Second‑Line Antitubercular Drugs for Multidrug‑Resistant Tuberculosis (MDR‑TB)

Introduction/Overview

Multidrug‑resistant tuberculosis (MDR‑TB) presents a significant public health challenge worldwide, necessitating the use of second‑line antitubercular agents. These drugs are employed when Mycobacterium tuberculosis isolates remain resistant to at least isoniazid and rifampicin. The clinical relevance of second‑line agents lies in their ability to salvage treatment regimens that would otherwise fail, thereby reducing morbidity, mortality, and transmission risk. The selection and optimization of these agents require a comprehensive understanding of their pharmacology, safety profiles, and interaction potentials.

Learning objectives

• Identify the main classes of second‑line antitubercular drugs used in MDR‑TB therapy.
• Explain the pharmacodynamic mechanisms that underlie the antibacterial activity of each drug class.
• Describe key pharmacokinetic properties, including absorption, distribution, metabolism, and excretion, and their impact on dosing strategies.
• Recognize the spectrum of therapeutic indications, adverse effect profiles, and black‑box warnings associated with these agents.
• Appreciate special considerations for use in pregnancy, lactation, pediatrics, geriatrics, and patients with organ dysfunction.
• Apply knowledge of drug interactions to prevent clinically significant complications.

Classification

Drug Classes and Categories

Second‑line antitubercular drugs are conventionally divided into three primary pharmacologic families:

• Aminoglycoside‑derived agents – e.g., amikacin, kanamycin, capreomycin.
• Oxazolidinones – e.g., linezolid, tedizolid.
• Fluoroquinolones – e.g., levofloxacin, moxifloxacin, gatifloxacin, ofloxacin.

Additional agents, such as clofazimine, cycloserine, and ethionamide, are often incorporated into MDR‑TB regimens but are typically categorized under “other second‑line drugs.” The classification reflects both chemical structure and primary mechanism of action, facilitating clinical decision‑making.

Chemical Classification

Aminoglycosides are β‑amino‑α‑hydroxy sugars linked to a polypeptide backbone, conferring a high affinity for the 30S ribosomal subunit. Oxazolidinones possess a 2‑(2‑(methoxy‑2‑oxo‑1‑H‑pyrrol‑3‑yl)-2‑oxoethyl)‑2‑oxo‑1‑H‑pyrrol‑3‑yl structure that impedes initiation complex formation. Fluoroquinolones are 1,4‑β‑pyridone derivatives with a fluorine atom at the 6‑position, enhancing bactericidal potency and pharmacokinetic stability.

Mechanism of Action

Aminoglycoside‑Derived Agents

These drugs bind to the 30S ribosomal subunit, specifically the A‑site of the 16S rRNA. Binding induces misreading of mRNA, leading to the incorporation of incorrect amino acids and subsequent production of dysfunctional proteins. The bactericidal effect is concentration‑dependent, with peak plasma concentrations required for optimal activity. Resistance mechanisms include enzymatic modification (acetylation, phosphorylation, adenylation), reduced drug uptake through altered porin channels, and mutations in the 16S rRNA gene that reduce binding affinity.

Oxazolidinones

Oxazolidinones inhibit the initiation of protein synthesis by preventing the formation of the 70S ribosomal initiation complex. They bind to the 50S subunit, specifically the 23S rRNA domain V, interfering with the interaction between the initiator tRNA and the ribosomal P‑site. This inhibition is reversible and concentration‑dependent. Resistance often arises from mutations in the 23S rRNA gene or from overexpression of efflux pumps.

Fluoroquinolones

Fluoroquinolones target bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, enzymes essential for DNA replication, transcription, and repair. Binding of the drug–DNA complex stabilizes the cleavage complex, preventing religation of the DNA strands and ultimately causing double‑strand breaks. The activity is concentration‑ and time‑dependent; higher concentrations increase the rate of bacterial killing. Resistance mechanisms include mutations in the quinolone‑resistance‑determining regions (QRDRs) of gyrA and gyrB, efflux pump overexpression, and reduced permeability.

Pharmacokinetics

Amikacin

Absorption: Amikacin is not absorbed orally; it is administered intravenously. Distribution: It achieves a volume of distribution approximating 0.3 L/kg, reflecting limited penetration into adipose tissue. The drug binds minimally to plasma proteins (<10 %). Metabolism: Amikacin is not metabolized by hepatic enzymes. Excretion: Renal clearance is the primary route, with a half‑life of 2–4 hours in patients with normal renal function. Dose adjustments are required in renal impairment, with dosing intervals extended to 48–72 hours when creatinine clearance falls below 20 mL/min.

Linezolid

Absorption: Oral bioavailability exceeds 90 %, enabling flexible dosing. Distribution: It displays extensive tissue penetration, including the central nervous system and pulmonary alveoli, with a volume of distribution of 0.7 L/kg. Metabolism: Linezolid undergoes non‑enzymatic oxidation to inactive metabolites. Excretion: Renal and fecal routes contribute equally, with a half‑life of approximately 5.5 hours in healthy adults. Dose modifications are typically unnecessary for mild to moderate renal impairment, but caution is advised in severe impairment.

Moxifloxacin

Absorption: Oral absorption is rapid, with peak plasma concentrations reached within 1–2 hours. Distribution: It demonstrates extensive tissue penetration, achieving concentrations in the lungs that exceed plasma levels. Metabolism: Hepatic metabolism via CYP1A2, CYP3A4, and CYP2C9 leads to the formation of inactive metabolites. Excretion: Renal excretion accounts for 70 % of the drug, with a half‑life of 12 hours. Dose adjustments are recommended for patients with severe renal dysfunction (creatinine clearance <30 mL/min).

Therapeutic Uses/Clinical Applications

Approved Indications

• Amikacin: Treatment of MDR‑TB when resistance to first‑line agents is documented. It is often combined with other second‑line drugs to form a multi‑drug regimen.
• Linezolid: Utilized as part of MDR‑TB regimens, particularly in cases where resistance to fluoroquinolones or aminoglycosides exists. It may be employed in treatment of extensively drug‑resistant TB (XDR‑TB) when other options are limited.
• Moxifloxacin: Indicated for MDR‑TB regimens, especially when susceptibility testing confirms activity. It may be used in combination with other second‑line agents to achieve synergistic effects.

Off‑Label Uses

Amikacin, linezolid, and moxifloxacin are occasionally prescribed for extrapulmonary TB manifestations such as lymphadenitis, osteomyelitis, or meningitis, provided adequate drug penetration and susceptibility data support their use. These off‑label applications are guided by clinical judgment and available pharmacokinetic data.

Adverse Effects

Amikacin

• Ototoxicity – irreversible sensorineural hearing loss may occur, particularly with cumulative doses exceeding 30 mg/kg per month.
• Nephrotoxicity – acute tubular necrosis can develop, necessitating monitoring of serum creatinine and dose adjustment.
• Other effects: Hypersensitivity reactions, including rash and anaphylaxis, though less common.

Linezolid

• Myelosuppression – thrombocytopenia, anemia, and leukopenia may occur, especially after prolonged therapy (>4 weeks).
• Peripheral and optic neuropathy – neuropathies may emerge after extended treatment durations, warranting periodic neurologic assessment.
• Serotonin syndrome – risk increases when combined with serotonergic agents (SSRIs, SNRIs, MAOIs).
• Gastrointestinal disturbances – nausea, vomiting, diarrhea are common, often dose‑related.

Moxifloxacin

• QT interval prolongation – may lead to torsades de pointes, particularly in patients with electrolyte abnormalities or concurrent QT‑prolonging drugs.
• Gastrointestinal upset – nausea, abdominal pain, and dyspepsia are frequently reported.
• Severe skin reactions – Stevens–Johnson syndrome and toxic epidermal necrolysis, though rare, have been documented.
• Other adverse events include arthralgia, myalgia, and headache.

Black Box Warnings

• Linezolid: Myelosuppression and neuropathy after prolonged use; serotonin syndrome when combined with serotonergic agents.
• Amikacin: Ototoxicity and nephrotoxicity with cumulative dosing.
• Moxifloxacin: QT prolongation and potential for severe cutaneous adverse reactions.

Drug Interactions

Amikacin

• Concurrent use with other nephrotoxic agents (e.g., vancomycin, cisplatin) may potentiate renal injury.
• Ototoxic drugs (e.g., loop diuretics) can increase the risk of auditory toxicity.

Linezolid

• Serotonergic agents (SSRIs, SNRIs, MAOIs, tramadol) may precipitate serotonin syndrome; dose reduction or discontinuation is advised.
• Anticoagulants (warfarin) may have enhanced anticoagulant effects due to CYP inhibition; close monitoring of INR is required.

Moxifloxacin

• Drugs that prolong the QT interval (e.g., azithromycin, cimetidine, cisapride) should be avoided or used with caution.
• Phenytoin, carbamazepine, and phenobarbital may reduce plasma concentrations through induction of hepatic enzymes; therapeutic drug monitoring may be necessary.
• Oral contraceptives may have reduced efficacy when used concurrently with moxifloxacin; alternative contraception is recommended.

Contraindications for each agent typically include hypersensitivity reactions, severe organ dysfunction when dose adjustment is not feasible, and concomitant use of interacting drugs that cannot be safely managed.

Special Considerations

Pregnancy and Lactation

Amikacin is generally considered safe in pregnancy, with no teratogenic effects reported; however, monitoring for ototoxicity remains essential. Linezolid is classified as pregnancy category B, yet limited data exist; use is reserved for when benefits outweigh potential risks. Moxifloxacin is pregnancy category C; animal studies have shown fetal toxicity at high doses. Lactation: all three agents are excreted into breast milk in trace amounts; the clinical significance is considered low, but caution is advised if infant exposure is a concern.

Pediatric Considerations

Children require weight‑based dosing; pharmacokinetic parameters differ from adults, with higher clearance rates leading to shorter half‑lives. Amikacin dosing in children is typically 15–20 mg/kg/day IV. Linezolid dosing is 10 mg/kg twice daily, with a maximum of 600 mg/day. Moxifloxacin is dosed at 10 mg/kg twice daily, up to a maximum of 400 mg/day. Monitoring for ototoxicity and myelosuppression is critical in the pediatric population.

Geriatric Considerations

In older adults, reduced renal and hepatic function may necessitate dose reductions or extended dosing intervals. The risk of ototoxicity and nephrotoxicity with aminoglycosides increases with age, and polypharmacy raises the likelihood of drug interactions, particularly with serotonergic agents and QT‑prolonging drugs.

Renal and Hepatic Impairment

• Amikacin: Dose reduction and prolonged intervals are required when creatinine clearance falls below 30 mL/min.
• Linezolid: Mild to moderate renal impairment does not necessitate dose adjustment; severe impairment (<30 mL/min) warrants caution.
• Moxifloxacin: Renal dose adjustment is indicated for creatinine clearance <30 mL/min; hepatic impairment has minimal effect on clearance.

Summary/Key Points

• Second‑line antitubercular agents are essential for the management of MDR‑TB, each possessing distinct mechanisms of action targeting bacterial protein synthesis or DNA replication.
• Pharmacokinetic profiles guide dosing intervals and inform adjustments for organ dysfunction; careful monitoring of drug levels may be necessary in certain populations.
• Adverse effect surveillance is critical: ototoxicity and nephrotoxicity with aminoglycosides; myelosuppression and neuropathy with oxazolidinones; QT prolongation and cutaneous reactions with fluoroquinolones.
• Drug‑drug interactions can significantly alter therapeutic outcomes; vigilant assessment of concomitant medications is recommended.
• Special populations—pregnant women, lactating mothers, children, older adults, and patients with renal or hepatic impairment—require individualized dosing strategies and enhanced monitoring.
• Clinical decision‑making should integrate susceptibility testing, patient comorbidities, and potential for adverse events to optimize treatment outcomes for MDR‑TB.

References

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