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Antibacterials II - HP 2019 - Student
Antibacterials II - HP 2019 - Student
Antibacterials II - HP 2019 - Student
• Adverse effects
• Hypersensitivity reactions (~5% of patients)
• Degradation products (penicilloic acid) combine with host protein,
become antigenic and induce immune reaction
• Cation toxicity: sodium or potassium salts
• Diarrhoea
• Nephritis
• Neurotoxicity
• Hematological toxicity
• Decreased coagulation
β-lactams: Cephalosporins
• Produced semi-synthetically General poor oral
absorption
• Attachment of side chains to 7-aminocephalosporanic acid Well distributed in
• Classified as 1st, 2nd, 3rd and 4th generation fluids
• Based on bacterial susceptibility and β-lactamase resistance
• Generally
• Spectrum against gram (-) increase with ascending generation
• Spectrum against gram (+) decrease with ascending
generation
• Cefepime: 4th generation, wide spectrum
• Therapeutic levels in CSF
• Third generation cephalosporins
β-lactams: Cephalosporins
• Advanced generation cephalosporins:
• Ceftaroline: IV prodrug
• Broadspectrum: Gram- positive and negative
• Importantly also, P. aeruginosa, extended spectrum, β-lactamase (ESBL)-producing
Enterobacteriaceae, and Acinetobacter baumannii
• MOA:
• Unique structure binds to PBP2a found with MRSA and PBP2x found with
Streptococcus pneumoniae
Dihydropteroate
Sulfonamides
synthase
Dihydrofolic acid
Dihydrofolate
Trimethoprim Co-trimoxazole:
reductase
sulphamethoxazole and
Tetrahydrofolic acid trimethoprim
Sulfonamides
• Dihydrofolic acid synthesized from
• p-amino-benzoic acid (PABA), pteridine and glutamate
• Sulfonamides are synthetic analogues of PABA
• Competitive substrate for dihydropteroate synthase
• Bacteriostatic in organisms requiring de novo folate synthesis
• pKa dependent binding to serum albumin
• Short-acting: sulfadimidine
• Intermediate-acting: sulfamethoxazole
• Long-acting: sulfametopyrazone
Sulfonamides
Adverse effects
• Crystalluria
• Acetylated drugs precipitate at acidic or neutral pH in kidney
• Hypersensitivity and hemopoetic disturbances
• Kernicterus (mostly in newborns)
• Bilirubin entering CNS
Contraindications
• Infants under 2 months
• Pregnancy (third trimester)
Trimethoprim
• Inhibitor of bacterial dihydrofolate reductase
• Resembles pteridine moiety of folate
• Decreased conversion of dihydrofolic acid to active folate
• Potency 20 – 50 times more than sulphonamides
• Drug is a weak base
• High concentrations achieved in acidic fluids
• Prostate and vaginal fluids
• Produce effects of folic acid deficiency
• Reverse blood disorders using folinic acid
Co-trimoxazole
• Synergistic antimicrobial activity
• Inhibits two sequential steps in tetrahydrofolic acid
• Trimethoprim is more lipid soluble
• 1:5 ratio trimethoprim:sulphonamide
• Plasma ratio of 1:20
• Adverse effects
• Dermatological and gastrointestinal
• Hematological
• DDI: prolonged prothrombin
4. Inhibitors of protein synthesis
1. Tetracyclines
2. Glycylcyclines
3. Aminoglycosides
4. Macrolides
5. Other:
• Chloramphenicol
• Clindamycin
• quinupristine/dalfopristin
• linezoid
Inhibitors of protein synthesis
• Protein synthesis involves translation of mRNA at the ribosome
• Target bacterial ribosome
• Differ structurally from mammalian cytoplasmic ribosome
• Bacterial ribosome: 70S comprised of 50S and 30S
• Mammalian cytoplasmic ribosome: 80S comprised of 60S and
40S
• Bacterial ribosome resembles mammalian mitochondrial
ribosome
• Mitochondrial toxicity in host
Inhibitors of protein synthesis
Tetracyclines
• Four fused rings with a system of conjugated double bonds
• Oxytetracycline, minocycline, doxycycline, tetracycline
• Broad spectrum, bacteriostatic antibiotics
• MOA
• Enter via passive diffusion and energy-dependent transport
• Concentrate intracellularly
• Bind reversibly to 30S subunit of bacterial ribosomes
• Prevent binding of aminoacyl-tRNA
to mRNA–ribosome complex
• Inhibit bacterial protein synthesis
Tetracyclines
Tetracyclines
• Bind to tissues undergoing calcification
• Cross placenta and concentrate in fetal bones and dentition
• Contraindicated in pregnancy and children
• Widespread resistance limits clinical use
• Mg2+-dependent active efflux mediated by plasmid-encoded
resistance protein
• Enzyme inactivation
Only minocycline
penetrates CNS
Tetracyclines
• Administration with dairy products
or divalent and trivalent cations
(magnesium, aluminum or iron)
decreases absorption
• Formation of non-absorbable chelates
Tetracyclines
Adverse effects
• Gastric discomfort
• Hepatotoxicity
• Deposition in bones and primary dentition
• Discoloration (“orange tooth syndrome”) and hypoplasia
• Vestibular toxicity
• High concentrations (minocycline) in endolymph of ear
• Pseudotumor cerebri
• Intracranial hypertension – headache and blurred vision
• Superinfections
Glycylcyclines* First in class
Approved in 2005
• Tigecycline
• Derivative of minocycline
• Expanded broad spectrum
• Reversibly binds 30S ribosomal subunit
• Prevent amino-acyl tRNA from
binding to the A site of ribosomes
• Inhibits protein synthesis
• Indicated for the complicated skin, tissue infections and complicated intra-
abdominal infections
• Inhibits clearance of warfarin
• Monitor anticoagulation
• Reduce efficacy of oral contraceptives
Aminoglycosides
• Derived from Streptomyces and Micromonospora
• Amikacin, gentamicin, neomycin, streptomycin, tobramycin
• Two amino sugars with glycosidic link to central hexose
• Polycationic, highly polar: difficulty crossing membranes
• Bactericidal
• Empirical therapy against aerobic bacteria
• Not effective against anaerobes: no oxygen transport
• Additive or synergistic effects: β-lactams or vancomycin
• Resistance
• Altered oxygen-dependent transport
• Synthesis of inactivating enzymes:
• Acetyl transferases, nucleotidyltransferases, phosphotransferases
Aminoglycosides
• Dose-related toxicity
• Gentamicin, tobramycin, amikacin
• Ototoxicity (vestibular and cochlear)
• May be irreversible
• Vertigo and loss of balance
• Nephrotoxicity
• Disrupted calcium-mediated processes
• Neuromuscular paralysis
• Inhibition of presynaptic acetylcholine release
• Rare, preventable by slow infusion
• Allergic reactions
Macrolides
• Azithromycin, clarithromycin, erythromycin,
telithromycin
• Irreversibly bind to 50S unit of bacterial
ribosome
• Inhibit translocation steps of protein synthesis
• Bacteriostatic
• Bactericidal at high concentrations
• Alternative in individuals with β-lactam allergy
Telithromycin:
First “ketolide” antimicrobial
Active against many macrolide-resistant strains
Macrolides
• Resistance
• Efflux pumps limit intracellular concentrations
• Decreased affinity for 50S ribosomal subunit
• Plasmid-associated erythromycin esterase
• Reduce destruction of erythromycin by gastric acids
• Enteric-coated tablets or esterified forms
• Azithromycin and clarithromycin differ from
erythromycin
• Broader spectrum of activity
• Longer serum half-live
• Better GI tolerability
Macrolides
• Extensive metabolism
• Inhibit oxidation of other drugs via CYP450 interactions
• Eliminate intestinal flora responsible for warfarin
inactivation
• Adverse effects
• Epigastric distress
• Cholestatic jaundice
• Ototoxicity: transient deafness
• Contraindicated
• Hepatic dysfunction
• Congenital prolongation of the QTc interval
Chloramphenicol
• Broad spectrum: bactericidal or bacteriostatic
• Lipophilic
• Readily enters CSF
• Binds to bacterial 50S subunit
• Inhibits peptidyl transferase reaction
• Inactivated by acetyl coenzyme A transferase
• Disrupts mammalian mitochondrial ribosomes
• Inhibition of host mitochondrial protein synthesis
• Use limited to life-threatening infections for
which no alternatives exist
Chloramphenicol
Adverse effects
• Anaemias (haemolytic, reversible, aplastic)
• Reversible, dose-duration-dependent bone marrow toxicity
• Inhibit hepatic mixed-function oxidases
• Gray baby syndrome (premature babies or neonates)
• Excessive plasma chloramphenicol
• Low capacity for hepatic glucuronylation
• Relatively inadequate renal elimination
• Drug accumulation interferes with mitochondrial function
• Depressed breathing, cyanosis, cardiovascular collapse, death
Clindamycin
• Irreversibly bind to 50S unit of bacterial ribosome
• Inhibit translocation steps of protein synthesis
• Primarily used in treatment of anaerobic
infections
• Well absorbed orally: poor CSF penetration
• Oxidative metabolism to inactive product
• Adverse effects
• Impaired liver function
• Fatal pseudomembrane colitis from C. difficile
overgrowth
• Release necrotizing toxins
Quinupristin/dalfopristin
• Mixture of two streptogramins (30:70)
• Chemically modified derivative from Streptomyces
• Bind to separate sites in 50S bacterial ribosome
• Dalfopristin alters ribosome structure aiding quinpristin binding
• Stable ternary complex synergistically disrupts protein synthesis
• Drug penetrates macrophages and polymorphonucleocytes
• Adverse effects
• Venous irritation, arthralgia, myalgia
• Hyperbilirubinemia
Linezolid
• Combat methicillin and vancomycin resistance
• Spectrum primarily gram (+) organisms
• Inhibits formation of 70S initiation complex
• Bind N-formylmethionyl-tRNA
• Inhibit bacterial protein synthesis
• Bacteriostatic
• Adverse effects
• Thrombocytopenia
• Potential monoamine oxidase inhibition
• Cautioned against excessive tyramine-containing foods
• Clinical uses
• Urinary, respiratory, GI tract infections
• Prostatitis and STIs (gonorrhea)
Fluoroquinolones
• Altered absorption
• Aluminum, magnesium, iron and zinc
• Divalent cations: calcium
• Adverse effects
• CNS: dizziness, insomnia, seizures
• Photosensitivity
• Cardiovascular: QTC prolongation
• Musculoskeletal
• Articular cartilage erosion
• Contraindicated in pregnancy and children under 18
Rifampicin
• Macrolide antibiotic derived from Streptomyces
• Binds β-subunit of bacterial DNA-dependant RNA polymerase
• Inhibits transcription and mRNA synthesis
• Oral bioavailability decreased by food and 1st pass metabolism
• Lipid soluble
Adverse effects
• ’Flu-like’ syndrome, hepatotoxicity
• Drowsiness, mental confusion
• Reddish-orange colouration of body fluids
• Urine, tears, saliva, sweat
Consequences of antibiotic resistance
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Antibacterial resistance
• Classification as resistant if the maximal level of antibacterial
tolerated by the host does not alter bacterial growth
• Genetic alterations
• Spontaneous DNA mutations
• Transfer of DNA
• Protein alterations
• Modification of target site
• Decreased accumulation
• Reduced uptake or increased efflux
• Enzyme inactivation
• Beta-lactamases, acetyltransferases, esterases
Complications of Therapy
• Hypersensitivity or immune reactions
• To antibacterial drugs or their metabolic products
• Direct toxicity
• Directly affecting cellular processes in the host
• Superinfections
• Broad-spectrum antimicrobials or combinations of agents
• Alter normal microbial flora
• Upper respiratory, oral, intestinal, and genitourinary tracts
• Permitting overgrowth of opportunistic organisms
• Require secondary treatments
Antibacterial Abuse
• Irresponsible and erratic use
• 70-80% of prescriptions written unnecessarily
• Lack of confidence in accurate clinical diagnosis
• Shotgun therapy: achieve "dramatic" results
• Peer pressure: 'defensive' practice
• Patient pressure
• Safe in pregnancy
• Penicillins, cephalosporins, isoniazid