Section 9/ Chemotherapy 318 Table 9.3.1: Classification of penicillins I Penicillinase sensitive penicillins Benzyl penicillin (Penicillin G; sodium and potassium salt) Procaine penicillin G Benzathine penicillin G (PENIDURE) Phenoxymethyl penicillin (Penicillin V; KAYPEN) 0.5-5 MU* IM/IV 0.5-1 MU IM 0.6-2.4 MU IM 250-500 mg/day II Penicillinase resistant penicillin Cloxacillin (BIOCLOX) 250-500 mg hourly oral/IM/slow IV III Broad spectrum penicillins Ampicillin (BIOCILIN) Amoxycillin (NOVAMOX) 0.25-2 g hourly, oral/IM/slow IV 0.25-1 g/day IV β-Lactamase Inhibitors Clavulanic acid Sulbactam 125-250 mg/day oral, IV 0.25-1 g/day IM/IV V Antipseudomonal penicillins Carbenicillin (BIOPENCE) Piperacillin (PIPRACIL) Ticarcillin 1-2 g/day IM, 1-5 g IV 4-6 hourly 25-50 mg/kg IM/IV hourly 200-300 mg/kg/day IV 4-6 hourly * IU of crystalline sod benzyl penicillin = 0.6 mg of standard preparation (1 MU = 0.6 g or g = 1.6 million units) portion is rapidly excreted by the kidney mainly by tubular secretion and small amounts appear in bile, saliva, and milk Adverse Effects The penicillins are nontoxic and remarkably safe drug The hypersensitivity reaction leading to anaphylaxis is only major problem which is seen in approximately to 10% of the patients taking penicillin The minor adverse effects include nausea, vomiting, pain and inflammation at the site of injection after intramuscular administration has been reported After intrathecal administration (which is a contraindication) it may lead to convulsions, arachnoiditis and encephalopathy The major side effect is allergic reactions and anaphylaxis which is characterized by skin rash, pruritus, serum sickness like syndrome, eosinophilia, angioneurotic edema, asthma, haematuria, albuminuria, haemolytic anemia, granulocytopenia and anaphylaxis To avoid that, a skin test using a 10,000 U of benzyl penicillin per ml is to be done and if any local edema or wheal occurs within 15 minutes, it is considered to be as a positive test and in that person penicillin should not be used Therapeutic Uses Penicillin G is the drug of choice for the following categories of infection: • Dental infections: Penicillin G is effective in majority of infections caused by both aerobic and anaerobic bacteria in dentistry It is used in acute suppurative pulpits, pericoronitis, oral Beta Lactam Antibiotics • • • • • • • • • cellulitis, necrorotizing ulcerative gingivitis etc But due to penicillin resistance, its use in dentistry is restricted Streptococcal infections: Pharyngitis, rheumatic fever, otitis media and even for subacute bacterial endocarditis Staphylococcal infections: Penicillinase resistant penicillin can be used Meningococcal infections: Meningitis & other infections caused by meningococci Pneumococcal infections: Pneumonia and meningitis Gonococcal infection: Procaine penicillin along with probenecid can be used Sexually transmitted diseases: Penicillin is a drug of choice in the treatment of syphilis In the treatment of actinomycosis and anthrax In the treatment of diphtheria, tetanus and gas gangrene Penicillins are also used in the prophylaxis of rheumatic fever, sexually transmitted diseases e.g gonorrhoea and syphilis and bacterial endocarditis SEMISYNTHETIC PENICILLINS Semisynthetic penicillins are produced by combining the specific side chains in place of benzyl side chain They have been produced to overcome the shortcomings of benzyl penicillin like poor bioavailability, susceptibility to penicillinase and narrow spectrum of activity 319 PHENOXYMETHYL PENICILLIN It has an antibacterial spectrum similar to benzyl penicillin but is less active It is gastric acid stable and effective on oral administration Adverse effects include urticaria, fever, rashes, angioedema, anaphylaxis, haemolytic anemia, neutropenia, thrombocytopenia, coagulation disorders, diarrhoea etc It is used in tonsillitis, otitis media, erysipelas, prophylaxis of rheumatic fever and pneumococcal infections PENICILLINASE RESISTANT PENICILLIN It is resistant to degradation by penicillinase Mainly it exhibits activity against gram positive microorganisms and is useful against penicillinase producing Staph aureus CLOXACILLIN It has an isoxzalyl side chain and has weaker antibacterial activity than benzyl penicillin It is absorbed after oral administration partially and elimination occurs mainly by kidney and partly by liver It is devoid of any serious side effect but can cause hypersensitivity reaction in some patients Other analogs of cloxacillin are dicloxacillin and flucloxacillin They are relatively less protein bound, however, dicloxacillin gives approximately double the blood level than cloxacillin BROAD SPECTRUM PENICILLINS They have broad antibacterial spectrum and are effective against both gram positive and 320 gram negative organisms They are hydrolysed by penicillinase AMPICILLIN It is a broad spectrum penicillin which is not destroyed by gastric acid but is penicillinase susceptible It is more effective than benzyl penicillin against a variety of gram negative microorganisms After oral administration it is readily but incompletely absorbed and food interferes with its absorption Peak plasma level are reached within two hours after oral administration and one hour after IM administration It is excreted in urine in unchanged form and high amount is also present in the bile Adverse effects include skin rash, nausea, epigastric distress, diarrhoea, drug fever, urticaria etc It is used in infection caused by susceptible gram positive and gram negative organisms (respiratory tract, soft tissue, gonococcal, GI and genitourinary infections), septicaemia, meningitis, chronic bronchitis, otitis media, sinusitis, invasive salmonellosis and cholecystitis AMOXYCILLIN Amoxycillin is a semisynthetic penicillin, a close congener of ampicillin and active against gram positive and negative organisms Its absorption is more complete than ampicillin Food does not interfere with its absorption Its absorption after oral administration is complete hence less incidence of diarrhoea It is eliminated in urine in unchanged form Section 9/ Chemotherapy Adverse effects include nausea, epigastric distress, diarrhoea, skin rash, urticaria, serum sickness, thrombocytopenia, leucopenia, eosinophilia etc It is used in respiratory, genitourinary, skin and soft tissue, ENT infections caused by pneumococci, streptococci, staphylococci, H influenzae, E coli and other susceptible organisms Also useful in Chlamydia trachomatis in pregnancy, meningitis due to susceptible strains of gram negative microorganisms, enteric fever, gonococcal urethritis, bacteriaemia and septicaemia Amoxycillin is also used in chemoprophylaxis during dental procedures Amoxycillin is also used in combination with clavulanate potassium The formulation of amoxycillin with clavulanic acid protects amoxycillin from degradation by beta lactamase enzymes and effectively extends the antibiotic spectrum of amoxycillin to include β lactamase producing bacteria normally resistant to amoxycillin and other betalactam antibiotics Amoxycillin along with bromhexine and carbocisteine is used in bronchitis, bronchopneumonia, bronchiectasis, sinusitis and otitis media Amoxycillin along with cloxacillin is used in lower respiratory tract, skin and soft tissue, urinary tract and postoperative infections, osteomyelitis, gynaecological infections, septicaemia, bacterial endocarditis and bacterial meningitis Amoxycillin along with probenecid is used in bacterial septicaemia, skin and soft tissue infection, acute and chronic respiratory tract infections Beta Lactam Antibiotics β-LACTAMASE INHIBITORS CLAVULANIC ACID It ‘progressively’ inhibits a wide variety of β-lactamases produced by gram positive and negative organisms and is obtained from Streptomyces clavuligerus It has no antibacterial activity of its own It is used along with amoxycillin in various infections as discussed above SULBACTAM It is another semisynthetic β-lactamase inhibitor used along with ampicillin It is related to clavulanic acid both chemically and in activity Adverse effects include diarrhoea, rash, pain at site of injection and thrombophlebitis of injected vein It is indicated in gynaecological, intraabdominal, skin and soft tissue infections ANTIPSEUDOMONAL PENICILLINS These are indicated mainly to treat gram negative bacilli infection by pseudomonas, proteus and enterobacter CARBENICILLIN It is a penicillinase susceptible and is principally indicated for serious infection caused by Pseudomonas aeruginosa It is effective against certain other gram negative bacilli including Proteus species and Bacteroides fragilis Adverse effects include platelet dysfunction, hypokalemia and hypersensitivity reaction 321 It is indicated in bacteriaemia, septicaemia, genitourinary and respiratory tract infections, endocarditis and postoperative infections caused by pseudomonas or proteus PIPERACILLIN The unique advantages of piperacillin are broad spectrum of antibacterial activity and excellent antipseudomonal activity They have a synergistic effect with aminoglycosides (e.g gentamicin or netilmicin) and hence should be given concomitantly in pseudomonas septicaemia They should however, not be mixed in the same syringe Owing to the sodium content, high doses may lead to hypernatremia Adverse effects include platelet dysfunction leading to bleeding, superinfection, local pain and thrombophlebitis It is indicated in systemic and local infections, gynaecological infections, UTI, RTI, neonatal and lifethreatening paediatric infections, burns and septicaemia caused by susceptible organisms TICARCILLIN It is derived from penicillin nucleus 6aminopenicillanic acid It has broad spectrum of activity against both gram positive and negative organisms It is more potent than carbenicillin against Pseudomonas Adverse effects include hypersensitivity, thrombocytopenia, neutropenia, leucopenia, pain at the site of injection and GI disturbances It is indicated in bacterial septicaemia, skin and soft tissue infections, acute and chronic respiratory tract infections Section 9/ Chemotherapy 322 CEPHALOSPORINS Cephalosporins are important bactericidal broad spectrum β-lactam antibiotics used for the treatment of septicaemia, pneumonia, meningitis, urinary tract infections, peritonitis and biliary tract infections They are obtained from fungus Cephalosporium acremonium and are chemically related to penicillin It consists of beta lactam ring fused to a dihydrothiazine ring All cephalosporins act by inhibiting bacterial cell wall synthesis and are bactericidal Also the autolytic enzymes in cell wall may be activated leading to bacterial death They are widely distributed after administration throughout body fluids Cephalosporins are mainly excreted by the kidneys and dose should be altered in patients with renal disease Cephalosporins are classified as in table 9.3.2 Antibacterial activity: Cephalosporins are active against a wide range of gram positive and negative bacteria which includes pneumococci, C diphtheriae, E coli, N gonorrhoeae, Proteus mirabilis, S typhi and paratyphi The newer cephalosporins are effective against Pseudomonas aeruginosa In dentistry, cephalosporins is used only as alternative to penicillin or amoxycillin in patients who are allergic to penicillins The second generation cephalosporins are having good activity against oral anaerobes and are generally preferred in dentistry Pharmacokinetics Cephalosporins are distributed in the body after oral or parenteral administration in same manner as penicillin is distributed The majority are not metabolized and are eliminated by kidney Table 9.3.2: Classification of cephalosporins I First generation cephalosporins Cephalexin (SPORIDEX) Cefazolin (AZOLIN) Cefadroxil (ODOXIL) II Second generation cephalosporins Cefuroxime (CEFTUM) Cefaclor (KEFLOR) Cefoxitin III Third generation cephalosporins Cefotaxime (OMNATAX) Ceftriaxone (CEFAXONE) Ceftizoxime (CEFIZOX) Cefixime (BIOTAX-O) Cefoperazone (CEFOMYCIN) IV Fourth generation (Newer) cephalosporins Cefpirome (FORGEN) Cefepime (KEFAGE) 1-4 g QID 1-4 g/d IM/IV 0.5-1 g BD 250-500 mg BD 250-500 mg TDS 1-2 g/day IM/IV 1-2 g TDS, IM/IV 0.5-2 g OD IM/IV 1-3 g BD-TDS 200-400 mg OD-BD 1-2 g TDS IM/IV 1-2 g BD 1-2 g BD-TDS IV ... But due to penicillin resistance, its use in dentistry is restricted Streptococcal infections: Pharyngitis, rheumatic fever, otitis media and even for subacute bacterial endocarditis Staphylococcal... after oral administration and one hour after IM administration It is excreted in urine in unchanged form and high amount is also present in the bile Adverse effects include skin rash, nausea, epigastric... administration is complete hence less incidence of diarrhoea It is eliminated in urine in unchanged form Section 9/ Chemotherapy Adverse effects include nausea, epigastric distress, diarrhoea, skin