Quinolones

These are synthetic antimicrobials that are primarily active against gram negative bacteria. Fluorinated compounds also inhibit gram positive bacteria.

Nalidixic was the first member to be discovered. Fluorination of quinolone structure at position 6 and piperazine at position 7 results in formation of fluoroquinolones.

Nalidixic Acid

• Active against gram have ho u bacteria especially coli forms like E. coli, Proteus, Klebsiella, Enterobacter, Shigella but not Pseudomonas.
• Acts by inhibiting bacterial DNA gyrase and is bactericidal.
• Absorbed orally.
• Highly plasma protein bound.
• Partly metabolised in liver, one of the metabolites is active.
• Excreted in urine.
• Plasma half live is 8 hrs.
• High concentration is attained in urine and gut lumen is lethal to the common urinary pathogens and diarrhoe causing coliforms.

Adverse Effects

Vertigo

• Rashes and g.i. upset.
• Neurological toxicity.
• Seizures in children especially.
• Individuals with G-6-PD deficiency develop haemolysis.

Nalidixic acid is contraindicated in infants

DOSE: 0.5-1 g TDS or QID

Preparations

• GRAMONEG 0.5 g tab, 0.3 g/5 ml susp,
• DIARLOP 0.3 g/5 ml susp.

Fluoroquinolones

These are broad spectrum antimicrobials active against both gram negative and positive cocci.

Classification of Fluoroquinolones

Mechanism of Action

In gram negative bacteria

Bacterial DNA gyrase has two subunits A and B, A subunit nicks the DNA and B subunit carries out negative supercoiling.

Fluoroquinolones inhibits bacterial DNA gyrase by binding to A subunit with high affinity and interfere with strand cutting and resealing function.

In gram positive bacteria

Topoisomerase IV nicks and separates daughter DNA strands after DNA replication. Fluoroquinolones inhibits topoisomerase IV.

Bactericidal action is due to the digestion of the DNA by exonucleases.

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Mammalian cells have topoisomerase II which has very low affinity for FQs, so low toxicity to host cells.

Resistance

Resistance noted in FQs is slow to develop and is noted among Salmonella, Pseudomonas, gonococci, staphylococci and pneumococci. Resistance is mainly due to-

• Chromosomal mutation of DNA gyrase or topoisomerase IV which has low affinity for FQs, or
• Reduced permeability or increased efflux of drugs across bacterial membrane.

Drugs

Ciprofloxacin (prototype)

It is the most potent first generation FQ having broad spectrum of activity, most succeptible ones are aerobic gram negative bacilli. The MIC against these bacteria is < 0.1 microgram/ml.

Gram positive bacteria are inhibited at high concentration.

Spectrum of Activity

1. Highly succeptible
   • E. coli
   • K. pneumoniae
   • Enterobacter
   • Neisseria gonorrhoea
   • N. meningitidis
   • H. influenzae
   • Salmonella typhi
   • Non typhoid Salmonella
   • Shigella
   • Proteus
   • H. ducreyi
   • Campylobacter jejuni
   • Yesinia enterocolitica
   • Vibrio cholerae
2. Moderately succeptible
   • Pseudomonas aeruginosa
   • Brucella
   • Listeria
   • Staphylococcus epidermidis
   • Branhamella catarrhalis
   • Legionella
   • Mycoplasma
   • Chlamydia pneumophilia
   • Bacillus anthracis
   • Mycobacterium tuberculosis
3. Low/variable succeptible
   • Streptococcus pyrogenes
   • Streptococcus faecalis
   • Streptococcus pneumoniae
   • MRSA
   • Mycobacterium kanasii
   • Mycobacterium avium
4. Resistant
   • Bacteroides fragilis
   • Clostridia
   • Anaerobic cocci

Characteristics

• Bactericidal activity and potency: MBCs are close to MICs.
• Long post anabolic effect on Enterbacteriaceae, Pseudomonas and Staphylococcus.
• Low frequency of mutational resistance.
• Protective intestinal streptococci and anaerobes are spared.
• Less active in acidic pH.

Pharmacokonetics

• Rapidly absorbed orally.
• Food and antacids delays absoprtion.
• First pass metabolism occurs.
• FQs except norfloxacin attains bactericidal levels in blood and have good tissue penetrability.
• CSF and aqueous levels are lower.
• Excreted in urine by glomerular filteration and tubular secretion.
• Urinary and biliary excretion are 10-50 folds higher than plasma.

Adverse Effects

• Gastrointestinal: Nausea, vomiting, bad taste, anorexia.
• CNS: Dizziness, headache, anxiety, restlessness, insomnia, impairment of concentration and dexterity. Tremor and seizures are are rare, occur only at high dose or when predisposing factors are present.
• Skin: Hyperventilation
• Tendonitis and tendon rupture: Higher in patients above 60 yrs and those taking corticosteroids.

Ciprofloxacin and other FQs are contraindicated in pregnancy.

Interactions

• Metabolism of theophylline, caffeine and warfarin is decreased. CNS toxicity occurs by concurrent use of theophylline and FQs.
• NSAIDS enhance CNS toxicity of FQs such as seizures.
• Antacids, sucralfate and iron results reduce absoprtion.

Preparations

CIFRAN, CIPLOX, CIPROBID, CIPROLET 250, 500, 750 mg tab, 200 mg/100 ml i.v. infusion, 3 mg/ml eye drops.

Use

• Urinary tract infections: High cure rates. Chronic Pseudomonas infections respond less, but ciprofloxacin is most active among all FQs.
• Gonorrhea: Earlier was 100% curative in non PPNG as well as PPNG, but is non dependable now so not used.
• Chancroid: 500 mg BD for 3 days is second line alternative to ceftriaxone/azithromycin.
• Typhoid: First line drug. 75 mg BD for 10 days. Patients unable to take it orally are treated with 200 mg i.v. 12 hourly in the beginning. Treat typhoid carriers 750 mg BD for 4-8 weeks. 92% eradication rate is found. Nowdays, number of non responsive cases are increasing so ceftriaxone or cefoperazone are used.
• Bone, soft tissue, gynaecological and wound infections: Caused by Staphylococcus and gram negative respond efficiently. Used along with clindamycin/metronidazole for diabetic foot.
• Respiratory infections: Should not be used as primary drug. But can be used for atypical pneumonia caused by Mycoplasma, Legionella, Chlamydiae, H. influenzae and Brnch. catarrhalis.
• Anthrax: Drug of choice.
• Tuberculosis: Less active against M. tuberculosis but most active against MAC (Mycobacterium avium complex).
• Gram negative septicemias: Parenteral ciprofloxacin is combined with third generation cephalosporins or an aminoglycosides.
• Meningitis: Gram negative bacterial meningitis.
• Prophylaxis: Of infections in neutropenic/cancer and other succeptible patients.
• Conjuctivitis: Topical therapy is effective for gram negative bacteria.

Norfloxacin

• Least potent FQ.
• MIC for most gram negative bacteria 2-8 times higher than ciprofloxacin.
• Many Pseudomonas and gram positive organisms are not inhibited.
• Primary used for UTI, 8-12 weeks for chronic UTI.
• Good for bacterial diarrhoeas, anaerobic flora in gut is not distrubed.

NORBACTIN, NORFLOX 200, 400, 800mg tab, 3 mg/ml eye drops. UROFLOX 200, 400 mg tab. BACIGYL400 mg tab, 100 mg/5 ml susp.

Pefloxacin

• Methyl derivative of norfloxacin.
• Completely absorbed orally.
• High plasma concentrations.
• Passage into CSF is greater than other FQs, so used in meningeal infections.
• High metabolised–partly to norfloxacin which contributes to activity.
• Accumulates on repeated dosing achieving plasma concentration twice as high as single dose.
• Effective in some system infections
• Dose should be reduced in liver diseases but not in renal insufficiency.

PELOX 200, 400 mg tab with meals, 400 mg inj

Ofloxacin

• Less active than ciprofloxacin against gram negative bacteria.
• Equally or more potent against Strep. pyrogenes, other gram positive cocci and certain anaerobes.
• Good activity against Chlamydiae and Mycoplasma.
• Alternative for non specific urethritis, cervcitis and atypical pneumonia caused caused Chlmydia trachomatis.
• Used in resistant cases if TB.
• Used as MDR in leprosy.
• Lipid soluble.
• High plasma concentration.
• Food does not interfere absoprtion.
• Largely excreted in urine.
• Dose needs to be reduced in reñal failure.
• Used in chronic bronchitis and other ENT infections.
• Inhibition of theophylline metabolism is less marked.

ZANOCIN, TARIVID 100, 200, 400 mg tab, 200 mg/100 ml i.v. infusion. ZENOFLOX 50 mg/5 ml suspension. ZANOCIN, OFLOX, EXOCIN 0.3% eye drops.

Levofloxacin

• Active levo(S) isomer of ofloxacin.
• Oral bioavailability is 100% nearly.
• Oral and i.v. doses are similar.
• Excreted unchanged in urine.
• Single daily dose is sufficient.
• Theophylline,warfarin, cyclosporine and zidovudine pharmcokonetics remain unchanged.
• Primary indication is CAP and excarbations of chronic bronchitis.
• Alternative drug for chlamydial urethritis.
• Second most effective drug FQ for TB.
• Standard regimen for MDR-TB.

TAVANIC, GLEVO 500 mg tab, 500 mg/100ml inj. LOXOF, GLEVO, LEVOFLOX, LEVODAY 250, 750 mg tabs, 500 mg / 100 ml injection. GLEVO 0.5% eye drops.

Lomefloxacin

• Second generation difluorinated quinolone, more active against some gram negative bacteria and chlmydia.
• Causes phototoxicity and Q-T prolongation.

LOMEF-400, LOMEDON, LOMEDAY 400 mg tab. LOMIBACT, LOX 0.3% eye drops.

Sparfloxacin

• Second generation difluorinated quinolone, active against gram positive bacteria, Bacteroides fragilis, other anaerobes and mycobacteria.
• Major indications are pneumonia, exacerbations of chronic bronchitis, sinusitis and other ENT infections.
• Causes phototoxicity, patients should not go out in sun.
• Causes QTc prolongation.

Dose : 200-400 mg OD oral.

TOROSPAR 200, 400 mg tab. SPARTA, SPARQUIN, SPARDAC 100, 200 mg tab. ZOSPAR, SPARC, EYEPAR 0.3% eye drops.

Moxifloxacin

• Long acting 2nd generation FQ.
• High activity against against Streptococcus pneumoniae, other gram positive bacteria including beta lactum/macrolide resistant and some anaerobes.
• Most potent FQ against Mycobacterium tuberculosis, and is used in MDR-TB.
• Used in pneumonia, bronchitis, sinusitis, otitis media, efficacy is comparable to beta lactum antibiotics.
• Not used for UTI because of low concentration in urine.
• Metabolised primarily in liver, so my given in liver diseases.
• Dose modification is not needed I renal failure.
• It should not be given in patients suffering from seizures and arrhythmias because it can prolong QTc interval.
• Phototoxicity rarely occurs.

Dose: 400 mg OD.

MOXIF, MOXICIP, STAXOM 400 mg tab, 400 mg/ 25 ml i.v. infusion. MOXICIP, MILIFLOX, VIGAMOX 0.5% eye for broad spectrum conjuctivitis.

Gemifloxacin

• Broad spectrum FQ active against aerobic gram positive and some multidrug resistant strains.
• Some anaerobes are also inhibited.
• Absorbed rapidly.
• Undergoes limited metabolism.
• Excreted in urine and faeces both as unchanged drug and metabolites.
• Dose is halved if creatinine clearence is <40 ml/min.
• Side effects: Diarrhoe, nausea, headache, dizziness, rise in serum amino transferase, skin rashes.
• Enhance warfarin effect and additive QTc prolongation with other drugs.
• Indicated in CAP and acute exacerbations of chronic bronchitis.

Dose: 320 mg OD for 5-7 days.

TOPGEM, GEMBAX, GEMISTAR, GEMI 320 mg tab.

Prulifloxacin

• Newer second generation FQ.
• Prodrug of Ulifloxacin.
• Broad spectrum antibiotic.
• Rapidly absorbed and converted into Ulifloxacin by first pass metabolism.
• Ulifloxacin excreted primarily unchanged in urine.
• Gastrointestinal and CNS disturbances, urticaria and photosensitivity are reported.
• Does not prolong QT interval.

Dose: 600 mg OD.

ALPRULI, PRULIFLOX, PRULIFACT 600 mg tab.