Antibacterial therapy 1. د. حامد الزعبي Dr Hamed Al-Zoubi
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1 Antibacterial therapy 1 د. حامد الزعبي Dr Hamed Al-Zoubi
2 ILOs Principles and terms Different categories of antibiotics Spectrum of activity and mechanism of action Resistancs
3
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5 Antibacterial therapy What is an Antibiotics? Egyptians 1500BC: Honey for wounds Alexander Fleming and Louis Pasteur
6 Antibacterial therapy 2000 B.C. - "Here, eat this root." 1000 B.C. - "That root is heathen, say this prayer." 1850 A.D. - "That prayer is superstition, drink this potion." 1940 A.D. - "That potion is snake oil, swallow this pill." 1985 A.D. - "That pill is ineffective, take this antibiotic." 2000 A.D. - "That antibiotic is useless and artificial. Here, eat this root." ~Author Unknown
7 The Bright side
8 Yet. even life savers may take life (remember! Antibiotics are DANGEROUS DRUGS!!)
9 Antibiotics are DANGEROUS DRUGS
10 C deathicille (difficile) A UK Consultant Microbiologists nightmare!
11 Antibacterial therapy > Antibiotics: natural products derived from soil bacteria and fungi Examples: Penicillin from penicillin notatum mould > Semisynthetic agents: Natural compounds that have been chemically modified to increase its activity and improve pharmacokinetics Examples: Amoxycillin, Ampicillin, Cephalosporins and Carbapenems, Rifampicin
12 Antibacterial therapy Synthetic chemicals: Trimethoprim and linezolid, quinolones are examples Antibiotics are loosely applied to all antibacterial agent Terms related to antibiotics use: Selective toxicity Static vs cidal (MIC vs MLC) Synergism Broad vs narrow spectrum Emperical use? Synergism: Meaning and example Spectrum of activity
13 Basic principles: Selective toxicity: Kill or inhibit the growth of microorganism without harming human tissue. Antibiotic susceptability testing Bactericidal versus bacteriostatic FIGURE 1 Bactericidal: MLC Bacteriostatic: MIC Some infections such as infective endocarditis or immunocompromised patients > Bactericidal is a must
14 MIC
15 Antibacterial therapy Figure 1
16 Antibacterial therapy Bacteriostatic allows for natural immunity to deal with the microbe Antibodies, Phagocytosis etc Bactericidial may lead to release of toxins and microbial contents leading to subsequent illness and inflammatory responses.
17 Antibacterial therapy/ Indications for use / to avoid abuse: 1. Treat infections empirically / culture sensitivity. 2. Prophylaxis/ limited situation. Abuse: Side effects Resistance Cost-effectivness
18 Antibacterial therapy/ Route of administration: Nature of infection Bioavailability and therapeutic index or window Tissue penetration, excretion, pharmakokinetics Precautions: >History of hypersensitivity >Glandular fever (Epstein-Barr virus infection), cytomegalovirus infection greatly increase the risk of developing a penicillin-induced rash >Impaired liver and kidney functions >Pregnancy, breastfeeding and children
19 Antibacterial therapy Target of antibacterial agents: Figure 2: Cell wall: Peptidoglycan? Protein synthesis: Ribosome 70S versus 80S Folate synthesis: Bacteria manufacture its own folates while human obtain it in food Nucleic acid synthesis Other sites such as bacterial cell membrane
20 Antibacterial therapy Figure 2/ Antibiotics target
21 Antibacterial therapy/inhibition of cell wall synthesis Most bacteria possess a cell wall to protect from osmotic pressures Microbe divides needs to create a new cell wall Interrupt this leads to new microbes being susceptible to external influences Cell ruptures Microbe death Beta lactam agents and glycopeptides
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23 Antibacterial therapy/inhibition of cell wall synthesis
24 Beta lactam agents Penicillins, cephalosporins, monobactams, carbapenems and beta lactamase inhibitors Bind penicillin binding proteins preventing cross linking Beta lactamases are enzymes produced by bacteria that break the antibiotic beta lactam ring < resistance
25 STRUCTURE OF PENICILLIN O C NH CH CH C S CH 3 O C N CH CH 3 COOH Site of penicillinase action. Breakage of the β lactam ring. 25
26 Penicillins: Beta lactam agents E.g Benzylpenicillin and penicillin G Narrow spectrum Short acting Resistance by beta lactamases Synthetic penicillins: Penicillin V Flucloxacillin and methicillin: Inactivated by S. aureus beta lactamase However, MRSA developed. MRSA? Ampicillin and amoxicillin: G+ and G- Amoxacillin+Clavulinic Acid (B-lactamase inhibitor) compound)/ Broad Spectrum.. Penicillinase-R
27 Beta lactam agents Monobactam/ Aztreonam used mostly against serious aerobic and Facultative G-ve infection. Carbapenem / imipenem & meropenem.. Broad Spectrum G- G+ aerobic anaerobic.., Penicillinase-R. Cephalosporins: Broader spectrum Less hypersensitivity reactions 5 Different generations
28 Inhibition Cell Wall-3 1 st (1960) Cephalexin, Cephradine, spectrum G+.. 2 nd (70s) Cefoxitin, Cefuroxime, Broad spectrum.. 3 rd (80s) Ceftriaxone, Cefotaxime.. mainly G-ve Enteric bacteria.. 4 th (1990s) Cefepime.. mainly G-ve, GPC and psudomonas 5 th generation 2000s: ceftaroline MRSA
29 Glycopeptides Vancomycin and teicoplanin Large molecules that are unable to penetrate the outer membrane of Gram-negative bacteria. The spectrum is consequently restricted to Gram-positive organisms. Gram-positive cocci with multiple resistance to other drugs such as Enterococci and staphylococci, including MRSA, that exhibit resistance or reduced sensitivity to glycopeptides are being reported more frequently.
30 Antibacterial therapy/disruption of microbial cell membrane Essentially, affect cell membrane transportation in and out Increases permeability of membrane External influences have greater effect Microbe death Examples: Polymyxin, Colistin These agents are more toxic systemically than those agents that inhibit cell wall synthesis.
31 The End
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