Tetracyclines, Chloramphenicol and Chemotherapy of UTI 10 ducreyi, granuloma inguinale caused by Calymmatobacterium granulomatis As an alternative drug in the treatment of gonorrhoea and syphilis in patients allergic to penicillin Dermatological infections: Acne vulgaris, when antibiotic therapy is considered necessary Ophthalmic infections: Due to susceptible strains of N gonorrhoeae, staphylococci, H influenzae and in the treatment of trachoma Prophylaxis and treatment of Traveller’s diarrhoea Miscellaneous infections caused by susceptible strains of bacteria causing psittacosis, cholera, melioidosis, leptospirosis, brucellosis, bartonellosis, plague, tularemia, Campylobacter fetus infection, rickettsial infections including typhus and Q fever, relapsing fever due to Borrelia recurrentis and actinomycosis in penicillin allergic patients As an adjunct in acute intestinal amoebiasis Prophylaxis of malaria due to P falciparum CHLORAMPHENICOL It is a broad spectrum antibiotic originally derived from Streptomyces venezuelae and later on became the first completely synthetic antibiotic It is used as palmitate and sodium succinate salt in given dosage Dose: 250-500 mg QID oral, 1-2 g IM injection, 0.5-1.0% topical (eye ointment/ drops/applicap and ear drops) Chloramphenicol is a potent inhibitor of microbial protein synthesis It acts by 313 binding reversibly to the 50S submit of the bacterial ribosome It inhibits the peptidyl transferase step of protein synthesis It is bacteriostatic broad-spectrum antibiotic active against gram positive and negative organisms, Rickettsia, the Chlamydia of the psittacosis, lymphogranuloma group and Mycoplasma pneumoniae The other organisms sensitive to chloramphenicol are E coli, K pneumoniae, Shigella, and certain strains of Brucella, Pasteurella, Proteus and Vibrio comma It exerts bactericidal against H influenzae, Strep pneumoniae and N meningitidis Pharmacokinetics Chloramphenicol is completely absorbed after oral administration, bound to plasma protein (approximately 60%) and widely distributed in body It crosses the blood-brain and placental barrier and shows its presence in CSF, bile and milk It is conjugated with glucuronic acid in liver and excreted in urine Small amount is excreted in urine in unchanged form Adverse Effects Allergic reaction includes skin rashes, drug fever, dermatitis, angioneurotic edema Bone marrow depression includes aplastic anaemia, leukopenia, agranulocytosis, thrombocytopenia Gray baby syndrome: Premature babies develop vomiting, hypothermia, abdominal distension, shallow irregular respiration and further leading to gray cyanosis, vascular collapse, shock and death CNS toxicity includes headache, mental confusion, internal ophthalmoplegia, peripheral neuritis, depression, optical neuritis 314 Other adverse effects include superinfection, hepatotoxicity and typhoid shock Therapeutic Uses Because of bone marrow toxicity of chloramphenicol, its use is restricted to the treatment of infection caused by S typhi and paratyphi (treatment of typhoid fever) Other indications in which chloramphenicol can be used are H influenzae meningitis, urinary tract infections, anaerobic infections caused by Bacteroides fragilis and locally in eye and external ear infections CHEMOTHERAPY OF URINARY TRACT INFECTIONS URINARY ANTISEPTICS Urinary antiseptics are orally administered agents that exert antibacterial activity in the urine but have no systemic antibacterial activity Urinary antiseptics are listed as in table 9.2.2 NITROFURANTOIN It is bacteriostatic and but bactericidal against many gram positive and negative organisms in higher concentration and acidic urine Pseudomonas aeruginosa and various strains of Proteus are resistant It Section 9/ Chemotherapy antagonizes the action of nalidixic acid and its activity is enhanced by lower pH After oral administration it is rapidly and completely absorbed from GIT, metabolized in liver and less than half is excreted unchanged in urine It is used exclusively for urinary tract infections The side effects include nausea, vomiting, diarrhoea, anorexia, leukopenia, haemolytic anaemia, jaundice, dizziness and headache On chronic use can lead to peripheral neuritis and interstitial pulmonary fibrosis METHENAMINE Methenamine mandelate is a salt of mandelic acid and methenamine and both of these possess property of urinary antiseptic It is rapidly absorbed in gastrointestinal tract and excreted unchanged in urine, where it broken down in acidic pH (< 5) of urine and formaldehyde is released, which inhibits most of the bacteria It is administered with sodium biphosphate, mandelic acid or ascorbic acid to keep the urinary pH below Its use is restricted to chronic, resistant type of UTI Adverse effects are gastritis, hematuria, chemical cystitis and skin rash It is contraindicated in renal failure and hepatic insufficiency Table 9.2.2: Classification of urinary antiseptics Nitrofurantoin (FURADANTIN) 50-100 mg QID Methenamine (as mendelate & hippurate) g TDS-QID Phenazopyridine (PYRIDIUM) 200-400 mg TDS Other antimicrobial agents used in urinary tract infection e.g sulfonamides, quinolones, penicillins, cephalosporins etc (details are discussed in respective sections) Tetracyclines, Chloramphenicol and Chemotherapy of UTI PHENAZOPYRIDINE It is used for symptomatic relief of urinary burning sensation and urgency due to cystitis It is a orange dye and excreted in urine It has no antibacterial property URINARY ALKALINIZERS AND ACIDIFIERS Certain antimicrobial agents used to treat urinary tract infections act better in acidic pH i.e nitrofurantoin, tetracycline, methenamine, cloxacillin Certain other antimicrobial agents such as gentamicin, cephalosporins, fluoroquinolones, cotri- 315 moxazole act better in alkaline medium In specific cases, where urine of desired reaction (acidic or alkaline), some acidifying or alkalinizing agents is sometimes used to get a desired clinical result Urinary pH can be increased by carbonic anhydrase inhibitors (e.g acetazolamide) and prolonged therapy requires bicarbonate administration In treatment of drug poisoning, the excretion of some drugs can be hastened by acidification and alkalinization of the urine Ammonium chloride is used to acidify urine and potassium acetate/citrate is used to alkalinize urine This page intentionally left blank r r e e t t p p a CChh 9.3 1.4 Beta Lactam Pharmacodynamics (Mode of Action of Drugs) Antibiotics PENICILLINS Penicillin was originally extracted from the mould Penicillium notatum but now it is extracted from its related mould Penicillium chrysogenum due to its high yield Penicillin consists of thiazolidine ring fused with a beta lactam ring which is essential for its antibacterial activity These two rings forms a nucleus named as 6-aminopenicillanic acid Mechanism of Action The bacterial cell wall is a rigid outer layer that completely surrounds the cytoplasmic membrane Penicillin and other betalactam antibiotics inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis Penicillins are classified as in table 9.3.1 BENZYL PENICILLIN It is the most potent β-lactam antibiotic and inhibits the growth of susceptible microorganism in vitro in lowest concentration and is available in water soluble sodium and potassium salts Penicillin is effective against gram positive and negative cocci and some gram positive bacilli Among the cocci, streptococci are highly sensitive Gonococci, pneumococci and meningococci are sensitive to penicillin Among the bacilli, gram positive Bacillus anthracis, Corynebacterium diphtheriae, Clostridium species are highly sensitive Among the spirochetes, Treponema pallidum is highly sensitive to penicillin Gram negative bacilli, fungi, protozoa, rickettsiae, chlamydiae, viruses and Mycobacterium tuberculosis are totally insensitive to penicillin Pharmacokinetics After oral administration, benzyl penicillin is destroyed by gastric acid It is mainly absorbed from the duodenum It is absorbed in aqueous solution rapidly after intramuscular or subcutaneous administration Penicillin is widely distributed in the body after absorption and approximately 60% of plasma penicillin is bound to albumin The major ... consists of thiazolidine ring fused with a beta lactam ring which is essential for its antibacterial activity These two rings forms a nucleus named as 6-aminopenicillanic acid Mechanism of Action The... gastrointestinal tract and excreted unchanged in urine, where it broken down in acidic pH (< 5) of urine and formaldehyde is released, which inhibits most of the bacteria It is administered with sodium biphosphate,... respective sections) Tetracyclines, Chloramphenicol and Chemotherapy of UTI PHENAZOPYRIDINE It is used for symptomatic relief of urinary burning sensation and urgency due to cystitis It is a orange dye