Quinolones

The important quinolones are synthetic fluorinated analogs of nalidixic acid, they are active against a variety of gm+ve and gm-ve bacteria.

-Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. -Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. -Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. -The effect of quinolones on these DNA enzymes is initially bacteriostatic but becomes bactericidal when bacteria are unable to repair the DNA lesions

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

First: Nalidixic acid Second: Norfloxacin, Ciprofloxin, and Ofloxacin Third: Levofloxacin Fourth:Moxifloxacin

Antibacterial spectrum
-First generation : limited gm-ve activity [E.coli, klebsiella, & proteus spp.] -Second generation : Ciprofloxin, and Ofloxacin active against gm-ve [Enterobacteriaceae, Hemophilus spp., P aeruginosa & sexually transmitted disease (STD) agents, such as Neisseria gonorrhoeae, Chlamydia triachomatis, Urea plasma spp.] While Norfloxacin is the least active of the fluoroquinolones against gm-ve and gm+ve organisms.
-Greater activity against gm+ve organisms, is demonstrated by

third & fourth generations particularlr S pneumonia and some staphylococci.

-Also quinolones are active against a variety of pathogens associated with respiratory tract infections such as chlamydia pneumonia, Mycoplasma pneumonia & mycobacterial spp.

Resistance
1-Mutation in the DNA gyrase 2-Altration in porins (gm-ve) that result in a decreased uptake of the drug 3-The appearance of an active efflux system

Clinical uses
1-Nalidixic acid is effective for UTIs 2-Second-generation Fluoro.: Equally efficacious in UTIs & in treating prostitis & 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 to E.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 causative agents & the rate of resistance development. 8- Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax.

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 should be avoided in pregnant women and patient under 18 years of age.

Ciprofloxacin

It is the most potent one among the fluoroquinolones . - It is used in treatment of pseudomonas infection associated with cystic fibrosis - Useful in treating infection caused by Enterobacteraceae & other gm-ve bacilli - Ciprofloxacin is an alternative to more toxic drugs such as the aminoglycosides - It may act synergistically with -lactam

Norfloxacin

Effective against both gm-ve [ including Pseudomonas aeruginosa ] & gm+ve in treating complicated & un complicated UTIs & prostatitis but not in systemic infection

Sulfonamides
The sulfonamides are a large group of compounds that are structural analogues of P-amino benzoic acid [PABA] Substitutions on the sulfonamide group modify the drugs solubility characteristics, resulting in members with different rate of absorption & excretion Sulfonamides are:

Sulfamethoxazole, Sulfasalazine, Sulfisoxazole, Sulfadiazine, Sulfamerazine,.

Mechanism of action
Both sulfonamides & trimethoprim sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines & some amino acids & consist of three components :

Pteridine moiety, PABA, Glutamate. The sulfonamides are structural analogues, competitively block PABA incorporation, sulfonamides inhibit the enzyme Dihydropteroate synthase : necessary for PABA to be incorporated into dihydropteroic acid, an intermediate comp. in the formation of folinic acid. Sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid & must acquire it in the diet ; thus, the sulfonamides selectively inhibit microbial growth.

Resistance to the sulfonamides can be the result of:

1-Decreased bacterial permeability to the drug 2-Increased production of PABA 3-Production of an altered dihydropteroate synthase that exhibits low affinity for sulfonamides

Antibacterial spectrum

The sulfonamides are broad-spectrum antimicrobials that are effective against gm+ve & gm-ve organism of the Enterobacteriaceae -good activity against E.coli -moderate activity against Proteus mirabilis & Enterobactor spp. -poor activity against indole-positive Proteus & Klebsialla spp. -no inhibitory activity against P.aeruginosa & serratia spp. -effective against Chlamydia spp and Nocardia spp. -sulfonamides are used in treating infection caused by Toxoplasma gondii & occasionally Chloroquine-resistant

Plasmodium falciparum

Sulfonamides are infrequently used as a single agent.

1-Acute uncomplicated UTIs 2-Sulfadiazine & Sulfisoxazole: prophylaxis of group A streptococcal infection 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 symptomatic toxoplasmosis

Clinical uses

5-Sulfadoxine with pyrimethamine: used in the treatment of chloroquineresistant malaria caused by Plasmodium falciparum
6-Topically active sulfonamides are useful in preventing infection in burn patients. 7-Oral non absorbable Salfasalazine is widely used in ulcerative colitis, enteritis and other inflammatory bowel disease.

Adverse effects
1-Crystalluria 2-Hypersensitive reaction: rash, angioedema, agranulocytosis, thrombocytopenia, photosensitivity & Stevens-Johnson syndrome [fever, malaise, erythema multiform, & ulceration of the mucous memb. of mouth & genitalia] 3-Hemolytic anemia: in G6PD deficiency 4-Cross-allergy with thiazides, carbonic anhydrase inhibitors, sulfonylurea hypoglycemic agent 5-Nausea, vomiting & diarrhea

C.I Newborns baby Last 2 months of pregnancy

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

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

-It competitively inhibits dihydrofolate reductase enzyme that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, the active form of folate dihydrofolate reductase is present in both mammalian tissue & bacteria, but 20000 to 60000 times more drug required to inhibit the mammalian enzyme, this account for it is selective toxicity against bacteria

-Was introduced as a fixed dose combination in 1968 -TMP was added to SMX to synergistically & sequentially inhibit bacterial synthesis of tetrahydrofolic acid -The combination was also designed to delay development of bacterial resistance -SMX has a half-life similar to that of TMP -TMP-SMX: is bactericidal, compared to the bacteriostatic activity of a Sulfonamide alone, & has broader spectrum of action than the sulfa drugs -TMP-SMX is active against most gm+ve & gm-ve organisms, especially Enterobacteriaceae

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 with recurrent 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 & prevention of infection caused by P.carinii, a protozoan that produced serious pneumonitis in patient with hematological malignancies & ADIS

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

Urinary Tract Antiseptics

Urinary antiseptic are drugs that exert their antimicrobial effect in the urine & are devoid of virtually any significant systemic 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 bacterial toxicity -Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes [e.g. DNA & RNA synthesis, protein synthesis] this observation may explain the lack of resistance development to these drugs

Antibacterial spectrum & Resistance

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

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

Adverse effects

1- nausea & vomiting 2- pulmonary hypersensitivity 3- intrahepatic cholestasis & hepatitis 4- hemolytic anemia 5- neurological problems : headache, polyneuropathy In pregnant women, in nursing infants.

C.I

Methenamine
- Is an aromatic acid that is hydrolyzed at an acid PH (<6 ) to liberate amonia & the active alkylating agent formaldehyde, which denaturates protein & itis bactericidal. - Administered as a salt of either mandelic acid or hippuric acid. Not only do these acids acidify the urine, which is necessary to generate formaldehyde, but also the resulting low PH is by itself bacteriostatic for some organisms. - Its primarily used for the long-term prophylactic or suppressive therapy of recurring UTIs. - It is not a primary drug for therapy of acute infection. - It should be used to maintain sterile urine after appropriate antimicobial agents have been employed to eradication the infection. - Gastric distress [ nausea & vomiting ] is the most frequently adverse effects.