Lecture 23-Antibiotic Therapy-2-Lecture Objectives Penicillins Cephalosporins Broad Spectrum Antibiotics Aminoglycoside Antibiotics

Lecture 23-Antibiotic Therapy-2-Lecture Outcomes At the end of this lecture, you should be able to: Classify giving examples & Discuss the Pharmacological actions ADRs & uses of: Penicillins Cephalosporins Broad Spectrum Antibiotics(Chloramphenicol, Tetracyclines) Aminoglycoside Antibiotics

Beta Lactams(Penicillins) Interfere with bacterial cell-wall synthesis Have high therapeutic index (remarkably non-toxic) Safe during pregnancy Allergy is the main adverse event, rarely anaphylaxis

Penicillins Four Classes Standard penicillins Antistaphylococcal penicillins Aminopenicillins Antipseudomonal penicillins

(A) Standard Penicillins Penicillin G - for parenteral therapy Penicillin V – for oral therapy Depot/Repository Penicillin: Procaine penicillin G– once a day Benzathine penicillin G – once a month Penicillin remains drug of choice for streptococcal, meningococcal infections,syphilis Penicillin with aminoglycoside for enterocococci

(B)Antistaphylococcal Penicillins Staphylococci resistant to std. penicillin Produce Pencillinase or β-lactamase Methicillin first developed but not used (due to nephro toxicity) Cloxacillin, Dicloxacillin, Oxacillin,Nafcillin All relatively acid-stable Used to treat staphylococcal infections

(C) Extended-Spectrum Penicillins (Aminopenicillins) Broad-spectrum penicillin Not effective against staphylococci, E. coli, Enterobacter, P. aeruginosa, Proteus, H. influenzae, Klebsiella, Salmonella etc. Ampicillin –preferred for IV therapy Amoxicillin- for oral therapy (better absorbed from gut) Uses: Respiratory tract infections, UTI, Meningitis- large IV dose of Ampicillin

(D) Antipseudomonal Penicillins Carboxypenicillins(Carbenicillin, Carbenicillin indanyl sodium, Ticarcillin) Ureidopenicillins (Azlocillin, Mezlocillin, Piperacillin) Spectrum same as aminopenicillin plus Pseudomonas aeruginosa Given parenterally

Penicillins-Adverse Reactions Local irritation Hypersensitivity(all penicillins are cross- sensitizing & cross-reacting) Seizures(in patients with renal insufficiency who are given very high doses) Suprainfections Jarisch–Herxheimer reaction

Salient Features: Carbapenems Imipenem, Meropenem Spectrum: streptococci, staphylococci, enterobacteriaceae, pseudomonas,B.fragilis May cause seizures in susceptible individuals Useful to treat infections resistant to other antibiotics

Four generations of Cephalosporins First generation: Active against streptococci and staphylococci Active against most E.coli, Proteus mirabilis and Klebsiella pneumoniae Cephalexin, Cefazolin, Cephalothin,Cephradine Used as alternative to penicillin in penicillin allergic individuals

Cephalosporins Second generation: Third generation: Cefaclor, Cefamandole, Cefuroxime Useful in Streptococcal, Staphylococcal and H.influenzae infections Third generation: Cefoperazone, Ceftazidime, Cefotaxime Enterobacteriaceae and H. influenzae Beta lactamase resistant Good CSF concentration Useful in meningitis and nosocomial pneumonia

Cephalosporins Fourth generation: Cefepime, Cefpirome Extended spectrum Good activity against P aeruginosa, Enterobacteriaceae, S aureus, S pneumoniae, Hemophilus, Neisseria, etc. Highly resistant to hydrolysis by many chromosomal β-lactamases & some extended-spectrum β-lactamases

Macrolides (Erythromycin- Structure) All macrolides contain a large 14- membered macrocyclic lactone ring with 1 or more deoxy sugars attached

Macrolides (Azithromycin- Structure) Azithromycin is a azalide Azithromycin has a 15-membered macrocyclic lactone ring

Macrolides-Salient Features Possess similar mechanism of action, resistance, and antimicrobial activity Reversibly bind to 50S ribosomal subunits and inhibit protein synthesis Macrolides- large lactone ring Erythromycin – prototype Others-Clarithromycin, Azithromycin, Telithromycin Usually given orally

Macrolides-Therapeutic Uses Active against-Streptococci/Staphylococci/B. pertussis/C. diphtheriae/H. pylori/M. pneumonia /Legionella & Chlamydia Drug of choice for community acquired pneumonia(Mycoplasma/Legionella/ Chlamydia) Used in respiratory tract infections Pertussis Campylobacter jejuni gastroenteritis MAC (Azalides) Alternative agents for Group A,C,G streptococcal infections, rheumatic fever prophylaxis, C. trachomatis urethritis, anthrax

Chloramphenicol Binds to 50S ribosomal subunit reversibly Prevents attachment of aminoacyl-tRNA to its binding site Amino acid substrate is unavailable for peptidyl transferase & peptide bond formation

Chloramphenicol(contd.) Broad spectrum and bacteriostatic Exerts dose dependent myelosuppression 1 in 30000 develop irreversible aplastic anemia Newborn infants lack effective glucuronide conjugation mechanism for chloramphenicol biotransformation(gray baby syndrome when dosage > 50 mg/kg/d given to infants) Seldom used now Low cost, broad spectrum and efficacy in enteric fever

Chloramphenicol-Therapeutic Uses Bacterial meningitis, alternative cephalosporin Brain abscess Enteric fever, majority are resistant Rocky Mountain spotted fever, alternative to tetracycline

Tetracyclines Broad spectrum and bacteriostatic Have four fused cyclic rings Usually used orally, IV and topical preparation are available Tetracycline/Doxy-cycline/Minocycline

Tetracyclines (contd.) Bind to 30 S ribosomal subunit Prevent binding of tRNA to mRNA Inhibit protein synthesis Chelated by cations- calcium, magnesium and aluminum containing antacids, dairy products, calcium supplementation and sucralfate

Tetracyclines(contd.) Gram +ve and Gram –ve bacteria Chlamydiae, mycoplasmas, spirochetes, rickettsial infections, Legionella species and Brucella species Useful in acne vulgaris Strong affinity for developing bone and teeth, to which they give yellow color Contraindicated in pregnant and breast feeding women and children under 8 years of age

Tetracyclines(contd.) All tetracyclines produce –ve nitrogen balance & increased BUN levels Clinically important in patients with impaired renal function Tetracyclines NOT to be used in anuric patients (with the exception of doxycycline)

Aminoglycosides-Salient Features Streptomycin, Neomycin, Gentamicin Bind to 30 S ribosomal subunit & inhibit protein synthesis Decrease accuracy of genetic code translation Proteins containing improper sequence of amino acids (nonsense proteins) are often non-functional Bactericidal action

Aminoglycosides-Salient Features Active against Gram –ve bacilli staphylococci and mycobacteria For enterococci they are combined with penicillin G or ampicillin or vancomycin

Aminoglycosides-PK Not absorbed from GIT (Minimal absorption following oral administration) Given parenterally (i.m., i.v.) Limited tissue distribution due to polarity Not metabolized & excreted unchanged by the kidney Toxicities Nephro toxicity Ototoxicity

Aminoglycosides-Therapeutic Uses Gentamicin is most frequently used against enterococci(e.g., enterococcal endocarditis) as synergistic combination with penicillins/ Vancomycin Ophthalmic preparation of gentamicin available Streptomycin can be used as part of multi drug regimen for tuberculosis and it is the drug of choice for plague, tularemia Neomycin not used parenterally but given orally in hepatic encephalopathy