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SYSTEMIC ANTIBIOTICS

SYSTEMIC ANTIBIOTICS. IHAB YOUNIS,MD. ß-LACTAM ANTIBIOTICS 1-Penicillins 2-Cephalosporins. ß-lactam ring. PENICILLINS. History Penicillin was discovered by Sir Alexander Fleming working at St. Mary's Hospital in London in 1928 He observed that a plate

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SYSTEMIC ANTIBIOTICS

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  1. SYSTEMICANTIBIOTICS IHAB YOUNIS,MD

  2. ß-LACTAM ANTIBIOTICS1-Penicillins2-Cephalosporins ß-lactam ring

  3. PENICILLINS History • Penicillin was discovered by Sir Alexander Fleming working at St. Mary's Hospital in London in 1928 • He observed that a plate culture of Staphylococcus had been contaminated by a blue-green mold & that colonies of bacteria adjacent to the mold were being dissolved

  4. Curious, Alexander Fleming grew the mold in a pure culture and found that it produced a substance that killed a number of disease-causing bacteria • Naming the substance penicillin, Dr. Fleming in 1929 published the results of his investigations, noting that his discovery might have therapeutic value if it could be produced in quantity

  5. It was not until 1939 that Dr. Howard Florey and three colleagues at Oxford University began intensive research and were able to demonstrate penicillin's ability to kill infectious bacteria • As the war with Germany continued to drain industrial and government resources, the British scientists could not produce the quantities of penicillin needed for clinical trials on humans and turned to the United States for help

  6. They were quickly referred to the Peoria Lab where scientists were already working on fermentation methods to increase the growth rate of fungal cultures • Ironically, after a worldwide search, it was a strain of penicillin from a moldy cantaloupe in a Peoria market that was found to produce the largest amount of penicillin when grown in the suitable conditions

  7. Penicillin production was quickly scaled up and available in quantity to treat Allied soldiers wounded on D-Day. As production was increased, the price dropped from nearly priceless in 1940, to $20 per dose in July 1943, to $0.55 per dose by 1946 • As a result of their work, two members of the British group and Dr. Andrew J. Moyer from the Peoria Lab became Nobel laureates

  8. Physicians and the industry seem to have decided to discard penicillin. In Switzerland, long-acting slow-release penicillin preparations are not available any longer. The oral penicillin V is also being superseded more and more, whether this is justified or not remains open. Only the intravenous treatment (e.g. of meningitis or other severe infections) is still relatively indisputable

  9. Variants in clinical use 1- Benzathine penicillin(Durapen,Penicid,Lastipen,1.2 megaunit/vial) • It is slowly absorbed into the circulation, after IM injection. It is the drug-of-choice when prolonged low concentrations of penicillin are required, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose e.g. for syphilis

  10. 2- Benzylpenicillin(Penicillin G,Aqua-pen,1 megaunit/vial) • Penicillin G is typically given by a parenteralroute of administrationbecause it is unstable to thehydrochloric acidof the stomach • It is used when higher tissue concentrations of penicillin e.g. in pneumonia

  11. 3- Phenoxymethylpenicillin(Ospen tab,1megaunit;Cliacil tab,1.2megaunit) • Commonly known aspenicillin V • Itis theorally-activeform of penicillin • It is less active than benzylpenicillin, so it is only appropriate in conditions where high tissue concentrations are not required e.g. in skin infections

  12. 4- Procaine penicillin(Penicillin procain vial,100,000 IU+300,000 IU proc./vial) • is a combination of benzylpenicillin with thelocal anaestheticagentprocaine. This combination is aimed at reducing the pain and discomfort associated with a largeIMinjection of penicillin

  13. 5-Ampicillin(Ampicillin,Epicocillin,Amphpen125*-250-500 mg) • It was approved by the FDA in 1963 • Ampicillin is one of the most widely prescribed antibiotics 6- Amoxicillin(Hiconcil,Ibiamox,Amoxil,Emox,125*-250-500 mg) • It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other ß-lactam antibiotics

  14. 7-Methicillin • It is deactivated bygastric acidso, it has to be administered byinjection • Methicillin was previously used to treatinfectionscaused bypenicillin resistant bacteria, e.gstaphbut it has now been largely replaced by theoxacillinseries

  15. Mode of action: • ß-lactam antibioticswork by inhibiting the formation ofpeptidoglycancross linksin the bacterialcell wall • Theß-lactammoietyof penicillin binds to theenzyme)transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium when it multiplies

  16. Adverse effects • Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent • Anaphylaxis will occur in approximately 0.01% of patients • Common reactions include: diarrhoea, nausea, urticaria, superinfection (including candidiasis)

  17. Resistance • Resistanceto penicillin is now common amongst many hospital acquired bacteria due to the rise ofß-lactamaseproducing bacteria which secrete anenzymethat breaks down the ß-lactam ring of penicillin, rendering it harmless to the bacteria. These bacteria may remain sensitive to otherß-lactam antibiotics • Resistance also arises through modifications to the bacterial cell wall; this resistance usually extends to otherß-lactam antibiotics

  18. Methicillin-resistantStaphylococcus aureus(MRSA) • Itis a strain of theStaphylococcus aureusthat has developedantibiotic resistance, first topenicillinsince1947and later tomethicillin and related anti-staphylococcal drugsand is now widespread • MRSA causes as many as 20% of Staphylococcus aureus infections in populations that use intravenous drugs • As of early 2005, the number of deaths in the UK attributed to MRSA has been estimated by various sources to lie in the area of 800 to 955 per year

  19. While an MRSA colonisation in an otherwise healthy individual is not usually a serious matter, infection with the organism can be life-threatening to patients with deep wounds, intravenouscathetersor as asecondary infectionin patients with compromisedimmune system • The antibiotic of choice for an infected inpatient is vancomycin given intravenously. Oralclindamycinmay be used in minor soft tissue infections in outpatients

  20. Drug Interactions Penicillin should be used with caution if the patient is taking the following drugs: • Anti-inflammatories, as these may compete for elimination and result in penicillin toxicity • Oral contraceptives, as penicillin antibiotics occasionally reduce their effectiveness

  21. Cephalosporins • Discovered in the 1940s by Giuseppe Brotzu, a professor at the University of Cagliari, Sardinia • He isolated a fungus called Cephalosporium acremonium • One product of this fungus, cephalosporin C, became the prototype of our current cephalosporins

  22. Mode of action As with the penicillins, the cephalosporins inhibit a series of enzymes, known as penicillin-binding proteins, that catalyze important steps in the formation of the bacterial cell wall

  23. Antimicrobial activity • They have been grouped into “generations” on the basis of their general antimicrobial activity

  24. I-First Generation Cephalosporins -Cephalexin(Ceporex,Keflex,125*-250-500 mg tab) -Cephradine(Velosef,Farcocef 125*-,250-500-1000 mg tab) -Cefadroxil(Duricef,Curisafe,Ibidroxil,125*-250-500-1000 mg tab) • The most active of all the cephalosporins against staph & nonenterococcal streptococci • Methicillin-resistant S. aureus are usually resistant to these agents

  25. II-Second Generation Cephalosporins • Cefprozil(Cefzil,125*-250-500 mg tab) • Cefuroxime) Zinnat,Cefumax 125*-250-500 mg tab) • Cefaclor (Cefaclor,Ceclor,250-500 tab) • Have increased gram-negative activity, but decreased gram-positive activity

  26. III-Third Generation Cephalosporins • Cefotaxime (Claforan,Cefotax, 250-500-1000 mg / vial) • Ceftriaxone )Rocephin,Cefotrix,500-1000 mg / vial) • Cefoperazone (Cefobid,Cefozone500-1000 mg / vial) • Demonstrate less activity against gram-positive organisms and an increased spectrum of gram-negative activity because of greater ß-lactamase stability

  27. IV-Fourth generation cephalosporins: -Cefepime) Maxipime 500,1000 mg/vial) -Cefpirome) Cefrom,500,1000 mg/vial) • They have a greater spectrum of activity against gram-positive organisms than the third generation cephalosporins • They also have a greater resistance to ß- lactamases than the third generation cephalosporins

  28. Pharmacokinetics • 1st generation cephalosporins & cefaclor, are best absorbed from an empty stomach • First- and second-generation cephalosporins are excreted primarily by the kidney. Dosage adjustment is required for patients with renal insufficiency

  29. Because of their excellent staph & strept coverage, the first-generation agents have proved to be excellent choices for the treatment of many skin and soft-tissue infections • Most comparative studies have not shown major differences in clinical efficacy of different cephalosporins in treating skin infections

  30. The second-generation agents have been effectively used to treat cellulitis when the causative organisms are H. influenzae or Enterobacteriaceae. They offer no advantage for the treatment of gram-positive aerobic organisms over the first-generation agents • The third-generation agents have also been used successfully to treat cellulitis, soft-tissue abscesses, and diabetic foot ulcers

  31. Adverse effects • The most frequent adverse reactions to cephalo-sporins are gastrointestinal • Skin reaction: urticaria, maculopapular eruptions and pruritus have been reported in frequencies varying from 1% to 3% • Approximately 5% to 10% of patients allergic to penicillins also will be allergic to cephalosporins

  32. ß-LACTAM ANTIBIOTIC/ß-LACtaMASE INHIBITOR COMBINATIONS • In 1940, soon after the introduction of penicillin, Abraham and Chain in Oxford discovered an enzyme (penicillinase) capable of inactivating penicillin & later other ß-lactam antibiotics e.g. cephalosporins; therefore the name was changed to ß-lactamase • ß-lactamase inhibitors, when combined with existing ß-lactam antibiotics, act synergistically to inhibit ß-lactamases

  33. Formulations available: • Amoxicillin-clavulanate (Augmentin, Megamox,Hibiotic,156*-375-625-1000-1200 tab & vial) • Ampicillin-sulbactam (Unasyn, Unictam,250*-375-750-1500 tab & vial)

  34. Antibacterial activity • In vitro activity is significant for Staph, Haemophilus, Klebsiella, E. coli, and Proteus

  35. Pharmacokinetics • Bioavailability of amoxicillin/clavulanic acid are unaffected by food • Serum concentrations are higher and half-lives of the combinations are prolonged in patients with renal impairment, thereby necessitating dosage adjustments

  36. Dermatologic indications • Ideally suited for the treatment of serious infections of the skin and soft tissue when polymicrobial organisms are suspected • Amoxicillin/clavulanic acid is the recommended oral agent after animal or human bites in which both aerobic and anaerobic organisms may be pathogens • These drugs often have no advantage for infections caused by single pathogens

  37. Adverse effects • Gastrointestinal complaints are common, with diarrhea occurring more frequently with use of amoxicillin/clavulanic acid (10%) • Sulbactam has been associated with pain at the intramuscular injection site, usually lasting 5 minutes to 1 hour. To minimize this, the powder may be diluted with lidocaine before injection

  38. MACROLIDES • Erythromycin(Erythrocin,Erythrocid,Erythrin,200*-250-500 tab) , the prototype of the macrolide antibiotics, was isolated in 1952 from the metabolic products of a strain of Streptomyces erythreus obtained from the soil samples in the Philippines • The new macrolides are: -Clarithromycin (Klacid,125*-250-500 tab) - Azithromycin (Zithromax,Azrolid,Zisrocin ,200*-250-500 tab)

  39. Mode of action They penetrate the cell walls of susceptible bacteria and reversibly bind to the 50S subunit of the ribosome, inhibiting RNA-dependent protein synthesis

  40. Antibacterial activity • In vitro, clarithromycin is generally equivalent to or 2-4 fold more potent than erythromycin against gram +ve organisms such as Staph & Strept • In contrast, the activity of azithromycin against gram +ve organisms is 2-4 fold less active than erythromycin • Clarithromycin and azithromycin possess increased activity against several gram -ve pathogens • Azithromycin is 4-8 times more potent than erythromycin against Mycoplasma

  41. Pharmacokinetics • Erythromycin has an erratic oral bioavailability.The major advantage offered by the new macrolides is their consistent oral bioavailability • Clarithromycin is well absorbed, with or without food.The absorption of azithromycin is decreased with food and should be taken 1 hour before or 2 hours after a meal

  42. Clarithromycin is extensively metabolized and cleared by the kidney. As renal function declines, the half-life increases. Therefore, dosage modifications are recommended in patients with severe renal impairment • Only 20% of azithromycin is excreted unchanged in the urine, so dosage adjustments in patients with renal impairment are not necessary

  43. Dermatologic indications • Azithromycin was compared with erythromycin in 82 patients with pyoderma, abscess, infected wound, ulcer, or erysipelas.S. aureus was the most common pathogen • The dose of azithromycin was 1 gm on day 1, followed by 250 mg every day for 4 days compared with erythromycin 500 mg every 6 hours • Clinical response rates were 86% for patients receiving azithromycin and 82% for patients receiving erythromycin

  44. In a randomized trial of 146 patients with mild to moderate skin infections, clarithromycin 250 mg taken twice daily was compared with oral erythromycin 250 mg four times a day for 7 to 14 days.The most frequently isolated organisms were S. aureus and S. pyogenes • Clinical success was seen in 96% of the clarithromycin-treated patients compared with 94% in erythromycin-treated patients

  45. Drug interactions • Erythromycin & Clarithromycin inhibit the hepatic cytochrome P- 450 enzyme system leading to a decrease in the metabolic clearance ofseveral drugs e.g. theophylline, phenytoin, digoxin, warfarin, nonsedating antihistamines , and methylprednisolone • Azithromycin does not affect the cytochrome P- 450

  46. Adverse effects • Nausea, abdominal pain and diarrhea • Azithromycin and clarithromycin appear to be well tolerated. Both cause fewer adverse gastrointestinal reactions (approximately 3% of patients) than erythromycin ) 5.8%)

  47. FLUOROQUINOLONES • The first quinolone, nalidixic acid, was introduced in 1962 • It had numerous clinical limitations, such as rapid emergence of resistance, narrow spectrum of activity, and frequent side effects • However, the introduction of a fluorine atom resulted in second-, third-, and fourth-generation fluoroquinolones, which have improved coverage of gram-positive organisms

  48. Quinolone generations I-First generation:Nalidixic acid (Nalidram,500 tab) II-Second generation:    Lomefloxacin (Lomex,Lomeflox,400 mg tab)Norfloxacin(Noroxin,Epinor, 400 mg tab) Ofloxacin(Tarivid,Ofloxacin, Kirol,200 mg tab)Ciprofloxacin(Ciprobay,Ciprofloxacin,Mifoxin,Serviflox,Rancif,Ciprofar,250-500-750 tab)10 generics

  49. III-Third generation:    Levofloxacin (Tavanic,Leoxin,Unibiotic,150-500 mg tab)Sparfloxacin (Sparcin,Spara,200 mg tab)Gatifloxacin (Tequin,400 mg tab or vial)Moxifloxacin (Avalox,400 mg tab) IV-Fourth generation: Trovafloxacin(Trovan tab & vial not available in Egypt)

  50. Mode of action: • Inhibition of bacterial DNA gyrase resulting in the interference of DNA replication

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