Antibiotics: Understanding for Effective Use

Antibiotics: Understanding for Effective Use

Antibiotics are drugs used to treat bacterial infections. They work by either stopping bacteria from growing or killing them directly. The effect of antibiotics occurs at the molecular level.

Key Features of Antibiotics:

• Specificity: Each antibiotic has a specific effect on a particular group of bacteria.

• Spectrum of Activity: The spectrum of activity of antibiotics is categorized into two types:

• Broad-spectrum: Affects a wide range of bacteria.

• Narrow-spectrum: Affects specific types of bacteria.

Differentiating Antibiotics from Other Drugs:

• Antiseptics: Kill bacteria on the surface of the body or objects.

• Disinfectants: Eliminate bacteria and other pathogens in the environment.

Mechanism of Action of Antibiotics:

Antibiotics target bacteria by:

• Inhibiting cell wall synthesis:

• Drugs bind to PBPs (penicillin-binding proteins) -> inhibit transpeptidation -> inhibit the synthesis of peptidoglycan, the main component of the cell wall.

• Gram-positive bacteria: The cell is destroyed, losing its cell wall (protoblast).

• Gram-negative bacteria: The cell wall is damaged, incomplete (sphenoblast).

• Disrupting cell membrane function:

• Drugs bind to the cell membrane -> change the membrane structure and function -> cell death.

• Example: Amphotericin B, polymyxin B, nystatin, colistin, imidazoles…

• Inhibiting nucleic acid synthesis:

• Drugs affect the replication and transcription of DNA, RNA -> prevent bacteria from producing essential proteins for survival.

• Example: Rifampin, quinolones, sulfonamides, trimethoprim…

• Rifampin: Binds to DNA -> inhibits RNA synthesis (treats tuberculosis).

• Quinolones: Block the activity of DNA gygrase and topoisomerase (involved in DNA replication and repair).

• Sulfonamides: Similar structure to PABA -> compete with PABA -> inhibit dihydrooteroate synthetase -> unable to synthesize folic acid (precursor for nucleic acid synthesis).

• Trimethoprim: Inhibits dihydrofolic reductase -> unable to synthesize purine in nucleic acid.

• Inhibiting protein synthesis:

• Drugs target ribosomes, where protein synthesis occurs -> blocking or disrupting the translation process -> bacteria cannot produce necessary proteins.

• Example: Aminoglycosides, tetracycline, chloramphenicol, macrolides-lincosamides, steptogramins, oxazolidonone.

• Aminoglycosides: Bind to the 30S subunit of the ribosome -> block the activity of the first complex (mRNA-formyl methionine-tRNA) -> produced proteins are non-functional.

• Tetracycline: Bind to the 30S subunit of the ribosome -> block charged aminoacyl tRNA -> prevent new AAs from binding to the newly formed peptide chain.

• Chloramphenicol: Bind to the 50S subunit of the ribosome -> inhibit peptidyl transferase -> prevent new AAs from binding to the newly formed peptide chain.

• Macrolides-lincosamides: Bind to the 50S subunit of the ribosome (at the 23S rRNA site) -> prevent the formation of the first complex and aminoacyl translocation.

• Streptogramins: Bind to the 50S subunit at different sites.

• Oxazolidinones: Inhibit the first complex at 23S ribosome.

Common Groups of Antibiotics:

• Sulfonamides:

• Newer drugs with strong effect and less toxicity.

• Broad spectrum and high drug resistance.

• Mechanism of action: Competition.

• Divided into four main groups:

• Treat systemic infection, rapid elimination: sulfapyridine, sulfadiazine.

• Treat systemic infection, slow elimination: sulfamethoxydiazine, sulfamethoxypyridazine.

• Not absorbed through the gastrointestinal tract: treat intestinal infection is sulfadiazine.

• Treat urinary tract infection: sulfamethooxazole.

• Beta-lactams:

• Mechanism of action: Inhibit cell wall synthesis.

• Includes main groups:

• Penicillin:

• Differ by the R group.

• Narrow and broad spectrums, usually broad.

• Groups of penicillin:

• Group 1: High activity against Gram-positive bacteria, spirochetes, and some Gram-negative bacteria. Degraded by beta-lactamase, not stable in acid: Penicillin G.

• Group 2: Not degraded by beta-lactamase: Nafcillin, methicillin, oxacillin.

• Group 3: Broad spectrum: ampicillin, piperacillin.

• Group 4: Acid-stable: penicillin V, amoxcillin, cloxacillin.

• Cephalosporin:

• Has 7-aminocephalosperanic acid core, differs by R1 and R2 groups.

• Divided into five generations:

• Generation 1: High activity against Gram (+) cocci, except enterococci and MRSA. Moderate activity against Gram (-) bacilli, mainly E.coli, Proteus, Klebsiella.

• Generation 2: Activity similar to generation 1, including Gram (-) bacilli, except Pseudomonas. Cefoxitin and Ceftetan are active against B.fragilis.

• Generation 3: Reduced activity against Gram (+) except S.pneumia, increased activity against Gram (-) bacilli, good penetration into CSF (except cefoperazone).

• Generation 4: Activity against Enterobater and Citrobacter resistant to generation 3 cepha.

• Generation 5: Similar spectrum to other cepha, but active against MRSA.

• Monobactam:

• Only active against Gram (-) bacteria, not active against Gram (+) and anaerobic bacteria.

• Resistant to beta-lactamase.

• Drug on the market: Aztreonam.

• Carbapenems:

• Includes: Imipenem, Meropenem, Ertapenem, Doripenem.

• Good activity against both Gram (-) and Gram (+) bacteria, and anaerobes.

• Resistant to beta-lactamase.

• Imipenem: Inhibited by dihydropeptidase in the kidneys -> used with cilastatin. Good penetration into tissue fluids, including CSF (cerebrospinal fluid).

• Meropenem: Similar to Imipenem but not inhibited by peptidase and less epileptogenic.

• Ertapenem: Long half-life -> once daily administration. Poor activity against Enterococci, P.aeruginosa, and non-fermenting Gram (-) bacilli.

• Doripenem: Good activity against non-glucose fermenting Gram (-) bacilli.

• Glycopeptides:

• Mechanism of action: Inhibit cell wall synthesis.

• Only active against Gram (+) bacteria, effective against bacteria resistant to other drugs.

• Includes: Vancomycin and Teicoplanin.

• Vancomycin: Bactericidal activity against Stap, some Clostridia and some bacilli.

• IV: Treat NT caused by MRSA.

• In case of bacteremia and endocarditis: Use vanco+1 other aminoglycoside.

• Oral: Pseudomembranous colitis.

• Teicoplanin: Good activity against Stap, Enterococci and other Gram (+) bacteria. Long half-life -> once daily administration.

• Tetracycline:

• Includes drugs with the cycline group.

• Active against both Gram (+) and Gram (-) bacteria, selective against mycoplasma, high resistance in SA and gram (-).

• Excreted through bile, feces, and kidneys.

• Side effects: Nausea, vomiting, diarrhea, skin rash, hepatitis, tooth discoloration in infants. Alteration of normal flora: Enterocolitis.

• Glycylcyclines:

• Used as Tigecyclines.

• Used against both Gram (+) and Gram (-) bacteria.

• Compared to tetracyclines, better activity against MRSA and enterococci.

• Compared to Gram (-) bacteria, better activity against intestinal bacteria, acinebacter.

• Active against anaerobic bacteria, B.fragilis.

• Only used intravenously.

• Excreted through bile and kidneys.

• Aminoglycosides:

• Includes: Steptomycin, neomycin, gentamycin, kanamycin, amkacin, tobramycin.

• Active against both Gram (+) and Gram (-) bacteria, acid-resistant, mainly gram (-).

• Activity at alkaline pH > acid pH.

• Used to treat intestinal infections, sepsis, endocarditis.

• Combined with penicillin (increased permeability of aminoglycosides).

• Side effects: Toxicity to the eyes and ears.

• Chloramphenicol:

• Well absorbed through the gastrointestinal tract, widely distributed to tissues and body fluids: including CSF and TKTW, good penetration into cells.

• Broad antibacterial spectrum.

• Excreted through urine.

• Side effects: Impaired TH pathway, prolonged use leads to high resistance, bone marrow suppression, severe anemia, so less used in clinical practice.

• Macrolides:

• Includes: Erythromycin, Dorithromycin, Clarithromycin, Azithromycin, Ketolides.

• Narrow antibacterial spectrum, mainly Gram (+).

• Side effects of erythromycin: Fever, gastrointestinal disorders, hepatitis, phlebitis, cholestasis due to hepatic venous metabolism, increased anticoagulant level when used concurrently.

• Dorithromycin: Similar activity to Ery, long half-life: once daily administration.

• Clarithromycin and Azithromycin: Also have side effects on the gastrointestinal tract but less than erythromycin.

• Lincosamides:

• Includes: Clindamycin and Lincomycin.

• Similar antibacterial spectrum and mechanism to macrolides.

• Acid-stable -> oral and intravenous.

• Well distributed in tissues, except TKTW.

• Excreted through liver, bile, and urine.

• Clindamycin: Treat severe NT caused by anaerobic bacteria, including B.fragilis.

• Lincomycin: Treat Gram (+) cocci, especially bone marrow infection caused by Staphylococci.

• Quinolones:

• Divided into three generations:

• TH1: nalidixic acid, oxalinic acid, conaxacin…

• TH2: Ciprofloxacin.

• TH3: Levofloxacin, Moxifloxacin…

• Disadvantages of TH1: Not reaching sufficient concentration to treat systemic NT, often used to treat urinary tract infections.

• Advantages of new TH: Higher activity, less toxicity, reaching therapeutic concentration in blood and tissues.

• Side effects: Nausea, dizziness, headache, insomnia, gastrointestinal disorders, cartilage and bone damage in children. Do not use TH2 containing fluorine for pregnant women and children under 15 years old, causing kidney failure, caution in liver failure.

• Trimethoprim-Sulfonamides:

• Use 5 sulfonamides + 1 trimethorprim, simultaneously inhibiting metabolic pathways (synergistic antibiotics), widely used to treat urinary tract infections and other infections caused by Gram (-) bacteria.

• Trimethoprim used alone: Treat uncomplicated urinary tract infections.

• Polypeptides:

• High bactericidal activity but highly toxic, only use some (polymyxin, bacitracin+tyrothrycin), avoid using with nephrotoxic drugs like aminoglycosides.

• Mechanism of action: Inhibit membrane function.

• Polymyxin: Polymyxin B + Polymyxin E.

• Poor absorption through the GI tract, good absorption through intravenous injection.

• High activity against Gram (-) bacteria, including Pseudomonas resistant to other drugs.

• Bacitracin+Tyrothrycin: Only active against Gram (+) bacteria, highly toxic -> topical treatment.

• Daptomycin:

• Mechanism of action: Binds to the membrane, creates pores for ion passage, membrane depolarization, disrupts membrane function, inhibits DNA, RNA, protein synthesis.

• Function: Treat skin and soft tissue infections caused by multidrug-resistant Gram (+) cocci, treat endocarditis caused by SA.

• Not used for pneumonia.

• Side effects: Myopathy -> Monitor creatine phosphokinase continuously and stop the drug when the concentration is five times normal.

• Streptogramins:

• 30:70 mixture of streptogram B and streptogramin A.

• Spectrum of activity: Active against MRSA, VRE, PRP. Active against some anaerobic bacteria and some Gram (-) bacteria, not active against VKĐR and Acinebacter.

• Oxazolidinones:

• Used as Linezolid.

• Similar spectrum to glycopeptide (only active against gram (+), especially resistant to other drugs).

• Better penetration into respiratory secretions than vancomycin, good penetration into bone, fat, and urine.

• Used to treat: Pneumonia, sepsis, skin and soft tissue infections caused by Staphylococci and Enterococci.

• Side effects: Thrombocytopenia can be reversed.

• Rifampin:

• Spectrum: Good activity against some Gram (+) bacteria, Gram (-) bacteria and VKĐR.

• Well absorbed through the gastrointestinal tract, mainly excreted through the liver, a small amount excreted through urine.

• High mutation frequency -> combined with other drugs.

• Isoniazid:

• Mechanism of action: Inhibit mycolic acid synthesis.

• Spectrum: High activity against Mycobacteria, especially M.tuberculosis.

• Rapid and complete absorption through the gastrointestinal tract, good penetration into tissues, including CSF.

• Easy to develop resistance -> combined with other drugs.

Mechanisms of Drug Resistance:

• Reduced permeability and pumping antibiotics out of the cell:

• Gram (+): Beta-lactam does not have a reduced permeability mechanism.

• Gram (-): Pseudomonas, Acinebacter, VKĐR change porin channels.

• Alteration of the drug’s target site:

• Penicillin: Lack of PBPs or alteration of PBPs. SA resistant to methicillin due to the change of PBP2 to PBP2a.

• Vanco: Alteration of PBPs.

• Tetracycline: Alteration of the ribosomal target.

• Macrolides-Lincosamides: Alteration of the target site on ribosomes.

• Aminoglycosides: Alteration of the target site on ribosomes.

• Quinolones: Mutation of DNA gyrase.

• Sulfonamides/Trimethoprim: Alteration of dihydrooteroate synthetase.

• Bacterial secretion of enzymes that destroy the drug’s activity:

• Beta-lactamase: Opens the beta-lactam ring of penicillin and cepha -> loss of activity.

• PNCase: Not inhibited by clavulanic acid. Often found in Staphylococci, N.gorrhea, H.influza…

• ESBLs: Degrade penicillin, generation 1, 2, 3, 4 cepha, sensitive to carbapenems. Inhibited by clavulanic acid, sulbactam, tazobactam.

• AmpC: Has a gene encoding on the chromosome/plasmid. Resistance to all beta-lactams except generation 4 cepha and carbapenems. Not inhibited by clavulanic acid.

• KPC (Klebseilla carbapenems): Resistant to generation 3, 4 cepha and carbapenems. Resistance mediated by plasmids.

• NDM-1: Resistance to many antibiotics, including carbapenems.

• Altered metabolic pathways: Bacteria self-nourishing resistant to sulfonamides do not use external PABA to synthesize folic acid but use available folic acid.

Origin of Drug Resistance:

• Genetic:

• Due to the chromosome: Mutation on the chromosome according to two mechanisms: transposition and transduction.

• Extra-chromosomal: R factor: plasmid (80-90%).

• Non-genetic:

• Bacterial multiplication is required for drug activity, bacteria do not multiply -> drug resistance.

• Loss of drug target structure.

• Bacteria infection in places where the drug cannot reach or act.

Dangers of Indiscriminate Antibiotic Use:

• Hypersensitivity reactions, allergies, hepatitis, cholestasis.

• Alteration of normal flora -> superinfection with resistant bacteria.

• Mask serious NK, but do not eliminate bacteria -> NK continues.

• Drug toxicity -> especially prolonged use.

• Development of drug-resistant bacterial strains: Elimination of sensitive bacteria creates opportunities for development.

Choosing Antibiotics:

• Clinical diagnosis.

• Laboratory diagnosis:

• Antibiotic sensitivity testing of bacteria.

• Bactericidal activity testing in serum.

Synergistic Antibiotics:

• Both drugs sequentially inhibit the bacterial metabolic pathway.

• One drug acts on the cell wall, making it easier for the second drug to enter the cell.

• One drug acts on the membrane, making it easier for the second drug to enter the bacteria.

• One drug prevents the inactivation of the second drug by enzymes secreted by bacteria.

Classification of Antibiotics:

• Bactericidal:

• Beta-lactam

• Aminoglycosides

• Glycopeptide

• Quinolones

• Trimethoprim-Sulfonamides.

• Bacteriostatic:

• Tetracycline

• Chloramphenicol

• Macrolides

• Lincosamides

• Sulfonamides

Note:

• Do not self-medicate with antibiotics.

• Always follow your doctor’s instructions on dosage, duration of use, and how to take the medication.

• Using antibiotics correctly helps effectively treat infections and prevent the development of drug-resistant bacteria.