Quinolones

- Non fluorinated quinolones include nalidixic acid; fluorinated quinolones (fluoquinolones) include norfloxacin, ciprofloxacin, ofloxacin, pefloxacin, sparfloxacin
- Nalidixic acid has been in use for many years, but has limited therapeutic utility (UTI, GI infections), and bacterial resistance occurs rapidly
- Fluoquinolones, e.g., norfloxacin and ciprofloxacin have broad spectrum of activity, and relatively infrequent development of resistance

 

 

Ciprofloxacin-Chemistry


- Ciprofloxacin is a fluoroquinolone with a fluorine atom at position 6 of the 4-quinolone nucleus. This enhances the antibacterial spectrum and drug potency - Piperazine group at position 7 results in anti-pseudomonal activity

 

Mechanism of Action

- Bactericidal
- Inhibits bacterial DNA gyrase, inhibiting supercoiling of DNA and interfering with bacterial replication
- Post antibiotic effect

 

Antibacterial Spectrum

- Similar to other quinolones (mainly gm -ve bacteria)
- More potent than norfloxacin

Important organisms covered
- E.coli
- Klebsiella pneumoniae
- Proteus mirabilis & vulgaris
- Salmomella typhi, paratyphi & typhimurium
- Shigella,
- Yersinia, enterocolitica
- H. influenzae
- Pseudomonas aeruginosa,
- Campylobacter jejuni
- Neosseria meningitidis & gonorrhoeae
- Serratia marcescens
- Some staphylococci& streptococci

 

Resistance

- Rare (1 in 107-109)
- Due to chrosomal mutation
- Not plasmid mediated

 

Pharmacokinetics

Absorption
- Well absorbed following oral administration
- Peak levels in 0.5-2.3 hours
- Peak serum conc. 0.76 -1.5 and 1.6 - 2.9 mg/ml after 250 and 500 mg orally respectively
- Food decreases rate but not extent of absorption

 

 

Pharmacokinetics (contd.)

Distribution
- Widely distributed in body tissues and fluids after oral/IV administration
- High concentrations in bile, lungs, kidney, gall bladder, uterus, seminal fluid, prostate, endometrium, fallopian tubes, ovaries
- Effective against intracellular organisms
- Low concentrations in CSF; increased when meninges are inflamed
- Crosses placenta and distributed in milk

 

Pharmacokinetics (contd.)

Elimination
- Serum half life 3-5 hours
- In renal failure, serum concentration is higher and half life is prolonged
- Partially metabolised in liver; metabolites have some activity, though less than the parent drug
- Excreted in urine and faeces

 

Adverse Effects

- Well tolerated
- Most frequent effects involve GI tract, CNS and skin
- Effects include nausea, vomiting, diarrhoea, abdominal pain/discomfort, headache, restlessness and skin rash

 

 

Precautions & Contraindications

- Crystalluria is a rare adverse effect. Adequate fluid intake is advised
- Caution in patients with CNS disorders / predisposition to seizures because of CNS stimulation with ciprofloxacin. Caution also in patients on theophylline and caffeine
- Reduce dosage/frequency in serious renal impairment
- Contraindicated in hypersensitivity
- Animal studies showed damage to articular cartilage; avoid in children and pregnancy

 

Drug Interactions

- Antacids containing magnesium, aluminium or calcium decrease absorption
- Probenecid decreases renal excretion
- Theophylline levels are raised

 

Dosage
250 - 750 mg 12 hourly,depending upon severity

In renal impairment

Clinical Uses

1. Urinary Tract Infections (UTI)
- Covers E.coli, Klebsiella, Proteus, Pseudomonas, Serratia, staphylococci and some streptococci
- Useful for uncomplicated or complicated infections
- Single dose therapy may be effective in uncomplicated infections
- Good concentration in prostate; useful in prostatitis

 

2. Lower Respiratory Infections
- Covers H.influenzae, Klebsiella, Proteus, Pseudomonas, M.catarrhalis, staphylococci and some streptococci
- Useful for bronchitis, bronchiectasis, lung abscess, pneumonia
- Employed for Ps. aeruginosa infections in patients with cystic fibrosis

 

3. Skin & Soft Tissue Infections
- Effective in cellulitis, abscesses and infected ulcers, burns or wounds
- Useful for hospital acquired decubitus ulcers (bed sores)

4. Bone & Joint Infections
- Especially if caused by gm -ve organisms

 

5. Gastrointestinal (GI) Infections
- Covers E.coli, Shigella, Salmonella, Aeromonas, Vibrio, Yersinia enterocolitica and Campylobacter.
- A drug of choice for infectious diarrhoea
- Poor coverage of anaerobes; does not disturb normal anaerobic bowel flora

6. Salmonella infections
- Effective in typhoid and paratyphoid, including chloramphenicol resistant cases
- Useful in typhoid carriers
- Can be used for S. typhimurium septicaemia and osteomyelitis in AIDS / immunocompromised patients

 

7. Gonorrhoea
- Effective against penicillinase producing and non penicillinase producing N. gonorrhoeae
- Single dose (500 mg) therapy adequate for uncomplicated gonorrhoea

8. Chancroid
- Covers H. ducreyi.
- 500 mg twice daily for 3 days

9. Perioperatively
- Covers Pseudomonas aeruginosa and staphylococci. Useful in preventing / treating hospital-acquired infections

10. Nosocomial Infections
- Covers Pseudomonas aeruginosa and staphylococci. Useful in preventing / treating hospital-acquired infections

10. Other uses
- Eliminates staphylococcal colonisation in seriously ill patients
- Eliminates nasopharyngeal carriage of N. meningitidis

 

Salient Features

- Broad spectrum coverage especially gm -ve bacteria
- Oral therapy for Pseudomonas aeruginosa infection
- Effective against bacteria resistant to other important agents e.g., penicillins and cephalosporins
- Significant post antibiotic effect
- Bactericidal even in presence of pus
- Resistance is not common
- Effective against intracellular (“resting”) organisms
- Does not disturb normal anaerobic bowel flora
- Wide distribution in the body
- Convenient twice daily dosing
- Effective in GI infections, enteric fever, UTI, gonorrhoea, nosocomial and other infections
- Well tolerated

 

 

 

Advantages over other agents

Other fluoroquinolones
- Norfloxacin is poorly distributed in the body and is used in GI and genitourinary infections only
- Sparfloxacin & Ofloxacin are relatively expensive
- Adverse effects with pefloxacin

 

 

 

Penicillins (e.g., ampicillin, amoxycillin)

- Ampicillin & Amoxycillin may still be used for ENT / Respiratory infections
- However, resistance due to beta-lactamase production is common; ciprofloxacin not affected by bacterial beta-lactamases
- Ciprofloxacin has better activity against gm -ve bacteria; hence preferred for GI infections, enteric fever, UTI

 

 

Cephalosporins

- Ciprofloxacin is effective orally, whereas many cephalosporins are given parenterally
- Oral therapy even for Pseudomonal infections
- Compared to oral cephalosporins (e.g., cephalexin, cefadroxil, cefaclor), ciprofloxacin has better gm -ve coverage
- Ciprofloxacin is not affected by beta-lactamase produced by bacteria

 

 

Macrolides

- Macrolides (erythromycin, roxithromycin, azithromycin) are chiefly used for infections caused by gm +ve bacteria; hence mainly used in RTI, ENT infection and Skin & soft tissue infection
- Ciprofloxacin has broader coverage and wider applicability