1. Affect the bacterial cell wall
1.1. Bete - Lactam
1.1.1. Block the final cross linking stage
1.1.1.1. Pencillins
1.1.1.1.1. Narrow
1.1.1.1.2. Very Narrow
1.1.1.1.3. Extended
1.1.1.1.4. [Anti pseudomonal] Broad
1.1.1.2. Cephalosporins
1.1.1.2.1. • Bacteriocidal • Inhibit the cross-linking of peptidoglycan. •They are 5 Generations •first isolated (from fungi) •They have a six-membered ring adjacent to the β-lactam ring and are substituted in two places ------------------------------------------------ Advantages over pencillin: • Broader spectrum of activity, • Stable to staphylococcal penicillinase, • Being more resistant to the action of β-lactamases, • Producing fewer hypersensitivity
1.1.1.3. Carbapenems
1.1.1.3.1. structurally differ from penicillins in having methylene group instead of sulfur They are three: • Are IV antibiotics • Have very short serum half-lives • Infusion every 6 to 8 hours, at high doses.
1.1.1.3.2. They have the broadest spectrum of all β-lactam antibiotics
1.1.1.4. Monobactams [Aztreonam]
1.1.1.4.1. •β-lactam ring is alone and not fused to another ring. • Works only against aerobic, G- including [Neisseria and Pseudomonas]. • Inactive against G+ and anaerobic bacteria. It have minimal side effects. • It is very useful in patients who are hypersensitive to penicillin, because there is no cross-reactivity. • Aztreonam is poorly absorbed when given O, so it must be I.V - I.M or by inhalation.
1.2. Glycopeptide
1.2.1. Vancomycin
1.2.1.1. • Affect second and third stages of C.W synthesis • Large molecule [Active on G+] • Inhibit transglycosylation • Inhibit cross-linkages • Treatment of MRSA and 2 endocarditis
1.3. Miscellaneous
1.3.1. Cycloserine
1.3.1.1. • Affect first step of C.W synthesis • Inhibit Isomerase and Ligase enzymes • Second line drug for TB • Neurological side effects
1.3.2. Bacitracin
1.3.2.1. • Inhibit cell wall synthesis • Blocks the regeneration of the lipid carrier • Treatment of superficial skin infections • Toxic for systemic use
1.3.3. Isoniazide
1.3.3.1. • First line drug for TB • Active only againt growing cells • Inhibit mycolic acid synthesis
2. Affect bacterial cell membrane
2.1. Polymyxin
2.1.1. • Polymyxin B • Polymyxin E [Colistin]
2.1.1.1. Mechanism of action: • cyclic peptides act like cataionic detergent • Have +ve charged free NH2 bind to the -ve PO4 of G- disrupting phospholipid structure of cell membrane forming abnormal openings cause leaky. -------------------------------------------------------------------- Characterstics: • Clinically most useful compounds [Polymyxin B,E] • Selectively toxic G- due to their specificity for the lipopolysaccharide. • Polymyxins have less effect on G+• Polymyxins have less effect on G+ • Polymyxins are not absorbed from GIT. • Sometimes combined with other agents [trimethoprime/polymyxin] To broaden the effective spectrum. --------------------------------------------------------------------- Side effects: • Neurotoxic • Nephrotoxic. --------------------------------------------------------------------- Treatment: • Typical uses are for infections caused by strains of multiple drug- resistant Pseudomonas aeruginosa. • Infantile diarrhea (colistin) • Used externally as a cream or drops to treat many infections • Eye infections • otitis externa (swimmers ear).
2.2. Daptomycin
2.2.1. Mechanism of action: • Aggregates into the cell membrane without penetration of cytoplasm • Alters the curvature of the membrane • Creates holes that leak ions • Causes rapid depolarization • Cell death. ----------------------------------------------- Characteristics: • It is a lipopeptide antibiotic • Exhibits concentration - dependent bactericidal activity. • Can't penetrate outer membrane G-. • Not orally absorbed and is a highly protein bound large molecule with a small volume of distribution.Not orally absorbed and is a highly protein bound large molecule with a small volume of distribution. • It has a unique spectrum against Vancomycin-resistant (VRE) [E. faecalis and E. faecium].It has a unique spectrum against Vancomycin-resistant (VRE) [E. faecalis and E. faecium]. •Inactivated by pulmonary surfactants, so can't be used for pneumonia.Inactivated by pulmonary surfactants, so can't be used for pneumonia. ----------------------------------------------- Treatment: • Systemic and life-threatening infections caused by G+ bacteria only. • Skin infection caused by G+infections [S. aureus bacteraemia -S. aureus endocarditis]Treatment: • Systemic and life-threatening infections caused by G+ bacteria only. • Skin infection caused by G+infections [S. aureus bacteraemia -S. aureus endocarditis]
3. Interfere with protein synthesis
3.1. Inhibitors of 30S units
3.1.1. Amino Glycosides
3.1.1.1. Mechanism of action: • They disrupt the shape of the A-site • Causing premature chain termination • RNA codon misreading [formation of toxic, non functional proteins]. • B. Diffuses through porin channels in outer membrane G-. • Binds to and alters bacterial cell membrane causing leakage of the outer G- membrane and disruption of the cell wall ------------------------------------------------ Characters: • They are Bactericidal agents • Active aerobic G –ve rods • Poorly active G +ve • No activity anaerobes or Streptococci [except synergistically with penicillin] • Not absorbed by mouth. • All are potentially neurotoxic causing ototoxicity [Irreversible deafness]
3.1.1.1.1. Streptomycin
3.1.1.1.2. Kanamycin
3.1.1.1.3. Gentamycin and Tobramycin
3.1.1.1.4. Amikacin
3.1.1.1.5. Neomycin
3.1.1.1.6. Spectinomycin
3.1.2. Tetracyclines
3.1.2.1. Mechanism of action: • A-site changing ts shape • Thus preventing the access of aminoacyl tRNA molecules to the mRNA ribosome peptide complex [Blocks tRNA binding to ribosome] ------------------------------------------------ •Tetracyclin - minocycline - doxycyclin General characters of Tetracyclines: • Oral , Topical • They are bacteriostatic agents • Active against G+ and G- rods and cocci • Aerobics and anaerobics and some intracellular bacteria [Mycoplasma, Rickettsia, Chlamydia] • Orally absorbed but Cations such as Ca2+ and Mg2+ in dairy products chelates tetracyclines and interfere with their absorption • GIT side effects. • Limit use in pregnancy and children because of calcium chelation and dental staining (permanent yellow staining of teeth)
3.2. Inhibitors of 50S units
3.2.1. Chloramphenicol
3.2.1.1. • Preventing elongation step. • Broad spectrum as tetracyclines ----------------------------------------------- Treatment: • Meningitis due to Haemophilus influenzae, typhoid fever, and Bacteroides fragilis. • It exerts a static effect against all bacteria but a cidal effect against [H. influenza]. • Readily absorbed and diffused into most body compartments including CSF. • Bone marrow suppression and aplastic anemia limit • use to severe infections. Chloramphenicol drops and ointments are extensively used for treating eye infections.
3.2.2. Macrolides or Ketolides
3.2.2.1. Erythromycin – Azithromycin O, IV) Clarithromycin O Mechanism of Action: • Reversibly blocking the binding of tRNA to theacceptor site. This blocks translocation of the peptidechain. • Most G+ • some G- including [Neisseria]. not G- rods. • Atypical organisms as Campylobacter • Erythromycin first and still the most common usedmacrolides [generally well tolerated]. • Others have enhanced G- spectrum and have longerhalf-life ------------------------------------------------------------ Telithromycin (ketolides) (O) (Ketek) • Used for community acquired pneumonia caused by various bacteria including multi-drug resistant pneumococci. • Many bacteria that are resistant to macrolides are susceptible to telithromycin
4. Inhibit DNA or RNA
4.1. DNA inhibitors
4.1.1. Quinolones
4.1.1.1. • Four generations • Synthetic broad-spectrum • Two fused six-member rings substituted with fluorine become fluroquinolones. • Inhibit DNA replication by inhibiting two enzymes topoisomerase II [DNA gyrase] and topoisomerase IV that human cells lack and that are essential for bacterial DNA replication • Selectively toxic and bactericidal. ------------------------------------------------- Side effects: • Neurological disorder myasthenia gravis. • Increased risk of tendinitis and tendon rupture. • Contraindicated if a patient has epilepsy, QT prolongation, CNS lesions. • They are best avoided in the athlete population. • Contraindicated in children due to the risks of damage to the musculoskeletal system (cartilage). • They can be administered orally or by injection and they have good distribution into prostate, CSF, and eye.
4.1.1.1.1. First: [little used Carcinogenic] Nalidixic acid - Cinoxacin • G- [not Pseudomonas] • Uncomplicated urinary tract infections, --------------------------------------------- Second: Ciprofloxacin - ofloxacin - Norfloxacin lomefloxacin - Enofloxacin • G- and Pseudomonas species some G+ not Sreptococcus pneumonia. Treatment • Uncomplicated and complicated UTI, •pyelonephritis, • Sexually transmitted diseases • Prostatitis • Skin and soft tissue infections --------------------------------------------- Third: (Levofloxacin, Sparfloxacin, Gatifloxacin) • Same as for second + expanded G+. coverage including penicillin sensitive and resistant S.pneumonia, Clamydia, Mycoplasma. Treatment: • Acute Exacerbation of Chronic Bronchitis (AECB) • Community-acquired pneumonia (CAP) • Sinusitis • Prostatitis • Sexually transmitted diseases (but not syphillis) ---------------------------------------------- Fourth: (Trovafloxacin) • Same as for third-generation plus broad anaerobic coverage. Treatment: • Same as previous generations (excluding UTI) • Abdominal infections • Nosocomial pneumonia • Pelvic infections.
4.2. RNA inhibitors
4.2.1. Rifampicin and rifabutin
4.2.1.1. • They are bactericidal. • They inhibit RNA by inhibiting bacterial RNA-polymerase, thereby preventing the production of mRNA, without affecting RNA polymerase of human cells. • Rifampicin or rifampin is used primarily for the treatment of tuberculosis • Prophylaxis in close contacts of patients with meningitis caused by either N.meningitidis or H. influenzae. • Rifampicin is given in combination with other drugs because resistant mutants appear at a high rate when it is used alone. • It is red, and the urine, saliva, and sweat of patients taking • Rifabutin, is useful in the prevention of disease caused by Mycobacterium avium complex in patients with severely reduced numbers of helper T cells, e.g., AIDS patients. • Mycobacterium avium complex (MAC) is a group of genetically related bacteria belonging to the the genus Mycobacterium. It includes Mycobacterium avium and Mycobacterium intracellulare. • MAC causes disseminated disease in up to 40% of patients with human immunodeficiency virus (HIV) producing fever, sweats, weight loss, and anemia. • Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons.
5. affect metabolic pathways
5.1. Inhibition of Pteroic acid sythetase
5.1.1. Sulphonamides
5.1.1.1. are structural analogues to PABA. They competitively inhibit the incorporation of PABA into Dihydropteroic acid synthesis.
5.2. Inhibition of dihydrofolate reductase
5.2.1. Trimethoprime
5.2.1.1. is a selective inhibitor of bacterial DHFR. The bacterial enzyme is several thousand times more sensitive than the mammalian enzyme.