Cephalosporin Facts

Property—

o     It is a β-Lactum antibiotic

o     It is bactericidal

o     It inhibits the cell wall synthesis

o     It is relatively stable to β-lactamase

o     It is relatively non-toxic drug

History—we can get it from fungal mold, Cephalosporium acromonium.

Chemistry—it is structurally related to the Penicillin nucleus named 7-Amino-cephalosporanic acid

Cephalosporin consists of—

1.   Dihydrothiazine ring (6 membered sulphur containing ring)

2.   β-Lactum ring (4 membered nitrogen containing ring)

3.   Side chain, R₁ which is attached with the 7 position of the β-Lactum ring, R₂ is attached with the 3 position of the dihydrothiazine ring.

o     β-Lactum ring is responsible for the antimicrobial activity

o     R₁ is responsible for degree of antimicrobial activity

o     R₂ is responsible for pharmacokinetic activity

o     Β-Lactum ring can be cleaved by β-lactamase (cephalosporinase)

Pharmacokinetics—

o     Most of the Cephalosporin are given parenterally

o     Some of them are acid stable and are well absorbed from the GIT and can be given orally. Such as, Cephalexin, Cephradine, Cefixime. These drugs are widely distributes in the tissue body fluids.

o     Serum protein binding and half life vary from agent to agent

o     Cephalosporin cannot cross the BBB except the 3^rd generation (given in meningitis)

o     Most of the drugs are excreted through the urine, mainly by tubular secretion. So, Probenecid can block the secretion

o     Some drugs are excreted via bile. Such as Ceftriaxone, Cefoperazone. These drugs can be given in renal failure.

Classification—

It is classified as generations (1^st, 2^nd, 3^rd, 4^th) depending mainly upon—

a.      Anti-microbial activity

b.      β-Lactum activity (relatively stable than Penicillin)

c.       Potency

General criteria of generation—

a.      All are active against gm –ve aerobic bacilli and activity increases from 1^st to 3^rd generation.

b.      Antistaphylococcal activity (gm +ve activity) decreases from 1^st to 3^rd generation.

c.       There is no antistreptococcal activity.

d.     They have no activityagainst enterococci and Listeria monocytogenes. (Penicillin is active against them)

e.      3^rd generation can cross BBB.

1^st generation—

Criteria—

more gm +ve activity

less gm –ve activity

Example—

Cephalexin	Cefazolin
Cephradine	Cephalothin
Cefadroxil	Cephapirin

2^nd generation—

Criteria—

it has more gm –ve activity than the 1^st generation.

Example—

With Haemophilus activity—	Cefaclor Cefonicid Cefamandole	Cefprozil Cefuroxime
With Bacillus fragilis activity—	Cefmetazole Cefoletam Cefoxitin

3^rd generation—

Criteria—

it has extended gm –ve activity

gm +ve activity is less than 1^st generation

it can cross the BBB

achieved in higher concentration in CSF

Examples—

Cefotaxime Ceftriaxone

Ceftizoxime Cefoperazone

With pseudomonus activity—

Ceftazidime

Cefixime

4^th generation—

Criteria—

usually between 3^rd and 4^th generation there is no difference

Example—

Cefixime

Cefpodoxime

Clinical uses and anti-microbial spectrum—

First generation

It is given against—

Staphylococcus

Streptococcus

Proteus mirabilis

Klebsiella pneumoniae

Clinical uses—

a.   Drug of choice in surgical prophylaxis

b.  Skin and soft tissue infection

c.   As an alternative to Penicillin in non-IgE mediated allergic patient. (it may be IgE & IgG mediated)

Second generation

It is given against—

Staphylococcus

Streptococcus

Proteus mirabilis

Klebsiella pneumoniae

Haemophillus influenzae

Bacteroid fragilis

Clinical uses—

a.   It can be given with these disease with Haemophillus influenzae—

o     Community acquired respiratory tract infection.

o     Also useful in variety of infections except meningitis in children.

b.  It can be given with these disease with Bacteroid fragilis—

o     Mixed aerobic + anaerobic infections such as Peritonitis, Diverticulitis, Pelvic infection.

Third generation

It is given against—

It has extended gram negative activity, particularly against enterobactericeae and H. influenzae.

Bactericidal against enterobactericeae

It has reduced gm +ve activity.

Stable to Neisseria gonorrhoeae.

Few have activity against Pseudomonus

Pre major pathogens of meningitis such as Streptococcus pneumoneaea, Neisseria meningitis, Haemophillus influenzae.

Clinical uses—

a.      Treatment of bacterial meningitis

b.      Severe infection like sepsis

c.       Nosocomial pneumonia, specially when Aminoglycosides cannot be given

d.     Given in Gonorrhoea (Ceftriaxone, Cefixime)

e.      Salmonella infection (Ceftriaxone, Cephtazin)

f.        Given in infection caused by Pseudomonus (Ceftazidime)

g.      In sepsis of unknown origin in both immuno-compromised and immuno-competent patients as a n empirical therapy.

Adverse effects—

~ relatively non toxic

~ cross sensitive with Penicillin is only 10%

~ not given in patients with IgE mediated allergy such as anaphylactic shock

A. Local adverse effects—it occurs when the Cephalosporin is given IV or IM routes. There may be Induration or Thrombophlebitis.

B. Allergic reactions—

Skin rash	Anaphylaxis
Nephritis	Urticaria
Fever	Eosinophilia

C. Bleeding disorders— It usually occurs in Cefoperazone and Cefamandole due to vit-K activity.

D. Disulfiram like effect— It usually occurs in Cefoperazone and Cefamandole. These drugs blocks the oxidative pathway of alcohol and there is accumulation of acetaldehyde.

E. Superinfections—some of the drugs of 2^nd generation and mainly 3^rd generation are responsible for supreinfection

F. Cholelithiasis.

Contraindication—renal failure and hypersensitivity reactions.

1.1)            Cephalosporin:

(a)    1^st generation

(i)     Cephradine

(ii)   Cephalexin

(iii) Cefadroxil

(iv)   Cephazolin

(v)     Cephalothin

(b)   2^nd generation

(i)                 Cefaclor

(ii)               Cefuroxime

(iii)             Loracarvef

(i)                 Cefproxil

(ii)               Cefamandol

(c)    3^rd generation

(i)           Ceftriaxone

(ii)         Cefixime

(iii)       Cefodoxine

(iv)       Cefotaxine

(v)         Cefdinir

(d)   4^th generation

(i)              Flomoxef

(ii)            Cefpirome

(iii)          Cefepime

(e)    5^th generation

(i)     Ceftobiprole (on the US FDA fast-track)

(f)    Yet to be classified

(i)              Cefaloram

(ii)            Cefetrizole

(iii)          Ceftioxide