ANTIFOLATE DRUGS

Sulfonamides are derivatives of p -aminobenzoic acid (PABA)

Mechanism of Action inhibit dihydropteroate synthase inhibit incorporation of para- aminobenzoic acid (PABA) into dihydropteroic acid Mammalian cells require preformed folic acid dihydropteroate synthase

Mechanism of Action Synergists of sulfanamides Trimethoprim exerts a synergistic effect with sulfonamides potently and selectively inhibits microbial dihydrofolate reductase reduces dihydrofolate to tetrahydrofolate dihydropteroate synthase dihydrofolate reductase

Antimicrobial Activity of sulfanamide gram-positive and gram-negative bacteria nocardia, Chlamydia trachomatis Protozoa Some enteric bacteria, such as Escherichia coli, klebsiella, salmonella, shigella, and enterobacter

Resistance Sulfanamides – cause overproduction of PABA – production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides – impair permeability Trimethoprim – reduced cell permeability – overproduction of dihydrofolate reductase – production of an altered reductase with reduced drug binding

Pharmacokinetics oral, absorbable – short-, intermediate-, or long-acting absorbed from the stomach and small intestine and distributed widely to tissues and body fluids, placenta, and fetus, Protein binding varies from 20% to over 90% oral, nonabsorbable topical

Clinical Uses Sulfisoxazole and sulfamethoxazole – urinary tract infections Sulfadiazine in combination with pyrimethamine – first-line therapy for treatment of acute toxoplasmosis Sulfadoxine in combination with pyrimethamine (Fansidar) – second-line agent in treatment for malaria ORAL ABSORBABLE AGENTS

Clinical Uses Sulfasalazine (salicylazosulfapyridine) – ulcerative colitis, enteritis, and other inflammatory bowel disease ORAL NONABSORBABLE AGENTS

Clinical Uses Sodium sulfacetamide ophthalmic solution or ointment – bacterial conjunctivitis and as adjunctive therapy for trachoma mafenide (CAHIs), Silver sulfadiazine – prevention of infection of burn wounds TOPICAL AGENTS

Clinical Uses ORAL TRIMETHOPRIM – Treatment of acute urinary tract infections ORAL TRIMETHOPRIM-SULFAMETHOXAZOLE (TMP-SMZ) – treatment for P jirovecii pneumonia, – shigellosis – salmonella infections, urinary tract infections – prostatitis – nontuberculous mycobacterial infections. – Staphylococcus aureus strains, both methicillin-susceptible and methicillin- resistant, – Haemophilus sp – Moraxella catarrhalis – Klebsiella pneumoniae (but not Mycoplasma pneumoniae). – E coli

INTRAVENOUS TRIMETHOPRIM- SULFAMETHOXAZOLE moderately severe to severe pneumocystis pneumonia gram-negative bacterial sepsis enterobacter and serratia; shigellosis; typhoid fever

Adverse Effects fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea Stevens-Johnson syndrome URINARY TRACT DISTURBANCES – crystalluria, hematuria HEMATOPOIETIC DISTURBANCES – hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid

Stevens-Johnson syndrome

Adverse Effects Trimethoprim – megaloblastic anemia, leukopenia, and granulocytopenia

Drug Interaction SMX-TMP: – Phenytoin, tolbutamide, chlorpropamide, warfarin

FLUOROQUINOLONES Gemifloxacin

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

MECHANISM OF ACTION

Resistance mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV By active transport of the drug out of the bacteria – Pseudomonas and staphylococci

Pharmacokinetics well absorbed (bioavailability of 80–95%) distributed widely in body fluids and tissues Oral absorption is impaired by di- and trivalent cations (2 hours before or 4 hours after) eliminated by renal mechanisms, either tubular secretion or glomerular filtration (exception moxifloxacin)

Antibacterial Activity gram-negative aerobic bacteria newer agents have improved activity against gram- positive cocci Staphylococci (but not MRSA) E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis)

Antibacterial Activity Ciprofloxacin is the most active agent of this group against gram-negatives, Pseudomonas aeruginosa Activity against streptococci is limited to a subset of the quinolones: – levofloxacin (LEVAQUIN), gatifloxacin, and moxifloxacin (AVELOX) activity against anaerobic bacteria – Garenoxacin and gemifloxacin

Clinical Uses urinary tract infections – Pseudomonas bacterial diarrhea – shigella, salmonella, toxigenic E coli, and campylobacter infections of soft tissues, bones, joints, intra- abdominal and respiratory tract infections gonococcal infection urethritis or cervicitis – Chlamydia

Adverse Effects most common effects are nausea, vomiting,diarrhea headache, dizziness, insomnia, skin rash QT c prolongation may occur – gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin damage to cartilage and cause an arthropathy, Tendonitis – not routinely recommended for patients under 18 years of age