ANTIBIOTICS(Antibacterials)
By Nelson Gozah⚕️
OUTLINE
1.Overview
2.Selective Toxicity/ Therapeutic index
3.Classification
4.Broad mechanism
5.Therapeutic classes : Agents
- MOA
- Indication
- Side effects..
- Contraindication
1.Overview
Introduction to Antibacterials
Antibiotics/antibacterials are agents that destroy, eliminate or cause toxicity to microbes(bacteria) by eliminating or reducing the infecting bacteria.
– Antibacterials are used to treat bacteria only
– Some antimicrobials like metronidazole treat both bacterial and protozoal infections
2.Selective Toxicity and Therapeutic Index
-Toxicity generally refers to adverse drug reactions.
-Selective Toxicity in antibiotic therapy refers to the ability of an antibacterial agent to selectively destroy or eliminate the offending bacteria with minimal toxicity to the host cells
-Thus, inhibiting microbial growth with minimal harm to host cells
– The goal is to destroy or inhibit infecting organisms without damaging host
– Antibacterials target unique bacteria structures or processes absent in host
– Bacteria and human cells are very different – many selective antibacterial targets
– Fungal and human cells are more similar -hence, fewer selective antifungal targets
– Viruses use host cells – damaging viruses often damages infected host cells
Therapeutic Index
This refers to the ratio of toxic dose to therapeutic dose. It indicates the margin of safety or degree of selectivity. Higher the therapeutic index, the safer the drug.
– Compares amount causing therapeutic effect to amount causing toxicity
– Higher therapeutic index indicates safer antibacterial agent
– Penicillin has high index due to unique bacterial cell wall target
3.Classification of antibiotics
Antibacterials can be classified based on spectrum of activity, Source and function.
– Classification based on spectrum
They can classified as either broad or narrow-spectrum
– Broad-spectrum act against wide range bacteria (ex. meropenem)
– Narrow-spectrum target specific bacteria families (ex. penicillin G/V)
– Broad-spectrum risk disrupting normal flora more than narrow-spectrum
– Broad-spectrum properly used when wide illness possibilities, serious illness could result without quick treatment, or empirically before identifying causative agent
Classification by source;
– From natural sources (ex. penicillin G, cephalosporin C)
– Synthetic antibiotics (ex. sulfonamides, chloramphenicol)
– Semi-synthetic – natural product modified (ex. ampicillin, cephalosporins)
Classification based on function;
– Can inhibit bacterial growth (bacteriostatic) or kill bacteria (bactericidal)
– Bacteriostatic inhibit bacterial protein synthesis (ex. tetracyclines)
– Require functioning immune system
– Bactericidal directly kill bacteria (ex. penicillin, gentamicin)
4.Mechanisms of Antibacterial Action
– Inhibit cell wall synthesis
– Inhibit protein synthesis
– Inhibit nucleic acid synthesis
– Disrupt plasma membrane
– Inhibit essential metabolite synthesis
5.Therapeutic Classes
1.Penicillin eg Amoxycillin,flucloxacillin,
2.Cephalosporins-eg Ceftriazone, cefuroxime
3.Carbapenem-eg Imipenem/cilastatin
4.Monobactam-eg Aztreonam
5.Vancomycin-eg Vancomycin,
6.Bacitracin-eg Bacitracin
7.Aminoglycosides-eg Gentamycin, Amikacin
8.Tetracycline-eg Tetracycline, Doxycycline
9.Chloramphenicol-eg Chloramphenicol
10.Macrolides-eg Erythromycin, Azithromycin
11.Lincosamide-eg Clindamycin
12.Quinolones-eg Ciprofloxacin,Levofloxacin
13.Rifampin-eg Rifampin
14.Sulphonamides-eg Sulphamethoxazole, Trimetoprim
15.Nitroimidazoles-eg Metronidazole, Tinidazole
16.Antikochs(antituberculous drugs)-eg HRZE
17.Polymyxins-Colistin ,Polymycin B
1.Penicillins
Definition: First systemic antibiotic discovered from the fungus Penicillium.
Selective toxicity: Targets bacterial cell wall synthesis via inhibition of transpeptidases with minimal human toxicity.
Therapeutic index: Wide margin between therapeutic and toxic doses.
Classification: Beta-lactam antibacterial.
Mechanism: Inhibits transpeptidation and cross-linking of peptidoglycan in the bacterial cell wall.
Therapeutic classes: Natural penicillins (penicillin G, V), antistaphylococcal penicillins (flucloxacillin, methicillin, nafcillin), aminopenicillins (amoxicillin, ampicillin), antipseudomonal penicillins (piperacillin, ticarcillin), penicillin/beta-lactamase inhibitor combinations (amoxicillin/clavulanate, ampicillin/sulbactam).
Agents: See above.
Indications: Streptococcal infections (pneumonia, pharyngitis), skin and soft tissue infections (cuts, boils).
Side effects: Hypersensitivity reactions (hives, anaphylaxis), seizures, GI intolerance, candidiasis.
Contraindications: Penicillin allergy.
2. Cephalosporins
Definition: B-lactam antibiotics derived from the fungus Cephalosporium acremonium
Selective toxicity: Targets bacterial cell wall synthesis via inhibition of transpeptidases with minimal human toxicity.
Therapeutic index: Wide margin between therapeutic and toxic doses.
Classification: B-lactam antibacterial.
Mechanism: Inhibits transpeptidation and cross-linking of peptidoglycan in the bacterial cell wall.
Therapeutic classes/Agents:First gen. (cefazolin, cephadroxil, cephalothin,cephalexin), second gen(cefuroxime, Cefocinid,cefotetan), third gen.(ceftriaxone, cefixime,cefotaxime), fourth gen.(cefipime), fifth gen.(anti-MRSA Ceftaroline, Ceftobiprole,Ceftolozane).
Cephalosporin/Beta-Lactamase Inhibitor Combinations—ceftazidime/avibactam, ceftolozane/tazobactam
Indications: Respiratory, skin, urinary tract infections. Surgical prophylaxis.
Side effects: Hypersensitivity reactions, seizures, GI intolerance.
Contraindications: Hypersensitivity to cephalosporins or penicillins.
4. Monobactam
Definition: β-lactam containing a four-member ring without any other ring structures.
Selective toxicity: Targets cell wall via binding to penicillin-binding proteins with minimal toxicity.
Therapeutic index: Adequate margin between toxic and therapeutic concentrations.
Classification: β-lactam antibacterial (monobactam).
Mechanism: Inhibits peptidoglycan cell wall synthesis.
Therapeutic agents: Aztreonam.
Indications: Gram-negative respiratory, urinary, intra-abdominal, and skin/soft tissue infections.
Side effects: Hypersensitivity reactions.
Contraindications: Hypersensitivity to β-lactams or monobactams.
5. Vancomycin
Definition: Glycopeptide antibiotic.
Selective toxicity: Bactericidal activity against Gram-positive organisms. Poor stability and absorption.
Therapeutic index: Narrow. Monitoring of drug levels recommended.
Classification: Glycopeptide.
Mechanism:
Glycopeptides bind to terminal D-ala-D-ala chains on peptidoglycan in the cell wall, preventing further elongation of peptidoglycan chains.
Telavancin works by interfering with the cell membrane , thus disrupting membrane function.
Therapeutic agents: Vancomycin.
Indications: MRSA, MSSA, penicillin-resistant streptococci, C. difficile.
Side effects: “Red man syndrome”, ototoxicity, nephrotoxicity.
Contraindications: Hypersensitivity to vancomycin or glycopeptides.
6. Bacitracin
Definition: Cyclic polypeptide antibiotic.
Selective toxicity: Active against gram-positive cocci including staphylococci. Low systemic absorption.
Therapeutic index: Wide. Rare allergic reactions reported.
Classification: Polypeptide.
Mechanism: Inhibits bacterial cell wall peptidoglycan synthesis.
Therapeutic agents: Bacitracin.
Indications: Topical for skin/eye infections and urinary anti-infective.
Side effects: Rare allergic reactions.
Contraindications: Hypersensitivity.
7. Aminoglycosides
Definition: Protein synthesis inhibitors isolated from actinomycetes.
Selective toxicity: Poor mammalian protein synthesis inhibition. High nephrotoxicity, ototoxicity risks.
Therapeutic index: Narrow. Therapeutic drug monitoring recommended.
Classification: Aminoglycosides.
Mechanism: Inhibits bacterial ribosomes by binding to 30s subunits altering correct reading of mRNA transcript.
Therapeutic agents: Gentamicin, tobramycin, amikacin, neomycin, streptomycin.
Indications: Serious Gram-negative infections in combination—
Side effects: Nephrotoxicity, ototoxicity, neuromuscular blockade.
Contraindications: Hypersensitivity, vestibular or auditory toxicity.
8. Tetracycline
Definition: Protein synthesis inhibitor isolated from Streptomyces species.
Selective toxicity: Chelation of ions reduces mammalian bioavailability. Photosensitivity risk.
Therapeutic index: Adequate.
Classification: Tetracycline class.
Mechanism: Binds 30S ribosomal subunit, inhibiting bacterial protein synthesis.
Therapeutic agents: Doxycycline, minocycline, tetracycline.
Indications: Respiratory tract, skin, and genital infections. Rickettsial diseases.
Side effects: Photosensitivity, gastrointestinal intolerance.
Contraindications: Pregnancy, pediatric patients, dental enamel formation.
9. Chloramphenicol
Definition: Protein synthesis inhibitor isolated from Streptomyces venezuelae.
Selective toxicity: Generally safe but rare severe toxicity risks.
Therapeutic index: Wide.
Classification: Miscellaneous.
Mechanism: Inhibits peptidyl transferase activity of the 50S ribosomal subunit.
Therapeutic agents: Chloramphenicol.
Indications: Typhoid fever, respiratory infections, eye infections.
Side effects: Rare aplastic anemia, gray baby syndrome.
Contraindications: Pregnancy, pediatric patients.
10. Macrolides
Definition: Protein synthesis inhibitor isolated from Streptomyces species.
Selective toxicity: Generally well-tolerated. Cardiac toxicity risk.
Therapeutic index: Adequate.
Classification: Macrolide.
Mechanism: Binds 50S ribosomal subunit, blocking peptide bond formation.
Therapeutic agents: Erythromycin, azithromycin, clarithromycin.
Indications: Respiratory tract infections, skin/soft tissue infections, STD treatment.
Side effects: GI intolerance, hepatic effects, drug interactions.
Contraindications: Hypersensitivity, QT prolongation risk.
11. Lincosamide
Definition: Protein synthesis inhibitor isolated from Streptomyces lincolnensis.
Selective toxicity: Well-tolerated aside from hypersensitivity.
Therapeutic index: Adequate.
Classification: Lincosamide.
Mechanism: Binds 50S ribosomal subunit, preventing translocation.
Therapeutic agents: Clindamycin.
Indications: Pelvic inflammatory disease, skin/soft tissue infections.
Side effects: Hypersensitivity, diarrhea, C. difficile infection risk.
Contraindications: Hypersensitivity to lincosamides.
12. Quinolones
Definition: Synthetic antibacterial agents targeting bacterial DNA gyrase/topoisomerase.
Selective toxicity: Generally well-tolerated. Tendon, CNS, cardiac risks.
Therapeutic index: Adequate.
Classification: Fluoroquinolone.
Mechanism: Binds to DNA gyrase/topoisomerase complexes, preventing DNA replication.
Therapeutic agents: Ciprofloxacin, levofloxacin, moxifloxacin, others.
Indications: Respiratory, urinary, skin/soft tissue infections.
Side effects: Nausea, phototoxicity, CNS effects, tendon rupture.
Contraindications: Pediatric patients, pregnancy. Tendon rupture/aches/weakness.
13.Rifampin
Definition: Ansamycin antibiotic isolated from Amycolatopsis mediterranei.
Selective toxicity: Generally well-tolerated but potent inducer of drug metabolism.
Therapeutic index: Adequate when dosed correctly.
Classification: Rifamycin.
Mechanism: Inhibits DNA-dependent RNA polymerase in bacteria/mycobacteria.
Therapeutic agents: Rifampin.
Indications: Tuberculosis, staphylococcal infections, Legionella, meningococcal carriage.
Side effects: Hepatotoxicity, “flu-like” syndrome, reddish secretions, drug interactions.
Contraindications:Hepatic dysfunction, porphyrias. Concomitant use of interacting drugs
.
14. Sulphonamide
Definition: Competitive inhibitors of bacterial folic acid synthesis from PABA.
Selective toxicity: Bone marrow suppression most concerning toxicity.
Therapeutic index: Adequate when dosed correctly.
Classification: Sulphonamide antibacterial.
Mechanism:competitively inhibits synthesis of folic acid needed for bacterial growth.
Sulfamethoxazole competitively inhibits folate synthase activity preventing the synthesis of dihydrofolate halting the folic acid synthetic pathway.
Trimetoprim inhibits dihydrofolate synthase preventing synthesis of tetrahydrofolate halting the folic acid synthetic pathway.
Therapeutic agents: TMP/SMX.
Indication; Respiratory infections, GIT infections, Genitourinary infection,
Contraindications: G6PD, hypersensitivity to sulphur drugs.
15.Nitroimidazoles:
These are Antibacterial and antiprotozoal agents.
Mechanism: Undergo metabolic reduction by microbial nitroreductases to generate reactive intermediates like nitroso and hydroxylamine derivatives which damage microbial DNA, proteins and other biomolecules. Anaerobic bacteria are more susceptible due to greater reductive activity.
Therapeutic classes: Antibacterial – Metronidazole, Tinidazole. Antiprotozoal – Tinidazole, Ornidazole, Secnidazole.
Agents: Metronidazole – Flagyl (Bacterial vaginosis, Anaerobic infections, Parasitic infections like amebiasis, giardiasis)
MOA: Undergo reduction by nitroreductase enzymes in anaerobic bacteria and form reactive intermediates which damage DNA,RNA and proteins.
Indications: Anaerobic infections, Bacterial vaginosis, Amebiasis, Giardiasis
Side effects: Nausea, vomiting, metallic taste, headache, dizziness, peripheral neuropathy (with prolonged use)
Contraindication: Pregnancy (first trimester), breastfeeding
Produce disulfiram-like symptoms when used with alcohol
NB:should not be used with alcohol
16.Antituberculous drugs
These are combination of antibacterials of different MOA used in anti-Kochs regimen.
Therapeutic index: Varies according to drug. Isoniazid has higher therapeutic index.
Agents: – Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, Fluoroquinolones-(levofloxacin, Ofloxacin,Moxifloxacin) Aminoglycosides-(Streptomycin, Amikacin, )Cycloserine, Para-aminosalicylic acid, kanamycin, ehtionamide, cycloserine,,, Capreomycin
Therapeutic class: Antituberculous drugs
Mechanism: Interfere with cell wall synthesis, metabolism, DNA/RNA synthesis in mycobacteria.
Thus;
Isoniazid prevents the synthesis of mycolic acids in the cell wall by inhibiting enzymes that catalyze their production.
Active only against M. tuberculosis and M. kansasii.
Rifamycins inhibit RNA polymerase, preventing transcription by blocking the production of messenger RNA.
Pyrazinamide is a prodrug with an unclear mechanism of action. In its active forms it is thought to prevent the production of mycolic acids by inhibiting the enzyme fatty acid synthetase I, though it likely has other effects as well.
Ethambutol inhibits the enzyme aribinosyl transferase III, which blocks production of arabinogalactan in the cell wall.
Because arabinogalactan is a component of the cell wall of mycobacteria but not “typical” bacteria, the microbial activity of ethambutol is limited to mycobacteria.
Indication: Tuberculosis
Side effects:
- Isoniazid, H- Risk of polyneuropathy- Prescribe additional pyridoxine 10 mg.
- Rifampicin, R- Risk of elevated liver enzymes, thrombocytopenia, pink staining of body secretions.
- Pyrazinamide, Z- Risk of hepatotoxicity, precipitates hyperuricemia.
- Ethambutol, E- Risk of optic neuritis- colour blindness
- Streptomycin, S- Risk of damage to vestibule-cochlear nerve.
Side effects are very common. Use only in multi drug resistance or when initial therapy fails.
Contraindication: Hepatic impairment, severe sensitivity to the drugs.
17.Polymyxins:
- Older class of antibiotics that have regained popularity due to bacterial resistance.
- Main agents: colistin (colistimethate sodium) and polymyxin B.
- Limited evaluation and data on pharmacokinetics and efficacy.
- Effective against highly resistant Gram-negative organisms (e.g., Acinetobacter baumannii, Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae).
- Mechanism of action: bind to outer membrane of Gram-negative bacteria, causing membrane disruption and leakage of cellular contents.
- Spectrum: Good against many multidrug-resistant Gram-negative rods, moderate against Stenotrophomonas maltophilia, poor against Gram-positive organisms, anaerobes, Proteus, Providencia, Burkholderia, Serratia, and Gram-negative cocci.
Adverse Effects:
- Renal: Nephrotoxicity is the most common adverse effect, causing acute kidney injury.
- Neurological: Neurotoxicity is less common and can manifest as dizziness, weakness, paresthesias, or mental status changes. Neuromuscular blockade leading to respiratory arrest can occur.
Important Facts:
- Colistin (colistimethate sodium) and polymyxin B are similar drugs. Colistin is administered as colistimethate sodium and converted to active colistin in the body.
- Polymyxin B has more predictable pharmacokinetics and is not renally eliminated.
- Different dosing standards exist for colistin and polymyxin B in different countries.
- Combination therapy with other drugs is common due to polymyxins being last-line antibiotics.
- Oral formulation of colistin is only for bowel decontamination, not for systemic infections.
- Aerosolized polymyxins are used to decrease colonization with Gram-negative bacteria, particularly in cystic fibrosis patients.
Indication:
- Treatment of multidrug-resistant Gram-negative infections, including pneumonia, bacteremia, sepsis, and complicated urinary tract infections.
- Close monitoring of renal function is important, and avoidance of other nephrotoxic drugs is recommended.
Reference with additional information on Antibiotics—Textbook and slide
https://drive.google.com/drive/folders/1-4k52t9xhR-SEGP4HgvuuIVEOLcyxuC_