Antimicrobials

1. Antimicrobials Dr. Shehla Baqi Infectious Diseases King Saud University

2. Principles of Anti-infective Therapy • Identification of infecting organism • Determining antimicrobial susceptibility • Host factors: allergies, age, pregnancy, renal and hepatic function, site of infection • Antimicrobial combinations: indications, synergism, antagonism, cost, adverse effects • Dosing: route, regimen, monitoring response/effectiveness

3. Mechanisms of Antibiotic Resistance: Molecular Genetics • Microevolutionary change: point mutation • Macroevolutionary: large segments of DNA • Plasmids • Transposable Genetic Elements: these are transposons and insertion sequences • DNA Integration Elements: integrons

4. Mechanisms of Antibiotic Resistance: Enzymatic Inhibition • B-lactamases: Broad spectrum, extended spectrum, carbenicillinase, cephamycinases, carbapenemases • Aminoglycoside Resistance-Modifying Enzymes: acetyl/nucleotidyl/phosphoryl • Chloramphenicol Acetyltransferase • Macrolide/Lincosamide/Tetracycline inactivating enzymes

5. Other Mechanisms of Antibiotic Resistance • Outer and inner membrane permeability • Antibiotic efflux: Tetracyclines, Macrolides, B-Lactams, Fluoroquinolones • Altered target sites: ribosomal, cell wall • Alteration of target enzymes • Protection of target site CONTROL ANTIBIOTIC RESISTANCE

6. PHARMOKINETICS • Bioavailability, first pass effect, distribution • Metabolism: Phase I and II, CYP system • Elimination: Renal and non-renal • Antimicrobial activity: MIC90 IC/EC50 • Concentration dependent killing • Time dependent killing • Postantibiotic effect

7. PENICILLINS • B-lactam ring • Inhibits cell wall synthesis • 5 classes based on antibacterial activity • Pharmacologic properties; PO absorption, protein binding, excretion, distribution • Adverse events: allergic, serum sickness rare, hematologic rare, renal toxicity, CNS, GI with PO forms

8. CLASSES OF PENICILLINS • Natural PCNs: PCN G and PCN V • PCNase resistant PCNs: methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin • AminoPCNs: ampicillin, amoxicillin • Carboxypenicillins: carbenicillin, ticarcillin with clavulanate • UreidoPCNs: mezlocillin, piperacillin

9. Penicillins • Natural PCN used in gas gangrene, syphilis, strep. throat and other Strep. Gp A infections • Nafcillin, dicloxacillin for MSSA, will also cover Strep. so good for cellulitis • AminoPCNs more active against enterococci. Amox better absorbed than Ampicillin • Tic-clav and Pip-Tazo extended spectrum so Pseudomonas, enterobacteraciae, anaerobes, MSSA (not MRSA), strep. so good for diabetic foot, VAP, secondary peritonitis

10. CLINICAL USES OF PENICILLINS • Meningitis • Endocarditis • Upper and lower respiratory infections • STDs • Anaerobic infections • Staphylococcal infections • Gram negative infections

11. CEPHALOSPORINS • Antimicrobial activity of sewage outflow • Chemistry • Inhibits cell wall synthesis • Classification: 4 based loosely on activity • Pharmacologic properties • Adverse reactions: hypersensitivity reactions, GI, hematologic, renal , CNS

12. Cephalosporins • First generation: PO cephalexin, IV cefazolin. More gram positive activity, also E. coli • Second generation: PO cefuroxime, loracarbef, cefaclor: IV cefuroxime and cephamycins (cefotetan and cefoxitin). Maintain G+ activity but increased G- too. Cephamycins have anaerobic coverage also.

13. CEPHALOSPORINS • 3rd generation: PO cefixime, cefpodoxime; IV cefotaxime, ceftriaxone, Ceftazidime. IV have good CNS penetration. Cefotaxime & Ceftriaxone have pneumococcal coverage. Only Ceftazidime for Pseudomonas. • 4rth generation: non PO, IV cefipime with good CSF penetration, widest spectrum of all ceph., Pseudomonas, Enterobacter, but also MSSA, pneumococcus, Strep. so febrile neutropenia drug

14. 5th Generation cephalosporins • Ceftaroline active against MRSA, VISA, VRSA, resistant pneumococci but minmal activity against enterocicci • Cover gonococcus • Gram negative activity limited to respiratory pathogens such as Moraxella and Hemophilus • Weak activity against Pseudomonas • Variable activity against anerobes Ceftobiprole covers MRSA, resistant pneumococcus and Pseudomonas

15. Other B-Lactam Antibiotics • Carbapenems: imipenem, meropenem and ertapenem, doripenem • Monobactams: aztreonam • B-Lactamase inhibitors: clavulanate, sulbactam, tazobactam

16. Carbapenems • Gram positive, gram negative, anaerobes • Strep; MSSA, not MRSA; PCN sensitive enterococcus, Morganella, Proteus, Citrobacter, Enterobacter • Mero. better Pseudomonas than Imipenem • Ertapenem not active for Pseudomonas and Acinetobacter, so not a VAP drug

17. Aztreonam • Pure gram negative coverage • No anaerobic or atypical coverage • Antipseudomonal • No major toxicities • Can use in PCN allergic • Cystitis, pyelonephritis, lower respiratory tract infections, wounds, diabetic foot but add g+ and anaerobic coverage

18. B-lactam Allergy • Classification of reactions • Risk factors for reactions • Diagnosing B-Lactam allergy • Desensitization • Cross reactivity

19. AMINOGLYCOSIDES • Isolated from soil actinomycetes • 6 membered group with amino group • Bind to m RNA of 30S subunit of ribosome • Highly soluble in water • Aminoglycoside antibacterial activity: 3 facets are concentration-dependent killing, postantibiotic effect and synergism • Rapidly bactericidal

20. Aminoglycoside Spectrum of Activity • Gram negatives: Enterobacteraciae, Hemophilus to Pseudomonas spp • MSSA, not MRSA, are inhibited • Mycobacteria, Yersinia • No activity against pneumococcus, bacteroides, Clostridium, rickettsiae, fungi • Srepto/kanamycin spectrum limited but is identical for Gentamicin, tobra & amikacin

21. Pharmacology: Aminoglycosides • Administration • Distribution: vascular and interstitial space; increases in edematous states, decreases in obese individuals. Low concentrations in bronchial secretions, CSF. High in urine. • Renal excretion • Nephrotoxicity, ototoxicity, NM blockade

22. Clinical Indications for Aminoglycosides • Empirical Therapy • Specific Therapy • Prophylaxis

23. Dosing of Aminoglycosides • Multiple Daily Dosing: Loading dose is independent of renal function. Maintenance dose adjusted to renal function, dialysis. Obtain levels • Once Daily Dosing: Less toxicity, less cost, increased efficacy, simpler. Not to be used in endocardidtis. Obtain serum levels. Can also obtain random level and use nomogram

24. Polymyxins • Old drug, but now increasingly in use for MDRO • We use Colistin (polymyxin E), now higher doses • Purely gram negative coverage • Bactericidal, does not go into lung parenchyma well, so Colistin nebulizers used in HAP/VAP • Monotherapy has poor results so combine with carbapenems always even if resistant • Nephrotoxicity, neurotoxicity but less than thought

25. TETRACYCLINES • Broad-spectrum, widely used. • Used in animal feeds, so resistance. • Inhibit protein synthesis by binding to 30S ribosomal subunit • Short acting: Tetracycline • Intermediate acting: Democlocycline • Long acting: Doxycycline, Minocycline, Tigecycline (third generation)

26. Pharmacology: Tetracyclines • Absorption • Tissue Distribution • Placenta and breast milk • Elimination, renal/hepatic insufficiency • Toxicity: allergy, photosensitivity, pigmentation, teeth/bones, GI/Liver, CNS • Food-drug and drug-drug interactions

27. Indications for Tetracyclines • Anthrax, Bartonella, Brucella, Borrelia • Chlamydia, Cholera, CAP, Coxiella, Campylobacter, Clostridium • Leptospirosis, Treponemal infections • Mycobacterium, Nocardia, Pasteurella • Rickettsial, rat-bite, louse/tick-borne fever • Prophlaxis in anthrax, malaria, plague

28. MACROLIDES: Erythromycin • Derived in 1952 from soil • PO, IV, topical; inconsistent PO absorption • Inhibits RNA-dependent protein synthesis, binds to 50S subunit of bacterial ribosome • Broad spectrum: gram positives/negatives, actinomycetes, mycobacteria, treponemes, chlamydia, mycoplasma, rickettsiae • Bacteriocidal or bacteriostatic

29. Erythromycin • Macrolide R in pneumococcus upto 36% • Group A streptococcus R 14% worldwide • Most MRSA and many MSSA resistant • Enterobacteraciae usually resistant • Good activity against B.Pertussis, Campylobacter, some G neg anaerobes, S. viridans (R in some areas), Legionella, Mycoplasma, Ureaplasma, Chlamydia

30. Erythromycin • Erratic PO absorption, so enteric-coated • High alveolar macrophage concentration • Poor CSF, synovial penetration • Biliary excretion, Motilin receptor agonist • Safe, but irritative/allergic reactions, cholestatic hepatitis, V-tach, candida superinfection, Pmcolitis. Drug-Drug interactions. Avoid estolate in pregnancy

31. USES OF ERYTHROMYCIN • Alternative to PCN • CAP but macrolide resistance high in areas • Pertussis, gastroenteritis caused by Campylobacter jejuni, anthrax, prophylaxis before colorectal surgery, bacillary angiomatosis, do not use for deep-seated Staph infections since R can emerge

32. Azithromycin/Clarithromycin • Improvement over Erythromycin, better PO absorption, less GI AEs, long ½ life, wider activity • Also bind to 50S bacterial ribosome subunit • Considered bacteriostatic, sometimes cidal • Azithro bioavailability 37%, Clarithro 50% • High conc. in alveolar macrophages, liver metabolism, adjust in severe renal insufficiency • Adverse events GI, Drug-Drug interactions

33. Uses of Clarithro/Azithromycin • CAP but R ; if hospitalized, add B-Lactam • Pharyngitis, sinusitis, otitis media, skin and soft tissue infections, Pertussis, MAC infection and prophylaxis, other Mycobacteria, Lymes, Babesia, malaria, H. pylori, Campylobacter, Cryptosporidia • Single Azithro dose for STDs, trachoma • Chronic infections in CAD

34. CLINDAMYCIN:A Lincosamide • Bind to 50S bacterial ribosomal subunit • High activity against pneumococcus and Group A streptococci, but R increasing • MSSA and some MRSA • Most anaerobes, including B. Fragilis but R seen, also in Clostridial species • PCP, Toxo, plasmodia • All Enterobacteraciae are resistant

35. Pharmacology of Clindamycin • 90% absorbed after PO • Good penetration into most tissues, except CSF. Excellent in bone • Metabolized mostly by liver, adjust dose if renal and hepatic impairment • Adverse reactions: rash, fever, diarrhea in 20%, C.difficile colitis in up to 10%, hematologic, drug-drug interactions

36. USES OF CLINDAMYCIN • Most importantly for B.fragilis and other anaerobes such as polymicrobial Gyn and intra-abdominal infections • Anaerobic broncho-pulmonary infections • Clostridium infections • Staphylococcal • Acne, bacterial vaginosis, Toxo, PCP, malaria, life threatening Group A infections

37. VANCOMYCIN • Glycopeptide • Inhibition of bacterial cell wall synthesis • Active against gram positive organisms; Staph, Strep, Enterococci, G+ anaerobes • Active against Listeria, Corynebacterium, Bacillus • No activity against gram neg organisms

38. Vancomycin: Pharmacology • Time dependent killing • IV usually, never IM, sometimes PO, intrathecal, intraventricular, intraperitoneal • Variable CSF penetration, steroid decreases • Renal clearance, monitor levels • Red man or Red neck syndrome • Ototoxicity, nephrotoxicity, neutropenia, rash, category C in pregnancy

39. Clinical uses of Vancomycin • Endocarditis • Meningitis/Ventriculitis • Osteomyelitis • Pseudomembranous Colitis • Febrile Neutropenia • Prophylaxis • Other Uses

40. STREPTOGRAMINS: Quinupristin-Dalfopristin • Active against most G +, except E. fecalis • Good MIC for Staph aureus and epidermidis, regardless of R to vanco/erythro/Clinda; Strep. Pyogenes, pneumococcus, viridans. • Active for Listeria, Corynebacterium, g+ anaerobes, clostridium, some G negatives • Uses: VRE. Faecium, MSSA, S. pyogenes

41. DAPTOMYCIN • Binds to cell membrane of G+ organisms • Similar spectrum to glycopeptides, but also against those with decreased susceptibiity • MRSA, VISA, MSSA, coagulase – Staph., Strep, pneumococcus (including R), enterococcus including VRE, G+ anaerobes • Once daily dosing, no levels needed

42. LINEZOLID: Oxazolidinone • Inhibit protein synthesis • Active against MRSA, MSSA, coag – staph, enterococcus (VRE), streptococci R also • Corynebacterium, Listeria, Bacillus • Uses: VRE, pneumonia with MRSA, pneumococcus, skin and soft tissue infections, ventriculitis, meningitis, endocarditis

43. Trimethoprim/Sulfamethoxazole • Sulfonamides inhibit bacterial growth by interfering with microbial folic acid synthesis. • Trimethoprim blocks the next enzyme step in folic acid synthesis by inhibiting DHFR • Adverse effects: GI, rash, hypersensitivty, SJS, megaloblastic marrow with prolonged use (rare)

44. Clinical Uses of TMP/SMX • Urinary tract infections, don’t use if high R, chronic suppressive therapy, prostate also • Not first choice in RTIs, otitis media, STD • Gastrointestinal infections; salmonella • Nocardia, stenotrophomonas, atypical mycobacteria, meningitis with Listeria, SBP, PCP, Toxo (both Rx and prophylaxis) • MRSA infections

45. Nalidixic acid the first, then fluorine added Inhibit bacterial synthesis, by inhibiting DNA gyrase and topoisomerase Nalidixic acid , Norfloxacin, Ciprofloxacin, Ofloxacin, Levofloxacin, Gatifloxacin, Moxifloxacin, Gemifloxacin QUINOLONES

46. Antimicrobial Activity • Aerobic gram negative bacilli such as Enterobacteraciae, Haemophilus; & G - cocci e.g. Neiserria and Moraxella • Cipro considered most potent G neg FQ • Pseudomonas: only Levo and Cipro • Streptococci: Levo/Gati/Moxi/Gemi with pneumococcal coverage i.e respiratory FQs • Agents of atypical pneumonia

47. Antimicrobial Activity • Genital pathogens • MSSA, not MRSA • Mycobacteria • Anaerobes: Gati/Moxi/Gemi • Quinolones not recommended for enterococci

48. Pharmacology of Quinolones • Good bioavailability • Vol of distribution high • Concentrations in prostate, stool, bile, lung exceeds serum, not so in saliva, bone, CSF • No renal adjustment for Moxifloxacin • Drug-drug interactions

49. ADVERSE EFFECTS • GI • CNS with c/o of mild headache, dizziness, insomnia. Delirium and seizures are rare. • Allergic and skin reactions; phototoxicity • Arthropathy, cartilage toxicity, so not peds • Tendon rupture in older patients • QT prolongation, leukopenia, eosinophilia

50. Clinical Uses of Quinolones • UTI • Prostatitis • STDs • GI and Abdominal Infections • Respirotory Tract Infections • Bone and Joint • Skin and Soft tissue in some cases