Cephalosporins
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A nice introduction to Cephalosporins, how they work, the different generations, spectrum, uses, side effects, pharmacokinetics and common trade names in Egyptian market.
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Cephalosporins
- 1. Cephalosporins (Spectrum, uses, side effects, and common trade names in Egyptian market) N S OAc CO2HO H N H H C O R
- 2. A little Introduction… The Cephalosporins are antibacterial agents that inhibit bacterial cell wall synthesis. They are β-lactam antibiotics that are closely related both structurally and functionally to the Pencillins. They were discovered from a fungal colony Cephalosporium acremonium in 1948. Cephalosporin C was identified in 1961. Most Cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
- 3. Mode of Action… The cephalosporin antibiotics interfere with cell-wall synthesis of bacteria, leading to lysis of the infectious organism. To achieve this effect, the antibiotic must cross the bacterial cell wall and bind to the transpeptidases involved in the cross-linking of peptidoglycan polymers.
- 4. Classification and Spectrum… Cephalosporins are divided into 1st , 2nd , 3rd , 4th and 5th generations according to their spectrum. As the 1st, 2nd and 3rd generations progress they an increase in the sensitivity of gram-negative microorganisms and a decrease in the sensitivity of gram-positive microorganisms . The 4th and 5th generations show activity towards both.
- 5. Classification… Generation Parenteral Agents Oral Agents 1st generation Cefazolin, Cephalothin Cefadroxil, cephalexin,cephradine 2nd generation Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil 3rd generation Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, Cefoperazone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime 4th generation Cefepime, cefpirome 5th generation Ceftaroline, Ceftobiprole
- 6. 1 st Generation – Common Trade Names Cefazoline (Parentral) Cefadroxil (Oral)
- 7. 1 st Generation – Pharmacokinetics • Oral cephalosporins are generally well absorbed. • Cephalothin IM is very painful and hence given by IV route. • Except for cefazolin, which is 80-90% protein bound, others exhibit a poor protein binding. • They have good distribution to most tissues except in CSF so, can’t be used in meningitis. •Metabolism is not a major elimination path as it is primarily excreted through kidney. •Probenecid increases plasma half life. •Sensitive to β-lactamase enzyme degradation.
- 8. 1 st Generation – Antimicrobial Spectrum
- 9. 1 st Generation – Uses UTI. Minor Staphylococcal Infections. Cellulitis / Soft Tissue Abcess. Cefazoline is the drug of choice for prophylaxis before cardiac surgeries and orthopedic prosthesis due to its good tissue penetration. Cellulitis
- 10. 2 nd Generation – Common Trade Names Cefuroxime axetil (Oral) Cefaclor (Oral)
- 11. 2 nd Generation – Pharmacokinetics •Cefaclor has very good oral bioavailability. •Cefuroxime axetil is an ester prodrug. •Only cefuroxime crosses BBB among 2nd generation. •Only cefoxitin is 80-90% protein bound while others have poor protein binding. •More stable to β-lactamase degradation than 1st generation. •Their IM injections are painful and hence preferably given administered by IV route. •These are excreted unchanged through kidney. •Probenecid increases plasma half life.
- 12. 2 nd Generation – Antimicrobial Spectrum
- 13. 2 nd Generation – Uses UTI. Minor Staphylococcal Infections. Cellulitis / Soft Tissue Abcess. Cefuroxime is the only 2nd generation that is effective in meningitis due to its ability to cross BBB.
- 14. 3 rd Generation – Common Trade Names Cefotaxime (Parentral)
- 15. 3 rd Generation – Common Trade Names Ceftriaxone (Parentral) Cefoperazone (Parentral)
- 16. 3 rd Generation – Common Trade Names Ceftazidime (Parentral) Cefdinir (Oral)
- 17. 3 rd Generation – Common Trade Names Cefditren (Oral) Cefixime (Oral)
- 18. 3 rd Generation – Pharmacokinetics • Cefoperazone and ceftriaxone are excreted through bile, so no dose adjustment required for renal insufficiency. •Urinary excretion is the major elimination route. •Probenecid may increase the plasma half life. •Highly resistant to β-lactamases. •Can pass BBB so, used for meningitis.
- 19. 3 rd Generation – Antimicrobial Spectrum Spirochetes: Borrelia burgorferi
- 20. 3 rd Generation – Uses: • Ceftriaxone, Cefotaxime, CefoperazoneMeningitis • Ceftriaxone, Cefotaxime, CefoperazoneGonorrhoae • Ceftriaxone, CefotaximeChancroid. • Ceftriaxone, CefotaximeCommunity acquired pneumonia • CeftriaxoneLyme disease • Ceftriaxone, Cefixime, CefpodoximeComplicated UTI. • CeftriaxoneAbdominal sepsis. • Ceftriaxone, Cefoperazonesepticemia • CeftriaxoneMulti drug resistant typhoid fever • CefotaximeAnaerobic and hospital acquired infections • CeftazidimeNosocomial Infections • Cefoperazone, CeftazidimePseudomonal Infections • CefoperazoneIn immuono-compromised
- 21. 3 rd Generation – Uses: Ceftriaxone Meningitis caused by N.meningitidis, Pneumococci, H. influenza and susceptible enteric gram-negative rods but not by Listeria monocytogenes. Gonorrhoae (single 250mg IM dose ). Chancroid. Community acquired pneumonia caused by pneumococci, H. influenzae and staph aureus . Lyme disease caused by Borrelia burgdorferi Complicated UTI. Abdominal sepsis. septicemia Multi drug resistant typhoid fever (requires high doses).
- 22. 3 rd Generation – Uses: Cefotaxime Meningitis. Gonorrhoea (single 0.5-1g IM dose). Community acquired pneumonia. Used in respiratory, genitourinary, abdominal infections, septicaemia, anaerobic and hospital acquired infections. 3 rd Generation – Uses: Cefoperazone Meningitis, gonorrhoae, bacteremia and septicemia. More active than cefotaxime against pseudomonas but less active than ceftadizime. Good for Salmonella typhi and B. fragilis. Pseudomonal UTI. Infections in immunocompromised patients.
- 23. 3 rd Generation – Uses: Ceftazidime Has excellent activity against pseudomonas (better than cefoperazone). Ceftadizime+aminoglycosides is the treatment of choice for pseudomonal meningitis. Useful for nosocomial infections. 3 rd Generation – Uses: Ceftizoxime More active against B. fragilis than cefotaxime.
- 24. 3 rd Generation – Uses: Cefixime Used to treat respiratory, urinary, biliary infections. Uncomplicated gonorrhoea (single 400 mg dose). Not effective against Staph. aureus and Pseudomonas. 3 rd Generation – Uses: Cefpodoxime similar to cefixime but it is active against Staph. Aureus.
- 25. 4 th Generation – Common Trade Names Cefepime (Parentral)
- 26. 4 th Generation – Pharmacokinetics *Zwitter ionic compounds (Oximinocephalosporins). *Could be given by IM /IV. *Protein binding is only 10-20%. *Widely distributed in tissues and body fluids with will accumulation in CSF. *It is eliminated 85-90% through kidney. *Good affinity for the transpeptidases with high resistance to β-lactamases. *Active vs. Gram +ve cocci and a broad array of Gram –ve Bacteria (including P. Aeruginosa).
- 27. 4 th Generation – Antimicrobial Spectrum - Cocci and - Bacilli > + Cocci (no + Bacilli or Anaerobes) • Streptococcus pyogenes. • Viridans streptococci. • Streptococcus pneumoniae. • Modest activity against Staphylococcus aureus. Gram-positive bacteria • Escherichia coli. • Klebsiella pneumoniae. • Proteus spp. • Haemophilus influenzae. • Neisseria spp. • Many other Enterobacteriaceae. Pseudomonas aeroginosa. Gram-negative bacteria
- 28. 4 th Generation – Uses Hospital acquired pneumonia. Bactreamia . Septicaemia.UTI. RTI. Empiric therapy in febrile neutropenia.
- 29. 5 th Generation – Ceftaroline Antimicrobial Spectrum: MSSA, streptococci, enteric GNRs, MRSA. Less gram negative coverage than 4th generation. No Pseudomonas activity. Uses: Complicated skin and soft tissue infections . Community acquired pneumonia.
- 30. Common Cephalosporins Side Effects… Hypersenstivity Hypoprothrombinemia Disulfiram-like Rx Diarrhea Nephrptoxicity Hepatotoxicity
- 31. Common Cephalosporins Side Effects… •Hypersensitivity reaction: Since Cephalosporins are structurally related to Penicillins but does that mean that a patient with Penicillins also has a cross-reactivity with Cephalosporins? •In the 70s Cephalosporins were contraindicated to any patient who showed allergic reaction to Penicillins or Carbapenams, •Recent studies suggests that for many second-generation (or later), the cross-reactivity rate with penicillin is much lower, having no significantly increased risk of reactivity over the first generation. •Pain after IM injection: •with cephalothin.
- 32. Common Cephalosporins Side Effects… •Hypoprothrombinemia: May happen with Cefperazone, Ceftriaxone and other cephalosporins with N-methylthiotetrazole side-chain, which blocks the enzyme vitamin K epoxide reductase. •Disulfiram like reaction: With cefoperazone, causes alcohol intolerance and hangover. •Diarrhea: with ceftriaxone and cefoperazone are mainly excreted from bile leading to high biliary concentrations of the active drug, increasing the risk of diarrhoea which may be caused by selection of cytotoxin- producing strains of Clostridium difficile. Nephrotoxicity (cephaloridine, cephalothin).
- 33. •Nephrotoxicity: cephaloridine, cephalothin cause toxicity both alone and in combination with aminoglycosides. Ceftazidime is nephrotoxic in patient with preexisting renal impairment (require dose adjustment). •Hepatotoxicity: Parentral Cephalosporins are usually associated with transient minor elevations in ALT, AST & ALP but with no development of liver injury. Cefazolin has been connected to cholestatic jaundice, even though it is idiosyncratic and rare. Common Cephalosporins Side Effects…
- 34. 1st generation oral Cephalosporins should be taken with food while other generations are taken without regard of food. Use it for the complete course and take the doses in time. Patients with phenylketonuria should consult the physician before using it. Warn patients about using antidiarrheal drugs (ex: Diphenoxylate Atropine). Breastfeeding women should consult the physician as cephalosporins pass into the milk. Alcohol should be prevent during and few days after using it. For Diabetic patients it may cause false sugar levels in urine test. Check immediately with the doctor in cases of (Skin reddening & blistering, Diarrhea & sever abdominal cramps, Unusual bleeding & bruises, Yellowing of eyes & skin). Counseling tips…
- 35. In case of diarrhea the patient shouldn’t reside to using Antidiarrheal drugs (as Diphenoxylate Atropine) as it may worsen the case. Oral Contraceptives may fail (other methods should be recommended). Increased risk of bleeding with Warfarin. Increased nephrotoxicity risk with Aminoglycosides, specially Cephalothin. Hangover effect upon Ethanol consumption. My cause slight increase in Phenytoin and Warfarin levels. Antacids and H2 antagonists decrease their absorption. Interactions…
- 37. References…
Editor's Notes
- Duricef: Capsules: 500 mg Tablets: 1 g Oral suspension: 125 mg, 250 mg, & 500 mg per 5 ml
- Ceclor: Capsules :250 mg and 500 mg Extended Release Tablets: 375 mg and 500 mg (Ceclor CD®) Administer with food – as it may cause GI disturbances. Powder for Oral Suspension: 125 mg, 187 mg, 250 mg, and 375 mg per 5 ml. Suspension should be refrigerated after reconstitution. Discard after 14 days.
- The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci.
- Powder for Injection: most commonly 1g and 2g doses. Injection: 1 g and 2 g in 50 ml (premixed, fozen).
- Ceftriazone: Powder for injection: 250 mg and 500 mg in vials, 1g and 2g. Injection: 1 g and 2 g in 50 ml plastic containers (premixed, frozen). Cefperazone: Powder for injection: 1 g and 2 g in vials and piggyback units. Injection: 1 or 2 g in 50 ml (premixed, frozen). Contains 1.5 mEq sodium/gm.
- Ceftazidime: Powder for Injection: 500 mg, 1 g, 2 g in vials. Injection: 1g or 2 g in 50 ml (premixed, frozen). Cefdinir: Capsules: 300 mg (Omnicef®) Powder for Oral Suspension 125mg per 5mL.
- chancroids Veneral ulcers by Haemophilus duceryi Ceftadizime+aminoglycosides : treatment of choice for pseudomonal meningitis. Cefixime: Not effective against Staph. aureus and Pseudomonas Cefpodoxime: Not effective against Pseudomonas
- chancroids Veneral ulcers by Haemophilus duceryi
- UTI - urinary tract infection RTI - respiratory tract infection Empiric therapy: therapy based on experience and, more specifically, therapy begun on the basis of a clinical educated guess in the absence of complete or perfect information. Febrile neutropenia - development of fever, often with other signs of infection, in a patient with neutropenia.
- “ The CLSI designates ceftaroline as a member of a new subclass of antimicrobials, cephalosporins with anti-methicillin-resistant Staphylococcus aureus(MRSA) activity. Ceftaroline has also been described in the literature as a ‘fifth-generation’ cephalosporin; however, such classification suggests a broader Gram-negative profile whereas ceftaroline's spectrum of activity is truly unique for its expanded Gram-positive activity beyond all other presently available cephalosporins (i.e. MRSA).” Ceftaroline fosamil: a new broad-spectrum cephalosporin - By: Joseph B. Laudano http://jac.oxfordjournals.org/content/66/suppl_3/iii11.full
- Cephalosporins generally cause few side effects (less than 1% of the patients)
- So, in the absence of suitable alternatives, oral cefixime or cefuroxime and injectable cefotaxime, ceftazidine, and ceftriaxone can be used with caution, but the use of cefaclor, cefadrocil, cefalexin, and cefradine should be avoided.
- Disulfiram like reaction – inhibiting alcohol dehydrogenase causing hangover upon alcohol consumption.
- DIPHENOXYLATE ATROPINE = lamotil For Breastfeeding women: Most antibiotics can produce excessively loose motions in the baby, with the appearance of diarrhoea. Some infants appear more unsettled with tummy aches or colic. These effects are not clinically significant and do not require treatment. The value of continued breastfeeding outweighs the temporary inconvenience. Cephalosporins are generally safe & no problems in lactating infants have been reported yet discussing its use while breastfeeding with physician is important.
- DIPHENOXYLATE ATROPINE = lamotil => anticholinergic (stops diarrhea but doesn’t solve the clostridium difficile problem).
- AST/ALT levels – increase with ceftazidime (3rd g) & Cefipime (4th g) With Cefipime > 10% reported positive direct Coombs test without hemolysis