Rifampicin (Rifampin)

Mechanism of Action

• It is bactericidal against actively dividing mycobacteria
• Acts on both intracellular and extracellular organisms
• Also kills "persisters" - semidormant bacilli that are otherwise hard to eradicate

Uses

Adverse Drug Reactions (ADRs)

1. Orange-Red Discoloration

• Body fluids (urine, tears, saliva, sweat, sputum) turn orange-red - harmless but alarming to patients
• Can permanently stain soft contact lenses

2. Hepatotoxicity (Most Important)

• Transient elevation of liver enzymes common (up to 15%)
• Frank hepatitis in ~1% - more likely with pre-existing liver disease or alcoholism
• Mechanism: toxic metabolites + immune-mediated injury
• Monitor LFTs before and during therapy

3. Drug Interactions - Enzyme Induction (Critical)

• Oral contraceptives (contraceptive failure)
• Warfarin (loss of anticoagulation)
• HIV antiretrovirals (major interaction)
• Cyclosporine, tacrolimus
• Oral hypoglycemics, corticosteroids, methadone, azole antifungals

4. Flu-like Syndrome

• Intermittent/high-dose regimens cause fever, chills, headache, myalgia, bone pain
• Immunologically mediated

5. Thrombocytopenia & Hemolytic Anemia

• Immune-mediated, more common with intermittent dosing

6. GI Effects

• Nausea, vomiting, abdominal cramps (take on empty stomach for best absorption, but food reduces GI upset)

7. CNS Effects

• Headache, dizziness, drowsiness, visual disturbances (uncommon)

8. Renal Effects

• Interstitial nephritis (rare), hemoglobinuria

Key Pharmacokinetics Note

• Well absorbed orally; food reduces absorption - best taken 30 min before meals
• Widely distributed; penetrates CSF, macrophages, caseous lesions
• Undergoes enterohepatic circulation; auto-induces its own metabolism (accelerated clearance after first few weeks)
• Excreted primarily in bile/feces

NRTIs - Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Mechanism of Action

1. Phosphorylation: After entering the cell, NRTIs are sequentially phosphorylated by host kinases to their triphosphate active form (e.g., zidovudine 5'-triphosphate)
2. Chain termination: The active triphosphate:
   • Competes with natural nucleotides for incorporation into viral DNA by HIV reverse transcriptase
   • Once incorporated, they terminate DNA chain elongation because they lack a 3'-hydroxyl (OH) group - this prevents addition of the next nucleotide

NRTIs have low affinity for human DNA polymerases (except mitochondrial DNA polymerase γ - the basis of mitochondrial toxicity).

Members & Key Uses

• HBV treatment - TDF, TAF, lamivudine, emtricitabine
• HIV PrEP - TDF/FTC (Truvada) or TAF/FTC (Descovy)
• PMTCT - ZDV ± single-dose nevirapine

Adverse Drug Reactions (ADRs)

Class-wide ADRs

Drug-Specific ADRs

Key Point on Resistance

• M184V mutation (in reverse transcriptase): confers high-level resistance to lamivudine and emtricitabine - but also restores ZDV sensitivity and reduces viral fitness
• TAMs (Thymidine Analogue Mutations): K70R, K219Q, M41L etc. - confer cross-resistance across multiple NRTIs
• K65R mutation: caused by tenofovir, abacavir; confers multi-NRTI resistance

Third-Generation Cephalosporins

Mechanism of Action

1. Bind to Penicillin-Binding Proteins (PBPs) - specifically transpeptidases on the bacterial cell surface
2. Inhibit transpeptidation - the final cross-linking step in peptidoglycan cell wall synthesis
3. The β-lactam ring acylates (inactivates) the transpeptidase by mimicking the D-Ala-D-Ala substrate
4. With no intact cell wall, bacteria undergo autolysis and osmotic lysis → bactericidal effect

Note: Cephalosporins do NOT bind essential PBPs in Enterococcus spp. → no activity against enterococci.

Members

Uses

1. Meningitis (Major Indication)

• Bacterial meningitis - N. meningitidis, H. influenzae, penicillin-sensitive S. pneumoniae
• Ceftriaxone + vancomycin is standard empiric therapy for pneumococcal meningitis (until susceptibilities known)
• CSF penetration is adequate at therapeutic doses

2. Community-Acquired Pneumonia (CAP)

• Ceftriaxone or cefotaxime + macrolide is a recommended regimen for hospitalized CAP

3. Gonorrhea

• IM ceftriaxone 500 mg - current first-line for uncomplicated gonorrhea (dose recently increased due to rising resistance)

4. Septicemia / Gram-negative bacteremia

• Empiric coverage of Enterobacterales (E. coli, Klebsiella, Proteus)

5. Typhoid fever

• Ceftriaxone is effective for drug-resistant typhoid

6. Urinary tract infections

• Cefixime, cefpodoxime for oral outpatient treatment

7. Intra-abdominal / biliary infections

• Ceftriaxone (biliary excretion makes it useful for biliary tract infections)

8. Otitis media, sinusitis, pharyngitis

• Oral agents: cefixime, cefdinir, cefpodoxime

9. Pelvic inflammatory disease (PID)

• IM ceftriaxone as part of combination therapy

10. Lyme disease (disseminated/neurological)

• Ceftriaxone IV for neuroborreliosis and Lyme carditis

Adverse Drug Reactions (ADRs)

1. Hypersensitivity Reactions (Most Common)

• Maculopapular rash, urticaria - 1-3% of patients
• Anaphylaxis (rare, ~0.02%)
• Cross-reactivity with penicillin: ~1-2% (much lower than historically thought; share β-lactam ring but differ in side chains)
• Contraindicated in patients with prior anaphylaxis to penicillins

2. GI Effects

• Nausea, vomiting, diarrhea
• Ceftriaxone-specific: Pseudolithiasis (biliary sludge/gallstones) - calcium-ceftriaxone precipitates in bile; more common in children; usually reversible on stopping
• C. difficile-associated diarrhea / colitis - disruption of gut flora

3. Hematological

• Thrombocytopenia, hemolytic anemia (rare, immune-mediated)
• Hypoprothrombinemia - especially cephalosporins with N-methylthiotetrazole (NMTT) side chain (cefoperazone) - inhibits vitamin K-dependent clotting factor synthesis; bleeding risk

4. Nephrotoxicity

• Mild; rarely clinically significant with 3rd gen alone
• Additive with aminoglycosides

5. Superinfection

• Prolonged use can select for resistant organisms (Pseudomonas, Enterococcus, fungi)
• Resistance via inducible AmpC β-lactamases (SPACE organisms: Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter) - can emerge on therapy

6. Disulfiram-like reaction

• Only with NMTT-containing agents (e.g., cefoperazone) + alcohol

7. Injection site reactions

• Pain/phlebitis at IV site; pain at IM injection site

8. Pregnancy / Lactation

• Generally considered safe in pregnancy (no controlled studies); some excreted in breast milk (may interfere with neonatal sepsis culture results)

Key Resistance Mechanisms

• ESBLs (Extended Spectrum β-Lactamases) - hydrolyze 3rd gen cephalosporins; common in E. coli, Klebsiella - major clinical problem
• KPC (Klebsiella pneumoniae Carbapenemase) - confers resistance
• AmpC β-lactamases (inducible, chromosomal) - SPACE organisms
• PBP alterations in S. pneumoniae (PBP 1A and 2X mutations) - pneumococcal resistance

ACT (Artemisinin-Based Combination Therapy) and Malaria Prophylaxis

Important Distinction: ACT is Primarily for Treatment, NOT Routine Prophylaxis

Standard Malaria Chemoprophylaxis (Travelers)

Start prophylaxis 1-2 weeks before travel (2 days for doxycycline/Malarone), continue 4 weeks after leaving (1 week for Malarone).

Where ACT Fits in Preventive Strategy

1. Seasonal Malaria Chemoprevention (SMC)

• WHO-recommended for children under 5 in the Sahel sub-region of Africa during high-transmission months (July-November)
• Uses sulfadoxine-pyrimethamine + amodiaquine (SP+AQ) - not strictly ACT but combination therapy
• Dihydroartemisinin-piperaquine (DHA-PPQ) is being studied/used as an ACT for SMC - piperaquine's long t½ (~20 days) provides extended posttreatment prophylaxis, making it well-suited for this purpose

2. Intermittent Preventive Treatment (IPT)

• IPTp (in pregnancy): Sulfadoxine-pyrimethamine given at each antenatal visit - NOT an ACT (artemisinins avoided in 1st trimester)
• IPTi (in infants): SP given at time of routine vaccinations

3. Post-Treatment Prophylactic Effect of ACTs

• DHA-piperaquine specifically offers a period of post-treatment prophylaxis due to piperaquine's long half-life - this is unique among ACTs and makes it preferred in high-transmission settings

4. Standby Emergency Treatment (SBET)

• Some authorities accept carrying an ACT (e.g., artemether-lumefantrine) as standby emergency self-treatment for travelers to lower-risk remote areas where rapid medical access is unavailable - not a substitute for chemoprophylaxis

Common ACT Regimens (Treatment, not prophylaxis)

Why ACTs Are Used in Combination

1. Artemisinin acts rapidly, killing most parasites within 3 days
2. The partner drug (lumefantrine, piperaquine, mefloquine, amodiaquine) has a longer half-life and clears residual parasites
3. Combination prevents development of artemisinin resistance - a major global concern, especially in Southeast Asia (partial artemisinin resistance - K13 mutations)

Summary Table: ACT vs. Standard Prophylaxis

Chloroquine

Mechanism of Action

1. Antimalarial MOA - Heme Polymerization Inhibition

1. Chloroquine enters the parasite-infected red blood cell and concentrates in the acidic food vacuole of the Plasmodium parasite via ion trapping (the weak base becomes protonated and trapped in the acidic environment)
2. Inside the food vacuole, the parasite digests host hemoglobin to extract amino acids - this releases large amounts of free heme (ferriprotoporphyrin IX), which is toxic to the parasite
3. Normally, the parasite protects itself by polymerizing free heme into hemozoin (an insoluble, non-toxic "malaria pigment")
4. Chloroquine binds to free heme and blocks its polymerization into hemozoin
5. The resulting accumulation of free heme + raised vacuolar pH causes oxidative membrane damage → lysis of both parasite and RBC

Chloroquine is a blood schizonticide - it acts on the erythrocytic (asexual intraerythrocytic) stage only. It has NO reliable activity against liver stage parasites (hypnozoites) or gametocytes.

2. Immunomodulatory MOA (for rheumatic diseases)

• Chloroquine and hydroxychloroquine accumulate in lysosomes of immune cells (macrophages, dendritic cells)
• Raises lysosomal/endosomal pH → inhibits antigen processing and presentation
• Suppresses Toll-like receptor (TLR) signaling (TLR7, TLR9) by preventing acidification needed for TLR activation
• Reduces production of pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
• Net effect: broad anti-inflammatory and immunomodulatory activity

Pharmacokinetics

• Absorption: Rapidly and almost completely absorbed orally; peak plasma in ~3 hours
• Distribution: Extremely large Vd (100-1000 L/kg); concentrates in erythrocytes, liver, spleen, kidney, lung, melanin-containing tissues (retina, skin), leukocytes
• Half-life: Initial t½ 3-5 days; terminal t½ 1-2 months (due to slow release from tissues) - allows once-weekly dosing for prophylaxis
• Metabolism: Hepatic dealkylation (CYP enzymes); metabolites retain some antimalarial activity
• Excretion: Predominantly renal

Uses

Antimalarial Uses

Limitation: Resistance in P. falciparum is now widespread (almost all endemic areas) - replaced by ACTs in most regions. P. vivax resistance emerging in Indonesia and Papua New Guinea.

Non-Malarial Uses

Adverse Drug Reactions (ADRs)

At Prophylactic / Low Doses (generally well tolerated)

At Higher / Prolonged Doses (rheumatic disease doses)

Acute Overdose (Medical Emergency)

• As little as 5 g can be fatal in adults
• Cardiovascular: severe hypotension, cardiac arrhythmias, respiratory and cardiac arrest
• IV/IM administration → severe hypotension; must be avoided
• Treatment: mechanical ventilation, anticonvulsants, vasopressors

Contraindications

• Psoriasis - may precipitate severe exacerbation
• Porphyria - may trigger acute attack
• Pre-existing retinal or visual field abnormalities
• Pre-existing myopathy
• Caution: hepatic disease, neurologic disorders, hematologic disorders, G6PD deficiency

Safe in pregnancy and in young children at recommended doses.