Assoc. Prof. Ivan Lambev e-mail: itlambev@mail.bg www.medpharm-sofia.eu

1. BETA-LACTAM ANTIBIOTICS Assoc. Prof. Ivan Lambev e-mail: itlambev@mail.bg www.medpharm-sofia.eu

2. Antimicrobial agents are among the most dramatic examples of the advances of modern medicine. Many infectious diseases once considered incurable and lethal now can be treated. The remarkably powerful and specific activity of antimicrobial drugs is due to their selective totoxicity for targetsthat are either unique to microorganisms or much more important in them than in humans. Among these targets are bacterial and fungal cell wall-synthesizing enzymes, the bacterial ribosome, the enzymes required for nucleotide synthesis and DNA replication, the mechanism of viral replication, etc. The much older and less selective cytotoxic drugs are the antiseptics and disinfectants.

7. Antiinfective agents may be classified according to their antimicrobial activity: 1. Antibacterial drugs (antibiotics and synthetic drugs) 2. Antiviral drugs 3. Antifungal drugs 4. Antiprotozoal drugs 5. Anthelmintic drugs 6. Insecticides for ectoparasites 7. Antiseptics and Disenfectant (Not are drugs) 8. Prepartaions for Disinsection (Not are drugs) 9. Prepartaions for Deratisation (Not are drugs) 10. Vaccines, Serums, and Immunoglobulins

8. Antibacterial drugs have been classified broadly into: 1.bacteriostatic, i.e. those that act primarily by arresting bacterial multiplication, such as tetracyclines, chloramphenicol, macrolides, lincosamides, sulphonamides, etc. 2.bactericidal, i.e. those which act primarily by killing bacteria, such as penicillins, cephalosporins, aminoglycosides, isoniazid, rifampicin, quinolones, etc.

10. ANTIBIOTICS – mechanism of action β-lactams, Glycopeptides Polymyxins Rifampicin 30S: Aminoglycosides 30S: Tetracyclines 50S: Chloramphenicol 50S: Macrolides, Lincosamides 50S: Linezolide, Streptogramins

11. Adverse Drug Reactions (ADRs) Antibacterial drugs may cause: ●direct host toxicity (aminoglycosides, peptides) ●toxic interactions with other drugs ●interference with protective effects of normal host microflora (by suppressing obligate anaerobes, for example selection or promotion of drug resistance ●tissue lesions at injection sites (tetracyclines) ●impairment of host immune or defense mechanisms (chloramphenicol)

12. ●reduced phagocytosis, and chemotactic activity of neutrophils (tetracyclines) ●inhibition of phagocytosis (aminoglycosides) ●hypersensitivity reactions (beta-lactams, aminosides, sulfonamides) ●hepatic microsomal enzyme induction (e.g. rifampin) or inhibition (e.g. chloramphenicol) that interferes with their own metabolism as well as that of concurrent medications,

13. Selection or promotion of resistance Although many previously fatal bacterial infections can now be treated successfully with antibacterial drugs, the widespread use of these agents has resulted in other problems, such as emergence of antibacterial-resistant pathogens and the resultant rising health-care costs as new drugs are developed to counteract drug resistance. Antibacterial agents do not cause bacteria to become resistant but their use preferentially selects resistant populations of bacteria. Some genes that code for resistance have been identified in bacterial cultures established before antibacterial agents were used.

14. The most clinically important being resistance plasmids. These plasmids are cytoplasmic genetic elements that can transfer drug resistance to previously susceptible bacteria. Acquired resistance is not a problem in all bacterial species. For example, Gram-positive bacteria (with some exceptions, incl. Staphylococcus spp) are often unable to acquire resistance plasmids (and thus acquire resistance through mutation, a slower process), whereas resistance is an increasing problem in many Gram-negative pathogens such as the Enterobacteriaceae.

15. BETA-LACTAM ANTIBIOTICS (inhibitors of cell wall synthesis) • Their structure contains a beta-lactam ring. • The major subdivisions are: • penicillins whose official names • usually include or end in “cillin” • (b) cephalosporins which are • recognized by the inclusion • of “cef” or “ceph” in their • official names. • (c) carbapenems (e.g. meropenem, • imipenem) • (d) monobactams (e.g. aztreonam) • (e) beta-lactamase inhibitors (e.g. • clavulanic acid, sulbactam).

16. I. PENICILLINS • A. FLEMING • (1881–1955) • Penicillin G • - P. notatum (1929)

17. The cell wall completely surrounds the cytoplasmic membrane, maintains cell shape and integrity, and prevents cell lysis from high osmotic pressure. The cell wall is composed of a complex cross-linked polymer of polysaccharides and polypeptides, peptidoglycan (murein, mucopeptide). The polysaccharide contains alternating amino sugars, N-acetylglucosamine, and N-acetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide. Cross-links give the cell wall its structural rigidity. Beta-lactam antibiotics covalently bind to the active site of PBPs.This inhibits the transpeptidation reaction, halting peptidoglycan synthesis, and the cell dies. Beta-lactams kill bacterial cells only when they are activelygrowing and synthesizing cell wall.

20. NARROW SPECTRUM PENICILLINS • Biosynthetic (natural) penicillins • Antistaphylococcal beta-lactamase • resistant penicillins • BROAD SPECTRUM PENICILLINS • Aminopenicillins • Antipseudomonal penicillins • - Carboxypenicillins • - Ureidopenicillins

21. Adverse effects The main hazard with the penicillins is allergic reaction. These include itching, rashes (eczematous or urticarial), fever, and angioedema. Rarely (about 1 in 10 000) there is anaphylactic shock which can be fatal (about 1 in 50 000 – 100 000 treatment courses). Allergies are least likely when penicillins are given orally and most likely with local application. Metabolic opening of the β-lactam ring creates ahighly reactive penicilloyl group which polymerizes and binds with tissue proteins to form the major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can be detected in the plasma of susceptible persons.

22. Amoxicillin: rash 11 hours after administration

23. There iscross-allergy betweenall the various forms of penicillin, probably due in part to their common structure, and in part to the degradation products common to them all. Partial cross-allergyexists between penicillins and cephalosporins (a maximum of 10%) which is of particular concern when the reaction to either group of antimicrobials has been angioedema or anaphylactic shock. Carbapenems and the monobactams apparently have a much lower risk of cross-reactivity.

24. When the history of allergy is not clear and it is necessary to prescribe a penicillin, the presence of of IgE antibodies in serum is a useful indicator of reactions mediated by these antibodies, i.e. immediate (type 1) reactions. Additionally, an intradermal test for allergy may be performed; appearance of a flare and wheal reaction indicates a positive response. Only about 10% of patients with a history of “penicillin allergy” respond positively.

25. Other (nonallergic) adverse effects include diarrhoea due to alteration in normal intestinal flora which may progress to Clostridium difficile-associated diarrhoea. Neutropenia is a risk if penicillins or other β-lactam antibiotics are used in high dose and usually for a period of longer than 10 days. Rarely penicillins cause anaemia, sometimes haemolytic, and thrombocytopenia or interstitial nephritis. Penicillins are presented as their sodium or potassium salts. Physicians should be aware of this unexpected source of sodium or potassium, especially in patients with renal or cardiac disease. Extremely high plasma penicillin concentrations cause convulsions. Co-amoxiclav, flucloxacillin, or oxacillin given in high doses for prolonged periods in the elderly may cause hepatic toxicity.

26. 1. NARROW SPECTRUM PENICILLINS a) Biosynthetic (natural) penicillins Benzylpenicillin (Penicillin G®) is used when high plasma concentrations are required. The short t1/2 (0.5 h) means that reasonably spaced doses have to be large to maintain a therapeutic concentration. The unusually large therapeutic ratio of penicillin allows the resulting fluctuations to be tolerable. Benzylpenicillin is eliminated by the kidney, with about 80% being actively secreted by the renal tubule and this can be blocked by probenecid.

28. Penicillin G® is a drug of choice for infections caused by streptococci, meningococci, enterococci, penicillin- susceptible pneumococci, non-β-lactamase-producing staphylococci, T. pallidum and many other spirochetes, clostridium species, actinomyces, and other Gram- positive rods and non-β-lactamase-producing Gram- negative anaerobic organisms. Depending on the organism, the site, and the severity of infection, effective doses range is between 4 and 24 million units per day administered i.m. or i.v. in 4 to 6 divided doses.High-dose Penicillin G® Sodium can also be given as a continuous i. v. infusion.

29. Phenoxymethylpenicillin Potassium (Penicillin-VK®) the oral form of penicillin, is indicated only in minor infections (e.g. tonsillitis) because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Benzathine penicillin and Procaine Penicillin G® maintain low but prolonged drug levels. A single i.m. injection of benzathine penicillin, 1.2 million units, is an effective treatment for β-hemolytic streptococcal pharyngitis; given once every 3–4 weeks, it prevents reinfection. Benzathine penicillin G, 2.4 million units i.m. once a week for 1–3 weeks, is effective in the treatment of syphilis.

30. Penicilline G Sodium® Phenoxymethylpenicillin Potassium (Penicillin-VK®)

31. Procaine penicillin G is rarely used nowadays because many strains are penicillin-resistant. • b) Antistaphylococcal penicillins • Isoxazolyl penicillins • - Cloxacillin, Dicloxacillin • - Flucloxacillin, Oxacillin • Others • - Methicillin • - Nafcillin

32. 500 mg Flucloxacillin

33. These semisynthetic penicillins are indicated for infection by beta-lactamase-producing staphylococci, although penicillin-susceptible strains of streptococci and pneumococci are also susceptible. Listeria, enterococci, and methicillin-resistant strains (MRS) of staphylococci are resistant. An isoxazolyl penicillin (cloxacillin, dicloxacillin, or oxacillin), 250–500 mg orally every 4 to 6 h (25 mg/kg/d for children), is suitable for the treatment of mild to moderate localized staphylococcal infections. All are relatively acid-stable but food interferes with their absorption, and the drugs should be administered 1 h before or after meals.

35. 2. BROAD-SPECTRUM PENICILLINS a) Aminopenicillins The aminopenicillins have identical spectrum and activity, but amoxicillin is better absorbed orally (70–90%). They are effective against streptococci, enterococci, and some Gram-negative organisms (including H. pylori) but have variable activity against staphylococci and are ineffective against P. aeruginosa. Amoxicillin and Ampicillin

37. Amoxicillin, 500 mg 3 times daily, is equivalent to the same amount of ampicillin given four times daily. These drugs are given orally to treat urinary tract infections, sinusitis, otitis, and lower respiratory tract infections. Aminopenicillins are the most active of the oral beta-lactams against penicillin-resistant pneumococci and are the preferred beta-lactams for treating infections suspected to be caused by these resistant strains.

38. Amoxicillin in VM

39. Ampicillin (but not amoxicillin) is effective for shigellosis. Ampicillin, at dosages of 4–12 g/d i.v., is useful for treating serious infections caused by penicillin- susceptible organisms, including anaerobes, enterococci, L. monocytogenes, and beta-lactamase- negative strains of Gram-negative cocci and bacilli such as E. coli, and salmonella species. Non-beta- lactamase-producing strains of H. influenzae are generally susceptible. Many Gram-negative species produce beta-lactamases and are resistant.

40. b) Antipseudomonal penicillins These drugs retain activity against streptococci and possess additional effects against Gram-negative organisms, including various Enterobacteriaceae and Pseudomonas. • Carboxypenicillins • Carbenicillin • Ticarcillin • Ureidopenicillins • Azlocillin • Mezlocillin • Piperacillin

41. Carbenicillin, the very first antipseudomonal carboxypenicillin, is obsolete. There are more active, better tolerated alternatives. A carboxypenicillin with activity similar to that of carbenicillin is Ticarcillin. It is less active than ampicillin against enterococci.

42. The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are also active against selected Gram-negative bacilli, such as K. pneumoniae. Although supportive clinical data are lacking for superiority of combination therapy over single-drug therapy, because of the propensity of P. aeruginosa to develop resistance, an antipseudomonal penicillin is frequently used in combination with an aminoglycoside or fluoroquinolone for pseudomonal infections outside the urinary tract.

43. II. CEPHALOSPORINS The nucleus of the cephalosporins, 7-aminocephalo- sporanic acid, bears a close resemblance to 6-amino- penicillanic acid. The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R1 and R2 groups has yielded hundreds of potent compounds of low toxicity. Cephalosporins can be classified into four major groups or generations, depending mainly on the spectrum of their antimicrobial activity.

44. 7-Aminocephalosporanic acid nucleus

45. Cephalosporins are similar to penicillins, but more stable to many bacterial beta-lactamases and therefore have a broader spectrum of activity. However, strains of E. coli and Klebsiella species expressing extended-spectrum beta-lactamases that can hydrolyze most cephalosporins are becoming a problem. Cephalosporins are not active against enterococci and L. monocytogenes. Klebsiella pneumoniae

46. 1. First-generation cephalosporins • cefadroxil, cefazolin, cefalexin, • cefalothin, cefapirin, cefradine • These drugs are very active against Gram-positive • cocci (such as pneumococci, streptococci, and • Staphylococci). Cephalosporins are not active • against methicillin-resistant strains of staphylococci. • E. coli, K. pneumoniae, and P. mirabilis are • often sensitive. Anaerobic cocci (e.g., peptococcus, • peptostreptococcus) are usually sensitive, but • Bacteroides fragilis is not. They do not cross BBB.

47. Cefalexin p.o.

48. Although the first-generation cephalosporins are broad spectrum and relatively nontoxic, they are rarely the drug of choice for any infection. Oral cephalosporins (cefalexin, cefadroxil, and cefradine) are absorbed from the gut to a variable extent. They may be used for the treatment of urinary tract infections, for staphylococcal, or for streptococcal infections including cellulitis or soft tissue abscess. However, oral cephalosporins should not be relied on in serious systemic infections.

49. Cefazolin penetrates well into most tissues. It is a drug of choice for surgical prophylaxis. Cefazolin (i.m./i.v.) may be a choice in infections for which it is the least toxic drug (eg, K. pneumoniae) and in persons with staphylococcal or streptococcal infections with a history of penicillin allergy. Cefazolin does not penetrate the CNS and cannot be used to treat meningitis. Cefazolin is an alternative to an antistaphylococcal penicillin for patients who are allergic to penicillin.

50. 2. Second-generation cephalosporins • cefaclor, cefamandole, cefprozil, • cefotetan, cefuroxime, cefoxitin In general, they are active against organisms inhibited by first-generation drugs, but in addition they have extended Gram-negative coverage. Klebsiellae (including those resistant to cefalothin) are usually sensitive. Cefamandole, cefuroxime, and cefaclor are active against H. influenzae but not against serratia or B. fragilis. In contrast, cefoxitin, and cefotetan are active against B. fragilis and some serratia strains but are less active against H. influenzae. As with first-generation agents, none is active against enterococci or P. aeruginosa.