Chemotherapy Principles and Applications

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Questions and Answers

What is the primary indication for chemotherapy in cases where surgery is not feasible?

Maintenance therapy following successful surgery

Adjuvant therapy for micrometastases

Disseminated cancer not amenable to surgery (correct)

Neoadjuvant therapy to shrink tumors

Which condition typically requires a 5-log kill to achieve clinical remission in leukemia?

During bacterial infection treatment

With acute lymphoblastic leukemia

In the presence of 10^9 leukemic cells (correct)

Following chemotherapy for solid tumors

Which type of chemotherapy drug is likely to be used for hematologic malignancies?

Chemotherapy agents for solid tumors

High growth fraction drugs (correct)

Cell-cycle nonspecific drugs

Adjuvant drugs following surgery

What is a common adverse effect associated with chemotherapy?

Severe vomiting Signup and view all the answers

What is a characteristic of primary drug resistance in cancer treatment?

Is demonstrated on first exposure Signup and view all the answers

What can precipitate renal failure in the presence of uric acid and calcium phosphate crystals?

Dehydration Signup and view all the answers

Which of the following is NOT a common adverse effect of Methotrexate (MTX)?

Skin rash Signup and view all the answers

Which drug is primarily used as an antidote to Methotrexate by restoring folate levels?

Leucovorin Signup and view all the answers

During which phase of the cell cycle do antimetabolites exhibit maximal cytotoxic effects?

S phase Signup and view all the answers

What impact do alkylating agents used in chemotherapy have on cancer treatment?

They are mutagens that can cause secondary tumors. Signup and view all the answers

Which class of drugs does Aprepitant belong to in the management of chemotherapy-induced nausea and vomiting (CINV)?

NK-1 antagonist Signup and view all the answers

What is a potential consequence of administering thiopurines to patients with weak thiopurine methyltransferase (TPMT) activity?

Severe toxicity risk including myelosuppression Signup and view all the answers

Which of the following medications is classified as a corticosteroid used for the prevention of CINV?

Dexamethasone Signup and view all the answers

What is the primary mechanism of action of 6-mercaptopurine (6-MP)?

Inhibits the first step of de novo purine synthesis Signup and view all the answers

What are the potential side effects of 6-mercaptopurine (6-MP)?

Nausea, vomiting, and bone marrow suppression Signup and view all the answers

How is 5-fluorouracil (5-FU) metabolized to exert its effects?

Converted to 5-FdUMP, which inhibits thymidylate synthase Signup and view all the answers

What reaction is inhibited by the formation of 5-FdUMP in the context of 5-fluorouracil treatment?

Conversion of uracil to thymidine Signup and view all the answers

Which of the following drug interactions is significant when considering 6-mercaptopurine (6-MP) treatment?

Metabolized by xanthine oxidase Signup and view all the answers

What complication is associated with a deficiency of dihydropyrimidine dehydrogenase (DPD) in the context of 5-fluorouracil treatment?

Severe myelosuppression and neurotoxicity Signup and view all the answers

Which of the following statements regarding 6-thioguanine (6-TG) is correct?

It is used primarily for acute nonlymphocytic leukemias. Signup and view all the answers

What is the mechanism of action of Cytarabine (ARA-C)?

Phosphorylated to trisphosphate, incorporated into DNA Signup and view all the answers

What is the primary mechanism of action of anthracyclines?

Inhibition of topoisomerase II Signup and view all the answers

Which of the following is a common side effect of doxorubicin?

Myelosuppression Signup and view all the answers

Which drug combination is used to prevent hemorrhagic cystitis associated with cyclophosphamide?

Mesna Signup and view all the answers

Bleomycin is cell-cycle specific during which phase?

G2 phase Signup and view all the answers

What is the mechanism of action of vinca alkaloids?

Destabilizing microtubules Signup and view all the answers

Which side effect is most commonly associated with paclitaxel?

Peripher neuropathy Signup and view all the answers

What condition is primarily treated with asparaginase?

Acute lymphoblastic leukemia Signup and view all the answers

Which of the following agents inhibits ribonucleotide reductase?

Hydroxyurea Signup and view all the answers

What is a major adverse effect of cisplatin?

Ototoxicity Signup and view all the answers

Which of the following drugs is a reversible and competitive aromatase inhibitor?

Letrozole Signup and view all the answers

What adverse effect is associated with the use of interferons?

Flu-like symptoms Signup and view all the answers

In the treatment of tuberculosis, what is the action of isoniazid?

Inhibition of mycolic acid synthesis Signup and view all the answers

Which of the following describes the mechanism of action of carboplatin?

Covalent binding to DNA Signup and view all the answers

Study Notes

Chemotherapy: Antimetabolites

Chemotherapy Regimens:
- Use a "log kill" model. For example:
  - A 1-log kill means a 90% reduction in tumor cells.
  - A 5-log kill is required for clinical remission in leukemia, reducing the cell count from 10^9 to 10^4 cells.
Drug Resistance:
- Primary Resistance: displayed on first exposure to the drug by the tumor.
- Acquired Resistance: Resistance that develops after exposure to a drug. Can be specific to one drug or to multiple drugs.
  - Single-drug resistance is often related to an increased expression of one or more genes.
  - Multi-drug resistance can occur after exposure to a single agent and can involve overexpression of membrane efflux pumps like P-glycoprotein.
Adverse Effects of Chemotherapy:
- Primarily targets rapidly dividing cells, leading to toxic effects on normal cells.
- Common adverse effects include:
  - Severe vomiting, stomatitis, myelosuppression, and alopecia.
- Tumor Lysis Syndrome (TLS):
  - A medical emergency caused by the rapid breakdown of tumor cells.
  - Mainly seen in patients with leukemia or lymphoma.
  - Symptoms include hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia due to precipitation of calcium phosphate.
  - Management involves IV hydration, allopurinol, or rasburicase.
Antimetabolites:
- Cycle-specific agents that act as structural analogs of purines, pyrimidines, or folate cofactors.
- Interfere with pathways related to nucleotide and nucleic acid synthesis.
- Most are prodrugs, requiring modification within the cell to become active.
- Maximal cytotoxic effects are in the S-phase of the cell cycle.

Folate Analogs

Methotrexate (MTX):
- Inhibits dihydrofolate reductase, reducing levels of tetrahydrofolate.
- Decreases the synthesis of dTMP and purine nucleotides.
- Undergoes polyglutamation, trapping it within the cell.
- Adverse Effects:
  - Common: Stomatitis, mucositis, myelosuppression, alopecia, and nausea/vomiting.
  - Renal Damage (uncommon, high-dose), Hepatic Fibrosis/Cirrhosis, Pneumonitis, Neurological toxicity with intrathecal administration.

Purine Analogs

Thiopurines (6-MP and 6-TG):
- Partially metabolized by the enzyme thiopurine methyltransferase (TPMT).
  - Low TPMT activity can lead to severe toxicity (myelosuppression).
6-Mercaptopurine (6-MP):
- Thiol analog of hypoxanthine.
- Converted to the nucleotide analog thio-IMP (TIMP) by HGPRT.
- TIMP inhibits de novo purine synthesis and blocks the formation of AMP and GMP from IMP.
- Adverse Effects: Nausea, vomiting, diarrhea, bone marrow suppression, and hepatotoxicity
- Drug Interactions:
  - Metabolized to thiouric acid by xanthine oxidase.
  - Allopurinol dose must be decreased to avoid accumulation of thiouric acid.
6-Thioguanine (6-TG):
- Thiol analog of guanine.
- Converted to 6-thioGMP (TGMP) by HGPRT.
- TGMP inhibits purine synthesis and the conversion of IMP to GMP.
- Clinical Use: Acute nonlymphocytic leukemias.
- Drug Interactions: Allopurinol does not potentiate 6-TG action.
- Similar toxicities to 6-MP.

Pyrimidine Analogs

5-Fluorouracil (5-FU):
- Converted to 5-FdUMP, which inhibits thymidylate synthase.
- 5-FdUMP blocks the formation of thymine, leading to "thymineless death."
- Also converted to 5-FUTP and incorporated into RNA.
- Dihydropyrimidine dehydrogenase (DPD): Deficiency leads to severe toxicity (myelosuppression, neurotoxicity, diarrhea).
- Potentiation by Leucovorin: Increases cofactor levels, enhancing the effectiveness of 5-FU.
- Clinical Use: Colorectal cancer in combination with leucovorin.
- Adverse Effects: Nausea, vomiting, alopecia, bone marrow depression, and hand-foot syndrome.
- Hand-Foot Syndrome: Erythematous desquamation of palms and soles, more common with extended infusions.
Cytarabine (ARA-C):
- Analog of deoxycytidine.
- Phosphorylated to trisphosphate and incorporated into DNA.
- Inhibits DNA polymerase.

Antitumor Antibiotics

Bind to DNA via intercalation between bases, which blocks the synthesis/replication of new RNA and DNA, and breaks strands.
Anthracyclines
- Inhibit topoisomerase II, intercalate in DNA, block synthesis, break DNA strands, bind to cell membranes, alter fluidity and ion transport, and generate free radicals.
- Adverse effects include myelosuppression and cardiotoxicity.
- Cardiotoxicity is dose-dependent and can lead to dilated cardiomyopathy associated with heart failure.
- Dexrazoxane IV is the treatment for cardiotoxicity.
- Examples include doxorubicin (widely used) and daunorubicin.
Bleomycin
- Cell-cycle specific: G2 phase.
- Causes DNA breakage by oxidative processes.
- Mixture of glycopeptides.
- Reacts with oxygen to form free radicals, which break DNA strands.
- Adverse effects include pulmonary toxicity (pneumonitis, fibrosis) and very mild myelosuppression.

Alkylating Agents

Cytotoxic effects via transfer of alkyl groups, which alkylate DNA leading to cell death.
Alkylation can occur on a single or both strands of DNA, with cross-linking being more common.

Nitrogen Mustards

Mechlorethamine:
- Powerful vesicant given IV.
- Replaced by cyclophosphamide and melphalan (more stable).
- Adverse effects include severe nausea, vomiting, bone marrow suppression, alopecia, and immunosuppression.
Cyclophosphamide:
- Most used, especially in combination therapy.
- Activated by CYP2B.
- Oral or IV administration.
- Broad spectrum.
- Prodrug.
- Adverse effects include nausea, vomiting, bone marrow suppression, alopecia, sterility, and hemorrhagic cystitis.
- Adequate fluid intake prevents hemorrhagic cystitis.
- Mesna (sulfhydryl) is administered parenterally to bind acrolein metabolites to prevent hemorrhagic cystitis.
Ifosfamide:
- Analog of cyclophosphamide.
- Infused IV.
- Activated by CYP3A4 (liver).
- Adequate hydration and mesna allow for its use.
- Adverse effects include greater platelet suppression, neurotoxicity, and urinary tract toxicity compared to cyclophosphamide.
- High-dose can lead to severe neurotoxicity (hallucinations, coma, death).
Melphalan:
- Adverse effect: Bone marrow suppression.

Nitrosoureas

Carmustine and Lomustine:
- Very lipophilic and cross the blood-brain barrier, targeting brain tumors.

Other Alkylating Agents

Busulfan:
- Adverse effects include pulmonary fibrosis and myelosuppression.
Dacarbazine:
- IV prodrug.
- Methylating agent.
- Adverse effects include nausea, vomiting, and myelosuppression.
Procarbazine:
- Converted to alkylating metabolites by liver P450 enzymes.
- Adverse effects include nausea, vomiting, bone marrow suppression, mutagenicity, teratogenicity, disulfiram-like reactions, and weak MAO inhibitor.
- Can cause high blood pressure if given with sympathomimetic drugs or tyramine-containing foods.

Platinum Coordination Complexes

Cisplatin and Carboplatin:
- Do not alkylate DNA; they form covalent bonds.
- Broad antineoplastic activity.
- Foundational for cancers like testicular, ovarian, head & neck, lung, esophagus, bladder, and colon.
- Inhibit DNA synthesis and cross-linking.
Cisplatin:
- Adverse effects include nausea, vomiting, ototoxicity, peripheral neuropathy, myelosuppression, and nephrotoxicity.
- Hydration and diuresis reduce nephrotoxicity.
- Amifostine is used to treat nephrotoxicity.
Carboplatin:
- Myelosuppression is the dose-limiting toxicity.
- Less nausea, neurotoxicity, ototoxicity, and nephrotoxicity compared to cisplatin.

Microtubule Inhibitors

Stabilize (polymerization) or destabilize (depolymerization) microtubules.
Vinca Alkaloids:
- Natural alkaloids isolated from the Madagascar periwinkle plant.
- Destabilize microtubules.
- Bind to β-tubulin, inhibiting its ability to polymerize.
- Lead to mitotic arrest in metaphase.
Vincristine:
- Adverse effects include peripheral neuropathy (most common), alopecia, and bone marrow depression.
Vinblastine:
- Adverse effects include myelosuppression (most common), peripheral neuropathy, and alopecia.
Taxanes (Paclitaxel):
- Alkaloid derived from the bark of the Pacific yew tree.
- Stabilize microtubules.
- Bind to β-tubulin and promote polymerization.
- Lead to mitotic arrest in metaphase.
- Adverse effects include myelosuppression, peripheral neuropathy, alopecia, and hypersensitivity.
- Pre-medications like dexamethasone, diphenhydramine, and H2 blockers reduce hypersensitivity.

Epipodophyllotoxins

Etoposide:
- Semisynthetic derivative of podophyllotoxin (mandrake plant/may-apple).
- Inhibits topoisomerase II.
- Blocks cells in late S-G2 phase.
- Adverse effects include nausea, vomiting, alopecia, and myelosuppression.

Camptothecins

Topotecan and Irinotecan:
- Derived from the Camptotheca acuminata tree.
- Inhibit topoisomerase I.
- Adverse effects include diarrhea and myelosuppression.

Hormonal Agents

Glucocorticoids (Prednisone):
- Lytic to lymphocytes and suppress lymphocyte mitosis.
- Clinically used for acute leukemia and malignant lymphomas.

Estrogen Inhibitors

Selective Estrogen Receptor Modulators (SERMs):
- Act as agonists or antagonists, depending on the tissue.
- Tamoxifen:
  - Agonist in non-breast tissues, antagonist in breast tissue.
  - Metabolism via CYP2D6 leads to a more potent SERM. Avoid CYP2D6 inhibitors like bupropion, fluoxetine, and paroxetine.
  - Used for metastatic breast cancer (male and female), adjuvant treatment of breast cancer (female), and breast cancer prevention (female).
  - Adverse effects include nausea, vomiting, hot flashes, fluid retention, vaginal bleeding, venous thromboembolism, and endometrial cancer.
- Raloxifene:
  - Antiestrogen in the uterus and breast.
  - Estrogenic in bone, inhibiting resorption.
  - Used in postmenopausal women for treatment and prevention of osteoporosis as well as breast cancer prophylaxis in high-risk patients.
  - Adverse effects include hot flashes, leg cramps, and deep vein thrombosis.
Estrogen Receptor Antagonists:
- Fulvestrant:
  - Inhibits receptor dimerization, leading to receptor degradation and abolishing ER-mediated transcription.
  - No agonist activity.
  - Used in postmenopausal women with hormone receptor-positive metastatic breast cancer that progresses after antiestrogen use.
Aromatase (CYP19A1) Inhibitors:
- Inhibit aromatase function, which converts androgens to estrogens via aromatization.
- Primarily used in postmenopausal women, as this stage is the primary source of estrogens.
- Used to reduce estrogen-mediated cancers in hormone receptor positive (HRP) breast cancer.
- Used as adjuvant treatment for HRP breast cancer, first-line treatment for metastatic HRP breast cancer, for advanced breast cancer with progression after tamoxifen, and off-label for prevention of breast cancer in high-risk patients.
- Examples include anastrozole, letrozole (reversible, competitive, non-steroidal), and exemestane (irreversible, steroidal).

Androgen Inhibitors

Gonadotropin-Releasing Hormone (GnRH) Agonists:
- Synthetic analogs of GnRH.
- Initially cause a surge in LH and FSH, leading to a transient increase in circulating gonadal steroids.
- Continuous administration leads to a sustained inhibition of gonadotropin release.
- Suppress ovarian/testicular steroidogenesis reversibly.
- Testosterone levels fall to 10% within a month, which initially increases leading to tumor flare/symptoms.
- Flutamide is used to treat flare symptoms.
- Used in advanced prostate carcinoma (with/without flutamide), advanced breast cancer (post-menopausal female), and management of endometriosis.
Androgen Receptor Blockers:
- Competitively inhibit binding of testosterone and dihydrotestosterone to the androgen receptor.
- Used in the management of metastatic prostate carcinoma, often combined with GnRH agonists.
- Second generation (more potent) is replacing the first generation (less potent).
  - First generation: bicalutamide, flutamide, nilutamide.
  - Second generation: enzalutamide, apalutamide, darolutamide.
Androgen Synthesis Inhibitors (Abiraterone):
- Irreversible inhibitor of CYP17A1, leading to very low testosterone levels.
- Used with a GnRH analog for metastatic castration-resistant prostate cancer and high-risk castration sensitive prostate cancer.
- Given with prednisone to treat adrenal insufficiency.
- Adverse effects include:
  - Adrenocortical insufficiency
  - High blood pressure
  - Low potassium
  - Fluid retention
  - Hepatotoxicity
  - Arrhythmia

Receptor Tyrosine Kinase Inhibitors/Monoclonal Antibodies

Mutations that constitutively activate tyrosine kinases are implicated in malignancy.
Gefitinib:
- Used for non-small cell lung cancer and targets EGFR tyrosine kinase.
Erlotinib:
- Used for non-small cell lung cancer, pancreatic cancer, and targets EGFR tyrosine kinase.
Lapatinib:
- Used as a second-line treatment for breast cancer with Her2 overexpression and targets EGFR and Her-2 tyrosine kinases.
Imatinib:
- Targets the tyrosine kinase of Bcr-Abl.
- Used for Ph+ CML, Ph+ ALL, myelodysplastic/myeloproliferative diseases.
Trastuzumab:
- Monoclonal antibody against Her2.
- First-line treatment for breast cancer with Her2 overexpression.
Bevacizumab:
- Monoclonal antibody against VEGF.
- Used for metastatic colorectal cancer, non-small cell lung cancer, glioblastoma multiforme, and renal cell carcinoma.

Cyclin Dependent Kinase (CDK) Inhibitors

Palbociclib:
- CDKs modulate intracellular signaling during the cell cycle.
- CDK 4 and 6 control progression from G0/G1 to S phase, regulating initiation, growth, and survival of many cancers.
- Taken orally.
- Used for advanced HRP breast cancer (first-line/standard therapy), HER2-negative advanced/metastatic breast cancer.
- Combined with aromatase inhibitors (initial endocrine therapy) for improved outcomes.
- Also combined with fulvestrant for patients who have progressed after endocrine therapy.
- Adverse effects include bone marrow suppression, infections (stomatitis), fatigue, nausea, diarrhea, and headaches.

PARP Inhibitors

Olaparib:
- PARP repairs single-strand breaks through base excision.
- Prevents cancer cells from repairing their DNA after chemotherapy, leading to double-strand breaks that accumulate during DNA replication.
- Still possible for HRD cancer cells to repair DNA damage using homologous recombination via BRCA1/BRCA2 genes, but BRCA 1/2 deficient cells are less likely to repair damaged DNA, leading to apoptosis.
- Used to target homologous recombination-deficient (HRD) cancers, particularly those with BRCA deficiency.
- Used for HRD ovarian, breast, prostate, and pancreatic cancers.
- Oral drug.
- Adverse effects include AML, myelodysplastic syndromes, pneumonitis, deep vein thrombosis, anemia, nausea, vomiting, loss of appetite, fatigue, myalgia, and arthralgia.

Miscellaneous Agents

Asparaginase:
- Some cancers require exogenous asparagine.
- Asparaginase hydrolyzes asparagine in serum.
- Deprives cells of asparagine, leading to low protein synthesis and apoptosis.
- Adverse effects include hypersensitivity, low clotting factors, liver abnormalities, and ammonia toxicity (can lead to pancreatitis, seizures, and coma).
Hydroxyurea:
- Inhibits ribonucleotide reductase, leading to a decreased concentration of dNTP, which is required for DNA synthesis.
- Induces apoptosis during the S phase.
- Oral administration.
Interferons (IFN-alpha):
- Used for hairy cell leukemia, chronic myeloid leukemia, malignant melanoma, and Kaposi's sarcoma.

Antituberculars

Most antitubercular agents require 6 months of treatment, while CNS and bone diseases require 12 months.
Dosage is dictated by patient weight.
Direct Observed Therapy (DOT) is essential for individual case management.

First Line (RIPE)

Rifampin/Rifampicin, Isoniazid, Pyrazinamide, Ethambutol.
Monotherapy leads to rapid resistance.

Rifamycins (Rifampin/Rifampicin or Rifabutin)

Rifampin:
- Binds to the bacterial RNA polymerase subunit, inhibiting RNA synthesis.
- Resistance develops via point mutations in rpoB (gene for RNA polymerase subunit).
- CYP P450 inducer.
- Well distributed throughout the body, including the CSF.
- Excreted in the feces.
- Broad antimicrobial spectrum, including MRSA, gram-positive/negative bacteria, and dividing/non-dividing mycobacteria.
- Used for serious staphylococcal infections, MRSA (with vancomycin), active TB infections, latent TB in isoniazid-intolerant patients, leprosy, and prophylaxis for meningitis and H. influenzae type B in exposed individuals.
- Adverse effects include red-orange body fluids, hepatotoxicity (elevated LFTs), GI upset, flu-like symptoms, rashes, anemia, thrombocytopenia, and renal issues (light-chain proteinuria, nephritis, acute tubular necrosis).
- Safe for pregnancy.
Rifabutin:
- Used for HIV patients, as it induces CYP less than rifampin.
- Can substitute for rifampin in intolerant patients.
- Safety for pregnancy has not been confirmed.

Isoniazid (INH)

Synthetic analog of pyridoxine.
Most potent anti-TB drug.
Inhibits synthesis of mycolic acids, disrupting the cell wall.
Resistance can develop via deletion of KatG or overexpression of inhA and mxts of KasA.
CYP P450 inhibitor.
Metabolized by the liver via N-acetyltransferase (genetically determined).
Fast acetylators = Asians and Native Americans.
Well distributed, readily diffusing into body fluids, tissues, and caseous material.
Adverse effects include hepatotoxicity, neurotoxicity, GI upset, drowsiness, and lupus-like syndrome and hemolysis.
Treatment for adverse effects includes pyridoxine (vitamin B6).
Safe for pregnancy.

Pyrazinamide

Relative of nicotinamide.
Used for active infections in combination therapy.
Rapid resistance if used alone.
Works best in an acidic pH.
Must be hydrolyzed by the mycobacterial enzyme pyrazinamidase to the active form, pyrazinoic acid.
Resistance arises from impaired uptake of pyrazinamide or mutations in the pncA gene.
Adverse effects include hepatotoxicity, myalgia, GI irritation, maculopapular rash, porphyria, and photosensitivity.
Only given during pregnancy if the benefits outweigh the risks.

Ethambutol

Part of combination therapy for active infections.
Rapid resistance if used alone.
Least potent antitubercular agent.
Inhibits arabinosyltransferases, decreasing carbohydrate polymerization of the cell wall.
Resistance arises from mutations in the emb gene.
Oral administration.
Well distributed, excreted in the urine and feces.
Dose adjustment may be needed in patients with renal insufficiency.
Adverse effects:
- Visual disturbances (dose-dependent): decreased visual acuity, red-green color blindness, optic neuritis, retinal damage.
- Other rare adverse effects include headache, confusion, peripheral neuritis, and hyperuricemia.
Safe for pregnancy.
Not given to children too young to assess visual acuity or color blindness.
Baseline and monthly visual acuity and color discrimination testing required with particular attention to patients on higher doses or with renal impairment.

Second Line Drugs (SEAL)

Streptomycin, Ethionamide, Amikacin, Levofloxacin.
Used for multidrug-resistant TB, when resistance to first-line drugs exists or there is a failure of clinical response.
Also used if serious treatment-limiting adverse drug reactions occur.

Streptomycin

Aminoglycoside.
Bactericidal against dividing mycobacteria.
Inhibits protein synthesis by binding to the 30S ribosomal subunit of the mycobacterium.
Used in combination therapy for life-threatening TB, including TB meningitis, miliary dissemination, and severe organ TB.
Parenteral administration.
Adverse effects include ototoxicity (vertigo, hearing loss - common and permanent), nephrotoxicity (decreased urine output, elevated BUN and creatinine), and teratogenicity.
Toxicity is dose related and can be reduced by limiting therapy to no more than 6 months.
Increasing resistance reduces the use of this drug.

Ethionamide

Related to isoniazid but NO cross-resistance.
Rapid resistance if used alone.
Inhibits mycolic acid synthesis.
Oral administration.
Adverse effects include gastric irritation, neurotoxicity, and hepatotoxicity.

Amikacin

Aminoglycoside, similar to streptomycin.
Inhibits protein synthesis by binding to the 30S ribosomal subunit of the mycobacterium.
Parenteral administration.
Used for streptomycin-resistant or multidrug-resistant mycobacterial strains.
Most multidrug-resistant strains remain susceptible to this drug.
Low prevalence of amikacin-resistant strains.

Levofloxacin

Fluoroquinolone.
Oral administration.
Used in combination with other agents (e.g., streptomycin) to treat multidrug-resistant TB.
Adverse effects include nausea, vomiting, diarrhea, and abnormal liver function tests.
Safety for pregnancy has not been established.

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