Alternative Second-Line

Drugs for Tuberculosis

TONY LIWA MD
JUNE, 2023
Introduction
The alternative drugs are usually considered (1) in the case
of resistance to the drugs of first choice; (2) in case of failure of
clinical response to conventional therapy; and (3) when expert
guidance is available to deal with the toxic effects.
For many of the second-line drugs, the dosage, emergence of
resistance, and long-term toxicity have not been fully
established.
MDR-TB
Is TB that does not respond to at least isoniazid and rifampicin, the 2
most powerful anti-TB drugs.
The 2 reasons why MDR continues to emerge and spread are
mismanagement of TB treatment and person-to-person transmission.
MDR- and XDR-TB need prolonged treatment duration, from 18 to 24
months after sputum culture conversion, as recommended by the WHO.
A prolonged duration of treatment may lead to poor adherence, higher
cost and undue toxicity.
MDR-TB
When MDR-TB is suspected, start treatment empirically before
culture results become available; obtain molecular drug
susceptibility testing, if possible.
Modify the initial regimen, as necessary, based on susceptibility
results.
Never add a single new drug to a failing regimen.
Administer at least 5 drugs for the intensive phase of treatment
and at least 4 drugs for the continuation phase
XDR-TB
XDR-TB is a rare type of multidrug-resistant
tuberculosis (MDR TB) that is resistant to isoniazid and
rifampin, plus any fluoroquinolone and at least one of
three injectable second-line drugs (i.e., amikacin,
kanamycin, or capreomycin).
Ethionamide
Is chemically related to INH and also blocks the synthesis of mycolic
acids.
It is poorly water soluble and available only in oral form.
It is metabolized by the liver.
Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 μg/mL,
or less.
Some other species of mycobacteria also are inhibited.
Ethionamide
CSF concentrations are equal to those in serum.
A 1 g/d dosage, although effective in the Rx of Tb, is poorly
tolerated because of the intense gastric irritation and
neurologic symptoms that commonly occur.
Ethionamide is also hepatotoxic.
Neurologic symptoms may be alleviated by pyridoxine.
Ethionamide
ETH is administered at an initial dosage of 250 mg once daily,
which is increased in 250 mg increments to the recommended
dosage of 1 g/d (or 15 mg/kg/d) if possible.
The 1 g/d dosage, although theoretically desirable, is seldom
tolerated, and one often must settle for a total daily dose of
500–750 mg.
Ethionamide
Resistance to ethionamide as a single agent develops rapidly in
vitro and in vivo.
There can be low level cross-resistance between isoniazid and
ethionamide.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus.
Daily injection of 1 g intramuscularly results in blood levels of 10
g/mL or more.
Such concentrations in vitro are inhibitory for many mycobacteria,
including MDR strains of MTb.
Capreomycin
Capreomycin (15 mg/kg/d) is an important injectable agent
for treatment of drug-resistant tuberculosis.
Strains of MTb that are resistant to streptomycin or amikacin
usually are susceptible to capreomycin.
Capreomycin
Capreomycin is nephrotoxic and ototoxic.
Tinnitus, deafness, and vestibular disturbances may occur.
The injection causes significant local pain, and sterile
abscesses may occur.
Cycloserine
Cycloserine is an inhibitor of cell wall synthesis.
Concentrations of 15–20 μg/mL inhibit many strains of M
tuberculosis.
Cycloserine is cleared renally, and the dose should be reduced by
half if creatinine clearance is less than 50 mL/min.
Cycloserine
The most serious toxic effects are peripheral neuropathy and CNS
dysfunction, including depression and psychotic reactions.
Pyridoxine 150 mg/d should be given with cycloserine as this
ameliorates neurologic toxicity.
Adverse effects, which are most common during the first 2 weeks of
therapy, occur in 25% or more of patients, especially at higher doses.
Aminosalicylic Acid (PAS)
Aminosalicylic acid is a folate synthesis antagonist that is
active almost exclusively against M tuberculosis.
It is structurally similar to p-aminobenzoic aid (PABA) and
to the sulfonamides.
Pharmacokinetics
Tubercle bacilli are usually inhibited in vitro by PAS, 1–5
μg/mL.
PAS is readily absorbed from the gastrointestinal tract.
The drug is widely distributed in tissues and body fluids
except the cerebrospinal fluid.
Pharmacokinetics
Aminosalicylic acid is rapidly excreted in the urine, in part as
active aminosalicylic acid and in part as the acetylated
compound and other metabolic products.
Very high concentrations of aminosalicylic acid are reached
in the urine, which can result in crystalluria.
PAS
PAS, formerly a first-line agent for Rx of Tb, is used
infrequently now because other oral drugs are better-tolerated.
Gastrointestinal symptoms often accompany full doses of PAS.
Anorexia, nausea, diarrhea, and epigastric pain and burning
may be diminished by giving PAS with meals and with
antacids.
PAS
Peptic ulceration and hemorrhage may occur.
Hypersensitivity reactions manifested by fever, joint pains,
skin rashes, hepatosplenomegaly, hepatitis, adenopathy,
and granulocytopenia, often occur after 3–8 weeks of PAS
therapy, making it necessary to stop PAS administration
temporarily or permanently.
Kanamycin & Amikacin
Kanamycin has been used for Rx of Tb caused by streptomycin-
resistant strains, but the availability of less toxic alternatives (eg,
capreomycin and amikacin) have rendered it obsolete.
The role of amikacin in Rx of Tb has increased with the increasing
incidence and prevalence of MDR-Tb.
 Prevalence of amikacin-resistant strains is low (less than 5%), and
most MDR strains remain amikacin-susceptible.
Amikacin
MTb is inhibited at concentrations of 1 μg/mL or less.
Amikacin is also active against atypical mycobacteria.
There is no cross-resistance between streptomycin and
amikacin, but kanamycin resistance often indicates resistance
to amikacin as well.
Amikacin
Amikacin is indicated for Rx of TB suspected or known
to be caused by streptomycin-resistant or MDR strains.
Amikacin must be used in combination with at least
one and preferably two or three other drugs to which the
isolate is susceptible for Rx of drug-resistant cases.
Ciprofloxacin &
Levofloxacin
Fluoroquinolones are an important recent addition to the
drugs available for Tb, especially for strains that are resistant
to first-line agents.
In addition to their activity against many gram-positive and
gram-negative bacteria, ciprofloxacin and levofloxacin inhibit
strains of MTb at concentrations less than 2 μg/mL.
Fluoroquinolones
They are also active against atypical mycobacteria.
Ofloxacin was used in the past, but levofloxacin is
preferred because it is the L-isomer of ofloxacin, the
active antibacterial component of ofloxacin, and it can be
administered once daily.
Rifabutin (Ansamycin)
This antibiotic is derived from rifamycin and is related to rifampicin.
It has significant activity against MTb, M avium-intracellulare and M
fortuitum.
Its activity is similar to that of rifampicin, and cross-resistance with
rifampin is virtually complete.
Some rifampicin-resistant strains may appear susceptible to rifabutin
in vitro, but a clinical response is unlikely because the molecular basis
of resistance is the same.
Rifabutin
Rifabutin is both substrate and inducer of CYP450 enzymes.
Because it is a less potent inducer, rifabutin is indicated in
place of rifampicin for Rx of Tb in HIV-infected patients who
are receiving concurrent antiretroviral therapy with a PI or
NNRTI (e.g, efavirenz)—drugs which also are CYP450
substrates.
Rifabutin
The usual dose of rifabutin is 300 mg/d
If efavirenz (also a CYP450 inducer) is used, the recommended
dose of rifabutin is 450 mg/d.
Rifabutin is effective in prevention and Rx of disseminated
atypical mycobacterial infection in AIDS patients with CD4
counts below 50/μL.
 It is also effective for preventive therapy of TB, either alone in
a 6-month regimen or with PZA in a 2-month regimen.
Rifapentine
Rifapentine is an analog of rifampicin.
It is active against both M tuberculosis and M avium. It is a
bacterial RNA polymerase inhibitor, and cross-resistance
between rifampicin and rifapentine is complete.
Like rifampicin, rifapentine is a potent inducer of CYP450
enzymes, and it has the same drug interaction profile.
Toxicity is similar to that of rifampicin.
Rifapentine
Rifapentine and its microbiologically active metabolite, 25-
desacetylrifapentine, have a half-life of 13 hours.
Rifapentine is indicated for Rx of Tb caused by rifampin-
susceptible strains.
Whether rifapentine is as effective as rifampicin has not been
established, and rifampicin therefore remains the rifamycin of
choice for Rx of Tb.
Linezolid
Is a synthetic antimicrobial agent
Is active against gram +ve organisms, gram positive rods and
listeria monocytogenes.
Poor activity against gram -ve bacteria
MTB is moderately susceptible, with MIC of 2μg/ml.
Linezolid- M/A
Inhibits protein synthesis by binding to the P site of the 50S
ribosomal subunit and preventing formation of the larger
ribosomal fMet-tRNA complex that initiates protein synthesis.
There is no cross resistance with other drug classes.
Adverse effects
Myelosupression.
Platelet counts should be monitored to in Pt with risk of
bleeding.
Peripheral and optic neuropathy in prolonged use.
Is neither a substrate nor an inhibitor of CYPs.
Drugs Active Against Atypical Mycobacteria
Species Clinical Treatment Options
Features
M kansasii Resembles Ciprofloxacin, clarithromycin, ethambutol,
tuberculosis isoniazid, rifampin,
trimethoprimsulfamethoxazole
M marinum Granulomatous Amikacin, clarithromycin, ethambutol,
cutaneous doxycycline, minocycline, rifampin,
disease trimethoprim-sulfamethoxazole
M scrofulaceum Cervical adenitis Amikacin, erythromycin (or other macrolide),
in children rifampin, streptomycin. (Surgical excision is
joften curative and the treatment of choice.)
Typical Mycobacteria
Species Clinical Features Treatment Options
M avium Pulmonary disease in patients Amikacin, azithromycin, clarithromycin,
complex with chronic lung disease; ciprofloxacin, ethambutol, ethionamide,
disseminated infection in AIDS rifabutin

M chelonae Abscess, sinus tract, ulcer; bone, Amikacin, doxycycline, imipenem,

joint, tendon infection macrolides, tobramycin

M fortuitum Abscess, sinus tract, ulcer; bone, Amikacin, cefoxitin, ciprofloxacin,

joint, tendon infection doxycycline, ofloxacin,
trimethoprimsulfamethoxazole
Drugs Used in Leprosy
Mycobacterium leprae has never been grown in vitro, but
animal models, such as growth in injected mouse footpads, have
permitted laboratory evaluation of drugs.
Because of increasing reports of dapsone resistance, treatment
of leprosy with combinations of the drugs is recommended.
Dapsone
The most widely used drug for leprosy is dapsone .
Like the sulfonamides, it inhibits folate synthesis.
Resistance can emerge in large populations of M leprae, eg, in
lepromatous leprosy, if very low doses are given.
The combination of dapsone, rifampin, and clofazimine is
recommended for initial therapy.
Dapsone
Dapsone may also be used to prevent and treat Pneumocystis jiroveci
pneumonia in AIDS.
Sulfones are well absorbed from the gut and widely distributed
throughout body fluids and tissues.
Dapsone's half-life is 1–2 days, and drug tends to be retained in skin,
muscle, liver, and kidney.
Skin heavily infected with M leprae may contain several times as much
of the drug as normal skin.
Dapsone
Sulfones are excreted into bile and reabsorbed in the intestine.
Excretion into urine is variable, and most excreted drug is
acetylated.
In renal failure, the dose may have to be adjusted.
The usual adult dosage in leprosy is 100 mg daily.
Dapsone
Dapsone is usually well tolerated. Many patients develop some
hemolysis, particularly if they have G-6-PD deficiency.
Gastrointestinal intolerance, fever, pruritus, and various rashes occur.
During dapsone therapy of lepromatous leprosy, erythema nodosum
leprosum often develops.
It is sometimes difficult to distinguish reactions to dapsone from
manifestations of the underlying illness.
Rifampicin
This drug in a dosage of 600 mg daily can be strikingly
effective in lepromatous leprosy.
Because of the probable risk of emergence of rifampin-resistant
M leprae, the drug is given in combination with dapsone or
another antileprosy drug.
A single monthly dose of 600 mg may be beneficial in
combination therapy.
Clofazimine
Clofazimine is a phenazine dye that can be used as an alternative to
dapsone.
 Its mechanism of action is unknown but may involve DNA binding.
Absorption of clofazimine from the gut is variable, and a major
portion of the drug is excreted in feces.
Clofazimine is stored widely in reticuloendothelial tissues and skin,
and its crystals can be seen inside phagocytic reticuloendothelial cells
Clofazimine
It is slowly released, so that the serum half-life may be 2 months.
Clofazimine is given for sulfone-resistant leprosy or when patients are
intolerant to sulfone.
A common dosage is 100 mg/d orally.
The most prominent untoward effect is skin discoloration ranging from
red-brown to nearly black.
Gastrointestinal intolerance occurs occasionally.