Cephalosporins Antimicrobials PDF

ANTIMICROBIALS 2. CEPHALOSPORINS Tefttriaxon Ceefi ceftazitin  ORAL CEPHALOSPORINS Many of the oral cephalosporins, such as cefaclor, cefadroxil, cefprozil, Cephalexin cephalexin, ceftibuten are acid-stable and have high bioavailability (80%--- as 95%). The bioavail...

ANTIMICROBIALS 2. CEPHALOSPORINS Tefttriaxon Ceefi ceftazitin  ORAL CEPHALOSPORINS Many of the oral cephalosporins, such as cefaclor, cefadroxil, cefprozil, Cephalexin cephalexin, ceftibuten are acid-stable and have high bioavailability (80%--- as 95%). The bioavailability of cefixime, however, is lower (40%---50%). Cephradine Because most drugs are absorbed from the intestinal mucosa by passive Cefadroxil diffusion, absorption across the intestinal epithelium is enhanced if the drug is lipophilic. absorption enhanced if dry lipophilic Cefaclor Therefore, some oral cephalosporins are esterified ( eg, cefuroxime axetil) Cefprozil to increase lipid solubility and enhance absorption. Cefixime These prodrugs are hydrolyzed after intestinal absorption by esterases in Cefuroxime the intestinal epithelium to their active metabolites. Nevertheless, their bioavailability is relatively low (25%---50%) and is enhanced by concomitant axetil food intake. Is so 1ST GENERATION CEPHALOSPORINS Cephalexin Oral oval Cephradine Oral + parenteral oral Parted Cefadroxil Oral Long acting OH ord long acting Cefazolin Parenteral (IV, IM) High plasma protein binding (85%) Para EVIN get a plasmaproteinbinding Excretion: mainly renally excreted unmetabolized by glomerular filtration in urine Dose adjustment (reduction) in case of renal impairement  cefuy Na Par IV hbioavaibl absorbtion 2ND GENERATION CEPHALOSPORINS cefuaxtel 91poporal Parenteral (IV) as cefuroxime sodium poor oral bioavailability Oral (suspension, tablets) as Cefuroxime axetil prodrug more Cefuroxime lipophilic better oral absorption Can be orally combined with clavulanic acid. axe ti sustablets Half Cross the BBB Cefaclor from o Oral More lipophilic (due to Cl) better oral absorption Cefprozil oralacts Oral Long acting long O IV Cefoxitin t ½ < 1h Excreted unchanged by the kidney Cefoxitlin IV I th e th Excerted Unchanged  y ey 3RD GENERATION CEPHALOSPORINS Parenteral (IV, IM) High potency Ceftriaxone Long acting High protein binding Crystallization with Ca Gonorrhea, meningitis Parenteral (IV, IM) taxis th d par distrCns menyati Cefotaxime Short t ½ (1h)f Good distribution in CNS meningitis e Metabolized into less active metabolite I N Ceftazidime Parenteral (IV, IM) 8 Short t ½ (1.5 h) Excreted unchanged renally dose adjustment with renal dysfunction Oral suspension, tablets & capsules Cefixime Oral bioavailability 40 – 50 % regardless of food Moderate t ½ (3 - 4 h) Excreted unchanged renally dose adjustment with renal dysfunction orally 40 so  4hr ADME t1/2 = 30 - 90 min Cefixime 3-4h Absorption Ceftriaxone 8h Unmetabolized Metabolism Cefotaxime: Metabolized in vivo to desacetyl-cefotaxime (less active ) metabolized to less active metabolite Glomerular filtration Excretion Urine & bile Dose adjustment with renal impairment  to plasma protein 9 long half life extensive binding CEFTRIAXONE & PROTEIN BINDING Ceftriaxone undergoes extensive binding to plasma proteins (albumin) longer half-life (i.e. the drug circulates for longer duration with the blood). The antimicrobial activity & elimination are limited to the unbound fraction of the drug. É The free/unbound drug concentration should exceed the minimal inhibitory concentration (MIC) at steady state. This behavior may be advantageous because sustained concentrations above the MIC are preferable to a high peak and then rapidly decreasing concentrations. Patients with hypoalbuminaemia (low albumin level in blood) will affect the PK of ceftriaxone (reduced protein binding, higher level of free drug in blood, shorter half-life, higher volume of distribution).  y emnal b d fuckn f y freedry unbound exceed MIC at steady state SAFETY CRITERIA FOR CEFTRIAXONE ADMINISTRATION TO NEONATES Hyperbilirubinemia (high bilirubin blood level) is one of the most common neonatal disorders at the first days and weeks of life (jaundiced premature infants). Ceftriaxone should be avoided in neonates with hyperbilirubinemia due to potential risk for displacement of bilirubin from albumin which increases the risk of bilirubin encephalopathy. Ceftriaxone competes with bilirubin for binding to human serum albumin (Competitive binding). Ceftriaxone displaces bilirubin from albumin-binding sites concentrations of free bilirubin in the blood. Canby higher This very high bilirubin levels in the blood are deposited in the brain tissue causing irreversible damage to the brain known as bilirubin encephalopathy. ceftriaxone  Pel an I hum am a main ca gustone M ca couplet w CEFTRIAXONE & CALCIUM biliary pseduthialsis 3. CARBAPENEMS  most broad spectrum antimicrobial avail ble GENERAL FEATURES OF CARBAPENEMS gu poor oral ab IM IM There are four FDA-approved carbapenems (imipenem, meropenem, ertapenem, and doripenem) Carbapenems resemble penicillins -lactam ring fused to a five-membered ring. The five- membered ring, however, is unsaturated and does not contain sulfur. -lactams and are among the most broad- spectrum antimicrobials available. offshnsa They are highly resistant to a variety of beta-lactamases. I They are administered via IV infusion due to poor oral absorption as they do not readily cross GI membranes. Imipenem-cilastatin and ertapenem can also be delivered intramuscularly. Carbapenems are distributed widely in the body and are mostly excreted by the kidneys. Due to the significant renal elimination of carbapenems, patients with reduced renal function require adjusted dosages/dosing intervals to avoid drug accumulation broadshe emitter elmnat kidney word absorbtion IM IMIPENEM FORMULATIONS Imipenem is rapidly metabolized (deactivated) by the human kidney enzyme dehydropeptidase-1 (DHP-1) in the humanbrushbrode renal brush border. Coadministration with the DHP-1 inhibitor, cilastatin increases the in vivo half-life, increases tissue penetration and prevents nephrotoxicity. Nephrotoxicity is associated with imipenem if administered without cilastatin due to the renal metabolism of the carbapenem compound. Combination of imipenem-cilastatin with relebactam extends the spectrum against carbapenemase producing bacteria, a MDR G-ve bacteria. qspectrumagnisttatbapenemmnrojneph.ro toxicityrifimpwlout Clastatin  p cup 70 excreted ughayyedinuvine longer half if 2x got recovered in urine MEROPENEM & ERTAPENEM no need elastin Mero Etra Meropenem and ertapenem show greater stability towards the DHP-1 system and can be administered without cilastatin. Ertapenem has longer t ½ relative to meropenem allowing once daily dosing (IV infusion). Meropenem (70% of the dose) is excreted unchanged in urine over 12 h. Whereas 80% of ertapenem is recovered in urine, with nearly half intact and the other half as the ring-opened metabolite. Mero d soy recovert inurne To un CONTRAINDICATION OF CARBAPENEMS & VALPROIC ACID Coadministration of meropenem with the antiepileptic agent valproic acid significantly lowers the serum concentrations of valproic to sub acid to subtherapeutic levels leading to the aggravation of seizures. To solve this: Therapeutic drug monitoring (TDM) of the serum valproate concentration. If carbapenem treatment is required, patients should be given an alternative treatment to valproic acid M P VaPg conc of ralporicacid THANK YOU