Antibiotics

1. Antibiotics

2. מבנה דופן חיידק

5. סינתזת דופן החידק

8. Resistance mechanism • Beta-lactamases (eg. ESBLs, Carbapenemase) • Target modifying enzymes (PBP) • Drug modifying enzymes • Porin loss • Efflux pump • VISA/VRSA • VANs

9. Resistance mechanism Penicillin Binding Protein (PBP) • Low affinity of beta lactam to penicillin binding proteins (transpeptidases) • MRSA- low affinity to PBP2a (mecA gene) • Pneumococci- PBP2b, 2x • Enteroccoci- PBP5 (also some of them have beta-lactamase)

11. Resistance mechanismBeta-lactamase • Enzymes produced by some bacteria, hydrolyzing the beta-lactam ring • Plasmid, chromosomal • Class A(all inhibited by calvulanate) • Penicillinase (SA, E.coli, KP, HI, NG) • penicillinase+cefalosporinase • penicillinase+cefalosporinase+ cefalosporinase s 3 (ESBLS) • carbapenemase • Class B (metalloenzymes, not inhibited by calvulanate)) • hydrolyse penicillins, cefalosporins, carbapenems • Class C -Amp C chromosomal, induced, not inhibited by calvulanate (SPICE) • Cefalosporinase 3 • Class D • oxacillanase (usually with penicillinase, sometimes carbapenemase)

12. Resistance mechanismBeta-lactamase • ESBLs- Augmentin-S, Cefotaxime-R, Ceftazidime-R, cefamycin-S • Most of them also resistance to AG, resprim and quinolones, and beta lactam+inhibitor • Members of enterobacteriacea commonly express plasmid encoded beta lactamases (TEM, SHV) or extended beta lactamases (CTX-M) • AmpC- class C- chromosomal inducible • Augmentin-R, Cefotaxime-R, Ceftazidime-R, Cefamycin-R • Carbapenemase • PA, acinetobacter • KPC- derived from class A and contains carbapenemase

13. Resistance mechanismBeta-lactamase

14. Resistance mechanismBeta-lactamase

15. Resistance mechanism Staphylococcus aureus • Beta lactamase- resistance to penicillin • Low affinity to PBP2a (mecA gene)- resistance to methicillin (MRSA) • VISA • VRSA- VANA from enterococcus

16. Resistance mechanism- enterococci • Intrinsic resistance to AG • Modifying enzymes- acetyltransferase, adenyltransferase, phosphotransferase • Intrinsic (relative) resistance to penicillin through PBP5 (totally R to cefalosporins) • Beta lactamase- rare, fecalis, IE • VRE- • VANA– produced ligase which produces D-lactate end, resistance to vancomycin and teicoplannin • VANB- R to vancomycin

17. Beta lactams • Penicillins • Beta-lactamase inhibitors • Cephalosporins • Cephamycins • Carbapenems • Monobactams Bactericidal

18. Beta-lactamsPenicillins • Penicillin G • Antistaphylococcal penicillins • nafcillin, oxacillin, cloxacillin and dicloxacillin • Broad spectrum penicillins • Second generation (ampicillin, amoxicillin and related agents) • Third generation (carbenicillin and ticarcillin) • Fourth generation (piperacillin)

19. Beta-lactams Penicillin G- spectrum of activity • Penicillin G is highly active against: • Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci, enterococci, and oxacillin-resistant staphylococci) • Gram-positive rods such as Listeria • Gram-negative cocci such as Neisseria sp (except penicillinase-producing Neisseria gonorrhoeae) • Most anaerobes (with certain exceptions, such as Bacteroides)

20. Beta-lactams Penicillin G- spectrum of activity • Penicillin G is only bacteriostatic for enterococci • Serious infections with enterococci are generally treated with combination therapy of a cell wall active antibiotic such as penicillin, ampicillin, or vancomycin plus gentamicin or streptomycin • Penicillin G is not active against gram-negative bacilli because of poor penetration through the porin channel.

21. Beta-lactams Antistaphylococcal penicillinsnafcillin, oxacillin, cloxacillin and dicloxacillin • Inhibit penicillinase-producing staphylococci but are inactive against oxacillin-resistant staphylococci • for strains of S. aureus sensitive to oxacillin, antistaphylococcal penicillins are preferable to vancomycin • Antistaphylococcal penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria sp.

22. Beta-lactams Broad spectrum penicillins(2nd, 3rd, 4th generations) • Activity against gram-negative bacilli • None of the broad spectrum penicillins is effective against penicillinase-producing staphylococci • The third and fourth-generation penicillins are generally considered together as anti-Pseudomonal penicillins • Second generation • Ampicillin, amoxicillin • Can penetrate the porin channel of gram-negative bacteria but are not stable to beta-lactamases • Active against the majority of strains of Escherichia coli, Proteus mirabilis, Salmonella, Shigella, and Haemophilus influenzae • Active against non-type b hemophilus influenza.

23. Beta-lactams Broad spectrum penicillins(2nd, 3rd, 4th generations) • Third generation (Carbenicillin and ticarcillin) • Can penetrate the porin channel of gram-negative bacteria, but they are less active than ampicillin on a weight basis. • More resistant to the chromosomal beta-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and Pseudomonas aeruginosa. • Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa; • Ticarcillin is a disodium salt (which may cause a problem in patients with volume overload) and may cause a bleeding diathesis by inhibition of platelet function and prolongation of the bleeding time.

24. Beta-lactams Broad spectrum penicillins(2nd, 3rd, 4th generations) • Fourth generation (piperacillin) • Piperacillin is a derivative of ampicillin . • The same spectrum as carbenicillin and ticarcillin but is more active in vitro on a weight basis. • .It is more active than carbenicillin or ticarcillin against enterococci and Bacteroides fragilis • Piperacillinis somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin and more active than ticarcillin against P. aeruginosa. • Piperacillin has less effect than ticarcillin on platelet function

25. Beta-lactams Penicillins- pharmacology • Time dependent killing • High therapeutic levels in pleural, pericardial, peritoneal and synovial fluids, as well as urine • High bile level • Penetrate the CSF poorly in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy

26. Beta-lactams Beta lactamase inhibitors • A drug given in conjunction with a beta-lactam antibiotics. • The inhibitor does not have usually antibiotic activity • It inhibits activity of plasmid mediated beta lactamase • Calvulanic acid • Sulbactam • Tazobactam • Amoxicillin-calvulanate (Augmentin) • Oxacillin-sensitive SA and beta-lactamase producing HI in addition to the usual organisms inhibited by amoxocillin alone • Can be used orally for AOM, sinusitis, LRTI, UTIs and bite wounds

27. Beta-lactams Beta lactamase inhibitors • Ampicillin-sulbactam (Unasyn)- IV • Beta lactamase producing SA, HI and enterobacteriacea, anaerobes • Abdominal infections • Diabetic foot • Sulbactam has activity against AB • Ticracillin-calvulanate and piperacillin-tazobactam (timentin and tazocin) • Beta lactamase producing SA, HI, NG, enterobacteriacea and anaerobes • Not effective for ticracillin or piperacillin resistant strains of PA

28. Beta-lactams Cephalosporins • First generation (cefazolin) • Second generation • activity against Haemophilus influenzae (cefuroxime) • Cephamycin subgroup with activity against Bacteroides • Third generation • poor activity against Pseudomonas aeruginosa (cefotaxime, ceftriaxone) • good activity against Pseudomonas aeruginosa (cefoperazone and ceftazidime) • Fourth generation (cefepime)

29. Beta-lactams Cephalosporins • First and second generation should not be used to treat infections of the central nervous system • The third generation cephalosporins achieve much more reliable CSF levels in patients with meningeal irritation • Cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime are approved for the treatment of bacterial meningitis

30. Beta-lactams Cephalosporins Spectrum of activity • First generation- cefazolin • Most gram-positive cocci (including penicillinase-producing staphylococci) • Does not have clinically useful activity against enterococci, Listeria, oxacillin-resistant staphylococci, or penicillin-resistant pneumococci • Active against most strains of Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, but has little activity against indole-positive Proteus, Enterobacter, Serratia, and the non-enteric gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa. • Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae are generally resistant.

31. Beta-lactams CephalosporinsSpectrum of activity • Second generation • less active against gram-positive cocci than the first-generation agents but are more active against certain gram-negative bacilli • Two subgroups: • Activity against HI • Cephamycins- activity against bacteroides

32. Beta-lactams CephalosporinsSpectrum of activity • Second generation • Activity against HI- cefuroxime • More active than cefamezine against HI • Approved for HI meningitis but ceftriaxone preferred • Active against Beta- lactamase producing Moraxella catarrhalis • Cephamycin subgroup (active against Bacteroides)  • Cefoxitin, cefotetan • Active against gram negative the same as cefamezine • Stable to plasmid mediated beta-lactamase • prophylaxis and therapy of infections in the abdominal and pelvic cavities

33. Beta-lactams CephalosporinsSpectrum of activity • Third generation cefalosporins • stability to the common beta-lactamases of gram-negative bacilli • highly active against Enterobacteriaceae (E.coli, Proteus mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria and H. influenzae • Mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta-lactamase, are resistant to these antibiotics

34. Beta-lactams CephalosporinsSpectrum of activity • Third generation cefalosporins • Less active against most gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria,oxacillin-resistant staphylococci, and Acinetobacter • cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well

35. Beta-lactams CephalosporinsSpectrum of activity • Third generation cefalosporins • Poor activity against pseudomonas - Ceftriaxone, cefotaxime • Ceftriaxone- longest half life (6h), sludge • Activity against PA- • Ceftazidime - stable to the common plasmid-mediated beta-lactamases , highly active against Enterobacteriaceae, Neisseria, and H. influenzae, and against P. aeruginosa. • Ceftazidime has poor activity against gram-positive organisms

36. Beta-lactams CephalosporinsSpectrum of activity • Fourth-generation- cefepime • Better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli. • Similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. • Active against the Enterobacteriaceae, Neisseria, and H. influenzae (like cef3) • Greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia) • Cefepime is as active as ceftazidime for Pseudomonas aeruginosa, and is active against some ceftazidime-resistant isolates • increased all-cause mortality?

37. Beta-lactams CephalosporinsSpectrum of activity • Fifth generation- • Ceftobiprole • capable of binding to penicillin binding protein 2a, the protein conferring S. aureus resistance to beta-lactam antibiotics • It can also bind penicillin binding protein 2x in penicillin-resistant S. pneumoniae • It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it also has activity against enterococci

38. Beta-lactams CephalosporinsTreatment indicators for 3rd or 4th generation drugs • May be complicated by superinfection (particularly with enterococci or Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter, indole-positive Proteus, or P. aeruginosa infections) • Therapy of choice for gram-negative meningitis due to Enterobacteriaceae. Ceftriaxone is a therapy of choice for penicillin-resistant gonococcal infections and meningitis due to ampicillin-resistant H. influenzae. Ceftriaxone is also one of the recommended therapies for Lyme disease involving the CNS or joints

39. Beta-lactams Carbapenems • Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-lactamases and have a very broad spectrum of activity: • Gram negative organisms (including beta-lactamase producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa), including those that produce extended-spectrum beta-lactamases • Anaerobes (including B. fragilis) • Gram positive organisms (including Enterococcus faecalis and Listeria) • PA- resistance may emerge on therapy when used as single agent • Porins/membrane channels (not those used by other beta lactams)

40. Beta-lactams Carbapenems • Imipenem- • Inactivated in the proximal renal tubule by dehydropeptidase I, (prevented by co-administration of cilastatin) • Imipenem-cilastatintherapy has been associated with central nervous system (CNS) toxicity, especially evident in patients with underlying CNS disease or impaired renal function. • Imipenem should not be used for the therapy of meningitis. The dosing of imipenem should be carefully titrated; patients with glomerular filtration rates of <5 mL/min should generally not receive imipenem

41. Beta-lactams Carbapenems • Meropenem • Stable to dehydropeptisase1 • Can be administrated without cilastatin • Lower risk of seizures • Approved for bacterial meningitis • Ertapenem- • Enterobacteriacea and anaerobes but less active against PA, AB, gram positive bacteria particularly enterococci and PRSP • Doripenem

42. Monobactams • Aztreonam • Gram negative bacteria including PA • No activity against anaerobes or gram positive bacteria • Similar to AG • Absence of cross allergenicity

43. Macrolides/KetolidesAzithromycin, Clarithromycin and Telithromycin • Derivatives of erythromycin • Bind to the 50s ribosomal subunit • newer macrolides are more acid-stable than erythromycin, providing improved oral absorption, tolerance, and pharmacokinetic properties. • The newer macrolides have a broader spectrum of antibacterial activity than erythromycin • acquired resistance: • A methylase encoded by the ermB/A gene alters the macrolide binding site on the bacterial ribosome, usually confers a high degree of resistance (MLSB) • An active macrolide efflux pump encoded by the mef (macrolide efflux) gene, which confers a low to moderate degree of macrolide resistance (msrA in SA) • Pneumococcal resistance U.S- 15-20% • Azithro, clarithro, telithro have enhanced gram negative activity compared with erythromycin

44. Staphylococcus aureus Erythromycin R Clindamycin S No induction, macrolide efflux (msrA gene). Can use clindamycin D test, induction of ribosomal methylation (erm gene). Do not use clindamycin.

45. Azithromycin, Clarithromycin and Telithromycin • URT infections: erythro-sensitive SP, Hemophillus sp., M. catarrhalis, legionella, chlamidophila pneumonia, Mycoplasma pneumonia • usually active against other gram-positive organisms including Staphylococcus aureus (except for MRSA), and Group A, B, C, G streptococcus • The gram-negative spectrum includes activity against Escherichia coli, Salmonella spp, Yersinia enterocolitica, Shigella spp, Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, and Helicobacter pylori • MAC

46. Azithromycin, Clarithromycin and Telithromycin • Tissue and intracellular penetration — All macrolides and ketolides distribute and concentrate well in most body tissues and phagocytic cells • Prolonged half life- azithro • Major adverse events: • Hepatotoxicity (telithro) • GI upset 2-5% (azithro, clarithro) • Long QT- erythro, clarithro (usually with other drugs)

47. Aminoglycosides • Gentamicin, Aamikacin, Tobramycin • binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation • Treatment of serious infections caused by gram negative bacilli • Treatment of selected staphylococcal and enterococcal infections in combination with beta lactams • Antiprotozoa (paromomycin), NG (spectinomycin), mycobacteria (streptomycin) • bactericidal against susceptible aerobic gram-negative bacilli • The microbiologic activity of aminoglycosides is pH dependent

48. AminoglycosidesTwo important pharmacodynamic properties of aminoglycosides • Postantibiotic effect (PAE) • persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and excretion in vivo • described for gram-negative bacilli, also against Staphylococcus aureus (but not against other gram-positive cocci) • approximately 3 hours • Concentration-dependent killing • ability of higher concentrations of aminoglycosides (relative to the organism's MIC) to induce more rapid, and complete killing of the pathogen

49. AminoglycosidesResistance • Amikacin is usually reserved for serious gram-negative infections due to a gentamicin or tobramycin-resistant organism or as part of combination therapy against atypical mycobacterial infection • Gram negative organisms: (acquired resistance) • Inactivation of the drug by phosphorylation , adenylylation, or acetylation • Another mechanism is methylation of 16S ribosomal RNA, associated with high level resistance to all parenteral aminoglycosides in current use • Decreased accumulation of the drug

50. Aminoglycosides Resistance • Enterococci- Intrinsic resistance to low-moderate levels of aminoglycosides • synergy exists when enterococci with low-level resistance, are exposed to a combination of the aminoglycoside with a cell wall agent • increasing reports of acquired high-level enterococcal resistance to aminoglycosides (MIC >2,000)