Cephalosporins

Cephalosporins(Spectrum, uses, side effects, and common trade names

in Egyptian market)By: Marina Adel

Ibrahim

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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.

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.

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.

Classification…Generation Parenteral Agents Oral Agents

1st generation Cefazolin, Cephalothin Cefadroxil, cephalexin,cephradine

2nd generation Cefotetan, cefoxitin, cefuroxime

Cefaclor, cefprozil, cefuroxime axetil

3rd generationCefotaxime, ceftazidime, ceftizoxime, ceftriaxone, Cefoperazone

Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime

4th generation Cefepime, cefpirome

5th generation Ceftaroline, Ceftobiprole

1st

Generation – Common Trade Names

Cefazoline(Parentral)

Cefadroxil(Oral)

1st

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.

1st

Generation – Antimicrobial Spectrum

1st

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

2nd


Cefuroxime axetil(Oral)

Cefaclor(Oral)

2nd


•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 poorprotein binding.•More stable to β-lactamase degradation than 1st generation.•Their IM injections are painful and hence preferably givenadministered by IV route.•These are excreted unchanged through kidney.•Probenecid increases plasma half life.

2nd


2nd

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.

3rd


Cefotaxime(Parentral)

3rd

Generation – Common Trade NamesCeftriaxone

(Parentral)Cefoperazone

(Parentral)

3rd

Generation – Common Trade NamesCeftazidime

(Parentral)Cefdinir

(Oral)

3rd

Generation – Common Trade NamesCefditren

(Oral)Cefixime

(Oral)

3rd


• Cefoperazone and ceftriaxone are excreted through bile, sono 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.

3rd


Spirochetes: Borrelia burgorferi

3rd

Generation – Uses:Meningitis •Ceftriaxone, Cefotaxime, Cefoperazone

Gonorrhoae •Ceftriaxone, Cefotaxime, Cefoperazone

Chancroid. •Ceftriaxone, Cefotaxime

Community acquired pneumonia •Ceftriaxone, Cefotaxime

Lyme disease •Ceftriaxone

Complicated UTI. •Ceftriaxone, Cefixime, Cefpodoxime

Abdominal sepsis. •Ceftriaxone

septicemia •Ceftriaxone, Cefoperazone

Multi drug resistant typhoid fever •Ceftriaxone

Anaerobic and hospital acquired infections •Cefotaxime

Nosocomial Infections •Ceftazidime

Pseudomonal Infections •Cefoperazone, Ceftazidime

In immuono-compromised •Cefoperazone

3rd

Generation – Uses: CeftriaxoneMeningitis 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).

3rd

Generation – Uses: CefotaximeMeningitis.

Gonorrhoea (single 0.5-1g IM dose).

Community acquired pneumonia.

Used in respiratory, genitourinary, abdominal infections, septicaemia, anaerobic and hospital acquired infections.

3rd

Generation – Uses: CefoperazoneMeningitis, 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.

3rd

Generation – Uses: CeftazidimeHas excellent activity against pseudomonas (better than cefoperazone).

Ceftadizime+aminoglycosides is the treatment of choice for pseudomonal meningitis.

Useful for nosocomial infections.

3rd

Generation – Uses: Ceftizoxime

More active against B. fragilis than cefotaxime.

3rd

Generation – Uses: CefiximeUsed to treat respiratory, urinary, biliary infections.

Uncomplicated gonorrhoea (single 400 mg dose).

Not effective against Staph. aureus and Pseudomonas.

3rd

Generation – Uses: Cefpodoxime

similar to cefixime but it is active against Staph. Aureus.

4th

Generation – Common Trade NamesCefepime(Parentral)

4th


*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).

4th


- Cocci and - Bacilli > + Cocci (no + Bacilli or Anaerobes)

Gram-positive bacteria

• Streptococcus pyogenes.• Viridans streptococci.• Streptococcus pneumoniae.• Modest activity against Staphylococcus aureus.

Gram-negative bacteria

• Escherichia coli.• Klebsiella pneumoniae.• Proteus spp. • Haemophilus influenzae.• Neisseria spp. • Many other Enterobacteriaceae. Pseudomonas aeroginosa.

4th

Generation – Uses

Hospital acquired

pneumonia.

Bactreamia .

Septicaemia.UTI.

RTI.

Empiric therapy in

febrile neutropeni

a.

5th

Generation – Ceftaroline

Antimicrobial Spectrum:

MSSA, streptococci, enteric GNRs, MRSA.

Less gram negative coverage than 4th generation.

No Pseudomonas activity.

Common Cephalosporins Side Effects…

Hypersenstivity Hypoprothrombinemia

Disulfiram-like Rx Diarrhea


•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.


•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).

•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.


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…

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…

Monitor…

Allergy and Anaphylaxis.

Renal Function.

AST/ALT levels.

References…•This Presentation is mainly based on:•Review of the Pharmacology, Pharmacokinetics, and Clinical Use of Cephalosporins- by: Debra Kalman, PharmD and Steven L. Barriere, PharmD.•Ceftaroline Fosamil: A Brief Clinical Review - by: Debbie-Ann T. Shirley, Emily L. Heil and J. Kristie Johnson.•Lippincott's Illustrated Reviews: Medical Microbiology 3rd Ed. JB Lippincott

Health & Medicine

Cephalosporins