CEPHALOSPORINS

CEPHALOSPORINS
 CEPHALOSPORINS
- Cephalosporins are b-lactam
antibiotics that differ from the
penicillins in that the B ring is a 6-
membered dihydrothiazine ring.
Variations among the
cephalosporins are made on either
the acyl side chain at the 7-
position to change antibacterial
activity or at the 3-position to alter
the pharmacokinetic profile.
Cephalosporin C was first isolated
in 1948 by Dr. Abraham from a
fungus, Cephalosporium
acremonium, collected in
seawater near a sewage outlet in
Sardinia by Professor Guiseppe
Brotzu in 1945.

-
- They have a beta-lactam ring which
interferes with bacterial cell wall synthesis
by binding to penicillin binding proteins,
eventually leading to cell lysis and death.
Like amoxicillin clavulanate, cephalosporins
should be avoided when a narrower
spectrum antibiotic would be effective
because they increase the risk of
Clostridium difficile, MRSA and other
resistant infections.
 General structure of
the Cephalosporins

-Similar mechanism of action to penicillins.

-Bind to penicillin binding proteins (transpeptidases, endopeptidases, and
carboxypeptidases) and
inhibit cell wall biosynthesis in both Gm + and Gm bacteria.
-However, degree and extent of binding to different PBPs may be different
for the cephalosporins than for penicillins. For example, cephalothin
causes lysis of Staph. aureus, whereas cephalexin produces long
filamentous forms in E. coli.
-In general, cephalosporins are less susceptible to b-lactamases
compared to penicillins.
MECHANISM OF ACTION

Cephalosporins inhibit bacterial cell wall synthesis in a

manner similar to that of penicillin.

Resistance: inability of the antibiotic to reach its site of

action or to alterations in the PBP's (targets of
cephalosporins such that antibiotics bind to bacterial
enzymes( B-lactamases) that can hydrolyzed the B-lactam
ring and inactive the cephalosporin.

Alteration in two PBP's (1A and 2X)

-decrease their affinity for cephalosporins render
pneumococci resistant to third-genaration cephalosporins
because the other three high-molecular-weight PBP's have
inherently low affinity.
Cephalosporin Generations

FIRST-GENARATION CEPHALOSPORINS
This include:

cefazolin, cefadroxil, cephalexin, cephalotin,

cephapirin, and cephradine
They have good activity against a wide spectrum of
Gram-positive bacteria including penicillinase-
producing staphylococci.
-MRSA
FIRST-GENARATION CEPHALOSPORINS
A. Oral

P-Cephalexin, cephradine, cefazolin and cefadroxil

oral in dosages: of 0.25-0.5g four times daily ( 15-30mg/kg/d)
Excretion: (mainly) glomerular filtration ; urine.

-Cephalexin(oral) it has the same antibacterial spectrum as the other first

generation cephalosporin.
-Cephradine cephalexin (oral/IM/IV)
-Cefadroxil para-hydroxy analog of cephalexin.
-in plasma and urine are at somewhat higher levels than are those
cephalexin.
-the drug maybe administered orally once or twice a day for the treatment
of urinary tract infection.
CLINICAL USE:

- Upper respiratory tract infections due to Staph. and Strep.

-Lower respiratory tract infections due to susceptible bacteria
e.g. Strep.
pneumoniae in penicillin-allergic patient (previous rash)
-Uncomplicated urinary tract infections (Cephalexin)
- Surgical prophylaxis for orthopedic and cardiovascular
operations
(cefazolin preferred because of longer half-life)
- Staphylococcal infections of skin and skin structure
 Mechanism of Action
- Like all beta-lactam antibiotics, cefadroxil, cepalexin,
and cepharine binds to specific penicillin-binding
proteins (PBPs) located inside the bacterial cell wall,
causing the inhibition of the third and last stage of
bacterial cell wall synthesis. Cell lysis is then mediated
by bacterial cell wall autolytic enzymes such as
autolysins; it is possible that cefadroxil, cepalexin,and
cepharine interferes with an autolysin inhibiton

Adverse reaction
Nausea, vomiting, diarrhoea, allergic rashes may occur
 Parenteral
P-Cefazolin
-Is the only first generation parenteral cephalosporin still in general
use.
-usually preferred among the first generation ceph,
-administered less frequently owing to its longer t1/2.
-maybe also a choice in infections for w/c it is the least toxic drug and
in individuals with Stap. or strep. infections who have a history of
penicillin allergy other than immediate hypertensive.
-usual IV dosage: 0.5-2g every 8 hrs.
-excretion: glomerular filtration; plasma proteins (85%).

MOA: inhibits the 3rd and final stage of bacterial cell wall synthesis by
preferentially binding to specific PBPs.
-ability to interfere with PBP-mediated cell wall synthesis
cell lysis.
bacterial cell wall autolytic enzymes (i.e., autolysins).
ADVERSE REACTIONS:
interstitial nephritis, serum sickness ,hemolytic anemia
seizures, anaphylactic shock ,anaphylactoid reactions,
azotemia , renal failure (unspecified), toxic epidermal
necrolysis , angioedema , erythema multiforme

CONTRAINDICATIONS :
-HPLC techniques
-theophylline

PHARMACOKINETIC & DOSAGE:

-Cefonicid (1x) & Cefotetan (2x) half-lives

-cost savings
-highly protein bound - lower free levels, lower CSF
levels.
SECOND-GENERATION CEPHALOSPORINS
This include:
P-cefaclor, cefamendol, cefonocid, cefprozil, loracarbef,
cefuroxime and ceforande.
-more stable to hydrolysis by beta-lactamases produced by
Gram (-) bacteria
-enhanced activity against many of the
Enterobacteriaceae, e.g. Escherichia coli, Salmonella.
-have extended gram-negative coverage.
-Must reduce dose or give less often or both in renal failure,
except for cefpodoxime.
SECOND-GENERATION CEPHALOSPORINS

A. Oral
adults: 10-15mg/kg/d (2 - 4 divided doses)
children: 20-40mg/kg/d up to a maximum of 1g/d.
-Cefaclor is more susceptible to B-lactamase hydrolysis
compared with other agents

B.Parenteral
-after a 1g iv infusion, serum levels (75-125 mcg/ml)
-IM (painful)
 SECOND-GENERATION CEPHALOSPORINS
Clinical Uses:

-Cefoxitin, cefotetan
peritinosis, diverticulitis, and pelvic inflammatory disease.
-Cefuroxime
treat community-acquired pneumonia because of its
active against B-lactamase producing H-influenza and some
penicillin-non-susceptible pneumococci.
-Cefuroxime widely used for empiric therapy
-Has activity vs. many ampicillin-resistant H. influenzae
strains.
-Community-acquired pneumonia
CLINICAL USE
-Skin and soft tissue infection
-Urinary tract infections
- Upper respiratory tract infections (otitis media,
sinusitis). Some resistance to H. influenzae to cefaclor
(20-30%).
- Surgical prophylaxis - Cefoxitin or cefotetan are widely
used in cases where mixed aerobic & anaerobic
infections may occur, esp. intra-abdominal, colorectal,
and gynecologic operations.
- Cefuroxime; cefazolin
For cardiovascular and orthopedic procedures
cheaper and appears to work well.
 Mode of action:
-As with other cephalosporins, the bactericidal action
of this drugs result from inhibition of cell-wall synthesis.

Adverse Reactions:
-serum-sickness-like- reactions; hypersensitivity
-2nd (subsequent) course of therapy with Cefaclor.
 Contraindications
2nd generation cephalosporins is contraindicated in patients with known allergy to the
cephalosporin group of antibiotics.

Drug Interactions:
Patients receiving Cefaclor may show a false-positive reaction for glucose in the urine with tests
that use Benedict's and Fehling's solutions and also with Clinitest tablets.
Adverse Reactions:
CNS
Rarely, reversible hyperactivity, agitation, nervousness, insomnia, confusion, hypertonia, dizziness,
hallucinations, and somnolence have been reported.
Contraindications
2nd generation cephalosporins is contraindicated in patients with known allergy to the
cephalosporin group of antibiotics.
Drug Interactions:
Patients receiving Cefaclor may show a false-positive reaction for glucose in the urine with tests
that use Benedict's and Fehling's solutions and also with Clinitest tablets.
THIRD-GENERATION-CEPHALOSPORINS

P-Cefoperazone, cefotaxime, ceftazidime,

ceftizoxime,ceftriaxone,cefixime

- widest spectrum of activity compared to

other generations of cephalosporins
- active against Gram (-) organisms
-Enterobacteriaceae.
-very active against streptococci.
THIRD-GENERATION-CEPHALOSPORINS

Pharmakokinetics & Doasge:

-IV infusion: 1g of a parenteral cephalosporin
produces serum level of 60-140mcg/ml.
Third-generation cephalosporins penetrate body
fluids and tissues well.
-excretion: of cefoperazone and ceftriaxone
- billiary tract,
-kidney
(required dosage adjustment
in renal insufficiency)
 CLINICAL USES
-Third gen. cephalosporins shoud avoided in the treatment of
enterobacter infection-even if the clinical isolate appears
susceptible in vitro-because of emergence of resistance.
-Ceftriaxone and cefotaxime
-approved for treatment for meningitis, including
meningitis caused by pneumococci, H-influenza, but not by L.
monocytogenes.
-The most most active cephalosporins
-penicillin non-susceptible strains of pneumococci
-empirical therapy of serious infection that may caused by
these strains.
-Ceftazidine
-neurogenic, febrile immunocompromised patients,
+ceftazidine is often used in combination with other antibiotics.
FOURTH-GENERATION CEPHALOSPORINS
This include:
P-Cefepime and cefpirome

-Cefepime
-stable to hydrolysis by many of the previously
identified plasmid-encoded B-lactamases
-(TEM-1, TEM2 and SHV-1)
-It is a poor inducer/resistant type I
chromosomally encoded, extended-spectrum B-
lactamases.
-Thus, it is active against many Enterobacteriaceae
that are resistant to other cephalosporins via
induction of type I B-lactamases but remains
susceptible to many bacteria expressing extended-
spectrum plasmid-mediated B-lactames (such as
KPC , TEM3, and TEM10).

ADVERSE REACTION:
-The reaction (same with penicillins)

-Immediate reaction such as anaphylaxis,

bronchospasm, and urticaria are observed

-More commonly, maculopapular rash develops,

usually after several days of therapy.
A. HYPERSENSITIVITY REACTIONS (1-7%)
1. anaphylaxis (rare)
2. rash (maculopapular, urticarial) (1-3%)
3. serum sickness-like reaction, eosinophilia, + Coombs test -
esp. with cefaclor
4. Some cross-sensitivity with penicillins (5-10%), perhaps as
low as 1%.
B. PHLEBITIS, PAIN ON IM INJECTION
cephalothin ,cephapirin,Cefotaxime
C. HYPOPROTHOMBINEMIA - associated with methylthiotetrazole ring
cefoperazone, cefamandole, cefotetan, & moxolactam
Occurs in 20-60% of patients.
Give Vitamin K (menadione) as preventative. Less bleeding
problems with cefotetan.
Other cephs. may also cause bleeding due to reduction of gut
flora.
D. GI complaints (5-10%)
F. Disulfiram-like reaction.
Flushing, sweating, headache, tachycardia associated with
alcohol ingestion.
Associated with methylthiotetrazole
(cefoperazone, cefamandole, cefotetan)

G. Cholecystitis-like syndrome with Ceftriaxone (~20% with

chronic dosing).
Precipitation of ceftriaxone in bile biliary sludge.
May require surgery. Rarely with cefoperazone.

H. Displacement of bilirubin from albumin binding sites -

theoretical problem in neonates.
ceftriaxone & cefoperazone.