Cephalosporins

The basic nucleus of the cephalosporins is
7 amino cephalosporanic acid. This is composed of a beta-lactam ring and a dihydrothiazine ring

 

Cephalosporins

Cephalosporins - Spectrum

Relative antibacterial coverage of cephalosporins by generation

 

Ceftriaxone

Chemistry

- Semi-synthetic cephalosporin
- Aminothiazolyl side chain enhances
anti-bacterial activity, primarily against Enterobacteriaceae
- Methoxyimino group imparts stability against
beta-lactamases
- Acidic enol in triazine moiety at position 3 presumably responsible for long serum half life

 

Mechanism of Action

- Inhibits bacterial cell wall synthesis
- Bactericidal
- Resistant to hydrolysis by beta-lactamases of gram negative bacilli

Antibacterial Spectrum

Staph. aureus & Staph. epidermidisStrep. pneumoniae, S. pyogenes & S. viridans Neisseria meningitidis & N. gomorrhoeae

E.coli, H.influenzae, Klebsiella pneumoniae, Enterobacter, Salmonella, Shigella, Proteus, Yersinia enterocolitica.

Some strains of Campylobacter jejuni, Pseudomonas aeruginosa, Clostridium, Treponema pallidum & Chlamydia trachomatis

Pharmacokinetics

Absorption
- Not significantly absorbed after oral administration; given parenterally
- Peak levels 1.5-4 hours after IM dose

Distribution
- Widely distributed in body tissues and fluids
- Diffuses into CSF

Elimination
- Excreted in urine, faeces and bile
- Mostly excreted unchanged; only small amount of metabolism in intestine after biliary excretion
- Half life 5.8-8.7 hours; only slightly prolonged in renal impairment. Not affected by hepatic impairment.

 

Dosage & Administration

Usual dosage
1-2 grams once daily IM or in equally divided doses twice daily

CNS infection
Higher doses, i.e., 4 grams daily may be necessary

Gonorrhoea
Single 250 mg dose IM. Higher/Multiple doses for severe/complicated infections

Dosage & Administration (contd.)

Children
Usual: 50-75 mg/kg/day (not exceeding 2 gm/day)
CNS Infections e.g., meningitis: 100 mg/kg/dayUncomplicated gonorrhoea:125 mg IM single dose
> 12 years: Adult dose

Duration
Usually 4-14 days; longer in complicated infections

Renal/Hepatic Impairment
Generally no change in dosage. In severe renal or renal+ hepatic impairment, monitor serum
concentrations, and adjust dosage if necessary

 

Adverse Effects

- Well tolerated; discontinuation because of adverse effects in < 2% patients
- Adverse effects similar to other cephalosporins
- Haematologic effects e.g., eosinophilia, thrombocytosis, leucopenia; diarrhoea; hypersensitivity reactions; hepatic and renal adverse effects; local reactions at injection site

Precautions & Contraindications

- Contraindicated in patients hypersensitive to any cephalosporin; caution if hypersensitive to penicillins
- No adverse effects in pregnancy; however, use only when clearly needed
- Displaces bilirubin from serum albumin; do not give to hyperbilirubinaemic neonates

Indications

1. Bacterial Meningitis
- Useful for neonates, children and adults- Effective against H.influenzae, N.meningitidis, Strep.pneumoniae
- As effective as combination of ampicillin + chloramphenicol
- Effective against ampicillin-resistant H.influenzae- More convenient to administer than cefotaxime

2. Asymptomatic Meningococcus Carriers
- Single 125 or 250 mg dose is effective in eliminating nasopharyngeal carriage
- 250 mg dose is as effective as rifampicin

3. Typhoid
- Single daily dose 3-4 g for adults or 75 mg/kg in children for 7 days is as effective as 14 day oral or IV chloramphenicol

4. Gonorrhoea
- Drug of choice for uncomplicated penicillinase producing Neisseria gonorrhoeae (PPNG) infection
- Single 125, 250 or 500 mg IM dose
- Disseminated infection require high dose IV therapy, 1-2 g IV 12 hourly

5. Chancroid
- Single 250 mg dose is effective

6. Spirochaetal infections
- Some activity against Treponema pallidum

7. Other infections caused by gram-negative bacteria
- Lower RTI
- Skin & skin structure
- Bone & joint
- Septicaemia
- UTI
- Intraabdominal

8. Pseudomonal infections
- To be used in conjunction with other agents e.g., aminoglycosides and fluoroquinolones

9. Perioperative Prophylaxis
- Contaminated or potentially contaminated procedures e.g., cholecystectomy, intraabdominal surgery, hysterectomy
- Clean procedures, e.g, coronary artery bypass, open heart surgery, orthopaedic surgery
- For prophylaxis, administer 0.5-2 hours prior to surgery
- Single dose of ceftriaxone is as effective as multiple doses of cefazolin

 

Salient Features

- Third generation cephalosporin; generally more effective than first & second generations for gram negative bacteria
- Long serum half-life permits once-daily dosing; convenient for out patient treatment e.g., osteomyelitis
- Administered once daily IM / IV
- Useful in a variety of situations especially for perioperative prophylaxis, gonorrhoea and bacterial meningitis
- Well tolerated
- May be administered to children and pregnant women

 

Advantages over Cefotaxime & Ceftazidime

- Once daily administration with ceftriaxone (cefotaxime given 4-6 hourly for serious infections, 8 hourly for less serious infections; ceftazidime given 8 hourly for serious infections and 12 hourly for less serious infections)
- Dosing convenience may mean more cost effectiveness
- Superior gram positive coverage to ceftazidime