Quinolones, Folic Acid Antagonist, and Urinary Tract Antiseptics.pptx

7/30/2019 Quinolones, Folic Acid Antagonist, and Urinary Tract Antiseptics.pptx

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The important quinolones are synthetic fluorinatedanalogs of nalidixic acid, they are active against avariety of gm+ve and gm-ve bacteria.

Quinolones


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-Quinolones block bacterial DNA synthesis by inhibitingbacterial topoisomerase II (DNA gyrase) and topoisomeraseIV.

-Inhibition of DNA gyrase prevents the relaxation of positivelysupercoiled DNA that is required for normal transcription andreplication.-Inhibition of topoisomerase IV interferes with separation ofreplicated chromosomal DNA into the respective daughter cells

during cell division.

-The effect of quinolones on these DNA enzymes is initiallybacteriostatic but becomes bactericidal when bacteria areunable to repair the DNA lesions


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The quinolones are classified into generations, each one hasspectrum specificity & unique pharmacological properties

First: Nalidixic acid

Second: Norfloxacin, Ciprofloxin, and Ofloxacin

Third: Levofloxacin

Fourth:Moxifloxacin


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Antibacterial spectrum

-First generation: limited gm-ve activity [E.coli, klebsiella, &

proteus spp.]

-Second generation : Ciprofloxin, and Ofloxacin active againstgm-ve [Enterobacteriaceae, Hemophilus spp., P aeruginosa&sexually transmitted disease (STD) agents, such asNeisseria

gonorrhoeae, Chlamydia triachomatis, Urea plasma spp.]While Norfloxacin is the least active of the fluoroquinolonesagainst gm-ve and gm+ve organisms.

-Greater activity against gm+ve organisms, is demonstrated bythird & fourth generations particularlrS pneumoniaand somestaphylococci.

-Also quinolones are active against a variety of pathogensassociated with respiratory tract infections such aschlamydia

pneumonia, Mycoplasma pneumonia & mycobacterial spp.


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1-Mutation in the DNA gyrase

2-Altration in porins (gm-ve) that result in a decreased uptake of thedrug

3-The appearance of an active efflux system

Resistance


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Clinical uses

1-Nalidixic acid is effective for UTIs

2-Second-generation Fluoro.: Equally efficacious in UTIs & in treatingprostitis & alternative to TMP-SMX.

3-Acute & chronic bacterial sinusitis

4-Fluoro. For chronic bronchitis & chronic otitis media

5-Fluoro. Indicated for a variety of GI infections including diarrhea due toE.coli, shigellosis & typhoid fever.

6-In treatment of Chlamydial urethritis [ mainly ciprofloxacin & levofloxacin ]7-The use of Fluoro. In bone & joint infections is influenced by the causativeagents & the rate of resistance development.8- Ciprofloxacin is a drug of choice for prophylaxis and treatment ofanthrax.


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Adverse effects

1- Nausea, vomiting & abdominal pain

2- CNS effects : drowsiness, weakness, headache, dizziness& in sever cases convulsion & toxic psychosis

3- Hepatotoxicity

4- Photosensitivity

5-Connective tissue problem: Fluoro. May damage growing

cartilage and cause an arthropathy. Thus this drugs shouldbe avoided in pregnant women and patient under 18 years ofage.


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Ciprofloxacin

It is the most potent one among the fluoroquinolones .

- It is used in treatment of pseudomonas infection associatedwith cystic fibrosis

- Useful in treating infection caused by Enterobacteraceae &other gm-ve bacilli- Ciprofloxacin is an alternative to more toxic drugs such asthe aminoglycosides- It may act synergistically with -lactam


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Norfloxacin

Effective against both gm-ve [ includingPseudomonas aeruginosa] & gm+ve in treatingcomplicated & un complicated UTIs & prostatitis

but not in systemic infection


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Sulfonamides

The sulfonamides are a large group of compounds thatarestructural analogues of P-amino benzoic acid [PABA]

Substitutions on the sulfonamide group modify the drugs solubilitycharacteristics, resulting in members with different rate ofabsorption & excretion

Sulfonamides are:Sulfamethoxazole, Sulfasalazine, Sulfisoxazole,Sulfadiazine, Sulfamerazine,.


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Mechanism of action

Both sulfonamides & trimethoprim sequentially interfere with folicacid synthesis by bacteria.

Folic acid functions as a coenzyme in the transfer of one-carbonunits required for the synthesis of thymidine, purines & some aminoacids & consist of three components :Pteridine moiety, PABA, Glutamate.The sulfonamides are structural analogues, competitively block PABA

incorporation, sulfonamides inhibit the enzyme Dihydropteroatesynthase : necessary for PABA to be incorporated intodihydropteroic acid, an intermediate comp. in the formation offolinic acid.

Sulfonamides reversibly block the synthesis of folic acid, they arebacteriostatic drugs.Humans cannot synthesize folic acid & must acquire it in the diet ;thus, the sulfonamides selectively inhibit microbial growth.


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Resistance to the sulfonamides can be the result of:

1-Decreased bacterial permeability to the drug

2-Increased production of PABA3-Production of an altered dihydropteroate synthase thatexhibits low affinity for sulfonamides

Antibacterial spectrumThe sulfonamides are broad-spectrum antimicrobials that areeffective against gm+ve & gm-ve organism of theEnterobacteriaceae-good activity against E.coli-moderate activity against Proteus mirabilis& Enterobactorspp.

-poor activity against indole-positive Proteus& Klebsiallaspp.-no inhibitory activity against P.aeruginosa& serratiaspp.-effective against Chlamydiaspp and Nocardia spp.-sulfonamides are used in treating infection caused byToxoplasma gondii& occasionally Chloroquine-resistant

Plasmodium falciparum


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Clinical usesSulfonamides are infrequently used as a single agent.

1-Acute uncomplicated UTIs

2-Sulfadiazine & Sulfisoxazole: prophylaxis of group A streptococcalinfection in patient with rheumatic fever who are hypersensitive to penicillin

3-Chlamydia trachomatis such as trachoma, inclusion conjuctivitis, &urethritis

4-Sulfadiazine with pyrimethamine: drug of choice for symptomatictoxoplasmosis

5-Sulfadoxine with pyrimethamine: used in the treatment of chloroquine-

resistant malaria caused by Plasmodium falciparum6-Topically active sulfonamides are useful in preventing infection in burnpatients.

7-Oral non absorbable Salfasalazine is widely used in ulcerative colitis,

enteritis and other inflammatory bowel disease.


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Adverse effects

1-Crystalluria

2-Hypersensitive reaction: rash, angioedema, agranulocytosis,thrombocytopenia, photosensitivity & Stevens-Johnson syndrome[fever, malaise, erythema multiform, & ulceration of the mucous memb. ofmouth & genitalia]

3-Hemolytic anemia: in G6PD deficiency

4-Cross-allergy with thiazides, carbonic anhydrase inhibitors, sulfonylureahypoglycemic agent

5-Nausea, vomiting & diarrhea

C.INewborns babyLast 2 months of pregnancy


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Trimethoprim : is a structural analogue of the pteridine portionof dihydrofolic acid

-It acts at a second step in the folic acid synthetic pathway

-It competitively inhibits dihydrofolate reductaseenzyme that catalyzes the reduction of dihydrofolic acid totetrahydrofolic acid, the active form of folate

dihydrofolate reductase is present in both mammalian tissue &

bacteria, but 20000 to 60000 times more drug required to inhibitthe mammalian enzyme, this account for it is selective toxicityagainst bacteria


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-Was introduced as a fixed dose combination in 1968

-TMP was added to SMX to synergistically & sequentially inhibitbacterial synthesis of tetrahydrofolic acid

-The combination was also designed to delay development ofbacterial resistance

-SMX has a half-life similar to that of TMP

-TMP-SMX: is bactericidal, compared to the bacteriostaticactivity of a Sulfonamide alone, & has broader spectrum of actionthan the sulfa drugs

-TMP-SMX is active against most gm+ve & gm-ve organisms,especially Enterobacteriaceae


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Clinical use of TMP-SMX

1-TMP-SMX is used in the treatment of Genitourinary, GI, &respiratory tract infection

2-Recurrent UTIs, also used as chemoprophylaxis in women withrecurrent UTIs

3-Treatment of infection caused by ampicillin-resistant Shigella

spp., & for antibiotic-resistant Salmonella spp.

4-Treatment of prostitis caused by sensitive organisms

5-Otitis media & chronic bronchitis in children

6-Gonorrhea, typhoid fever, & brucellosis

7- TMP-SMX : drug of choice in both the treatment & preventionof infection caused by P.carinii, a protozoan that produced serious

pneumonitis in patient with hematological malignancies & ADIS


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Adverse effects

1-Skin rashes

2-CNS disturbances

3-Blood dyscrasias

4-Hepatotoxicity, Blood dyscrasias, Skin rashes

particularly common in ADIS patients

5-TMP may increase the hematological toxicity of SMX

Increased level of warfarin, methotraxate, zidovudine & sulfonylurea may

occur with TMP

C.I-In pregnant women-TMP is C.I in patient with Blood dyscrasias, hepatic damage &

renal impairment


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Urinary TractAntiseptics

Urinary antiseptic are drugs that exert their antimicrobialeffect in the urine & are devoid of virtually any significantsystemic effect.

Nitrofurans { Nitrofurantoin }

Used in the treatment &/or prophylaxis of microbial infections,primarily in urinary tract-

Reduction of 5-nitro group to the nitro anion results in bacterialtoxicity-Intermediate metabolites modify various bacterial macromoleculesthat affect a variety of biochemical processes [e.g. DNA & RNAsynthesis, protein synthesis] this observation may explain the lack ofresistance development to these drugs


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Antibacterial spectrum & Resistance

-primarily active against gm-ve bac. [ E.coli, P. mirabilis]

-some susceptible gm+ve organism such as S.aureus, Enterococcusfaecalis.

Adverse effects

1- nausea & vomiting

2- pulmonary hypersensitivity

3- intrahepatic cholestasis & hepatitis

4- hemolytic anemia

5- neurological problems : headache, polyneuropathy

C.IIn pregnant women, in nursing infants.


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Methenamine

- Is an aromatic acid that is hydrolyzed at an acid PH (


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Quinolones, Folic Acid Antagonist, and Urinary Tract Antiseptics.pptx

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