0.3%) and other hypersensitivity reactions,
as ashy dermatosis-like pigmentation, lichenoid eruptions, pulmonary infiltrates and toxic epidermal necrolysis
have been reported with Emb. Both non-immediate (mostly maculopapular rash) and immediate reactions (urticarial
reactions) have been described with these drugs [61A].
  
452 30.  DRUGS USED IN TUBERCULOSIS AND LEPROSY

• A
 66-year-old woman with pulmonary MAC disease was started on streptomycin (2 months), RMP, Emb
and clarithromycin. After 14 months of treatment, she presented with facial erythema and angioedema of
the neck and upper limbs followed by pruritic scaling maculopapular exanthema in the neck, trunk and
upper and lower limbs, associated with mild dyspnoea and no haemodynamic changes. All medications
were stopped, and she was treated with intravenous antihistamines and corticosteroid with complete
resolution in 1 week. Because MAC persisted in the sputum culture, she was restarted with RMP, EMb and
clarithromycin when again she developed similar reactions 3 h after Emb intake. Drugs were again stopped
and the patient recovered. After three such episodes, skin testing was performed, and hypersensitivity to
Emb was diagnosed taking into account the clinical presentation and reproducibility of the reaction upon
re-exposure.
  

In cases of clinically confirmed hypersensitivity reaction to Emb, successful desensitisation is required with lower
incremental doses and reintroduction of offending agent, so as to reach the target dose in few weeks along with the
use of antihistamines and prednisone to induce immunological tolerance.

PYRAZINAMIDE

PZA is one of the most effective ATDs and is generally well tolerated. Anaphylaxis secondary to PZA administra-
tion for tuberculous pleuritis has been recently reported [62A]. The skin prick test with the PZA tablet resulted in
positive findings in a 44-year-old woman with no known allergies or atopic disease, requiring desensitisation before
she could be continued on quadruple anti-TB treatment asymptomatically.
Haematology – Sideroblastic anaemia is a known side effect of both INH and PZA as they inhibit the enzyme
5-aminolevulinic acid synthase-2, catalysing the first step of haeme biosynthesis [63A, 64A].
  

 54-year-old African woman with heterozygous α-thalassaemia was hospitalised because of TB peritonitis.
• A
The bone marrow aspirate showed normal haematopoiesis with absent iron storage and negative cultures for
M. tuberculosis. She was started on INH, RMP, PYZ and Emb. However, INH had to be changed to moxifloxacin
early in the course of therapy due to hepatotoxicity. Haemoglobin dropped progressively to 53 g/l over
6 weeks despite intravenous iron substitution. Mild haemolysis was present with a negative Coombs test and
without hemosiderin in the urine. In the peripheral blood smear, increasing anisocytosis (Red cell distribution
width (RDW), 22.8%), poikilocytosis, polychromasia, target cells and basophilic stippling were noted. Perls’
stain peripheral blood revealed several siderocytes, sideroblasts with a few ring sideroblasts, suggestive of
Sideroblastic anaemia. Bone marrow aspiration showed pronounced dyserythropoiesis and heavily increased
iron stores with numerous ring sideroblasts. PYZ-induced sideroblastic anaemia with intramedullary
haemolysis was suspected, and PYZ was stopped. Pyridoxine was given, with normalisation of haemoglobin
and erythrocyte morphology within 3 months.

FLUOROQUINOLONES

With the exception of ciprofloxacin, fluoroquinolones are theoretically contraindicated in growing children and
adolescents because of reported adverse effects of these drugs on joint cartilage of developing animals. In the context
of MDR-TB in children and adolescents, the benefit–risk ratio of fluoroquinolones treatment appears to favour the
use of these drugs. In a report on six paediatric cases of TB treated with levofloxacin or moxifloxacin, two patients had
adverse effects of fluoroquinolone treatment – one developed bilateral metacarpophalangeal polyarthritis 1 month
after initiation of LFX treatment, requiring the treatment to be stopped. Recovery was complete and rapid, within a
few days. The second case developed transitory arthralgia of both ankles 4 days after initiation of LFX treatment, but
it was not necessary to stop the treatment [65A].

LINEZOLID

In a meta-analysis of 11 studies looking at the safety of linezolid (LNZ) for MDR-TB treatment, the pooled estimate
for the frequency of any adverse events was 61.48% (95%CI 40.15–82.80), with 36.23% (95%CI 20.67–51.79) discon-
tinuing LNZ due to adverse events [66M].
 Bedaquiline (BDQ) 453
Haematology – A casual relationship between LNZ concentrations and the risk of developing drug-related hae-
matological toxicity has been observed in a prospective observational study [67c]. Of the 50 patients, nine developed
haematological toxicity – four patients developed grade 2 thrombocytopaenia, three patients grade 2 anaemia, one
each of grade 2 leukopenia and grade 2 pancytopenia. A significant association between LNZ plasma concentrations
and haematological toxicity was confirmed by multivariate logistic regression analysis including age, serum creati-
nine and concomitant medications as independent variables. Therapeutic drug monitoring may improve the safety
outcome of patients receiving LNZ therapy.
Myopathy: In individuals receiving long-term LNZ therapy, rhabdomyolysis is possible and should be considered
in the differential diagnosis of elevated AST or creatine kinase (CK) level.
  

• A
 37-year-old male with >3-year history of chronic, sputum smear-positive XDR-TB was initiated on LNZ 600 mg
daily per the study protocol. This dose was well tolerated, and after sputum smear conversion, he was randomised,
on day 70 of therapy, to receive a reduced dose of 300 mg of LNZ daily along with companion ATDs. On day 76
of the therapy, as part of his routine blood chemistry monitoring, he was found to have an elevated AST level
of 280 IU/L. He was asymptomatic with regard to this abnormal laboratory finding. Prothionamide and LNZ
treatments were both considered potential causes of the elevated AST level and were discontinued that same day. His
AST level quickly normalised, and LNZ therapy was restarted (without prothionamide) on day 84 of therapy. His
AST level remained normal for >2 months, leading to the conclusion that the elevated AST level was likely a result
of prothionamide-induced hepatotoxicity. On day 155 of therapy, the subject experienced another elevation of the
AST level, to 411 IU/L. In addition, the ALT level was mildly elevated, to 60 IU/L and the CK level was markedly
elevated, to 18,511 IU/L. All TB drugs were stopped, and he was given a diagnosis of rhabdomyolysis and was
hydrated to prevent kidney damage. On further examination, 100% of the isoenzyme of CK in serum was found to be
of skeletal muscle origin. After the LNZ treatment was stopped (on day 155 of the therapy), his abnormal laboratory
values normalised, and his mitochondrial function rebounded to levels slightly higher than they were initially. LNZ
therapy was restarted on day 176, and the subject was warned to avoid excessive physical exertion [68A].
  

This patient’s recurring rhabdomyolysis was likely to have been due to LNZ-induced myopathy. This is sup-
ported by the timeline of events and their resolution with relationship to LNZ use and by the mechanistic plausibility
of the association.
Others: Lactic acidosis, pancreatitis and bone marrow hypoplasia have been reported when LNZ-containing regi-
mens were used to treat children with DR-TB in South Africa [69c].

CYCLOSERINE (CS)

Cycloserine is associated with a higher frequency of psychiatric and CNS-related ADRs than with other second-
line drugs [70M]. The pooled estimate for the frequencies of any ADR from CS was 9.1% (95%CI 6.4–11.7); it was 5.7%
(95%CI 3.7–7.6) for psychiatric ADRs, and 1.1% (95%CI 0.2–2.1) for central nervous system-related ADRs. Terizidone,
a structural analogue of cycloserine, shows a moderately better safety profile.

CLOFAZIMINE

Clofazimine has good activity against drug-resistant strains of Mycobacterium tuberculosis, both in vitro and in animal
studies. In a retrospective record review of 39 MDR-TB patients who received treatment with clofazimine for >1 month
as part of the expanded TB regimen in Shanghai, 34 had adverse events after starting clofazimine. Reddish black skin
discolouration occurred in 31 patients and 16 had the clofazimine dose reduced to manage adverse events. Gastroin-
testinal adverse events occurred in 17 patients, and seven of them had dose reduction to manage adverse event [71c].

BEDAQUILINE (BDQ)

BDQ contributes to the management of MDR-TB by effecting more rapid sputum culture negativity. Nausea
reported in 26% of patients receiving BDQ is the only adverse event reported in a randomised pilot trial of 8 weeks
of BDQ treatment for MDR-TB [72c]. In a phase I pharmacokinetic drug interaction trial, single-dose BDQ was well
tolerated alone and with steady-state efavirenz [73c].
454 30.  DRUGS USED IN TUBERCULOSIS AND LEPROSY

DELAMINID

Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new anti-TB medication that inhibits mycolic
acid synthesis and has shown potent in vitro and in vivo activities against drug-resistant strains of Mycobacterium tuber-
culosis. In a randomised, placebo-controlled, multinational clinical trial, 481 pulmonary MDR-TB patients received dela-
manid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for
2 months in combination with a background drug regimen. Most adverse events were mild to moderate in severity and
were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were
observed, QT prolongation was reported significantly more frequently in the groups that received delamanid [74C].

DAPSONE

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction, mostly drug related
or associated with viral infections. It can also manifest as a reaction to dapsone therapy in the setting of HIV infection
when used as prophylaxis for pneumocystis jirovecii pneumonia [75A].
  

• A
 34-year-old HIV-positive woman presented with a two-week history of widespread erythematosus eruptions
with extensive non-follicular pustules, fever and malaise. Her direct Coombs’ test was positive with raised
reticulocytes supporting haemolysis with a venous methaemoglobin level raised at 3.5%. Although her CD4
cell count was 176 cells/mm3, she had declined combination antiretroviral therapy and was only on dapsone
as prophylaxis for Pneumocystis jirovecii pneumonia since 3 weeks. She was commenced on broad spectrum
intravenous antibiotics, hydrocortisone and fluids. Dapsone was withdrawn in view of the severe rash and
methaemoglobinaemia. By day five, the pustular rash began to desquamate with a significant improvement in
erythema and oedema, methaemoglobin levels normalised following the withdrawal of dapsone. Her clinical
condition improved, and she made a full recovery. Skin biopsy supported the diagnosis of AGEP with histology
revealing intraepithelial and subcorneal neutrophilic pustules with spongiosis.
  

Treatment involves withdrawal of the causative drug and supportive measures. Many cases are self-limiting;
however, severe cases may require systemic steroids. Subjects with A− type of G6PD deficiency can no longer be
regarded as mild variants as these subjects too can have a life-threatening form of dapsone-induced acute haemolytic
anaemia, as shown by Pamba A et al. [76c].
Hypersensitivity reaction: With a prevalence rate of 1.4%, mucosal involvement, hepatitis and higher age were
associated with an increased risk of fatal outcome following hypersensitivity reaction to dapsone [77M].
Hyperbilirubinaemia: Symptomatic hyperbilirubinaemia due to haemolytic anaemia is a potential adverse event
when using the combination of atazanavir and dapsone (for pneumocystis jirovecii pneumonia prophylaxis) in the
treatment of patients with HIV [78A]. Symptoms and laboratory evidence of haemolysis resolved upon discontinua-
tion of dapsone, enabling successful antiretroviral therapy.

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