Antibiotics – (Beta-Lactams, Aminoglycosides, Macrolides, Tetracyclines & Sulfonamides)
By Arvind Sharma, B.Pharm, M.Pharm, Assistant Professor, MUIT
Antibiotics Masterclass
Beta-Lactam Antibiotics: Penicillins
Introduction & Properties
All penicillins are derivatives of 6-aminopenicillanic acid (thiazolidine ring attached to a β–lactam ring carrying a secondary amino group (RNH–)).
Contain a beta–lactam ring structure which is essential for antibacterial activity.
Generally narrow spectrum and bactericidal drugs.
Obtained from P. chrysogenum.
Degrade by acidic pH and amide linkage destruction via β–lactamase enzyme (penicillinase), primarily produced by gram-negative bacteria.
Act only on multiplying cells.
Mechanism of Action
Beta–lactams bind with specific receptors (penicillin-binding proteins; PBPs) and inhibit transpeptidase and carboxypeptidase enzymes.
These enzymes are crucial for cross-linking linear peptidoglycan chains, which form part of the bacterial cell wall.
Inhibition of cross-linking leads to the cell becoming incapable of withstanding the osmotic gradient, resulting in cell death.
Pro-Tip: PBP Mnemonic
Think of Penicillins working by inhibiting Bacterial Proteins (PBPs) involved in cell wall synthesis.
Pharmacokinetics
Degradation by acidic pH and β–lactamase enzyme.
Penicillins are organic acids excreted by tubular secretion.
Tubular secretion is inhibited by probenecid, which prolongs the action of penicillin.
Salts of penicillin with organic bases (e.g., Benzathine, Procaine) have limited water solubility and are useful in depot forms for prolonged action.
Conceptual Diagram: Beta-lactam - Penicillin Degradation
β–lactams + H2O (via penicillinase or acid) → penicilloic acid (further decarboxylated) → penilloic acid. This illustrates the degradation pathways that render penicillins inactive.
Adverse Effects
Thrombophlebitis: Pain and inflammation at the site of injection.
Hypersensitivity reaction: Due to degradation products of penicillin (e.g., penicilloic acid).
Anaphylactic shock (IgE-mediated).
Diarrhea: Due to disruption of normal intestinal microflora balance.
Jarisch–Herxheimer reaction: In syphilitic patients, due to sudden release of spirochetal antigens.
Specific Penicillins & Interactions
| Drugs | Features | Uses | Adverse Effects |
|---|---|---|---|
| Penicillin G (Benzyl penicillin) | Acid liable and penicillinase susceptible β–lactam antibiotic. | ||
| Penicillin V (Phenoxymethylpenicillin) | Acid resistant and penicillinase susceptible. Food ↓ its absorption. | ||
| Methicillin, Oxacillin, Cloxacillin | Penicillinase resistant. | Interstitial nephritis (Methicillin), Neutropenia (Oxacillin), Hepatitis (Cloxacillin) | |
| Extended Spectrum Penicillins: Ampicillin | Acid liable and penicillinase susceptible. | Meningitis, Gonorrhea, Subacute Bacterial Endocarditis (SABE). | Diarrhea |
| Amoxicillin | Similar to ampicillin but absorption not affected by food. | Respiratory tract infections. | |
| Carbenicillin | Acid liable and penicillinase susceptible. | Antipseudomonal. | |
| Piperacillin | Most potent antipseudomonal, used in neutropenic patients. |
Interactions
Hydrocortisone inactivates ampicillin if mixed in I.V. solution.
Ampicillin inhibits colonic microflora, interfering with deconjugation and enterohepatic cycling of oral contraceptives, leading to contraception failure.
Probenecid inhibits tubular secretion of ampicillin, increasing its duration of action.
β–Lactamase Inhibitors & Cephalosporins - Overview
β–Lactamase Inhibitors
Clavulanic acid: Obtained from Streptomyces clavuligerus. Inhibits β–lactamase (penicillinase), preventing degradation of β–lactam antibiotics. Considered a suicidal inhibitor.
Coamoxiclav = Amoxicillin + Clavulanic acid
Sulbactam: Semisynthetic β–lactamase inhibitor related to clavulanic acid.
Sultamicillin tosylate = Ampicillin + Sulbactam
Tazobactam: β–lactamase inhibitor similar to sulbactam.
Piperacillin in combination with Tazobactam is used in antibacterial therapy.
Pro-Tip: CAST Mnemonic for β–Lactamase Inhibitors
Revised: For inhibitors, remember CST: Clavulanic acid, Sulbactam, Tazobactam.
Cephalosporins: Introduction
Large group of semisynthetic drugs, mostly derived from cephalosporin C (from Cephalosporium species).
Contain a β–lactam ring and a dihydrothiazine ring (7–aminocephalosporanic acid).
Side chain modification at 7-position on β–lactam ring alters spectrum of activity.
Side chain modification at 3-position on dihydrothiazine ring alters pharmacokinetic properties.
All cephalosporins are bactericidal and have the same mechanism of action as penicillin (inhibit cell wall synthesis).
Greater acid and β–lactamase resistance and wider antibacterial activity compared to older penicillins.
Most are excreted primarily by renal tubular secretions; probenecid inhibits tubular secretion.
Cephalosporins: Adverse Reactions & Uses
Pain at the site of (I.M.) injection.
Diarrhea and hypersensitivity reactions (like penicillins).
Nephrotoxicity is highest with cephaloridine.
Platelet dysfunction and bleeding.
Disulfiram-like reaction (with some cephalosporins, e.g., Cefoperazone, Cefamandole).
Uses
Penicillinase-producing staphylococcal infections (e.g., cephalothin).
Gonorrhea caused by penicillinase-producing organisms (e.g., cefuroxime, cefotaxime).
Septicemias caused by gram-negative organisms.
Cephalosporin Generations
| Generation | Oral Compounds | Parenteral Compounds |
|---|---|---|
| First generation | Cefalexin, Cefradine, Cefadroxil | Cefalotin, Cefazolin |
| Second generation | Cefaclor, Cefuroxime axetil | Cefuroxime, Cefoxitin |
| Third generation | Cefixime, Cefpodoxime proxetil, Cefdinir | Ceftriaxone, Cefoperazone, Cefotaxime |
| Fourth generation | Cefepime, Cefpirome |
Pro-Tip: Cephalosporin Generations Trend
As you go from 1st to 4th generation:
- Gram-positive activity generally decreases (but still good).
- Gram-negative activity generally increases.
- Resistance to β-lactamases generally increases.
Other β–Lactam Antibiotics
Monobactams
Aztreonam
Monocyclic novel β–lactam antibiotic with resistance to β–lactamase.
Active against gram-negative bacilli (e.g., H. influenza, Pseudomonas), but not against gram-positive cocci.
Used in patients allergic to penicillin or cephalosporins (low cross-allergenicity).
Adverse effects: Hypersensitivity reactions and thrombophlebitis.
Carbapenems
Imipenem, Meropenem, Ertapenem
Penicillin-like structure, but sulfur atom of thiazolidine ring replaced with a carbon atom.
Potent and very broad-spectrum β–lactam antibiotics.
Resistant to β–lactamase.
Imipenem is rapidly inactivated by dehydropeptidase. Thus, it is combined with cilastatin (a dehydropeptidase inhibitor), which has similar pharmacokinetics (t1/2 = 1h).
Meropenem and Ertapenem are not inactivated by dehydropeptidase.
Probenecid inhibits tubular secretion of imipenem.
Exert cross-sensitivity with penicillins, cephalosporins, and other beta-lactams. Should not be administered to patients allergic to these drugs.
Contraindicated in epileptic patients; higher dosages can produce convulsions.
Chloramphenicol
Introduction & Properties
Broad-spectrum antibiotic with bacteriostatic activity.
Currently a backup drug for infections due to Salmonella typhi, B. fragilis, Rickettsia, and possibly bacterial meningitis.
Initially obtained from Streptomyces venezuelae.
Chloramphenicol palmitate: Prodrug designed for masking bitter taste.
Chloramphenicol succinate: Prodrug designed for increased water solubility.
Mechanism of Action
Binds with the 50S ribosomal subunit, blocking the transfer of aminoacyl t–RNA to the acceptor site for amino acid incorporation, thereby inhibiting protein synthesis.
Pro-Tip: Chloramphenicol (CHLOR-am-FEN-i-kol) - 50S
Think "Chloramphenicol has a C" which looks like part of a "5" (for 50S subunit). Or, "Chloramphenicol Limits Outstanding Ribosome function (50S)."
Adverse Effects
Dose-dependent bone marrow suppression (common); aplastic anemia (rare, 1 in 35,000) – IRREVERSIBLE.
Gray baby syndrome in neonates (due to decreased glucuronyl transferase activity in neonates and reduced renal excretion).
Optic neuritis in children.
Inhibits metabolism of phenytoin, sulfonylureas, and warfarin (CYP450 inhibition).
Hepatic failure requires dose adjustment.
Tetracyclines
Introduction & Properties
Bacteriostatic and broad-spectrum antibiotics.
Obtained from soil actinomycetes, characterized by a nucleus of four cyclic rings.
Water unstable.
Concentrated in liver and spleen, and bind to connective tissues of bones and teeth.
Mechanism of Action
Binds to the 30S ribosomal subunit and inhibits aminoacyl tRNA attachment to the acceptor site, thereby inhibiting protein synthesis.
Pro-Tip: Tetracyclines (TETRA-sy-kleens) - 30S
"TETRA" means four, but it hits the "30S" subunit. Remember: "Take 30 steps to reach TETRA's target".
Tetracycline Drugs and Adverse Effects
| Drugs | Adverse Effects |
|---|---|
| Tetracycline, Chlortetracycline, Oxytetracycline, Demeclocycline, Methacycline, Lymecycline, Doxycycline, Minocycline | GI distress (Nausea, Vomiting, Diarrhea), superinfections (candidiasis or colitis). Tooth discoloration and possible bone growth inhibition in children (avoid). Renal dysfunction, kidney damage (Fanconi syndrome) with outdated drugs (due to formation of epitetracyclines, anhydrotetracyclines, and epianhydrotetracyclines). Phototoxicity (*demeclocycline, *doxycycline). Liver dysfunction during pregnancy at very high doses (contraindicated). Vestibular dysfunction (*minocycline, *doxycycline). Diabetes insipidus (due to decreased ADH secretion with Demeclocycline). |
Uses
Used in Granuloma inguinale (due to Calymmatobacterium granulomatis), atypical pneumonia, cholera, brucellosis, plague, rickettsial infections, and prolonged therapy for acne.
Aminoglycoside Antibiotics
Introduction & Properties
Natural products or semisynthetic derivatives from soil actinomycetes.
Polybasic amino groups linked glycosidically to two or more amino sugars.
Water-soluble, stable in solution, and more active at alkaline pH.
Active against aerobic gram-negative bacilli.
Exert bactericidal action via irreversible inhibition of protein synthesis.
Mechanism of Action
Antibiotics penetrate the cell wall, bind with the 30S–50S ribosomal subunit (Streptomycin primarily 30S, others often affect both indirectly), interfere with the initiation of peptide formation and polysome formation, and cause misreading of mRNA.
This leads to irreversible protein synthesis inhibition and ultimately cell death.
Pro-Tip: Aminoglycosides - 30S (and 50S secondary effect)
"Amino" sounds like "A-mean-o", meaning it's really tough and destroys bacteria. It causes misreading of mRNA and its primary target is the 30S subunit.
Mechanism of Resistance
Microorganisms produce transferase enzymes that inactivate the aminoglycoside by adenylation, acetylation, or phosphorylation.
Impaired entry of aminoglycosides into the cell.
Mutation in the 30S ribosomal subunit receptor protein.
Aminoglycoside Drugs, Source, and Uses
| Drug | Source | Uses |
|---|---|---|
| Streptomycin | Streptomyces griseus | Tuberculosis, Tularemia, Subacute bacterial endocarditis (SABE), Plague. |
| Gentamicin | Micromonospora purpurea | SABE, Meningitis. |
| Kanamycin | S. kanamyceticus | |
| Tobramycin | S. tenebrarius | |
| Amikacin | Semisynthetic derivative of kanamycin | |
| Sisomycin | Micromonospora inyoensis | |
| Netilmicin | Semisynthetic derivative of sisomycin | |
| Neomycin | S. fradiae | Too toxic for parenteral use. Used topically only. |
| Framycetin | S. lavendulae | Similar to neomycin, used topically. |
Adverse Effects
Nephrotoxicity: Tubular damage in the kidney. Neomycin, Tobramycin, and Gentamycin are most nephrotoxic.
Ototoxicity (loss of hearing):
- Cochlear damage: Neomycin, Kanamycin, and Amikacin are most ototoxic.
- Disturbance of vestibular function: Vertigo and loss of balance (Streptomycin and Gentamycin are most vestibulotoxic).
Neuromuscular blockade: Curare-like effect.
Pro-Tip: Aminoglycoside Toxicity Mnemonic
Think "A-MEAN-O-GLYCOSIDES mean Nasty Otters and Kids" for Nephrotoxicity, Ototoxicity (vestibular/cochlear), and Kurari-like effect (neuromuscular blockade). Or for specific ototoxicity: "Streptomycin & Gentamicin make you S.G. (Stagger & Go)" (Vestibular). "N.K.A. (Neomycin, Kanamycin, Amikacin) for No Kochlear Auditory" (Cochlear).
Interactions
Concurrent use with loop diuretics (e.g., Ethacrynic acid, Furosemide) and other nephrotoxic drugs (e.g., Amphotericin B, Vancomycin, Cisplatin) potentiates nephrotoxicity.
Concurrently used with muscle relaxants and neuromuscular blockers, leading to muscular weakness.
Avoid during pregnancy: Risk of fetal ototoxicity.
Macrolides & Ketolides
Macrolides: Introduction & Mechanism
Group of closely related compounds characterized by a macrocyclic lactone ring (usually 14 or 16 atoms) with deoxy sugars attached.
Acid unstable, so administered in enteric-coated formulations (except Azithromycin and Clarithromycin).
Mechanism of Action
Binds with 50S ribosomal RNA, inhibiting aminoacyl translocation and formation of the initiation complex, thereby inhibiting protein synthesis.
Pro-Tip: Macrolides - 50S
"MAC" for Macrolides. Think of a big MAC (hamburger) that's too big to fit, blocking protein synthesis at the 50S subunit. Or "My Antibiotic Closes at 50S."
Erythromycin
Obtained from Streptomyces erythreus, has a 14-membered macrocyclic ring.
Used for infections caused by gram-positive cocci (not MRSA), atypical organisms (Chlamydia, Mycoplasma, Ureaplasma species), Legionella pneumophila, Campylobacter jejuni, Bordetella pertussis.
First choice drug for whooping cough and chancroid.
Erythromycin (estolate is best absorbed orally) has wide tissue distribution and is mainly eliminated via biliary excretion.
Adverse Reactions and Interactions
Gastrointestinal irritation (common), skin rashes, eosinophilia.
Hypersensitivity-based acute cholestatic hepatitis may occur with erythromycin estolate.
Inhibits several forms of hepatic cytochrome P450, increasing plasma levels of anticoagulants, carbamazepine, cisapride, digoxin, and theophylline.
Cardiac arrhythmias occurred when administered with astemizole or terfenadine (discontinued antihistamines).
Other Macrolides
Clarithromycin: Causes less GI distress than erythromycin. Inhibits P450 and can cause reversible deafness at high doses. Animal studies show teratogenic effects.
Azithromycin: Semisynthetic derivative (azalide congener) of erythromycin. Safe in pregnancy and does not significantly inhibit drug metabolism (less P450 interaction). Very long half-life.
Roxithromycin: Semisynthetic, acid-stable, and long-acting macrolide. Activity spectrum resembles erythromycin.
Ketolides
Semisynthetic 14-membered-ring macrolides, differing from erythromycin by substitution of a 3–keto group for L–cladinose.
Example: Telithromycin.
Used for treatment of respiratory tract infections, including community-acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and streptococcal pharyngitis.
Other Antibiotics (Protein Synthesis & Cell Wall)
Clindamycin
Chlorine–substituted derivative of lincomycin (from Streptomyces lincolnensis).
Clinical activity and mechanism of action resemble erythromycin (not effective against MRSA and aerobic gram-negative bacteria).
Adverse Effects
Rashes, urticaria, abdominal pain, and diarrhea.
Superinfection: Pseudomembranous enterocolitis due to Clostridium difficile (most notorious adverse effect).
Quinupristin-Dalfopristin
Combination of two streptogramins (quinupristin B and dalfopristin A) in a 30:70 ratio.
Rapidly bactericidal and has a prolonged post-antibiotic effect.
Active against most gram-positive cocci, including MRSA and VRSA.
Mechanism: Binds to 50S ribosomal subunit.
Fusidic Acid
Narrow-spectrum steroidal antibiotic that blocks bacterial protein synthesis.
Active against penicillinase-producing gram-positive bacteria.
Used topically only.
Linezolid
New class of synthetic antimicrobials (Oxazolidinones derivative).
Active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods.
Primarily bacteriostatic, except for streptococci (bactericidal).
Inhibits protein synthesis by binding with 23S ribosomal RNA of the 50S subunit, preventing formation of the ribosome complex that initiates protein synthesis.
Glycopeptides & Cell Wall Inhibitors (Non-Beta-Lactam)
Vancomycin
Glycopeptide antibiotic produced by Streptococcus orientalis.
Active only against gram-positive bacteria (with the single exception of Flavobacterium), particularly staphylococci and MRSA.
Mechanism of Action
Binds with the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide.
This inhibits transglycosylase, preventing further elongation of peptidoglycan and cross-linking (inhibits cell wall synthesis), leading to cell wall lysis and death.
Pro-Tip: Vancomycin Mechanism (D-Ala-D-Ala)
"Vancomycin Attacks Layers And Always Lyses All." (D-Ala-D-Ala terminal binding).
Adverse Reactions
Thrombophlebitis (pain and inflammation at site of injection).
“Red man” or “red neck” syndrome (histamine release from rapid infusion, infuse slowly).
Dose-dependent kidney damage (Nephrotoxicity).
Additively enhanced nephrotoxic and ototoxic effects with aminoglycosides, loop diuretics, etc.
Teicoplanin
Glycopeptide antibiotic resembling Vancomycin in mechanism of action and antibacterial spectrum.
Shows less toxicity than Vancomycin.
Fosfomycin
Analog of phosphoenolpyruvate.
Inhibits bacterial cell wall synthesis at a very early stage.
Mechanism of Action
Inhibits the cytoplasmic enzyme enolpyruvate transferase, blocking the addition of phosphoenolpyruvate to UDP–N–acetylglucosamine, thereby preventing the formation of UDP–N–acetylmuramic acid and inhibiting cell wall synthesis.
Use
Treatment of uncomplicated lower urinary tract infections in women.
Bacitracin
Cyclic peptide obtained from Bacillus subtilis.
Active against gram-positive microorganisms (both cocci and bacilli).
Mechanism of Action
Interferes with dephosphorylation in the cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall, thereby inhibiting cell wall formation.
Adverse Effects
Nephrotoxic (when administered systemically, so primarily used topically).
Proteinuria, hematuria, hypersensitivity.
Cycloserine
Produced by Streptomyces orchidaceus.
Water-soluble and very unstable at acid pH.
Inhibits many gram-positive and gram-negative organisms.
Used almost exclusively to treat tuberculosis caused by strains of M. tuberculosis resistant to first-line drugs.
Adverse Effects
Dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions.
Sulfonamides
Introduction & Structure
First effective chemotherapeutic agents used systemically for preventing and curing bacterial (pyogenic bacterial) infections.
Considered derivatives of para-aminobenzenesulfonamide (sulfanilamide).
NH2
|
O=S=O
|
NH2
The —SO2NH2 group (N1) governs solubility, potency, and pharmacokinetic properties.
The para–NH2 group (N4) is essential for antibacterial activity.
Most are relatively insoluble in water, but their sodium salts are readily soluble.
Mechanism of Action
Sulfonamides are structural analogs of para-aminobenzoic acid (PABA).
They competitively inhibit the bacterial enzyme dihydropteroate synthetase, which is involved in the synthesis of dihydrofolic acid from PABA and pteridine.
This blocks the synthesis of dihydrofolic acid, which is a precursor to tetrahydrofolic acid (folic acid), essential for bacterial DNA and RNA synthesis.
Thus, sulfonamides inhibit bacterial growth (bacteriostatic).
Pro-Tip: Sulfonamides (PABA Analogs)
"Stop Follicle Acid Production (SFAP) with Sulfonamides. They look like PABA and block dihydropteroate synthetase."
Sulfonamide Drugs and Adverse Effects
| Drugs | Adverse Effects |
|---|---|
| Short-acting: Sulfadiazine | Nausea, vomiting, crystalluria (precipitation in urine, ensure hydration). Photosensitization. Stevens–Johnson syndrome and exfoliative dermatitis (severe skin reactions). Hepatitis, hemolysis (especially in G6PD deficient patients). Kernicterus in newborns (contraindicated in late pregnancy and in newborns due to displacement of bilirubin from albumin). |
| Intermediate-acting: Sulfamethoxazole | |
| Long-acting: Sulfadoxine |
Special Purpose Sulfonamides
Silver sulfadiazine: Used for preventing infections of burnt surfaces (antibacterial action due to Ag+ ions).
Triple Sulfa: Mixture of equal quantities of Sulfadiazine, Sulfamerazine, and Sulfamethizine. Provides additive antibacterial action and minimizes crystalluria (due to different solubilities).
Sulfasalazine: Compound of 5–Amino salicylic acid (5–ASA) with sulfapyridine, linked through an azo bond. Sulfapyridine primarily acts as a carrier for 5–ASA; anti-inflammatory action is due to 5–ASA. Used in ulcerative colitis.
Olsalazine: Two molecules of 5–ASA coupled together by an azo bond. Used in ulcerative colitis.
Mesalazine (Mesalamine): 5–ASA formulation as a delayed-release preparation by coating with acrylic polymer. Formulation delivers 5–ASA in the small bowel and colon.
All 5–ASA prodrugs are used in ulcerative colitis.
Cotrimoxazole & Other Combinations
Cotrimoxazole
Combination of Sulfamethoxazole (5 parts) + Trimethoprim (1 part).
Combination is based on similar half-lives (approx. 10 hours).
Action of this combination is bactericidal (whereas individual components are bacteriostatic) due to sequential blockade of folic acid synthesis.
Adverse Effects
Megaloblastic anemia due to folic acid deficiency (counteracted by leucovorin).
Other sulfonamide adverse effects.
Interactions
Diuretics with Cotrimoxazole can produce a higher incidence of thrombocytopenia.
Uses
Urinary tract infection and prostatitis, respiratory tract infections, typhoid, chancroid, bacterial diarrhea and dysentery, pneumonia due to Pneumocystis carinii.
Pro-Tip: Cotrimoxazole (TMP-SMX) - Bactericidal Synergy
Trimethoprim inhibits dihydropteroate reductase and Sulfamethoxazole inhibits dihydropteroate synthetase. Together, they create a "Double Blockade" of folate synthesis, making them bactericidal.
Important Notes:
Trimethoprim (90 mg) + Sulfadiazine (410 mg) utility similar to that of Cotrimoxazole.
Sulfadiazine + Pyrimethamine: This combination is used in leishmaniasis and toxoplasmosis.
Sulfadoxine and Sulfamethopyrazine are ultra-long-acting compounds, showing >1 week action.