unit 10.3: beta-lactam - cephalosporins

Cephalosporin

* Derivatives of **7-aminocephalosporanic acid**
* With **2 sites** **of attachment** for various R1 and R2 groups
* More stable to many bacterial β–lactamases, has broader spectrum of activity

Giuseppe Brotzu

* Isolated Cephalosporin C compound in from the fungus **Acremonium**, previously known as "**Cephalosporium**” in 1945.
* Found in the sea near a sewage outfall in Su Siccu, by Cagliari harbour in Sardinia, Italy

R group at **7-position**

alters antibacterial activity

R group at **3-position**

modifies pharmacokinetic profile

* whether they can traverse the blood-brain barrier or not
* hydrophobic or hydrophilic
* biliary or urinary

* **Cephalexin**
* Cefazolin
* Cefadroxil
* Cephalotin
* Cephradine
* Cephapirin

First generation

* **Cefuroxime**
* Cefoxitin
* Cefotetan
* Cefamandole

Second generation

* **Ceftriaxone**
* **Cefotaxime**
* **Cefoperazone**
* **Ceftazidime**
* Cefixime

Third generation

Cefepime

Fourth generation

* Ceftaroline
* Ceftolozane

Fifth generation

Bind to PBPs

### Mechanism of Action

inhibit cell wall synthesis, similar to penicillins

Structural differences

### Mechanism of Action

___ render them less susceptible to penicillinases produced by staphylococci

MRSA

### Mechanism of Action

resistant to cephalosporins

Most are **parenteral**

### Pharmacokinetics

administered or occurring elsewhere in the body than the mouth and alimentary canal.

renal excretion

### Pharmacokinetics

Major elimination

hepatic metabolism

### Pharmacokinetics

some with **side chains**

Cefoperazone and ceftriaxone

### Pharmacokinetics

excreted in the **bile**

1st- and 2nd-generation

### Pharmacokinetics

Do not enter the CSF when the meninges are inflamed1st- and 2nd-generation

**1st Gen:** Cefazolin and cephalexin

### Clinical Use

* against G+ cocci, *E coli, K pneumoniae*
* Surgical prophylaxis
* Minimal activity *(Gram (-) cocci, Enterococci. MRSA, Most gram (-) rods)*

Second Generation

### Clinical Use

* Less activity against gram (+)
* Extended coverage for gram (-)
* Marked differences in activity occur among the drug

Cefotetan, Cefoxitin

### Clinical Use: *2nd Gen*

* Anaerobic coverage
* B. fragilis

Cefamandole, cefuroxime, cefaclor

### Clinical Use: *2nd Gen*

H influenzae, M catarrhalis

Ceftazidime, cefoperazone, cefotaxime

* penetrates BBB except cefoperazone, cefotaxime

### Clinical Use: *3rd Gen*

* Increased activity against **gram (-)** organisms resistant to other beta-lactam drugs
* Ability to **penetrate the blood-brain barrier**

Ceftriaxone

### Clinical Use: *3rd Gen*

* **gonococcal urethritis** - purulent discharge
* Single injection for acute otitis media
* As effective as 10 days of amoxicillin

Ceftriaxone (IV) and cefixime

### Clinical Use: *3rd Gen*

Drug of choice for **gonorrhea**

Cefepime

### Clinical Use: *4th Gen*

* more resistant to beta lactamases
* combines gram positive activity / coverage of 1st gen with wider gram neg

Ceftaroline

### Clinical Use: *4th Gen*

* active against MRSA that is resistant to Cephalosporins

rashes to **anaphylactic shock**

### Toxicity

* Allergy
* Complete **cross reactivity** should be assumed
* less frequently than penicillins

5-10%

### Toxicity: *Allergy*

* **Partial cross reactivity** between penicillin and cephalosporin

* Pain at **IM injection site**
* **Phlebitis** after IV injection
* Increase **nephrotoxicity** of aminoglycosides

### Toxicity:

Other adverse effects

Cefamandole, cefoperazone, cefotetan

### Toxicity: *Other adverse effects*

* Drugs containing a **methylthiotetrazole** group
* May cause **hypoprothrombinemia**
* Disulfiram-like reactions with ethanol

* Listeria
* Atypicals
* Methicillin-resistant staphylococcus aureus (MRSA)- except Ceftaroline
* Enterococcus

Cephalosporins are “**LAME**” because they are inactive against

Cephalexin

### First Generation:

* effective against **pharyngitis** (above umbilicus infections) which (back then) were mostly gram-positive
* cell wall will be **thicker for gram-positive**
* gram-negative are resistant with beta lactams

Cefazolin

### First Generation:

* parenteral route (IV)
* longer duration of action, but similar spectrum

Cefuroxime

### Second Generation:

* given parenterally
* longer half life
* it can cross blood brain barrier
* used for **community-acquired bronchitis & pneumonia**

Cefuroxime axetil

### **Second** Generation:

* twice daily
* quite resistant even against to beta-lactamase-producing organism

Ceftriaxone

### **Third** Generation:

* effective against **genital, anal and pharyngeal penicillin-resistant neisseria gonorrhoeae**
* excreted through the **bile**

Ceftazidine

### **Third** Generation:

* anti-pseudomonal coverage
* **Pseudomonas** are hospital-acquired germ with numerous resistance

Cefotaxime

### **Third** Generation:

* good choice for infections (bacterial encephalitis & bacterial meningitis)

Cefepime

### **Fourth** Generation:

* anti-pseudomonal property

**interstitial nephritis and tubular necrosis**

* if combined with **aminoglycoside** (protein synthesis inhibitor
* cephalosporin don’t go along well w/ aminoglycoside

### Adverse Reactions of Cephalosporins

Renal

Hypoprothrombinemia and bleeding disorders

### Adverse Reactions of Cephalosporins

Hematologic