First- and second-line drugs, MICs and mechanisms of drug resistance
Tuberculosis (TB) is caused by infection with
First-line antituberculosis drugs- Isoniazid (INH), rifampicin (RIF), ethambutol (EMB), pyrazinamide (PZA) and streptomycin (SM).
Second-line antituberculosis drugs- Sub divided into two
Fluoroquinolones- Ofloxacin (OFX), levofloxacin (LEV), moxifloxacin (MOX) and ciprofloxacin (CIP).
Injectable antituberculosis drugs- Kanamycin (KAN), amikacin (AMK) and capreomycin (CAP).
Less-effective second-line antituberculosis drugs- Ethionamide (ETH)/Prothionamide (PTH), Cycloserine (CS)/Terizidone, P-aminosalicylic acid (PAS).
|alkyl hydroperoxide reductase|
|Rifampicin||0.05–0.1 (7H9/7H10)||β-subunit of RNA polymerase|
|Streptomycin||2–8 (7H9/7H10)||S12 ribosomal protein|
|Ethambutol||1–5 (7H9/7H10)||arabinosyl transferase|
|Fluoroquinolones||0.5–2.0 (7H9/7H10)||DNA gyrase|
|Kanamycin||2–4 (7H9/7H10)||16S rRNA|
|Amikacin||2–4 (7H9/7H10)||16S rRNA|
|Capreomycin||2-4 (7H9/7H10)||16S rRNA|
|Ethionamide||2.5–10 (7H11)||enoyl reductase|
|0.5 (LJ)||thymidylate synthase A|
2. First-line antituberculosis drugs
Isoniazid (INH) is one of the most effective and specific antituberculosis drugs, which has been a key to treatment since its introduction in 1952 .
Resistance to isoniazid is a complex process. Mutations in several genes, including
A study by Hazbo´n et al.  analysed 240 alleles and found that mutations in
Rifampicin (RIF) was introduced in 1972 as an antituberculosis drug and has excellent sterilizing activity. Rifampicin acts by binding to the β-subunit of RNA polymerase (
Rifampicin MICs ranging from 0.05 to 1 μg/ml on solid or liquid media, but the MIC is higher in egg media (MIC = 2.5–10 μg/ml). Strains with MICs < 1 μg/ml in liquid or agar medium or MICs < 40 μg/ml in Lowenstein-Jensen (LJ) medium are considered RIF-susceptible. The great majority of
Pyrazinamide (PZA) is an important first-line antituberculosis (anti-TB) drug that is used in short-course chemotherapy and is one of the cornerstone drugs in the treatment of MDR-TB . One key characteristic of pyrazinamide is its ability to inhibit semidormant bacilli residing in acidic environments . Pyrazinamide is a structural analogue of nicotinamide and is a pro-drug that needs to be converted into its active form, pyrazinoic acid, by the enzyme pyrazinamidase/nicotinamidase (PZase) . PZA is only active against
PZase is encoded in
Ethambutol (EMB) [dextro-2,2’-(ethylenediimino)di-1-butanol], which is an essential first-line drug in tuberculosis treatment, plays an important role in the chemotherapy of drug-resistant TB . EMB is also an important antimycobacterial drug as it enhances the effect of other companion drugs including aminoglycosides, rifamycins and quinolones. The most common side effects observed with ethambutol are dizziness, blurred vision, color blindness, nausea, vomiting, stomach pain, loss of appetite, headache, rash, itching, breathlessness, swelling of the face, lips or eyes, numbness or tingling in the fingers or toes. Patients taking ethambutol should have their visual acuity and color vision checked at least monthly.
The MICs of EMB for
Arabinosyl transferase, encoded
Streptomycin (SM), an aminocyclitol glycoside antibiotic, was the first drug to be used in the treatment of TB, in 1948 . SM kills actively growing tubercle bacilli with MICs of 2–4 μg/ml, but it is inactive against non-growing or intracellular bacilli . The drug binds to the 16S rRNA, interferes with translation proofreading, and thereby inhibits protein synthesis [51, 52]. Ototoxicity and nephotoxicity are associated with SM administration. Vestibular dysfunction is more common than auditory damage. Renal toxicity occurs less frequently than with kanamycin or capreomycin. Hearing and renal function should be monitored in patients getting SM.
Mutations associated with streptomycin resistance have been identified in the genes encoding 16S rRNA (
3. Second-line antituberculosis drugs
The fluoroquinolones (FQs) have broad-spectrum antimicrobial activity and so are widely used for the treatment of bacterial infections of the respiratory, gastrointestinal and urinary tracts, as well as sexually transmitted diseases and chronic osteomyelitis . In contrast to many other antibiotics used to treat bacterial infections, the FQs have excellent in vitro and in vivo activity against
The cellular target of FQs in
Mutations within the QRDR of
3.2. Aminoglycosides (kanamycin, amikacin and capreomycin)
The aminoglycosides amikacin (AMK)/kanamycin (KAN) and the cyclic polypeptide capreomycin (CAP) are important injectable drugs in the treatment of multidrug-resistant tuberculosis. Although belonging to two different antibiotic families, all exert their activity at the level of protein translation. Renal toxicity occurs from these drugs. Regular monitoring of hearing and renal function is recommended.
AMK and KAN are aminoglycosides that have a high level of cross-resistance between them [78-80]. The cyclic polypeptide CAP is structurally unrelated to the aminoglycosides and thus is a potential candidate to replace AMK or KAN if resistance to either of them is suspected [81, 82]. It has been demonstrated that the risk of treatment failure and mortality increase when CAP resistance emerges among MDR-TB cases . However, cross-resistance in
AMK/KAN and CAP primarily affect protein synthesis in
Resistance to the cyclic peptide capreomycin has also been associated with mutations in
Ethionamide (ETH, 2-ethylisonicotinamide) is a derivative of isonicotinic acid and has been used as an antituberculosis agent since 1956. The MICs of ETH for
p-Amino salicylic acid
Cycloserine (CS) is an antibiotic that is used to treat TB. The exact mechanism of action of cycloserine is unknown, but it is thought to prevent the tuberculosis bacteria from making substances called peptidoglycans, which are needed to form the bacterial cell wall. This results in the weakening of bacteria’s cell wall, which then kills the bacteria. Cycloserine possesses high gastric tolerance (compared with the other drugs) and lacks cross-resistance to other compounds. But it causes adverse psychiatric effects; [96, 97] which is its main drawback. So, psychiatric interrogation is necessary before prescribing cycloserine drug. Cycloserine is one of the cornerstones of treatment for MDR and XDR tuberculosis [96, 97, 98]. Terizidone (a combination of two molecules of cycloserine) might be less toxic [96, 97], although studies of this drug are scarce.
Despite all the advances made in the treatment and management, TB still remains as one of the main public health problems that have plagued mankind for millennia. The challenges posed by
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