Chemotherapy – General Principles, Sulfonamides & Antibiotics
This unit introduces the foundational principles of chemotherapy — selective toxicity, spectrum of activity, MIC/MBC, resistance mechanisms, and combination therapy rationale. It then systematically covers Sulfonamides (the first synthetic antibacterials) and the major classes of antibiotics: Penicillins, Cephalosporins, Chloramphenicol, Macrolides, Quinolones/Fluoroquinolones, Tetracyclines, and Aminoglycosides — their mechanism, spectrum, pharmacokinetics, clinical uses, adverse effects, and resistance.
Syllabus & Topics
- 1General Principles – Selective Toxicity: The goal of chemotherapy is to kill/inhibit the pathogen while causing minimal harm to the host. Selective toxicity exploits differences between pathogen and host: (1) Unique target (bacterial cell wall — humans don’t have it → β-lactams). (2) Different enzyme affinity (Trimethoprim: 50,000x more affinity for bacterial DHFR). (3) Selective drug accumulation (Aminoglycosides transported into bacteria by O₂-dependent mechanisms — not into mammalian cells).
- 2Key Concepts: MIC (Minimum Inhibitory Concentration) = lowest drug concentration that prevents visible bacterial growth (bacteriostatic endpoint). MBC (Minimum Bactericidal Concentration) = lowest concentration that kills 99.9% of bacteria. Bactericidal drugs: kill bacteria (β-lactams, aminoglycosides, fluoroquinolones). Bacteriostatic drugs: inhibit growth (tetracyclines, macrolides, sulfonamides). Time-dependent killing (β-lactams — keep concentration above MIC) vs Concentration-dependent killing (aminoglycosides — peak:MIC ratio matters).
- 3Antibiotic Resistance Mechanisms: (1) Enzymatic inactivation: β-lactamases destroy β-lactam ring; aminoglycoside-modifying enzymes (acetylation, adenylation, phosphorylation). (2) Altered target: MRSA has altered PBP2a; vancomycin resistance changes D-Ala-D-Ala → D-Ala-D-Lac. (3) Decreased permeability: loss of porins (gram-negative → carbapenems). (4) Efflux pumps: actively pump drug out (tetracycline resistance). (5) Bypass pathway: MRSA acquires mecA gene. Resistance transfer: chromosomal mutation, plasmid (R-factor), transposon, transformation.
- 4Combination Therapy Rationale: (1) Broader spectrum (empiric therapy for serious infections before culture results). (2) Synergy: Cotrimoxazole (sequential blockade), β-lactam + aminoglycoside (cell wall damage enhances aminoglycoside entry). (3) Prevent resistance: anti-TB therapy (RIPE regimen). (4) Reduce dose and toxicity of individual drugs. Antagonism possible: bactericidal + bacteriostatic (tetracycline antagonizes penicillin — slowing growth reduces penicillin effectiveness which requires active cell wall synthesis).
- 5Sulfonamides: First synthetic antibacterials (Prontosil → Sulfanilamide, Domagk 1935, Nobel Prize 1939). MOA: competitive inhibitor of dihydropteroate synthase (DHPS) — blocks PABA incorporation into dihydrofolic acid → ↓folate → ↓DNA synthesis. Bacteriostatic. Key drugs: Sulfamethoxazole (medium-acting, in Cotrimoxazole), Sulfadiazine (with pyrimethamine for toxoplasmosis), Sulfacetamide (ophthalmic), Sulfasalazine (IBD/RA — cleaved in colon to 5-ASA + sulfapyridine). Silver sulfadiazine (burn wounds).
- 6Cotrimoxazole (TMP-SMX): Trimethoprim + Sulfamethoxazole (1:5 ratio, achieving 1:20 ratio in tissues — optimal for synergy). Sequential blockade: SMX blocks DHPS (step 1), TMP blocks DHFR (step 2) → synergistic bactericidal effect. Spectrum: UTI (E. coli), Respiratory (Pneumocystis jirovecii — drug of choice for PCP prophylaxis in AIDS), Shigellosis, Salmonella. ADR: rash (Stevens-Johnson syndrome rare), folate deficiency (megaloblastic anemia — supplement with folinic acid, NOT folic acid).
- 7Penicillins – Pharmacology: MOA: bind PBPs (Penicillin-Binding Proteins/transpeptidases) → inhibit peptidoglycan cross-linking → weakened cell wall → osmotic lysis → bactericidal. Classification: Natural (Pen G, Pen V), Anti-staphylococcal (Methicillin, Cloxacillin, Flucloxacillin — β-lactamase resistant), Aminopenicillins (Ampicillin, Amoxicillin — extended gram-negative), Anti-pseudomonal (Piperacillin, Ticarcillin). ADR: hypersensitivity (1-10%, anaphylaxis rare but fatal — ask about allergy before prescribing), diarrhea, superinfection.
- 8Cephalosporins: Spectrum broadens with each generation. 1st Gen (Cephalexin, Cefazolin): good gram+, surgical prophylaxis. 2nd Gen (Cefuroxime, Cefaclor): ↑gram−. 3rd Gen (Ceftriaxone, Cefotaxime, Ceftazidime): excellent gram−, CNS penetration (meningitis), Ceftazidime = anti-Pseudomonal. 4th Gen (Cefepime): broadest. 5th Gen (Ceftaroline): anti-MRSA. ADR: hypersensitivity (5-10% cross-reactivity with penicillin), disulfiram-like reaction (cefoperazone — avoid alcohol), hypoprothrombinemia (vitamin K deficiency — cefoperazone, cefamandole).
- 9Chloramphenicol: Broad-spectrum bacteriostatic. MOA: binds 50S ribosome → inhibits peptidyl transferase → blocks translocation. Excellent CNS penetration. Used for: typhoid fever (Salmonella typhi), bacterial meningitis (where alternatives unavailable), rickettsial infections, eye infections (topical). Serious ADR: (1) Dose-related bone marrow suppression (reversible). (2) Idiosyncratic aplastic anemia (irreversible, fatal, 1:20,000-40,000 — NOT dose-related). (3) Gray baby syndrome (neonates lack glucuronyl transferase → drug accumulates → cardiovascular collapse).
- 10Macrolides: Erythromycin: prototype, MOA → binds 50S ribosome, blocks translocation. Acid-unstable → enteric coated or ester prodrugs. CYP3A4 inhibitor (many drug interactions). Clarithromycin: acid-stable (6-O-methyl), better anti-H. pylori. Azithromycin: 15-membered azalide, longest t½ (68 h — 3-day course), tissue concentrated, fewer CYP interactions. Spectrum: gram+, atypical organisms (Mycoplasma, Chlamydia, Legionella). ADR: GI disturbance, QT prolongation (rare), hepatotoxicity (Erythromycin estolate).
- 11Quinolones & Fluoroquinolones: MOA: inhibit DNA gyrase (topoisomerase II) and topoisomerase IV → prevent DNA supercoiling → bactericidal. Nalidixic acid (1st gen, UTI only). Fluoroquinolones: Norfloxacin (UTI), Ciprofloxacin (broadest gram−, anti-Pseudomonal, systemic infections), Ofloxacin/Levofloxacin (respiratory), Moxifloxacin (respiratory + anaerobic). ADR: tendon rupture (Achilles tendon, risk ↑ with corticosteroids and age >60), QT prolongation, CNS effects (seizures, insomnia), cartilage damage (avoid in children and pregnancy).
- 12Tetracyclines: MOA: bind 30S ribosome → block aminoacyl-tRNA entry at A-site → bacteriostatic. Broad spectrum but increasing resistance. Doxycycline: most used, long-acting (t½ 18 h), safe in renal impairment (fecal excretion), antimalarial prophylaxis. Minocycline: most lipophilic, best tissue penetration, anti-MRSA activity. ADR: teeth/bone discoloration (chelates Ca²⁺ → contraindicated in children <8 years and pregnancy), photosensitivity, GI upset, Fanconi syndrome (degraded tetracycline).
- 13Aminoglycosides: MOA: bind 30S ribosome → cause mRNA misreading → bactericidal. Concentration-dependent killing with post-antibiotic effect. Gentamicin: most commonly used (gram− sepsis, endocarditis with β-lactam). Amikacin: most resistant to aminoglycoside-modifying enzymes. Tobramycin: anti-Pseudomonal (inhaled for CF). Streptomycin: TB, plague. MUST monitor: (1) Ototoxicity (irreversible cochlear/vestibular damage — tinnitus, vertigo, deafness). (2) Nephrotoxicity (reversible — monitor creatinine). (3) Neuromuscular blockade (rare). Once-daily dosing (extended-interval) preferred — ↑peak for efficacy, longer drug-free interval for ↓toxicity.
Learning Objectives
Exam Prep Questions
Q1. Why Is Penicillin Allergy Clinically Important?
Penicillin antibiotics are among the most commonly prescribed antibiotics, but they are also one of the most frequent causes of drug allergies. Approximately 1–10% of patients report penicillin allergy, although true severe reactions are much rarer. Allergic responses may range from mild skin rashes to severe and life-threatening Anaphylaxis.
The main allergenic determinant is the Penicilloyl group formed when penicillin degrades and binds to body proteins. Because of structural similarity, cross-reactivity may occur with other Beta lactam antibiotics such as Cephalosporins, particularly first-generation agents. For this reason, clinicians must always obtain a detailed allergy history before prescribing β-lactam antibiotics, and skin testing may be used to confirm true allergy.
Q2. What Is Gray Baby Syndrome?
Gray baby syndrome is a serious adverse reaction seen when Chloramphenicol is administered to neonates, especially premature infants. Newborns have immature hepatic enzyme systems, particularly UDP glucuronyl transferase, which is required for the metabolism of chloramphenicol.
Because the drug cannot be properly conjugated and eliminated, it accumulates to toxic levels in the bloodstream. This leads to symptoms such as abdominal distension, vomiting, hypothermia, circulatory collapse, and the characteristic gray discoloration of the skin. The condition can be fatal if untreated. Prevention involves avoiding chloramphenicol in neonates or using carefully monitored reduced doses if its use is unavoidable.
Q3. Why Should Fluoroquinolones Be Avoided in Children?
Fluoroquinolone antibiotics such as Ciprofloxacin have been shown in animal studies to cause damage to cartilage in the weight-bearing joints of immature animals. This raised concerns about possible effects on developing cartilage in children.
Although definitive evidence in humans is limited, health authorities such as the World Health Organization and U S Food and Drug Administration recommend avoiding fluoroquinolones in children under 18 years, as well as in pregnant or breastfeeding women, unless no safer alternatives exist. In certain severe infections—such as those associated with Cystic fibrosis, complicated urinary tract infections, or exposure to Anthrax—the benefits may outweigh the risks.
Q4. What Is the Post-Antibiotic Effect (PAE)?
Post antibiotic effect refers to the continued inhibition of bacterial growth even after antibiotic concentrations fall below the Minimum inhibitory concentration.
Certain antibiotics such as Aminoglycosides and Fluoroquinolones exhibit a prolonged PAE lasting several hours. This property allows once-daily dosing regimens, because bacterial growth remains suppressed even when drug levels temporarily fall below the MIC between doses. In contrast, Beta lactam antibiotics generally show minimal post-antibiotic effect, meaning their efficacy depends more on maintaining drug concentrations above the MIC for longer periods.