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1. Introduction to Clinical Pharmacology Chapter 7 Antibacterial Drugs That Disrupt the Bacterial Cell Wall Nadia Amro Fall 2024 1

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4. Penicillin The first discovered natural antibiotic was Penicillin by Dr.Flemming : which was obtained from multicellular fungi, "Penicillium molds ". Penicillin is a group of compounds having 6-amino penicillanic acid, contains ring like structure termed as a 6-lactam ring. Penicillin lyses the growing bacterial cells that are building cell walls; therefore, it is considered bactericidal . Penicillin action 4

5. Penicillin • Penicillin are of two different types, 1. Natural Penicillin (directly harvested from the penicillium mold ). 2. Semi-synthetic Penicillin consists of the basic Penicillin nucleus (6-APA), but with new side chain. It includes Ampicillin, Methicillin, Penicillin V 5

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7. Bacterial cell Sites of action of penicillins , cephalosporins, and other drugs are noted, which is together termed cell wall synthesis inhibition 7

8. What Are Beta-lactam Antibiotics? class of antibiotics that contain a beta-lactam ring in their molecular structure. work by inhibiting the synthesis of the bacterial cell wall, leading to the weakening or destruction of the bacterial cell. beta-lactam antibiotics include penicillins (such as amoxicillin) cephalosporins (like ceftriaxone) carbapenems (such meropenem), monobactams (like aztreonam). 8

9. Action: targeting an enzyme called penicillin-binding protein (PBP) responsible for catalyzing the formation of cross-links between peptidoglycan strands in the bacterial cell wall. Beta-lactams, such as penicillin, cephalosporins, and carbapenems, 9

10. Selection of antibiotic based on culture and sensitivity test Bacterial resistance is the ability of bacteria to produce substances that inactivate or destroy the antibiotic. MRSA is a type of bacteria that is resistant to certain antibiotics. 10

11. Type s of penicillins Natural penicillins: narrow therapeutic spectrum Penicillinase (B-lactamase) B- lactamase inhibitore, Augmentin B- lactamase inhibitors bind with the penicillin and protect the penicillin from destruction. 11

12. natural penicillin's,(Benzylpenicillin ) narrow spectrum of activity, which means that they are effective against only a few strains of bacteria Benzylpenicillin (Pen. G) is the drug of choice in (anthrax, diphtheria, syphilis, tetanus) is mainly indicated for the treatment of: throat infections, otitis media, endocarditis, meningitis . Penicillin G benzathine given I.M 12 1- natural penicillin's

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14. 2-penicillinase- resistant penicillins (Cloxacillin & flucloxacillin ) One example of bacterial resistance is the ability of certain bacteria to produce penicillinase , an enzyme that inactivates penicillin. The penicillinase-resistant penicillins were developed to combat this problem. 14

15. Aminopenicillins are broad spectrum active against some G+ve and G- ve organisms indicated for the treatment of chronic bronchitis and mild ear infections, which are usually due to Streptococcus pneumoniae and H- influenzae. They are also indicated for: urinary- tract infections, otitis media, sinusitis, chronic bronchitis . BRANDS: Ampicillin,Ampitricine ,Ampipharm , Amoxicillin : Amoxi ,Amoxicare ,Amoxitid ,Moxypen . 15

16. Two commonly used combinations in the market are ampicillin with flucloxacillin (Megacare, Magnicillin) and amoxicillin with cloxacillin (Clamoxin). BRANDS: Orbenil 16

17. (4) extended- spectrum penicillins ( Antipseudomonal) Penicillins Extended-spectrum penicillins are effective against Pseudomonas Co- amoxiclav consists of amoxicillin and the β- lactamase inhibitor clavulanic acid . Clavulanic acid itself has no significant antibacterial activity, but by inactivating penicillinase, it makes the combination active against penicillinase- producing bacteria that are resistant to amoxicillin. These include Staph. aureus, E. coli strains, and of H. influenzae . Brands: Augmentin ,Curam , Ogmin 17

18. Penicillin : A class of antibiotics that targets bacterial cell wall synthesis, weakening the cell wall and ultimately killing the bacteria. many bacteria have developed resistance to penicillin by producing an enzyme called beta-lactamase . Beta-lactamase : This is an enzyme produced by some bacteria that can break down the beta-lactam ring, the core chemical structure of penicillin and related antibiotics, rendering them ineffective. Beta-lactamase Inhibitors : These substances are added to penicillin antibiotics to block the action of beta-lactamase enzymes. They do not have much antibiotic activity on their own but are effective at protecting penicillin from degradation. Examples of these betalactamase inhibitors are clavulanic acid, sulbactam, and tazobactam. 18 Penicillin–beta-lactamase inhibitor:

19. Penicillin–Beta-Lactamase Inhibitor Combinations Tazosin:combination of piperacillin and tazobactam 19

20. Penicillin–Beta-Lactamase Inhibitor Combinations Augmentin—combination of amoxicillin and clavulanic acid 20

21. The concentration of any drug in the body is referred to as the blood level. An inadequate concentration ( or inadequate blood level) of an antibiotic may produce bacteriostatic activity, which may or may not control the infection. Identifying the Appropriate Penicillin: Sensitivity and Resistance 21

22. Used against infectious diseases Used as initial therapy for any suspected staphylococcal infection Prescribed as prophylaxis Potential secondary bacterial infection Potential infection in high- risk patients On a continuing basis to those with rheumatic fever or chronic ear infections Penicillin Uses 22

23. Drug resistance becomes an issue when: Antibiotics are regularly used by a patient A group of people live in close proximity Bacteria: Naturally resistant or acquired resistance to drug, such as MRSA Emergence of a new resistance associated with bacteria that have both a natural and an acquired resistance ability Resistance to Drugs 23

24. MRSA :methicillin-resistant Staphylococcus aureus staphylococcal infections, including, MRSA occur most frequently among dialysis centers/weakened immune systems. Treated by fifth generation cephalosporines vancomycin -resistant enterococci (VRE) . This drug resistance is affecting severely ill, immunocompromised patients in intensive care, transplant, and some cancer treatment units. 24

25. Gastrointestinal reactions Glossitis, stomatitis, gastritis Hypersensitivity reactions Anaphylactic shock Cross-sensitivity/cross-allergenicity Superinfections: Bacterial; fungal Hematopoietic (stem cell of formation of blood cell) changes Adverse Reactions 25

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27. Contraindicated in patients with history of hypersensitivity to penicillin or the cephalosporins Use cautiously in patients with renal disease, asthma, bleeding disorders, gastrointestinal disease, pregnancy or lactation, history of allergies Reason for caution: Any indication of sensitivity Contraindications and Precautions 27

28. Interactions Interactant drug Effect of interaction with penicillin Oral contraceptives Decreased effectiveness Tetracyclines Decreased effectiveness Anticoagulants Increase bleeding risks Beta-adrenergic blocking drugs May increase the risk for an anaphylactic reaction 28 **Some penicillins , particularly in large doses, can interfere with the function of platelets

29. Effective in the treatment of all strains of bacteria affected by penicillins and some strains resistant to penicillins Classification: Divided into first- , second- , third- , fourth- , and fifth- generation drugs Uses: Treat urinary tract, bone/joint, and respiratory infections; otitis media 29

30. Exert bactericidal effect: Have a beta- lactam ring Targets the bacterial cell wall, making it defective and unstable 30

31. Used to treat infections caused by bacteria: Respiratory Ear Bone/joint Genitourinary tract Culture and sensitivity tests: Help determine best antibiotic to control an infection Used throughout perioperative period 31

32. Broad spectrum. Expensive. Resistance will develop easily and rapidly for such agents (since they are broad spectrum). 32

33. First-generation cephalosporins effective cephalosporins against gram-positive bacteria( staphylococci ), have only moderate activity against gram-negative bacteria Second-generation cephalosporins : against gram-negative organisms than first-generation drugs,less sensitive to beta-lactamase than the first-generation drugs 33

34. Third-generation cephalosporins broader spectrum against gram-negative bacteria than the second-generation group. have a longer duration of action and are resistant to beta-lactamase. The preferred drugs against infections by Pseudomonas , Klebsiella , Neisseria , Salmonella , Proteus , and H. influenzae . Third-generation drugs are able to enter the CSF to treat CNS infections 34

35. Examples on cephalosporin's 35

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37. Cephalosporins: Adverse Reactions Gastrointestinal reactions: Nausea; vomiting; diarrhea Administration route reactions: Intramuscularly and intravenously therapy with cephalosporins may result in a bacterial or fungal superinfection. -Diarrhea may be an indication of pseudomembranous colitis, 37

38. Other body system reactions: Headache; dizziness; malaise; heartburn; fever; nephrotoxicity; hypersensitivity; aplastic anemia; toxic epidermal necrolysis Nursing alert: Allergy: Approximately 10% of people allergic to penicillin are also allergic to cephalosporins 38

39. Contraindicated in patients: Allergic to cephalosporins or penicillins Used cautiously in patients with: Renal disease; hepatic impairment; bleeding disorder; pregnancy; known penicillin allergy 39

40. Drug Common use Effect of interaction Aminoglycosides Anti-infective Increased risk for nephrotoxicity Oral anticoagulants Blood thinner Increased risk for bleeding Loop diuretics Hypertension, reduce edema Increased cephalosporin blood level 40

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42. Carbapenems Carbapenems are a group of beta-lactam antibiotics that are used to treat severe or high-risk bacterial infections, especially those caused by multi-drug resistant organisms. They are often considered antibiotics of last resort, used when other antibiotics fail to treat an infection. 42

43. Inhibit synthesis of the bacterial cell wall and cause the death of susceptible cells Meropenem : Used for intra-abdominal infections; bacterial meningitis Imipenem- cilastatin: Used to treat serious infections;endocarditis; septicemia .Combined with cilastatin to decrease nephrotoxicity Ertapenem: Used to treat serious infections; bacterial community- acquired pneumonia 43

44. Monobactam— inhibits bacterial cell wall synthesis For gram negative No cross sensitivity with penicillin 44

45. Common adverse reactions: Nausea Vomiting Diarrhea Rash Abscess, tissue sloughing, or phlebitis at the injection site 45

46. Contraindicated in patients who are allergic to cephalosporins and penicillins; patients with renal failure; children younger than 3 years; pregnant/lactating women Used cautiously in patients with CNS disorders; seizure disorders; renal or hepatic failure Excretion of carbapenems: Inhibited with probenecid(drug used to increase uric acid execration in the urine) 46

47. Vancomycin—inhibits bacterial cell wall synthesis and increases cell wall permeability Carbapenems—inhibit synthesis of the bacterial cell wall 47

48. Vancomycin —inhibits bacterial cell wall synthesis and increases cell wall permeability for gram positive bacteria ,alter the structure of pbp Pharmackokienetics : Absorption : i.v not orally Distribution: water soluble /large molecule does not pass BBB Metabolism : in liver Excretion: in kidney 48

49. Vancomycin is a glycopeptide used in the treatment of serious G+ infections that do not respond to treatment with other anti-infectives. It also may be used in treating anti-infective–associated pseudomembranous colitis caused by Clostridium difficile (C.diff) (bacteria that cause infection in large intestine). can be used as a second choice if metronidazole does not work Diarrhea may be an indication of pseudomembranous colitis , which is one type of bacterial superinfection 49

50. The main reason for showing different colors is the thick peptidoglycan layer which retains the color of crystal violet for Gram-positive 50

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54. Vancomycin side effects Thrombophelebities /allergy/nephrotoxicity the most common side effects - syndrome of flushing, hypotension, tachycardia, and rash on the upper body, a condition called red man syndrome . This syndrome can be minimized by infusing the drug over at least 60 minutes . Others nausea, rash, fever, and chills. Serious: confusion, seizures, and hallucinations. If extravasation occurs lead to tissue necrosis. 54

55. The most susceptible individuals are older adults and those on high doses. Nephrotoxicity occur in patients with therapeutic concentrations but is more common if trough serum concentrations are kept above 10 mcg/ mL. Ototoxicity is associated with serum concentrations of vancomycin above 60 to 80 mcg/ mL. Tinnitus and high-tone hearing loss precede deafness and may progress even after this drug is discontinued. 55

56. Vancomycin side effects : nephrotoxicity and ototoxicity . 56