Cell Wall Synthesis Inhibitors PDF

Cell wall synthesis inhibitors Cell wall synthesis inhibitors are divided to 2 main groups Non-β β-lactam lactam Penicillins...

Cell wall synthesis inhibitors Cell wall synthesis inhibitors are divided to 2 main groups Non-β β-lactam lactam Penicillins Vancomycin Cepalosporins Fosfomycin Carbapenems Teicoplanin Monobactams 1- Penicillins Mode of action of penicillins Inhibition of cell wall synthesis by ↓ transpeptidase (Penicillin Binding Protein) → ↓ cross linking of peptidoglycans which results in inhibition of cell wall synthesis. Pharmacokinetics  Absorption of oral penicillins is decreased by food (should be given 1-2 h before or after meals) except amoxicillin.  Distributed widely to most areas of body, with poor penetration to eye, prostate and CNS. However, inflamed meninges permit the passage of penicillin, thus used in bacterial meningitis.  Metabolized to limited extent in the liver.  Ampicillin undergoes enterohepatic circulation.  Most penicillins excreted unchanged by the kidneys mainly by tubular secretion; consequently, dose adjustment is required in renal impairment. CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY  Classification of penicillins Type Natural Broad- Anti-staph. Anti- spectrum pseudomonal Spectrum Narrow Broad Broad Broad B-lactamase Sensitive Sensitive Resistant Sensitive Examples Pen.G: Acid Ampicillin Cloxacillin Carbenicillin labile Amoxicillin Dicloxacillin Ticarcillin e.g, Flucloxacillin Piperacillin Benzathine N.B., pen. & Amoxicillin is procaine pen. better absorbed, Pen.V: less affected Acid stable by food and less GIT disturbances Uses 1- Respiratory tract infection (e.g., Pharyngitis, otitis media, tonsillitis, sinusitis, bronchitis and pneumonia 2- Urinary tract infection (e.g., nephritis and cystitis) Benzathine Ampicillin in Staph. Pseudomonas pen. shigellosis Infection infection -Treatment of β-hemolytic Streptococcal pharyngitis. -Prophylaxis against infective endocarditis -Syphilis Pen.V -Dental infection CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY Adverse reactions 1-Hypersensitivity  Most common drug implicated in drug allergy Rash, itching, urticaria, fever and anaphylaxis, Rare but fatal.  More common with parenteral administration.  Highest with procaine penicillin  Skin sensitivity test (A scratch test or intradermal test) should be done before parenteral administration 2- Thrombophlebitis of injected vein. 3- Diarrhea with ampicillin. 4- Seizures: especially in renal impairment. Drug interaction  Synergism Penicillin + Aminoglycosides Warning: both drugs shouldn’t be mixed in the same syringe. Why synergism occurs??? Because penicillin by inhibiting the cell wall synthesis facilitates the entry of aminoglycosides to act on protein synthesis. Furthermore, penicillin is mainly acting against gram +ve while aminoglycosides act mainly against gram -ve  Antagonism Penicillin + Tetracyclines Bacteriostatic (e.g.Tetracyclins) with bactericidal effect of penicillin.  Potentiation Penicillin + Probenecid Probenecid competes with penicillin on excretory pathway leading to increased plasma concentration of penicillins.  Penicillins decrease the effect of oral contraceptive pills CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY  Beta-Lactamase inhibitors Beta lactamases enzymes produced by gram positive and gram negative bacteria that inactivate beta lactam antibiotics by opening beta lactam ring. Beta lactamase inhibitors -Clavulanic acid -Sulbactam -Tazobactam Examples 1-Amoxicillin + Clavulanic Acid 2-Ampicillin + Sulbactam 3-Piperacillin + Tazobactam Note: Hepatotoxicity has been reported with the use of amoxicillin + clavulanic acid but not with amoxicillin alone. It may be due to immunologic reaction to clavulanic acid. CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY  2- Cephalosporins Antimicrobial activity  The cephalosporins have been grouped into "generations" corresponding to their development by the pharmaceutical industry in response to clinical needs.  In general, the later generations of cephalosporins have greater gram-negative activity at the expense of gram-positive activity.  Later generations are more resistant to β-lactamase. i.e., first generation is the strongest against gram +ve infection and fourth generation is the strongest against gram-ve infection and more resistant to β-lactamase. Cephalosporin generation 1st generation 2nd generation Examples  Cephradine  Cefaclor  Cephalexin  Cefamandole  Cefazolin  Cefuroxime Uses 1- Respiratory tract infection 1- Respiratory tract infection 2- Urinary tract infection 2- Urinary tract infection 3- Cefazolin: surgical 3- Cefazolin was used in meningitis prophylaxis (pass B.B.B.) Third generation agents Parenteral: 1- Cefotaxime 2- Ceftazidime Pass B.B.B. 3- Ceftriaxone Undergo biliary excretion so safe in renal excretion 4- Cefoperazone Oral: Cefixime & cefdinir CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY Pharmacokinetics - Cefotaxime, ceftazidime and ceftriaxone pass B.B.B. - Ceftriaxone and cefoperazone are biliary excreted so that they are safe in renal patient -Other members undergo renal excretion by combination of active tubular secretion and glomerular filtration. Accordingly, probenecid blocks secretion of some compounds and some of the drugs can accumulate to varying degrees in presence of renal failure. - Hemodialysis removes these drugs; peritoneal dialysis minimal effect. Therapeutic uses  Respiratory tract infection  Urinary tract infection  GIT infection  Bacterial Meningitis (cefotaxime, ceftazidime & ceftriaxone are used)  Gonorrhea (ceftriaxone is the Drug of choice). Fourth generation agents e.g., Cefepime. - Used parenteral only (IM or IV). - It passes B.B.B. - Renally excreted. - Cefepime is effective in gram-positive & gram-negative bacterial infections susceptible to its antimicrobial activity. Therapeutic uses 1. Empiric treatment for severe mixed infection. 2. Complicated intra-abdominal infections (with metronidazole). 3. Respiratory tract infection e.g., Pneumonia. 4. Urinary tract infections (Complicated and uncomplicated). 5. Skin and soft tissue infections. CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY Adverse effects of Cephalosporins 1. Nephrotoxicity 2. Hypersensitivity  Rash, urticaria, eosinophilia, fever, anaphylaxis (rare).  Cross allergy with penicillins due to β-lactam 3. Hypoprothrombinemia (cefoperazone) due to Vit k deficiency. 4- Alcohol intolerance (cefoperazone): nausea, vomiting, palpitation and flushing with alcohol consumption. 3. Hematologic: Leukopenia and rarely hemolytic anemia. 3- Monobactam -Active against only gram-negative rods. Including P. aeruginosa. -Used IV as alternative to penicillin in allergic patients. 4- Carbapenems -Imipenem -Meropenem -Ertapenem General characters  Used IV infusion  Pass B.B.B.  Very resistant to hydrolysis by most Beta lactamases. Imipenem Meropenem Role of  It is rapidly hydrolysed by a - It is not sensitive to renal DHP dehydropeptidase (DHP). Found dipeptidase. in the brush border of proximal renal tubules.  Given with an inhibitor of DHP, - Does not require co- Cilastatin. A preparation with administration with equal amounts of both. cilastatin Adverse  Seizures, when high doses given - Less likely to cause seizures effects in patients with CNS lesions and those with renal insufficiency. CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY  Non Beta-Lactam drugs 1- Vancomycin Kinetics:  Poorly absorbed orally.  Injection given IV infusion over 1-hr. Clinical uses: 1- MRSA infections: methicillin-resistant staphylococci (e.g. osteomyelitis, pneumonia, endocarditis). 2- Pseudomembranous colitis: used orally, although metronidazole is preferred due to less resistance. Adverse effects: 1- infusion-related reactions: Rapid intravenous infusion may cause urticarial reactions, flushing, tachycardia, and hypotension. 2- "Red-man" syndrome is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine. 2- Fosfomycin - Fosfomycin is used to treat urinary tract infection and cystitis (bladder infection) in women. - Safe with pregnancy. 3- Teicoplanin - Teicoplanin is used to treat serious staphylococcal and streptococcal infections but has no gram negative activity. - It has a Long duration of action. It may be indicated in the following situations: 1) Treatment of MRSA infection and multi-resistant gram positive infection e.g. Enterococcus faecium. 2) Treatment of serious gram-positive infections in patients allergic to other antimicrobials. CELL WALL SYNTHESIS INHIBITORS DR. REMON ROSHDY