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1.   Antimetabolites : Sulfonamides Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable (3) topical. The oral, absorbable sulfonamides can be classified as short-, medium-, or long acting on the basis of their half-lives .

2. Mechanism and activity: Sulfonamides are structural analogs of para-aminobenzoic acid (PABA) that competitively inhibit dihydropteroate synthase . They inhibit growth by reversibly blocking folic acid synthesis. Sulfonamides inhibit both gram-positive and gram-negative bacteria, Nocardia , Chlamydia trachomatis , and some protozoa. Some enteric bacteria, such as E coli, Klebsiella , Salmonella, Shigella , and Enterobacter , are inhibited.

3. Ristance : Sulfonamide resistance may occur as a result of mutations that (1) cause overproduction of PABA, (2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, (3) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely.

4. Clinical Uses Oral Absorbable Agents: Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents that are used to treat urinary tract infections, respiratory tract infections, sinusitis, bronchitis, pneumonia, otitis media, and dysentery. Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Sulfadoxine , long acting sulfonamide, in combination with pyrimethamine used as a second-line agent in treatment for malaria. Oral nonabsorbable agents: Sulfasalazine is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease. Sulfasalazine is split by intestinal microflora to yield sulfapyridine and 5-aminosalicylate. Salicylate released in the colon in high concentration is responsible for an antiinflammatory effect. Comparably high concentrations of salicylate cannot be achieved in the colon by oral intake of ordinary formulations of salicylates because of severe gastrointestinal toxicity.   Topical Agents: Sodium sulfacetamide ophthalmic solution or ointment is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to for prevention of infection of burn wounds.

5. Adverse Reactions : The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria , nausea, vomiting, and diarrhea. Stevens-Johnson syndrome, crystalluria , hematuria , hemolytic or aplastic anemia, granulocytopenia , and thrombocytopenia occur less frequently. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.

6. Trimethoprim : Trimethoprim is an inhibitor of bacterial dihydrofolic acid reductase . Pyrimethamine is an excellent inhibitor of dihydrofolic acid reductase in protozoa These reductases are required for the synthesis of purines and hence DNA. Inhibition of these enzymes are responsible for bacteriostatic and bacteriocidal activities. When trimethoprim or pyrimethamine is combined with sulfonamides ( sulfamethoxazole ) there is sequential blocking of the biosynthetic pathway leading to drug synergism and enhanced antimicrobial activity. Resistance to trimethoprim : usually by plasmid encoded trimethoprim -resistant dihydrofolate reductases . Trimethoprim typically used orally often in combination with sulfamethoxazole , a sulfonamide with a similar half-life.

7. Clinical Uses: Oral trimethoprim : Acute urinary tract infections. Oral trimethoprim-sulfamethoxazole ( Bactrim ) combination: Pneumocystis carinii pneumonia, shigellosis,systemic Salmonella infection, some nontuberculous mycobacterial infections. Respiratory tract pathogens: pneumococcus , Haemophilus , Moraxella catarrhalis , Klebsiella pneumoniae By I.V. administration trimethoprim - sulfamethoxazole : agent of choice for moderately severe to severe infections with Pneumocystis carinii pneumonia, especially in patients with HIV. May be used for gram-negative sepsis

8. Adverse effects: Trimethoprim adverse effects referable to antifolate properties: megaloblastic anemia, leukopenia granulocytopenia (avoided by coadminstration of folinic acid) . Combination of Trimethoprim-Sulfamethoxazole cause in addition, sulfonamide side effects--nausea, vomiting, vasculitis , renal damage.

9. DNA gyrase inhibitors Fluroquinolines Quinolones are synthetic fluorinated analogs of nalidixic acid. They are active against a variety of gram-positive and gram-negative bacteria. Mechanism of Action 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.

10. Antibacterial Activity The old quinolones , nalidixic acid did not achieve systemic antibacterial levels and were useful only in the treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin , enoxacin , lomefloxacin , ofloxacin , and pefloxacin ) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues. excellent activity against gram-negative aerobic bacteria; they had limited activity against gram-positive organisms. Several newer agents have improved activity against gram-positive cocci . Norfloxacin is the least active against both gram-negative and gram-positive organisms . Ciprofloxacin, enoxacin , lomefloxacin , levofloxacin , ofloxacin , and pefloxacin comprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against gram-positive bacteria. MICs for gram-negative cocci and bacilli, including Enterobacter sp, P aeruginosa , Neisseria meningitides , H aemophilus sp, and C ampylobacter jejuni , are 1–2 mcg/ mL and often less. Methicillin -susceptible strains of S aureus are generally susceptible to these fluoroquinolones , but methicillin -resistant strains of staphylococci are often resistant. Streptococci and enterococci tend to be less susceptible than staphylococci, and efficacy in infections caused by these organisms is limited. Ciprofloxacin is the most active agent of this group against gram-negative organisms , P aeruginosa in particular. Levofloxacin , the L-isomer of ofloxacin , has superior activity against gram-positive organisms, including Streptococcus pneumoniae .   Gatifloxacin , gemifloxacin , and moxifloxacin (a third group) of fluoroquinolones with improved activity against gram positive organisms, particularly S pneumoniae and some staphylococci. Fluoroquinolones also are active against agents of atypical pneumonia ( eg , mycoplasmas and chlamydiae ) and against intracellular pathogens such as Legionella pneumophila and some mycobacteria , including Mycobacterium tuberculosis and Mycobacterium avium complex. Moxifloxacin also has modest activity against anaerobic bacteria. Because of toxicity, it is no longer use.

11. Pharmacokinetics After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%) and distributed widely in body fluids and tissues . Serum half-lives range from 3 to 10 hours. The relatively long half-lives of levofloxacin , gemifloxacin , gatifloxacin , and moxifloxacin permit once-daily dosing. Oral absorption is impaired by divalent and trivalent cations , including those in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before or 4 hours after any products containing these cations . Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Most fluoroquinolones are eliminated by renal mechanisms, either tubular secretion or glomerular filtration. Dosage adjustment is required for patients with creatinine clearances less than 50 mL /min. Dosage adjustment for renal impairment is not necessary for moxifloxacin . Nonrenally cleared fluoroquinolones are relatively contraindicated in patients with hepatic failure.

12. Clinical Uses Fluoroquinolones (other than moxifloxacin , which achieves relatively low urinary levels) are effective in urinary tract infections caused by many organisms, including P aeruginosa . These agents are also effective for bacterial diarrhea caused by Shigella , Salmonella , toxigenic E coli, and Campylobacter . Fluoroquinolones (except norfloxacin , which does not achieve adequate systemic concentrations) have been used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections , including those caused by multidrug-resistant organisms such as Pseudomonas and Enterobacter . Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax, Ciprofloxacin and levofloxacin are no longer recommended for the treatment of gonococcal infection. However, both drugs are effective in treating chlamydial urethritis or cervicitis . Ciprofloxacin, levofloxacin , or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections. These agents may be suitable for eradication of meningococci from carriers or for prophylaxis of infection in neutropenic cancer patients. With their enhanced gram-positive activity and activity against atypical pneumonia agents ( chlamydiae , Mycoplasma , and Legionella ), levofloxacin , gatifloxacin , gemifloxacin , and moxifloxacin — so-called respiratory fluoroquinolones —are effective and used increasingly for treatment of upper and lower respiratory tract infections.

13. Adverse Effects Fluoroquinolones are generally well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache , dizziness , insomnia, skin rash, or abnormal liver function tests develop . Photosensitivity has been reported with lomefloxacin and pefloxacin . QT c prolongation may occur with gatifloxacin , levofloxacin , gemifloxacin , and moxifloxacin , which should be avoided or used with caution in patients with known QT c interval prolongation or uncorrected hypokalemia ; in those receiving class IA ( eg , quinidine or procainamide ) or class III antiarrhythmic agents ( sotalol , ibutilide , amiodarone ); and in patients receiving other agents known to increase the QT c interval ( eg , erythromycin, tricyclic antidepressants). Gatifloxacin has been associated with hyperglycemia in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious effects (including some fatalities. Fluoroquinolones may damage growing cartilage and cause an arthropathy . Thus, these drugs are not routinely recommended for patients under 18 years of age. However, the arthropathy is reversible. Fluoroquinolones should be avoided during pregnancy.