QUINOLONE, FOLIC-ACID ANTGONIST, UTI ANTISEPTICS - Drugs use in urinary tract infection

 Quinolone 

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Naldixic acid is precursor of Flouroquinolone

MOA

enter into bacterium by Passive Diffusion through Porin

ϴ replication of bacterial DNA by interfering Topoisomerase ll & Topoisomerase IV during bacterial Growth & Reproduction…

Topoisomerase ll(DNA Gyrase) change DNA topology by nicking, pass through , resealing mechanism…..ϴ of Topoisomerase ll inhibit resealing step….cell death by cleavage of DNA 

Topoisomerase lV required for cell division.

Antibacterial spectrum

1st Generation

in treatment of UTI, have moderate Gram-Ve rod activity.

2 nd Generation

Expanded Gram-Ve activity rod, some Gram+Ve cocci activity &  against atypical organisms (M.pneumoniae, Chlamydia pneumonia)  

3 rd Generation

improved activity against Gram-Ve rod, Gram+Ve cocci, atypical organism

4th Generation

activity against Gram+Ve cocci, Gram+Ve rod, Gram-Ve rods, Anaerobes

T.E

👉Ciprofloxacin is DOC in Anthrax, effective inTraveler‟s Diarrhea , Typhoid fever

👉Ciprofloxacin &Levofloxacin used in UTI infection

👉Levofloxacin & Minofloxacin known as “Respiratory Flouroquinolone” used in Pneumonia, Sinusitis 

👉Levofloxacin used in Prostatitis due to E.choli,Gonorrhea

Resistance

↓affinity for DNA Gyrase, ↓no. of pore

P.K

Ca, Divalent,Trivalent, Antacid interfere with Abs….↑distribution in bone (Except Moxifloxacin), urine, kidney,lung, prostatic tissue……accumulate in Macrophage/Leukocytes so effective against Legionella Pneumophila

S.E

👉cause “Articular Cartilage erosion” in pregnancy,lactation, children under 18yr…

👉black box warning FDA in 2008 due to “Tendinitis” , Archilles tendon mostly effected ..

👉Phototoxicity, Seizure, headache, diarrhea

Contraindicated

Moxifloxacin prolong QT-interval, contra in arrhythmic Patient

Flouroquinolone are Enzyme Inhibitor 

FOLATE ANATAGONISTS

Enzymes require Folate-derived Cofactor for Purine & Pyrimidine synthesis

Bacteria synthesize Folate De Novo..

Human obtain from diet.

Sulfonamides (Bacteriostatic)

ϴ de novo synthesis of Folate.. 

In Bacteria, Dihydrofolic acid obtained from PABA, pteridine, Glutamate…

Sulfonamide compete with DiHydroPteroate Synthetase.

ϴ DHFA synthesis by forming cofactor forms

Antibacterial synthesis

 active against Enterobacter in UTI & Nocardia

Resistance 

alter Dihydropteroate synthetase, ↓permeability

P.K

orally absorbed…

Sulfasalazine not absorbed orally reserves Chronic Inflammatory

👉Bowel Disease (Crohn‟s disease, Ulcerative colitis) & metabolize into Sulfapyridine & 5-Aminosalicylte, toxic in poor Acetylators

👉Cream of Silver sulfadiazine & Mafenide uesd in Burn-associated Sepsis…

👉Silver sulfadiazine preferred b/c Mafenide produce pain when applied

Extent of Protein binding depend on pKa value..

have smaller pKa ↑ binding. 

Distribute throughout water compartment & CSF, pass placental barrier

S.E: 

Crystalluria,

hypersensitivity, 

Hemolytic anemia, 

Kernicterus (in newborn sulfa displace Bilrubin from binding, Bilirubin pass CNS)

Warfarin & Methotrexate displace from binding ↑ toxicity

Contraindicated in infant, pregnancy, in Pt. receiving Mathenamine in UTI (bcz sulfa condense with Formaldehyde)

Trimethoprim (Bactericidal)

MOA:

ϴ FH2 Reduction into FH4 by Dihydrofolate reductase…↓FH4for purine and pyrimidine…

Pyrimethamine also exhibit same mechanism…

Preferred use in Toxoplasmosis.

Antibacterial spectrum

 used in the treatment of UTI & Prostatitis, Vaginitis

S.E:

 Megaloblastic anemia, Leukopenia, Granulocytopenia, in pregnant women..

Reversedby administration of FOLINIC ACID

Cotrimoxazole

Combination of Trimethoprim & 5- Sulfamethoxazole produce 1; 20 …>antimicrobial  activity

MOA:

 ϴ both synthesis & reduction of FH4

Antimicrobial spectrum:

used in UTI, Respiratory infection, Pneumocystis-jivoreci

pneumonia, Ampicillin/Chloramphenicol-resistant salmonella infection… 

used in Listerosis by Listeria monocytogenes, DOC in Nocardia, S.maltophilia

S.E: 

Deramatologic reactions, Glossitis, Stomasitis, Megaloblastic anemia, leukopenia, thrombocytopenia, ↑INR

HIV-patient show rash, diarrhea, Pancytopenia

Urinary Tract Antimicrobial/Antiseptics

VIDEO LECTURE OF UTI ANTISEPTIC 

✔️ UTI common in child-bearing & in elderly one…

✔️ E.coli most common 80% UTI…

✔️ S.aureus second more common… than Klebsiella, Proteus….

Classification

👍Methenamine ,

👍Nitrofurantoin,

👍Nalidixic acid

Methenamine

MOA

•  decompose at pH 5.5…produce Formaldehyde… acts locally toxic to bacteria…
• bacteria do not develop resistance….
• Methenamine formed by weak acid Mandelic acid or Hippuric acid….
• Ascorbic acid & Craberry juice used to ↓pH…
• Antacid avoided

Antibacterial spectrum

 Urea-splitting bacteria that alkalinize urine (Proteus) are resistant… 

effective only in lower UTI

NH4 produced in addition to formaldehyde toxic to CNS in hepatic insufficiency…

S.E

 GIT distress, Albuminuria… Contra in Renal impair b/cMandelic precipitate

Not used with Sulfonamide b/c ↑ crystalluria & mutual antaagonissm

Nitrofurantoin (Bacteriostatic / Bactericidal)

Reduce into Highly active intermediate that ϴ various enzymes & damage DNA…

activity> in Acidic urine.... Cause Hemolytic anemia, interstitial pulmonary fibrosis

Contra:

 in Anuria, Oliguria, renal impairment Creatinine CL<60ml/min, in pregnancy.