2nd Generation Ciprofloxacin 3



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Fluoroquinolones and Uroseptics

Classification

  1. Quinolone

    1. Nalidixic Acid

  2. Fluoroquinolones

    1. 2nd Generation

      1. Ciprofloxacin

    2. 3rd Generation

      1. Levofloxacin

    3. 4th Generation

      1. Moxifloxacin

Differences

Quinolones

Fluoroquinolone

Isnt Fluorinated

Fluorinated

No activity against Gram Positive

Have both activity against Gram Positive and Gram Negative

General Characteristic

  1. Both Quinolone and Fluoroquinolones are BACTERIOCIDAL

  2. Fluroquinolones have the capability to enter the infected host cell

    1. Enable it to kill intracellular organism such as

      1. Legionella spp.

      2. Mycoplasma spp.

      3. Chlamydia spp.

Mechanism of Action in General

  • Generally, bacteria has circular DNA. During replication, this circular DNA needs few enzymes for it to be replicated. They are

    • Helicase

      • Use in unwinding the double helix DNA to form the repilcation fork

      • It also stabilizes the unwinded DNA strands so that it wont stick back together

    • DNA Gyrase/ Topoisomerase II

      • During unwinding of DNA double helix, the in front of the DNA replication fork will be introduced with POSITIVE SUPERCOILING

      • If the positive supercoiling is too extensive, replication fork can be futher made; hence replication process may stop

      • DNA Gyrase is responsible in introducing NEGATIVE SUPERCOILING so that the DNA strands are not too streesful and coiled

    • Topoisomerase IV

      • When the replication forks meet at the end of the circular DNA, the strand tends to stick together

      • In order to unlink the strands, Topoisomerase IV takes part

  • Thus, Quinolones and Fluoroquinolones act by by acting on both DNA Gyrase/ Topoisomerase II and Topoisomerase IV

  • This inhibition will lead to BACTERIOCIDAL effect



  • Selectivity

    • Gram Positive

      • DNA Gyrase/ Topoisomerase II

      • Topoisomerase IV

    • Gram Negative

      • DNA Gyrase/ Topoisomerase II

  • Selective toxicity

    • Due to its selective activity towards DNAGyrase and Topoisomerase IV, in the normal dose use in antimicrobial therapy Quinolones and Fluoroquinolone wont have any activity against human DNA replication

    • Due to the fact humans possess only Topoisomerase III, Quinolones and Fluoroquinolones won’t be able to exert its activity against it unless the dose is super high


Adverse Effects of Quinolones and Fluoroquinolones

  • Abnormal growth of cartilage and bone

    • Should be avoided in

      • Pregnant women (Category C)

      • Children under the age of 18

  • Photodermatitis

    • Avoid sun and UV light during treatment

  • Tendonitis/ Tendon rupture

  • CNS effects

    • Confusion

    • Insomnia

    • Exacerbation of pshychosis

    • Depression

    • Somnolence

    • Seizures

  • CVS effects

    • QT prolongation

    • Therefore should not be prescribed with anti-arrhythmic agent which cause QT prolongation

      • Class 1A

        • Quinidine

        • Procainamide

      • Class 3

        • Amiodarone

        • Ibutilide



Group

Drug

Pharmacokinetic

Spectrum of Actitivy

Therapeutic Uses

Quinolone

Nalidixic Acid

Absorption

  • Well-absorbed through GIT

Distribution

  • Poos tissue penetration

  • Less being distributed into body compartments

  • Due to its less tissue penetration, it’s not being used in systemic infection

  • Low plasma level due to metabolism and extensive excretion

Metabolism

Excretion

  • Urine

  • Nalidixic Acid were found in the urine in high concentration

  • Gram Negative

    • E. coli

    • Klebsiella spp.

    • Proteus spp.

    • Shigella spp.

    • NOT Pseudomonas aeruginosa

  • NO activity against GRAM POSITIVE and ATYPICAL BACTERIA

  • Non-complicated lower UTI’s

  • Bacterial Gastroenteritis caused by

    • E. coli

    • Proteus spp.

    • Klebsiella spp.

    • Shigella spp.

Fluoroquinolone

Ciprofloxacin

**the most potent for P. aeruginosa



Absorption

  • Well absorbed orally

  • Can be administered through

    • Oral

    • IV

Distribution

Metabolism

  • Metabolized in the liver

  • Found to be a POTENT CYP450 INHIBITOR

    • Therefore may inhibit various drugs if prescribed together

Excretion

  • Excreted via urine




  • Gram Negative

    • Including Pseudomonas aeruginosa

  • Gram Positive

    • Only Staphylococcus spp.

    • NO activity against Streptococcus pneumoniae

  • UTIs

  • Peritonitis

  • Bacterial Gastroenteritis

  • Sepsis

  • Skin/soft tissue infection

  • Typhoid fever

    • Used as 1st line treatment

  • Tuberculosis

  • Gonnorhea

  • Conjunctivitis

Levofloxacin

Absorption

  • Very well absorbed in GIT

Distribution

  • Very well distributed across body compartments

  • Has a long post-antibiotic effect

  • Long acting drug, therefore only need a single daily dose

Metabolism

  • So far, found to be not metabolized by liver or other part of the body

Excretion

  • Excreted via urine unchanged

  • Gram Negative

  • Gram Positive

    • Improved activity against Strep. pneumniae

  • Atypical bacteria

    • Improved activity against

      • Mycobacterium spp.

      • Chlamydia spp.

  • Respiratory tract infections

    • Pneumonia

    • Exacerbated COPD

Moxifloxacin

Absorption

Distribution

  • Distributed across body compartment

  • Has a long post-antibiotic effect

Metabolism

  • Hepatic metabolism

Excretion

  • Excreted via liver

  • Gram Negative

  • Gram Positive

    • The best to fight against Strep. pneumoniae

  • Atypical bacteria

Urinary Antiseptics/ Uroleptics

  • Agents that exert antibacterial action not in the blood but in the URINE

    • Less effective for treatment of systemic infection

  • They used only in the treatment of LOWER UTI

    • They must never be used to treat pyelonephritis, renal abscess, and pyeloempyema because of extremely poor tissue penetration and low blood levels

    • Obstruction in the urine outflow may interfere it effective in combating organism, therefore it should not be given in patients having complicated UTI

Drugs

Pharmacokinetic

Mechanism of Action

Adverse Effects

Nitrofurantoin

**Bateriocidal agent

Spectrum of Antimicrobial Activity

  • High antibacterial activity

    • E.coli

    • Staph saprophyticus

  • Low antibacterial activity

    • Staph aureus

    • Strep. spp

    • Klebsiella spp

Clinical Uses

  • Prophylaxis and treatment of lower UTIs

    • Simple cystitis

Absorption

Distribution

  • Extremely poor tissue penetration

  • Very low Vd

Metabolism

Excretion

  • Excreted immediately via urine

    • Leads to very low plasma concentration

  • Compete with Probenecid for excretion

    • Probenecid may reduce Nitrofurantoin urine concentration

  • Activity best in acidic urine

  • Nitrofurantoin is a prodrug, once eliminated in the urine, it will be enter the bacterial cell and converted into a highly reactive electrophilic intermediates

  • This electrophilic intermediate will non-specifically attack

    • Bacterial ribosomal protein

    • DNA

    • Respiration

    • Pyruvate metabolism

    • Other macromolecules

    • Inhibition of protein synthesis

  • Allergic reactions

    • Rash

    • Urticaria

  • Pulmonitis and Pulmonary Fibrosis

    • Happens when it is given for too long

  • Heamolysis

    • Contraindicated in G6PDdeficiecny patient

  • Urine discoloration (harmless)

    • Orange-brown urine color

Contraindication

  • G6PD deficiecny

  • Pregnant women

Fosphomycin

**Bacteriostatic agent



Spectrum of Antimicrobial Activity

  • Gram Negative Bacteria

    • Effective against

      • E.coli

      • Salmonella spp.

      • Shigella spp.

      • Proteus spp.

    • Not effective against

      • Pseudomonas aeruginosa

      • Klebsiella spp.

  • Gram Positive Bacteria

    • Mostly resistant including

      • Staphylococci

      • Streptococci

  • Resistant to all Anaerobic bacteria

Absorption

  • Well absorbed in the GIT

  • Administered orally

Distribution

  • Extremely poor tissue penetration

  • Very low Vd

Metabolism

  • Does not undergo any metabolism

Excretion

  • Excreted immediately via urine

    • Leads to very low plasma concentration

  • The first stage of cell wall synthesis takes place in the bacterial cytoplasm

    • This stage is where the low-molecular-weight precursor of murein is synthesized

  • Fosphomycin is an antimetabolite of Phosphoenolpyruvate in the enzymatic process of N-Acetylmuramic Acid

  • Allergic reactions

    • Rash

    • Urticaria

  • CNS effects

    • Headache

    • Dizziness

  • GIT disturbances

    • Diarhhea

    • Nausea





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