Lecture 5
Aminoglycosides Streptomycin Amikacin ,gentamicin,Tobramycin Tobramycin,Neomycin, NetilmicinAntibacterial spectrum
The aminoglycosides are effective in the empirical treatment of infections suspected of being due to aerobic, gram-negative bacilli including Pseudomonas aeruginosa. To achieve an additive or synergistic effect, aminoglycosides are often combined with B-lactam antibiotic, or vancomycin, or a drug active against anaerobic bacteria. All aminoglycosides are bactericidal.Mechanism of action
aminoglycosides bind to specific 30S-subunit ribosomal proteins Protein synthesis is inhibited by aminoglycosides through (1) interference with the initiation complex of peptide formation (2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional or toxic protein andPHARMACOKINETICS
Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract. once-daily aminoglycoside dosing may be preferred in certain clinical situations. Aminoglycosides have concentration-dependent killing; that is, increasing concentrations kill an increasing proportion of bacteria and at a more rapid rate. They also have a significant postantibiotic effect, such that the antibacterial activity persists beyond the time duringTherapeutic uses
1- infection due to enterococci which is resistant to most antibiotic classes and require two synergistic antibiotic for effective therapy eg : Gentamycin or streptomycin + Vancomycin or B- lactam (P group ) 2- infected due to Pseudomonas aeruginosa which rarely attack healthy individual like immunocompromised treated include Tobramycin + anti Pseudomonal pencillin (ticarcillin )Clinical uses
Serious infections includes: Septicemia. Endocarditis Peritonitis and other severe intra-abdominal infections Urinary tract infections Respiratory tract infections. Other uses: Mycobacterium infections like TB Topically for ocular infections, infected burns and woundsSide effect of Aminoglycosides
1- Ototoxicity(Vestibular and Cochlear ) related to high peak plasma level and duration of treatment : deafness may be irreversible . 2- Nephrotoxicity :mild , reversible 3- neuromuscular paralysis : after direct intraperitoneal or intrapleural application of high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate (given promptly) or neostigmine. 4- Allergic reaction : contact dermatitis when neomycin applied topically .Resistance to aminoglycosides
due to: 1-failure of drug to penetrate intracellular 2-low affinity of drug for bacterial ribosome 3-drug inactivationGeneral notes on aminoglycosides
Combined with Penicillin or cephalosporin for serious gm-ve infections Should not be used more than few days. Never mix with P in same solution (inactivation) Contra indicated in pregnancy.Macrolides
- Erythromycin, Azithromycin (Zithromaz), Clarithromycin (Biaxin) - PO/IV it contain Macrocyclin lacton . Erythromycin used as alternative to penicillin in patient with allergic to penicillin. - Low to mild dose = bacteriostatic - high doses = bactericidal M of action Macrolide inhibit bacterial protein synthesis by binding reversibly to 50S ribosomal subunit and inhibit RNA dependant protein synthesisErythromycin
1- Erythromycin :effect against many of the same MO as Penicillin group so it use as alternative . - Absorption: incompletely but adequately absorbed from intestine - inactivated by gastric acid , so it is given as enteric coated tab. or as cap. food impair absorption Higher concentration can be achieved by I.V administrationClarithromycin
The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing Has significant activity against M.leprae.Azithromycin
Although less active against streptococci and staphylococci than erythromycin, azithromycin is far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Azithromycin is now the preferred therapy for urethritis caused by Chlamydia trachomatis. It also has activity against Mycobacterium in patients with acquired immunodeficiency syndromeazithromycin
The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases. For example, a single 1-g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500-mg loading dose, followed by a 250-mg single daily dose for the next 4 days.pharmacokinetic
Therapeutic uses of macrolidesDrug of choice for mycoplasma pneumonia Chlamydial infection Diphtheria Syphilis Streptococcal (alternative to P) Staphylococcal Prophylaxis for endocarditis Chronic periodontitis(azithromycin use as adjunct treatment)
Adverse effect macrolides
1- large dose cause epigastic pain , increase GIT motility 2- ototoxicity : transient deafness (high dose) 3-Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin 4- drug interaction : its enzyme inhibitor so it inhibit metabolism of number drugs which lead to toxic accumulation of drug like Warfarin . Others drugs interact with it : Carbamazepine, Glucocorticoids, Cyclosporine, theophyllineSpiramycin
It resembles erythromycin inactivity and properties . It specific for toxoplasmosis and recurrent abortion in pregnant women. Nowadays used in dental infection combination with other antimicrobial agent.Clindamycin
Mech. of action Bind to 50S subunit of bacterial ribosome and suppress protein synthesis. Antibacterial effects similar to erythromycin more than 90% of strains of streptococci ,including that are macrolides resistant are susceptible to clindamycin Clindamycin is more active against anaerobic bacteria than erythromycin and clarithromycinKinetic
-complete absorption orally , food not affect -t1\2 3hr -wide distribution including bone (not CSF) -excreted in urine and feces Dose Oral: 150-300 mg\6hr for sever infection : 300-600 mg\6hr Injection (i.v , i.m): 600-1200 mg\dayTheraputic uses
Side effects
1-pseudomembranous colitis, abdominal pain, fever, bloody diarrhea, it could be lethal 2-rashs, anaphylactic reaction 3-granulocytopenia, thrombocytopenia 4-local thrombophlebitis after i.v injection 5-minor effects: nausea , vomiting , esophagitis, , allergy , Glossitis ,stomatitis ,metallic tasteDNA synthesis inhibition
Metronidazole(antiprotozoal) Its synthetic Nitromidazol , its effective against obligate anaerobic and microaerophilic M.O involving acute orofacial infection . Metronidazole (Flagyl) - treatment of various disorders associated with organisms of GI tract - Orally and IV. Metronidazole is a concentration-dependent, not time dependent,antibioticMechanism of action
It enter into the cell and reduction of its Nitro group to produce metabolite that damage DNA this lead to cell damage .Spectrum
Metronidazole a nitroimidazole, is the mixed amebicide of choice for treating amebic infections; it kills the E. histolytica trophozoites. Metronidazole also use in the treatment of infections caused by Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, and anaerobic gram-negative bacilli ,anaerobes,Including Bacteroides and Clostridium speciesMetronidazole
distributes well throughout body tissues and fluids. Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF). Metabolism of the drug depends on hepatic oxidation of the metronidazole side chain by mixed-function oxidase, followed by glucuronylation.Therapeutic uses
1- anaerobic abdominal and CNS infection 2- treatment of clostridium difficile associated diarrhea and colitis.3- treatment of various human parasites. Uses in dentistry gram –ve anaerobic pathogen responsible for acute orofacial infections and chronic periodentitis .Also used to treat H. pylori associated with peptic ulcers . The typical dosage is 500 mg three times daily orally or intravenously (30 mg/kg/dTherapeutic uses in dentistry
Metronidazole is highly effective against gram-negative anaerobic pathogens responsible for acute orofacial infections and chronic periodontitis. Combination of metronidazole with a β-lactam antibiotic for oral infections may be indicated for serious acute orofacial infections and in the management of aggressive periodontitis..