USMLE1 -AntiBacterial- Cephalosporins

Cephalosporins:

Mechanism Of Action and Resistance:

• Bind to Penicillin Binding Proteins on cytoplasmic membrane.
• Are Bactericidal and require the intact Beta Lactam ring structure for activity.
• Resistance occurs mainly via production of Beta –lactamases, but changed PBPs and changes in porin structure may also be involved.

Cephalosporins are classified into 4 generations:
First generation:
• Acts as Pc G substitutes
• activity includes Gram positive cocci(not MRSA), E.coli, Klebsiella pneumoniae and some proteus species .
• Common use in Surgical prophylaxis
• Does not enter CNS
Drug list:
• Cefazolin is the DOC for surgical prophylaxis, good penetration into bones.
• Cephalexin
• Cephradineis the DOC oral preparation (Gram +ve + E.coli, Klebsiella pneumoniae)
Second Generation are effective against:
• Gram-negative organisms (Haemophilus, Enterobacter aerogenes, Neisserialus)
• Gram positive (less effective than 1st gen) including
• some Anaerobes.
Drug list:
Cefotetan
Cefaclor
Cefoxitin
Cefuroxime
Cefamandole
Cefmetazole
Cefonicid
Third Generation: Wider spectrum that includes Gram positive cocci and Gram negative cocci, plus many Gram negative rods.
Most of the drugs have effect on CNS.
3rd generation Cephalosporins are important in empiric management of Meningitis and Sepsis. Drugs includes:
Ceftriaxone
Cefotaxime
Ceftizoxime
Cefixime
Cefoperazone
Indications:

• Ceftriaxone(IM) or Cefixime (PO) used in single dose for Gonorrhea (DOC)
• Ceftriaxone and Cefotaxime-active against most bacteria causing Meningitis.
• Ceftizoxime is active against B.fragilis.
• Fluroquinolone--->Ofloxacin or ciprofloxacin is the treatment of choice for gonorrhea in Pc/Cephalosporin -allergic patients (or) If allergic to Pc (H/O anaphylaxis) or cephalosporin then chlorampehnicol.

Fourth generation:
Even wider spectrum, Resistant to most Beta-lactamases
Drug list:
• Cefepime --only IV
• Cefepime combines the Gram +ve, Gram –ve activities.
Organisms NOT covered by Cephalosporins are:
• Listeria monocytogenes
• Atypicals(Chlamydia,Mycoplasma)
• MRSA(Methicillin Resistant Staphylococcus aureus)
• Enterococci.
Bidisposition of Cephalosporins is through renal clearance with active tubular secretion, Hence dose modification are required in patients with renal dysfunction.
Note: Cefoperazone and Ceftriaxone are largely eliminated in the bile.
Adverse effects:
Hypersensitivity reactions (2% incidence):
• Rashes and drug fever most common.
• Positive coombs test, but rarely haemolysis
• Cefotetan,Cefoperazone,Cefamandole, cause hypoprothrombinemia (anti-vitamin K effect) cause bleeding
• I.V injections-Phlebitis (inflammation of a vein)
• I.M injections-Pain.
Note: Most authorities recommend avoiding cephalosporins in patients allergic to penicillins.
Clinical uses:
• Alternative to penicillins
• Respiratory,urinary and soft tissues injuries
• Staphylococcal infections
• surgical prophylaxis –cefazolin –long half life
• Meningitis-Cefotaxime/Ceftriaxone is DOC/ or I.V PcG
• Gonorrhea: Ceftriaxone(250 mg IM) and Cefixime (400 mg single dose PO) used in single dose .
• Typhoid fever : Ceftriaxone (azythromycin, fluroquinolone..also DOC)
• Acute epiglottitis
Recall: if meningitis caused by Listeria DOC is ampicillin and st. pneumoniae DoC is Pc G
some other Inhibitors of cell wall synthesis include:
• Carbapenams
• Vancomycin
• Monobactam
• Fosfomycin
Carbapenams: include Imipenam , Meropenam , Ertapenem
Mode of Action:
Imipenam,meropenam and ertapenem are carbapenams that are bactericidal and bind to PBPs with the same mechanism of action as penicillins and cephalosporins.However, they are resistant to Beta-Lactamases.
Carbepenams are broad spectrum antibiotics include
• Gram positive cocci
• Gram negative rods(Enterobacter,Pseudomonas species)
• Anaerobes (nocardia and actinomyces)
Mostly used in severe life threatening infections
These group of drugs are administered I.V only and the drugs undergo renal elimination hence drug adjustment is needed in patients with renal dysfunction.
Imipenam is given with Cilastatin (Imipenam +Cilastatin),which inhibits its rapid metabolism by renal dihydropeptidases
Adverse Effects:
Carbapenams:
• GI distress…..nausea, vomiting, diarrhea
• Drug fever(partial cross-allergenicity with penicillins)
• CNS effects,including seizures
• Renal dysfunction.
• Eosinophilia, Neutropenia, Neurotoxicity
Voncomycin:
Mode of Action:
Bactericidal drug that acts at an early stage in cell wall synthesis
Use and Excretion:
One of the DOC in antibiotic associated colitis due to clostridium difficile or staphylococci antibiotic associated colitis/pseudomembranous colitis--ampicillin, Tc, clindamicin, cephalosporin
RX: •Vancomycin…may be 1st choice but it is reserve drug.
•Metronidazole…1st choice)
enters most tissues (eg;bone) but not CNS.
Eliminated by renal filtration(important to decrease dose in Renal dysfunction)
Has a long half life
Adverse Effects:
• Ototoxicity (usually permanent)
• Hypotension/Shock (due to histamine release)
• diffuse hyperemia(“Red man syndrome”/Red neck syndrome) due to histamine release if given too rapidly IV
• nephrotoxicity
• hypersensitivity reactions
Monobactam:Aztreonam:
Mode of Action: Monobactam inhibits of early step in cell wall synthesis.
• It inhibits enterobacteriacea and gram –ve rods, e.g Pseudomonas
• Has no activity against gram +ve and anaerobes.
Use:
• I.V drug mainly used in Hospital acquired infections.
• No cross allergenicity with penicillins or cephalosporins
Fosfomycin:
• Inhibits initial steps in the bacterial wall synthesis
• Active against both gram +ve and gram –ve
• Orally used for UTI
• Safe in pregnancy