General Outline for Antibiotics

1. General Outline for Antibiotics • Chemistry –MIP • Effect on microbes - MIP • Spectrum of coverage • Mechanism(s) of action • Mechanism(s) of resistance • Pharmacology of antibiotic class – mostly new info • Absorbance • Fate after absorption • Excretion • Pharmacology of select agents – mostly new info • Therapeutic uses – somewhat new info • Toxicity/contraindications – mostly new info • Common (> 10%) • Uncommon (1-9%) • Rare (< 1%) Sir Alexander Fleming

2. Sulfonamides • Analogues of PABA • Broad spectrum • Competitive inhibitors of dihydropteroatesynthase – needed for folic acid synthesis • Cidal in urine • Mechanisms of resistance • Altered affinity of enzyme for drug • Decreased permeability or active efflux • New pathway of folic acid synthesis Gerhard Domagk gets a Nobel for Medicine, 1939.

3. Sulfonamides • Mostly absorbed from GI tract • Binds variably to serum albumin • Wide tissue distribution, including transplacentally • Variably inactivated in liver by acetylation and then excreted in urine • Some agents can precipitate in acid urine

4. Rapidly Absorbed and Eliminated Sulfonamides • Sulfisoxazole, sulfamethoxazole, sulfadiazine • Bind extensively to plasma proteins • Highly concentrated in urine (cidal) • Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI)

5. Poorly Absorbed Sulfonamides • Sulfasalazine • Poorly absorbed in GI tract • Used to treat ulcerative colitis and irritable bowel syndrome • Gut flora metabolize drug into 2 compounds, 1 toxic, 1 therapeutic (5-aminosalicylate) Ulcerative Colitis

6. Sulfonamides for Topical Use • Sulfacetamide • Good penetration in eye • Non-irritating • Silver sulfadiazine • Prevention and treatment of burn wound infections Bacterial corneal infection

7. Long Acting Sulfonamide • Sulfadoxine • Serum half-life is measured in days rather than minutes or hours • Combined with pyirethamine to treat malaria Plasmodium vivax

8. Therapeutic Uses of Sulfonamides • Urinary tract infections • Nocardiosis • Toxoplasmosis (avoid using in pregnant women) Nocardia asteroides

9. Toxicity/Contraindications of Sulfonamides - UT • Crystallization in acid urine • Common to uncommon depending on drug • Alkalize urine or increase hydration

10. Toxicity/Contraindications of Sulfonamides - blood • Acute hemolytic anemia • Rare to extremely rare • Associated with glucose-6-phosphate dehydrogenase activity in RBC • Agranulocytosis (extremely rare) • Aplastic anemia (extremely rare)

11. Toxicity/Contraindications of Sulfonamides - immune • Hypersensitivity reactions (common to uncommon) • Skin and mucous membrane manifestations (rashes) • Serum sickness • Focal or diffuse necrosis of the liver (rare)

12. Toxic Epidermal Necrolysis (TEN)

13. Toxicity/Contraindications of Sulfonamides - miscellaneous • Nausea, anorexia, vomiting (common) • Kernicterus • Displacement of bilirubin from plasma albumin to brain resulting in encephalopathy • Never give sulfa drugs to a pregnant or lactating woman • Potentiation of oral coagulants, sulfonylurea hypoglycemic drugs, and hydrantoin anticonvulsants Bilirubin deposits in neonatal brain

14. The Quinolones • Naladixic acid was a byproduct of chloroquine synthesis • Current drugs are fluoridated 4-quinolones • Broad coverage (some broader than others) • Targets DNA gyrase (G-) and topoisomerase IV (G+) • Resistance due to efflux and mutations in targets

15. Quinolones • Favorable pharmacological attributes • Orally administered, quickly absorbed, even with a full stomach • Excellent bioavailability in a wide range of tissues and body fluids (including inside cells) • Mostly cleared by the kidneys • Exceptions are pefloxacin and moxifloxacin which are metabolized by liver • Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk “Got Cipro?”

16. Therapeutic Uses of Quinolones • Urinary tract infections • Prostatitis • STD’s • Chlamydia • Chancroid • Not syphilis or gonorrhea (due to increased resistance)

17. Therapeutic Uses of Quinolones • GI and abdominal • Travelers diarrhea • Shigellosis • Typhoid fever • Respiratory tract • All work well against atypicals • New agents for strep. pneumonia

18. Therapeutic Uses of Quinolones • Bone, joint, soft tissue • Ideal for chronic osteomylitis • Resistance developing in S. aureus, P. aeruginosa, and S. marcesens • Good against polymicrobial infections like diabetic foot ulcers

19. Therapeutic Uses of Quinolones • Ciprofloxacin for anthrax and tuleremia • Combined with other drugs, useful for atypical Mycobacterium sp. or for prophylaxis in neutropenic patients Pulmonary Anthrax

20. Toxicity/Contraindications of Quinolones • Nausea, vomiting, abdominal discomfort (common) • Diarrhea and antibiotic-associated colitis (uncommon to rare) • CNS side effects • Mild headache and dizziness (common to rare) • Hallucinations, delirium, and seizures (rare) • Arthropy in immature animals (common) • Quinolones not given to children unless benefits outweigh the risks • Leukopenia, eosinophila, heart arythmias (rare)

21. The Beta-Lactams

22. Penicillins • Penicilliumnotatum produces the only naturally occuring agent – penicillin G or benzylpenicillin • Dosage and potency based on IU (1 IU = 0.6 micrograms pure penicillin G) • P. chrysogenum produces 6-aminopenicillanic acid, raw material for semi-synthetics • Dosage and potency based on weight

23. Penicillins • Spectrum of activity based on R groups added to 6-aminopenicillanic acid core • All are bactericidal and inhibit transpeptidases • Mechanisms of resistance • Alter affinity of transpeptidase • Enzymatically cleave the beta-lactam ring • Efflux pumps • Poor penetration into cell

24. Penicillins • Administered orally, intramuscularly, or intravenously depending on agent • After oral dose, widely distributed in tissues and secretions (except CNS, prostatic fluid, and the eye) • Do not kill intracellular pathogens • Food interferes with adsorption • Rapid elimination through kidney, secreted in breast milk

25. Penicillins G and V • Effective against aerobic G+ organisms except Staphylococcus, Pen G active against Neisseriaand anaerobes • 2/3 of oral Pen G destroyed by stomach acid, Pen V is more resistant so more is delivered to serum • Rapid elimination through kidney so probenecid, procaine, of benzathine added to slow excretion • Most drug is bound to serum albumin but significant amounts show up in liver, bile, kidney, semen, joint fluid, lymph, etc. • Cautious use in neonates and infants because renal function is not fully established • Patients with renal failure clear the drugs through liver although at a slow pace

26. Penicillins G and VTherapeutic Uses • Streptococcus pneumoniae infections • S. pyogenes infections • Viridans strep endocarditis (also given prophylactically) • Anaerobes except Bacteroides fragilis group • Meningococcal infections • Syphilis and other diseases caused by spirochetes

27. Isoxazolyl Penicillins • Oxacillin, cloxacillin, dicloxacillin, nafcillin • Designed to resist staphylococcal beta-lactamases • Like Pen V, stable in stomach acid but usually given parentally for serious staph infections • MRSA not covered • Absorption and fate of drugs after absorption, excretion similar to Pen G and Pen V

28. Aminopenicillins • Ampicillin and amoxicillin • Broad spectrum • Not effective against beta-lactamase producers • Beta-lactamase inhibitors extend spectrum • Both are acid resistant but amoxicillin is better absorbed, even with food • Don’t bind plasma proteins as much as predecessors • Secreted through the kidney

29. AminopenicillinsTherapeutic Uses • Upper respiratory tract infections • Otitis media • Uncomplicated UTI • Acute bacterial meningitis in kids • Typhoid fever

30. A Carboxypenicillin and a Ureidopenicillin • Ticarcillin and piperacillin • Ticarcillin is anti-Pseudomonas drug • Piperacillin + tazobactam has the broadest spectrum • Give parentally • Used for serious infections

31. Toxicity/Contraindications of Penicillins • Hypersensitivity reactions (uncommon) • Rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, SJS, anaphylaxis • Drugs act as haptens when bound to serum proteins • Rashes will disappear when drug is withdrawn or can treat with antihistamines • For patients with allergies, switch to a different class of antibiotics or try to desensitize

32. Toxicity/Contraindications of Penicillins • Pain and sterile inflammatory reaction at injection site (dose-related) • Large doses given to patients with renal failure can cause lethargy, confusion twitching and seizures • Sudden release of procaine can cause dizziness, tinnitus, headache and hallucinations • Pseudomembranous colitis

33. Cephalosporins • Base molecule is 7-aminocephalosporanic acid produced by a Sardinian sewer mold • R groups determine spectrum of activity and pharmacological properties • Mechanism of action/resistance and class pharmacology essentially the same as penicillins

34. First GenerationCephalosporins • Cefazolin, cephalexin, cephadroxil • Excellent against susceptible staph and strep • Modest activity against G- • Cefazolin given parentally, others orally • More than half of the drug is bound to plasma proteins • Excreted by kidneys unmetabolized • Good for staph and strep skin and soft tissue infections

35. Second GenerationCephalosporins • Cefaclor, cefuroxime, cefprozil • Modest activity against G+, increased activity against G-, works against anaerobes • Cefaclor and cefprozil given orally • Absorption and excretion same as first gen. • Good for treating respiratory tract infections, intra-abdominal infections, pelvic inflammatory disease, diabetic foot ulcers

36. Third GenerationCephalosporins • Ceftaxime, ceftriaxzone, cefoperazone, cefpodoxime • Broad spectrum killers • Drugs of choice for serious infections • No effect against Listeria and beta-lactamase producing pneumococci • Cefpodoxime given orally, others parentally • Most excreted by kidney • Therapeutic uses • Bacterial meningitis (2 exceptions) • Lyme disease • Life-threatening G- sepsis

37. Fourth GenerationCephalosporin • Cefepime • Same antimicrobial spectrum as third generation but resists more beta-lactamases • Given parentally, excellent penetration into CSF • Good for nosocomial infections

38. Toxicity/Contraindications of Cephalosporins • Hypersensitivity reactions (uncommon) essentially same as for penicillins • Cross-reaction between 2 classes

39. Carbapenems • Beta-lactam ring is fused to a 5 member ring system • Effect on microbes and pharmacology of carbapenems similar to penicillins

40. Select Carbapenems • Imipenem • Broad spectrum including anaerobes and Pseudomonas aeruginosa • Parentally administered • Must be combined with cilastatin to be absorbed • Excreted by kidneys • Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need co-administration with cilastatin

41. Aztrenam – a monobactam • Works only on G-, including Pseudomonas aeruginosa • Useful for treating G- infections that require a beta-lactam because it does not elicit hypersensitivity reactions

42. Toxicity/Contraindications of Carbapenems • Nausea and vomiting (common) • Hypersensitivity reactions (uncommon) • Essentially the same as for penicillins, exception is the monobactam • Cross-reactivity is possible, exception is the monobactam

43. The End? Nope.