B-Lactam Antibiotics + Macrolides PDF

Antimicrobials Dr. Amany Tawfik Elfakhrany Assistant Professor of Clinical Pharmacology Faculty of Medicine - Menoufia University Beta lactam antibiotic Penicillins, Cephalosporins, Monobactams, Carbapenems Dynamics (bactericidal antibiotics) They bind to specific penicillin...

Antimicrobials Dr. Amany Tawfik Elfakhrany Assistant Professor of Clinical Pharmacology Faculty of Medicine - Menoufia University Beta lactam antibiotic Penicillins, Cephalosporins, Monobactams, Carbapenems Dynamics (bactericidal antibiotics) They bind to specific penicillin binding protein (PBP), and inhibit formation of peptidoglycan, leading to inhibition of cell wall synthesis. Activate autolytic enzymes (autolysis) leading to lysis of cell wall. Bacteria imbibe water due to its interior high osmotic pressure leading to rupture and death of the microbe. They affect mainly growing bacteria rather than resting one. Human cells do not contain peptidoglycan cell wall. Resistance Natural absence of peptidoglycan cell wall e.g. mycoplasma. Decreased permeability to antibiotics. Production of B-lactamase enzymes. Alteration in the plasma protein binding. Penicillins Obtained naturally from penicillium molds and semi synthetically. Derivatives of 6-aminopenicillanic acid. They contain B-lactam ring which is essential for the anti- bacterial activity. Classification Natural penicillin Short Penicillin G acting Long Benzyl, soluble or crystalline penicillin G procaine penicillin G acting Benzathine penicillin G Acid (Orally) Phenoxymethyl penicillin (penicillin V, ospen,): resistant A natural penicillin. Penicillin G Short duration: 4-6 hours. Acid sensitive (not given orally). Lactamase (penicillinase) sensitive, so not effective in B-lactamase secreting organisms Narrow spectrum = not effective against gram – ve bacilli e.g. salmonella & H. influenza. IM or IV or IV infusion. Penicillin G  Benzyl, soluble or crystalline penicillin G: It is the drug of choice for severe infections such as pneumonia, endocarditis, meningitis, and septicemia because of its spectrum in addition it is widely distributed, rapidly acting, and given IM or IV.  Procaine penicillin G: given IM (never IV). Used in less severe infections & to prevent endocarditis after dental extraction because it acts more slowly & longer.  Benzathine penicillin G: This is very slowly absorbed following deep intramuscular injection and provides a low level in blood. Used for rheumatic fever prophylaxis by monthly IM injection. Phenoxy methyl penicillin (penicillin V): - It is acid resistant. - Given orally. - The antimicrobial spectrum is similar to those of penicillin G. - Less penicillinase sensitive than penicillin G.  II. Semisynthetic Penicillins A. B-lactamase (penicillinase)resistant penicillins  They are acid stable.  Given orally.  Spectrum: active against penicillinase-creating strains of gram positive cocci, more specifically against staphylococcal species. For this reason, these penicillins are often called as )anti-staphylococcal penicillins(.  They are penicillinase-resistant.  They include: o Oral: Oxacillin and Cloxacillin. o Parenteral: Nafcillin, Methicillin (obsolete due to nephrotoxicity). B. Aminopenicillins Broad spectrum penicillins  They are acid resistant.  Can be given orally and by injection.  Spectrum: as for penicillin G, plus some gram-negative bacteria (H. influenza, H. pylori, Salmonella, Shigella, E-coli).  They are penicillinase sensitive.  They include: Amoxicillin, ampicillin and proampicillins. Characteristics Amoxicillin Ampicillin Form available Oral Oral , parenteral % absorbed from GIT 95% 40% Effect of food None ↓ absorption Duration of action Short (6h) Longer (8h) Concentration in urine Very high High Concentration in lower and High and persists sputum decreases Activity against penicillin- None None Resistant staph. Activity against: Salmonella Good Fair-good Shigella Poor Good Toxicity Less diarrhea Diarrhea/rash C. Extended spectrum penicillin(antipseudomonal)  Most are acid labile as azlocillin and piperacillin, they are given parenterally, some are acid stable and given orally as carbenicillin.  Spectrum as for broad-spectrum drugs, plus pseudomonas.  Inactivated by B- lactamases.  Combination with tazobactam provides the advantage of extended-spectrum with relative resistance to B- lactamase.  Synergistic with aminoglycosides for treatment of pseudomonas infections. D. Reversed spectrum penicillin (Amidino-penicillin)  Acid stable.  Given orally  Spectrum: gram – negative bacteria e.g. Salmonella and Shigella. BUT NOT Pseudomonas, Klebsiella or H. influenza  Hydrolysed by B- lactamase.  Used for treatment of urinary tract infection and typhoid fever.  E.g. Mecillinam (IV, IM), pevmecillinam (oral).  B-lactamase inhibitors CLAVULANIC ACID, SULBACTAM & TAZOBACTAM. Powerful B-lactamase inhibitors. No antibacterial activity of their own. They protect penicillins from inactivation by B-lactamases secreted by some bacteria e.g. staph aureus, H. Influenza, E. coli, proteus & P. Aerugenosa Used in combination with other penicillines e.g.: Clavulanic acid + amoxicillin (co-amoxiclav) = Augmentin orally Sulbactam + ampicillin = Unasyn oral, IM & IV. Uses of penicillin Uses of penicillin in treatment of: 1. Staphylococcal infections: use penicillinase-resistant penicillin e.g. nafcillin, oxacillin. Or combination with B-lactamase inhibitor. 2. Streptococcal infections (pharyngitis, pneumonia, arthritis, meningitis, endocarditis, puerperal fever, and wound sepsis). 3. Pneumococcal infections (pneumonia, meningitis). 4. Salmonella infections (Typhoid and paratyphoid); a big dose of ampicillin is effective. 5. Shigella dysentery: amoxicillin or ampicillin. 6. Pseudomonas infections: use antipseudomonal penicillins. 7. Meningococcal infections (Penicillin G is the drug of choice) Gonococcal infection, anthrax, and syphilis. 8. Diphtheria: specific antitoxin is the most important, penicillin is used to eliminate the diphtheria bacilli from the pharynx. 9. H. influenza infections: ampicillin is the drug of choice. Uses of penicillin in prophylaxis of: 1. Streptococcal infections: penicillin G or penicillin V is used in outbreaks of streptococcal disease in closed populations. 2. Recurrences of Rheumatic fever: benzathine penicillin 1.2 million units once a month IM. 3. Gonorrhea and syphilis: for sexual contacts of patients with gonorrhea or syphilis. 4. To prevent gonorrheal ophthalmia in neonates: benzylpenicillin is instilled in the conjunctiva. 5. Surgical procedures in patients with valvular heart disease to prevent subacute bacterial endocarditis (600.000 units procaine penicillin are injected 2-3 hrs before the surgical procedure. Adverse effects of penicillin 1. Allergic reactions (including itching, rash, and anaphylaxis) 2. Pain and sterile inflammatory reactions at sites of IM injections. 3. Jariseh – herxheimer reaction in late syphilis: febrile reaction occurs after the 1st injections of penicillin. It is due to the abrupt massive destruction of treponemas in syphilitic lesions. Usually subside within 24-36 hrs. 4. Diarrhea: caused by a disruption of the normal balance of intestinal microorganisms. 5. Nephritis: All penicillins, but particularly methicillin, cause acute interstitial nephritis. 6. Neurotoxicity: penicillins are irritating to neuronal tissue and can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are especially at risk. 7. Cation toxicity: Hyperkalemia (with rapid IV injection of K- penicillins G, sodium overload (with carbenicillin and ticarcillin). 8. Other side effects: Agranulocytosis (with methicillin, cloxacillin), hepatitis (with oxacillin). Drug – interactions of penicillins: 1. Ampicillin and oral contraceptives, decreased effect of contraceptives. 2. Penicillins and probenecid block the excretion of penicillin causing higher serum levels. 3. Penicillins and aminoglycosides, have synergistic antibacterial effects. Cephalosporins B-lactam antibiotics. Derivatives of 7-aminocephalosporanic acid. Antibacterial activity: As penicillins (bactericidal & inhibit cell wall synthesis.) Classification First generation Second generation Third generation Forth generation Fifth generation First generation cephalosporins:  They have good activity against most gram- positive organisms and some gram-negative organisms.  Do not penetrate CSF.  t1/2 from 2 hr.  They are generally inactivated by B- lactamases.  They include cephradine and cefazolin. Second generation cephalosporins:  They have an extended spectrum of the first generation to include H. influenza, proteus, and enterobacter.  Don't penetrate CSF.  t1/2 from 4 hr.  They are relatively resistant to B- lactamases.  They include cefoxitin and cefaclor. Third generation cephalosporins:  Somewhat reduced activity against gram-positive organisms, but enhanced activity for gram-negative organisms.  Moderated activity against anaerobes.  Some members as cefoperazone and ceftazidime are active against p. aeruginosa.  Most penetrate CSF.  t1/2 from 8 hr.  They are resistant to destruction by B-lactamase.  They include ceftazidime, and cefoperazone. Forth generation cephalosporin:  Comparable to third-generation but more resistant to some B- lactamases.  They include cefepime. Fifth generation cephalosporin:  Broad spectrum prodrug of active metabolite ceftaroline.  Requires dose adjustment in renal impairment.  Include: Ceftaroline. 1st Generation 2nd 3rd Generation 4th 5th Generation Generation Generation -most gram -extended Reduced activity = 3rd Gen. Broad spectrum +ve spectrum against gram +ve, Active against -some gram-ve (+H. influenzas enhanced activity for methicillin resistant , Enterobacter gram-ve bacilli staph aureus (MRSA) &proteus) Moderate activity Not effective against against anaerobes pseudomonas Do not Do not most penetrate BBB = 3rd Gen. penetrate BBB penetrate BBB Inactivated by Inactivated by Resistant to B- More has limited activity B-lactamase B-lactamase lactamase resistant against B-lactamase producing bacteria  Uses of cephalosporin 1. First-generation and Second-generation cephalosporins are used mainly for urinary, respiratory, bone, and soft tissue infections that are commonly caused by gram-positive bacteria. 2. Third-generation cephalosporins are used primarily for serious hospital- associated gram-negative infections, septicemias, and infections in immunocompromised patients, alone or in combination with aminoglycosides. 3. Ceftriaxone is effective in the treatment of typhoid fever and is the drug of choice for: o all forms of gonorrhea. o meningitis in immunocompromised adults and children older than 3 months. o severe forms of late Lyme disease. 4. Ceftazidime plus an aminoglycoside is the treatment of choice for pseudomonas meningitis. 5. Prophylaxis against infections before surgery (A single dose of cefazolin). Adverse effects of cephalosporin: 1. Hypersensitivity reactions: Identical to those caused by the penicillins and this may be related to the shared B-lactam ring. Should be avoided in patients with serious penicillin allergy (cross allergy). 2. Nephrotoxicity especially with cephaloridine. 3. Serious bleeding either due to hypoprothrombinemia, thrombocytopenia, and/or platelet dysfunction especially with cefoperazone, and ceftriaxone. 4. Intolerance of alcohol (a disulfiram – like reaction) with cefamandole and cefaperazone. 5. Positive Coomb's reactions with parenteral high dose but hemolysis are rare. 6. Diarrhea especially with cefoperazone because of its greater biliary excretion. 7. Local irritation: severe pain after IM injection and thrombophlebitis after IV injection. 8. Cross-resistance with penicillin Drug interactions of cephalosporin: Cephalosporins and (aminoglycosides, probenecid, frusemide, ethacrynic acid and vancomycin) causes increased risk of nephrotoxicity Other B-Lactam antibiotics A. Carbapenems  Their mechanism of action is the same as that of penicillins.  They are resistant against B- lactamases. Imipenem  The antibacterial spectrum (widest spectrum) includes most gram-negative aerobic, gram-positive aerobic bacteria, and anaerobic microorganisms.  It is metabolized to an inactive nephrotoxic metabolite in the kidney by dehydropeptidase I (located on the brush border of renal tubular cells). So, it is combined with cilastatin (an inhibitor of dehydropeptidase I) to inhibit renal metabolism.  Its side effects include: o GIT: nausea, vomiting, diarrhea. o Blood disorders: eosinophilia, neutropenia. o Seizures occur with high dose. Meropenem Like imipenem but not inactivated by dehydropeptidase. B-Monobactams  Their mechanism of action is the same as that of penicillins.  It is resistant to B- lactamases.  In contrast to most other β-lactams, They are effective only against aerobic Gram-negative bacteria (e.g., Neisseria, Pseudomonas).  No cross allergy with B-lactams.  Currently the only commercially available monobactam antibiotic is aztreonam.