Antibacterial agents jp

1. ANTIBACTERIAL AGENTS Dr R . Jaya prada

2. Antibiotics - antibacterial substances produced by various species of microorganisms (bacteria, fungi, and actinomycetes) - suppress the growth of other microorganisms. Drugs that destroy microbes, prevent their multiplication or growth or prevent their pathogenic action. Differ in their physical, chemical, and pharmacological properties. Differ in their antibacterial spectrum of activity and their mechanism of action.

3. Antibiotics = “against life” Antibiotics can be either natural products or man-made synthetic chemicals. Old : An antibiotic is a chemical substance produced by various species of microorganisms that is capable of inhibiting the growth of other microorganisms in small concentrations. New : An antibiotic is a product produced by a microorganism or a similar substance produced wholly or partially by chemical synthesis , which in low concentrations, inhibits the growth of other microorganisms.

4. Antibiotics (i.e., anti-infective or antimicrobial drugs) may be directed at one of several disease-producing organisms including bacteria, viruses, fungi, helminthes, etc. The vast majority of antibiotics are bacteria fighters; although there are millions of viruses, there are only about half a dozen antiviral drugs. Bacteria are more complex than viruses (while viruses must “live” in a host (us), bacteria can live independently, and so are easier to kill.

5. Where do antibiotics come from? Several species of fungi including Penicillium and Cephalosporium E.g. penicillin, cephalosporin Species of actinomycetes, Gram positive filamentous bacteria Many from species of Streptomyces Also from Bacillus , Gram positive spore formers A few from myxobacteria , Gram negative bacteria New sources explored: plants, herbs, fish

6. Microbes in History Date Event 300Bc Aristotle, Greek philosopher and scientist, studied and wrote about living organisms. 1675 Antony van Leeuwenhoek discovered bacteria. 1796 Edward Jenner laid the foundation for developing vaccines. 1848 Ignác Fülöp Semmelweis discovered simple handwashing could prevent passage of infection from one patient to another. 1857 Louis Pasteur introduced the germ theory of disease. 1867 Joseph Lister showed evidence that microbes caused disease and pioneered the use of antiseptics during surgery to kill germs. 1876 Robert Koch, by studying anthrax, showed the role of bacteria in disease. 1928 Alexander Fleming is credited with discovering penicillin.

7. History of Antimicrobial Therapy 1909 Paul Ehrlich Differential staining of tissue, bacteria Search for magic bullet that would attack bacterial structures, not ours. Developed salvarsan , used against syphilis ultimately proved to be too toxic for human use. Arsphenamine was the opening event in the chemotherapeutic revolution for the treatment of human infections.

8. Ehrlich’s Magic Bullets (arsenicals)

9. In 1891, the Russian Romanovsky – suggested that usage of quinine to cure malaria. Ehrlich (1854–1915) coined the term chemotherapy. Ehrlich defined chemotherapy as “the use of drugs to injure an invading organism without injury to the host.”

10. Fleming and Penicillin Alexander Fleming was first to characterize penicillin’s activity. He found mold contaminating his culture plates, with clearing of staphylococcal colonies all around the mold. Fleming then isolated penicillin from the mold.

11. Staphylococcus aureus (bacterium) Penicillium chrysogenum (fungus) Zone where bacterial growth is inhibited

12. Thanks to work by Alexander Fleming (1881-1955), Howard Florey ( 1898-1968) and Ernst Chain (1906-1979), penicillin was first produced on a large scale for human use in 1943. E. Chain H. Florey A. Fleming

13. Florey developed penicillin during WWII when it was much needed; tons of mold was grown to produce it, and was even collected from the urine of people that had first been treated with it (because it is eliminated unchanged by the kidneys). 1935- Sulfa drugs discovered. 1943 -Streptomycin discovered. Gerhard Domagk Discovered sulfanilamide Selman Waksman Antibiotics Antimicrobial agents produced naturally by organisms

14. 1905 Atoxyl Trypanosomiasis 1909 Arsphenamine Syphilis 1912 Neoarsphenamine Syphilis 1912 Tartar emetic Leishmaniasis 1917 Tartar emetic Schistosomiasis 1919 Tryparsamide Trypanosomiasis

15. Selective toxicity means safer for host Antibiotics generally have a low MIC Minimum inhibitory concentration Effective at lower doses Good therapeutic index ( Ti) Safer; larger quantity must be administered before harmful side effects occur.

16. Drug-pathogen-patient Selective toxicity- kills harmful microbes without damaging the host • Resistance- intrinsic versus acquired • host defense -Immune response • Pharmacokinetics- absorption, distribution, metabolism, elimination • Pharmacodynamics -adverse effects, dose-related, allergy, idiosyncratic

17. What is the ideal antimicrobial drug ? Have highly selective toxicity to the pathogenic microorganisms in host body Have no or less toxicity to the host. Low propensity for development of resistance. Not induce hypersensitivies in the host. Have rapid and extensive tissue distribution Be free of interactions with other drugs. Be relatively inexpensive

18. Antimicrobial drugs are chemotherapeutic drugs. • Two categories: – Antibiotics : Antimicrobial drugs produced by microorganisms. – Synthetic drugs : Antimicrobial drugs synthesized in the lab. • Antibacterial synthetic drugs • Antifungal synthetic drugs • Antiviral agents

19. Definitions Chemotherapeutic Index ( CI): the ratio of median lethal dose (LD50) to median effective dose (ED50) of infective animals. LD50/ED50 or LD5/ ED95 Generally the bigger the CI of a drug is, the lower its toxicity, the better its curative effect and the greater its value of clinical application. However, a drug with big CI does not mean that it is definitely safety. Penicillin G has almost no toxicity and its CI is big, can cause anaphylactic shock and lead to death.

20. Definitions Antimicrobial spectrum : the scope that a drug kills or suppresses the growth of microorganisms. Narrow-spectrum: The drugs that only act on one kind or one strain of bacteria. ( isoniazid ) Broad-spectrum: The drugs that have a wide antimicrobial scope. ( tetracycline,chloramphenicol )

21. Definitions Antimicrobial activity: the ability that a drug kills or suppresses the growth of microorganisms. Potency- AMA activity per mg/µg. Expressed as MIC, MBC, MAC • The minimal inhibitory concentration (MIC) the minimum amount of a drug required to inhibit the growth of bacteria in vitro. • The minimal bactericidal concentration (MBC) the minimum amount of a drug required to kill bacteria in vitro.

22. MIC 90- inhibit 90 % m/o tested MBC- to kill m/o MAC- Conc of AMA, reduces the growth of m/o in vitro by a factor of 10. It may be 1 quarter or 1/10th of the MIC depends on the drug and organism. PAE – persistence of AMA for longer period ( few hrs) after brief exposure to or in absence of detectable conc of AMA. Biphasic (Eagle’s) effect- phenomenon , Low dose- cidal whereas High dose - No effect Common in BLA because of differential sensitivity of the PBPs to high doses of BLA.

23. The molecular basis of chemotherapy The biochemical reactions that are potential targets for antibacterial drugs There are three groups. Class I : Utilization of glucose / carbon source for the generation of energy (ATP) and synthesis of simple carbon compounds used as precursors in the next class of reactions. Class II : Utilization of these precursors in an energy-dependent synthesis of all the amino acids, nucleotides, phospholipids, amino sugars, carbohydrates and growth factors required by the cell for survival and growth.

24. Class III : Assembly of small molecules into macromolecules- proteins, RNA, DNA, polysaccharides and peptidoglycon . Other potential targets are the formed structures e.g., cell membrane microtubules other specific tissues muscle tissue in helminths ).

25. Bacterial Structures Flagella Pili Capsule Plasma Membrane Cytoplasm Cell Wall Lipopolysaccharides Teichoic Acids Inclusions Spores

26. Antimicrobial Agents Effect on microbes: Cidal (killing) effect Static (inhibitory) effect Spectrum of action Broad Spectrum – effective against procaryotes which kill or inhibit a wide range of Gram+ and Gram- bacteria Narrow spectrum – effective against mainly Gram+ or Gram- bacteria Limited spectrum – effective against a single organism or disease

27. VI. Antibacterial Agents A. Inhibitors of cell wall synthesis 1. Penicillins 2. Cephalosporins 3. Other antibacterial agents that act on cell walls B. Disrupters of cell membranes 1. Polymyxins 2. Tyrocidins C. Inhibitors of protein synthesis 1. Aminoglycosides 2. Tetracyclines 3. Chloramphenicol 4. Other antibacterial agents that affect protein synthesis a. Macrolides b. Lincosamides D. Inhibitors of nucleic acid synthesis 1. Rifampin 2. Quinolones E. Antimetabolites and other antibacterial agents 1. Sulfonamides 2. Isoniazid 3. Ethambutol 4. Nitrofurans

28. Inhibition of pathogen’s attachment to, or recognition of, host Arildone Pleconaril Inhibition of DNA or RNA synthesis Actinomycin Nucleotide analogs Quinolones Rifampin Inhibition of general metabolic pathway Sulfonamides Trimethoprim Dapsone Disruption of cytoplasmic membrane Polymyxins Polyenes (antifungal) Inhibition of protein synthesis Aminoglycosides Tetracyclines Chloramphenicol Macrolides Inhibition of cell wall synthesis Penicillins Cephalosporins Vancomycin Bacitracin Isoniazid Ethambutol Echinocandins (antifungal)

29. Inhibitors of Cell Wall Synthesis Penicillin G ( benzylpenicillin ) Cephalosporin

30. Cell wall structure

31. Mechanisms of antimicrobial agents Inhibition of cell wall synthesis – Penicillins and cephalosporins stop synthesis of wall by preventing cross linking of peptidoglycan units. – Bacitracin and vancomycin also interfere here. – Excellent selective toxicity

32. Vancomycin also inhibits cell wall synthesis but it is not a β lactam AMA. It does by interfering with the production of Peptidoglycan . It binds to D-Ala-D-Ala terminals of peptido glycan precursors on the outer surface membrane. As a result precursors cannot incorporate into the peptidoglycan . Bacitracin inhibits secretion of NAG and NAM subunits

33. STRUCTURE OF -LACTAM ANTIBIOTICS

34. “Penicillin Home” Looks like a house with a new room added to the side Think of the R-group as of a funky antenna Changing “antennae” and or finishing the “basement” will create better “homes” ( penicillins )

35. [Penicillin] Home Improvement Project Adding a new antenna creates broad spectrum penicillins Example: Ampicillin Adding additional antennae and finishing the basement creates cephalosporins Example: 1st, 2nd, 3rd, & 4th generation cephalosporins

36. Penicillins Penicillins contain a b - lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-positive organisms) Penicillins are bactericidal but can act only on dividing cells They are not toxic to animal cells which have no cell wall

37. Synthesis of Penicillin b - Lactams produced by fungi , some ascomycetes , and several actinomycete bacteria b - Lactams are synthesized from amino acids valine and cysteine

38. Penicillins (cont.) Clinical Pharmacokinetics Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis) They are actively excreted unchanged by the kidney, but the dose should be reduced in severe renal failure

39. Penicillins (cont.) Resistance This is the result of production of b - lactamase in the bacteria which destroys the b - lactam ring It occurs in e.g. Staphylococcus aureus , Haemophilus influenzae and Neisseria gonorrhoea

40. Penicillins (cont.) Examples There are now a wide variety of penicillins , which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in action

41. Penicillins (cont.) Examples It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes , S. pneumoniae , Neisseria meningitis or N. gonorrhoeae , treponemes , Listeria , Actinomycetes, Clostridia Benzylpenicillin (Penicillin G) is acid labile and b - lactamase sensitive and is given only parenterally

42. Penicillins (cont.) Examples Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections it is otherwise similar to benzylpenicillin

43. Ampicillin is less active than benzylpenicillin against Gram- possitive bacteria but has a wider spectrum including (in addition in those above) Strept . faecalis , Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains It is acid stable, is given orally or parenterally , but is b - laclamase sensitive

44. Amoxycillin is similar but better absorbed orally It is sometimes combined with clavulanic acid, which is a b - lactam with little antibacterial effect but which binds strongly to b - lactamase and blocks the action of b - lactamase in this way It extends the spectrum of amoxycillin

45. Flucloxacillin is acid stable and is given orally or parenterally It is b - lactamase resistant It is used as a narrow spectrum drug for Staphylococcus aureus infections

46. Azlocillin is acid labile and is only used parenterally It is b - lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus species It is used intravenously for life-threatening infections,i.e . in immunocompromised patients together with an aminoglycoside

47. Penicillins (cont.) Adverse effects Allergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effects Superinfections ( e.g.caused by Candida ) Diarrhoea : especially with ampicillin , less common with amoxycillin Rare: haemolysis , nephritis

48. Penicillins (cont.) Drug interactions The use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation

49. Antistaphylococcus penicillins Oxacillin, cloxacillin Resistant against staphylococcus penicillinas e s

50. Cephalosporins They also owe their activity to b - lactam ring and are bactericidal. G ood alternatives to penicillins when a broad -spectrum drug is required should not be used as first choice unless the organism is known to be sensitive

51. Cephalosporins BACTERICIDAL- modify cell wall synthesis CLASSIFICATION- first generation are early compounds Second generation- resistant to β- lactamases Third generation- resistant to β- lactamases & increased spectrum of activity Fourth generation- increased spectrum of activity

52. Cephalosporins FIRST GENERATION- eg cefadroxil , cefalexin , Cefadrine - most active vs gram + ve cocci . An alternative to penicillins for staph and strep infections; useful in UTIs SECOND GENERATION- eg: cefaclor and cefuroxime . Active vs Enterobacteriaceae eg E. Coli, Klebsiella spp , proteus spp. May be active vs H. influenzae and N. meningtidis

53. c THIRD GENERATION- eg cefixime and other I.V.s cefotaxime,ceftriaxone,ceftazidime . Very broad spectrum of activity inc gram - ve rods, less activity vs gram + ve organisms. FOURTH GENERATION- cefpirome better vs gram + ve than 3rd generation. Also better vs gram - ve esp enterobacteriaceae & pseudomonas aerugenosa . I.V. route only

54. Cephalosporins (cont.) Adverse effects Allergy (10-20% of patients with penicillin allergy are also allergic to cephalosporins ) Nephritis and acute renal failure Superinfections Gastrointestinal upsets when given orally

55. Vancomycin This interferes with bacterial cell wall formation and is not absorbed after oral administration and must be given parenterally . It is excreted by the kidney. It is used i.v . to treat serious or resistant Staph. aureus infections and for prophylaxis of endocarditis in penicillin-allergic people.

56. Vancomycin Adverse effects Its toxicity is similar to aminoglycoside and likewise monitoring of plasma concentrations is essential. Nephrotoxicity Allergy

57. Ribosomes : site of protein synthesis Prokaryotic ribosome's are 70S; Large subunit: 50 S 33 polypeptides, 5S RNA, 23 S RNA Small subunit: 30 S 21 polypeptides, 16S RNA Eukaryotic are 80S Large subunit: 60 S 50 polypeptides, 5S, 5.8S, and 28S RNA Small subunit: 40S 33 polypeptides, 18S RNA

58. Baseball player slides into home The ball is fielded by the catcher who makes a CLEan TAG The word CLEean lies over the base: these inhibit  50S The word TAG lies beneath the base: these inhibit 30S Ribosome Home Plate

59. Antibiotics that Inhibit Protein Synthesis Inhibitors of initiation – complex formation and tRNA -ribosome interactions Tetracyclines & Aminoglycosides

60. Antibiotics that Inhibit Protein Synthesis Inhibitors of peptide bond formation & translocation Chloramphenicol Erythromycin A

61. Tetracyclines Discovered in 1947 Bacteriostatic (almost always) Enter via porins (G-) and by their lipophilicity in (G+). Low toxicity, broad spectrum for both Gram- and Gram+ bacteria Selectivity results from transfer into bacterial cells but not mammalian cells Primary binding site is 30s ribosomal subunit. Prevents the attachment of amino acyl-tRNA to the ribosome and protein synthesis is stopped Resistance associated with ability of compound to permeate membranes and alteration of the target of the antibiotic by the microbe

62. Aminoglycosides (bactericidal) streptomycin , kanamycin , gentamicin , tobramycin , amikacin , netilmicin , neomycin (topical) Mode of action - The aminoglycosides irreversibly bind to the 60S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes. Spectrum of Activity -Many gram-negative and some gram-positive bacteria Resistance - Common Synergy - The aminoglycosides synergize with β - lactam antibiotics. The β - lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides .

63. Aminoglycosides Clinical pharmacokinetics These are poorly lipid soluble and, therefore, not absorbed orally Parenteral administration is required for systemic effect. They do not enter the CNS even when the meninges are inflamed. They are not metabolized.

64. Aminoglycosides Clinical pharmacokinetics They are excreted unchanged by the kidney (where high concentration may occur, perhaps causing toxic tubular demage ) by glomerular filtration (no active secretion). Their clearance is markedly reduced in renal impairment and toxic concentrations are more likely.

65. Aminoglycosides Resistance Resistance results from bacterial enzymes which break down aminoglycosides or to their decreased transport into the cells.

66. Aminoglycosides Examples Gentamicin is the most commonly used, covering Gram-negative aerobes, e.g. Enteric organisms ( E.coli , Klebsiella , S. faecalis , Pseudomonas and Proteus spp.) It is also used in antibiotic combination against Staphylococcus aureus . It is not active against aerobic Streptococci.

67. Aminoglycosides Examples Tobramycin : used for pseudomonas and for some gentamicin -resistant organisms. Some aminoglycosides,e.g . Gentamicin , may also be applied topically for local effect, e.g. In ear and eye ointments. Neomycin is used orally for decontamination of GI tract.

68. Aminoglycosides Adverse effects The main adverse effects are: Nephrotoxicity Toxic to the 8th cranial nerve ( ototoxic ), especially the vestibular division. Other adverse effects are not dose related, and are relatively rare, e.g. Allergies.

69. Macrolides ( bacteriostatic ) erythromycin , clarithromycin , azithromycin , spiramycin Mode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunit Spectrum of activity - Gram-positive bacteria, Mycoplasma , Legionella (intracellular bacterias) Resistance - Common

70. Macrolides Examples and clinical pharmacokinetics Erythromycin is acid labile but is given as an enterically coated tablet It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract. It may be given orally or parenterally

71. Macrolides Examples and clinical pharmacokinetics Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid The spectrum includes Staphylococcus aureus , Streptococcuss pyogenes , S. pneumoniae , Mycoplasma pneumoniae and Chlamydia infections.

72. Macrolides – side effects Although effective, aminoglycosides are toxic, and this is plasma concentration related. It is essential to monitor plasma concentrations ( shortly before and after administration of a dose) to ensure adequate concentrations for bactericidal effects, while minimising adverse effects, every 2-3 days.

73. Macrolides – side effects Nauzea, vomit ing Allergy Hepatitis, ototoxicity Interaction with cytochrome P450 3A4 (inhibition)

74. Chloramphenicol , Lincomycin , Clindamycin ( bacteriostatic ) Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range Resistance - Common Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.

75. Clindamycin Clindamycin , although chemically distinct, is similar to erythromycin in mode of action and spectrum. It is rapidly absorbed and penetrates most tissues well, except CNS. It is particularly useful systematically for S. aureus ( e.g.osteomyelitis as it penetrates bone well) and anaerobic infections.

76. Clindamycin Adverse effects Diarrhoea is common. Superinfection with a strain of Clostridium difficile which causes serious inflammation of the large bowel ( Pseudomembranous colitis)

77. Chloramphenicol This inhibits bacterial protein synthesis. It is well absorbed and widely distributed , including to the CNS. It is metabolized by glucoronidation in the liver. Although an effective broad-spectrum antibiotics, its uses are limited by its serious toxicity.

78. Chloramphenicol The major indication is to treat bacterial meningitis caused by Haemophilus influenzae , or to Neisseria menigitidis or if organism is unknown.It is also specially used for Rikettsia (typhus).

79. Chloramphenicol Adverse effects A rare anemia, probably immunological in origin but often fatal Reversible bone marrow depression caused by its effect on protein synthesis in humans Liver enzyme inhibition

80. Tetracyclines ( bacteriostatic ) tetracycline , minocycline and doxycycline Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl -t-RNA to the acceptor site on the 70S ribosome. Spectrum of activity - Broad spectrum; Useful against intracellular bacteria Resistance - Common Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.

81. Tetracyclines Examples and clinical pharmacokinetics Tetracycline, oxytetracycline have short half-lives. Doxycycline has a longer half-life and can be given once per day. These drugs are only partly absorbed. They bind avidly to heavy metal ions and so absorp t ion is greatly reduced if taken with food, milk, antacids or iron tablets.

82. Tetracyclines Examples and clinical pharmacokinetics They should be taken at least half an hour before food. Tetracyclines concen t rate in bones and teeth . They are excreted mostly in urine, partly in bile. They are broad spectrum antibiotics, active against most bacteria except Proteus or Pseudomonas. Resistance is frequent

83. Tetracyclines Adverse effects Gastrointestinal upsets Superinfection Discolouration and deformity in growing teeth and bones (contraindicated in pregnancy and in children < 12 years) Renal impairment (should be also avoid ed in renal disease)

84. 3- Metabolic inhibitors Sulfonamides (sulfanilamide) are structural analogs of PABA, a molecule crucial for Nucleic acid synthesis humans do not synthesize dihydropteroic acid from PABA Trimethoprim interferes in next step DHF -> THF

85. Mechanism of Action ANTIMETABOLITE ACTION

86. Sulfo n amides and trimethoprim Sulfo n amides are rarely used alone today. Trimethoprim is not chemically related but is considered here because their modes of action are complementary.

87. Sulfonamides , Sulfones ( bacteriostatic ) Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.

88. Trimethoprim , Methotrexate , ( bacteriostatic ) Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains .

89. p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Sulfonamides Trimethoprim

90. Sulfo n amides and trimethoprim Mode of action Folate is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid. Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria.

91. Sulfo n amides and trimethoprim Clinical pharmacokinetics It is the drug of choice for the treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients. Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective.

92. Sulfo n amides and trimethoprim Adverse effects Gastrointestinal upsets Less common but more serious: sul f o n amides: allergy, rash, fever, renal toxicity trimethoprim: anemia, thrombocytopenia - cotrimoxazole : aplastic anemia

93. 4-Interference with nucleic acid synthesis Bacterial DNA is negatively supercoiled Supercoiling is maintained by gyrase, a type II topoisomerase . Inhibition of gyrase and type IV topoisomerase interferes with DNA replication, causes cell death Eukaryotic topoisomerases differ in structure

94. Quinolones (bactericidal) nalidixic acid , ciprofloxacin , ofloxacin , norfloxacin , levofloxacin , lomefloxacin , sparfloxacin Mode of action - These antimicrobials bind to the A subunit of DNA gyrase ( topoisomerase ) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. Spectrum of activity - Gram-positive cocci and urinary tract infections Resistance - Common for nalidixic acid; developing for ciprofloxacin

95. Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS

96. Quinolones Examples and clinical pharmacokinetics Nalidixic acid , the first quinolone , is used as a urinary antiseptic and for lower urinary tract infe c tions , as it has no systemic antibacterial effect. Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas,

97. Quinolones Examples and clinical pharmacokinetics It can be given orally or i.v . to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such Salmonella. Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.

98. Quinolones Adverse effects Gastrointestinal upsets Fluoroquinolones may block the inhibitory neurotransmitter, and this may cause confusion in the elderly and lower the fitting threshold. Allergy and anaphylaxis

99. Quinolones Adverse effects Possibly damage to growing cartilage: not recommended for pregnant women and children

100. Metronidazole Metronidazole binds to DNA and blocks replication. Pharmacok i netics It is well absorbed after oral or rectal administration and can be also given i.v . It is widely distributed in the body (including into abscess cavities) It is metabolized by the liver.

101. Metronidazole Uses Metronidazole is active against anaerobic organisms (e.g. Bacteroides , Clostridia ), which are encountered particularly in abdominal surgery. It is also used against Trichomonas , Giardia and Entamoeba infections

102. Metronidazole Uses Increasingly, it is used as part of treatment of Helicobacter pylori infection of the stomach and duodenum associated with peptic ulcer disease. It is used also to treat a variety of dental infections, particularly dental abscess.

103. Metronidazole Adverse effects Nausea, anorexia and metallic taste Ataxia In patients, who drink alcohol, may occur unpleasant reactions. They should be advised not to drink alcohol during a treatment.

104. Nitrofurantoin This is used as a urinary antiseptic and to treat Gram-negative infections in the lower urinary tract. It is also used against Trypanosoma infections. It is taken orally and is well absorbed and is excreted unchanged in the urine.

105. Nitrofurantoin Adverse effects Gastrointestinal upsets Allergy Polyneuritis

106. Fucidin Fucidin is active only against Staphylococcus aureus (by inhibiting bacterial protein synthesis) and is not affected b - lactamase . It is usually only used with flucloxacillin to reduce the development of resistance. It is well absorbed and widely distributed, including to bone It can be given orally or parenterally . It is metabolized in the liver.

107. Antibiotics for leprosy Leprosy is caused by infection with Mycobacteria leprae . A mixture of drugs are used to treat leprosy, depending on the type and severity of the infection and the local resistance patterns.

108. Antibiotics for leprosy Rifampicin is used, which is related to the sulphoamides . Rifampicin and Rifamycin block synthesis of m-RNA. Its adverse effects include haemolysis , gastrointestinal upsets and rashes.

109. 5- Cell membranes as targets Bacterial cell membranes are essentially the same in structure as those of eukaryotes Antibiotics also affect Gram neg. cell walls, ie . Outer membrane together with cell membrane Anti-membrane drugs are less selectively toxic than other antibiotics. Many antifungal drugs ( Polyenes as Amphotericin B, Nystatin ) make use of cell membrane differences.

110. Cell membrane disruptors Amphotericin B binds to ergosterol of cell membranes of fungi, causing lysis of cell Azoles ( fluconazole ) and allyamines ( terbinafine ) block ergosterol synthesis Polymixin disrupts bacterial cell membranes, but is toxic to people

111. Inhibition of the synthesis of the nucleotides Alteration of the base-pairing properties of the template Agents that intercalate in the DNA have this effect. e.g., Acridines ( proflavine and acriflavine )- topically as antiseptics. The acridines double the distance between adjacent base pairs and cause a frame shift mutation , whereas some purine and pyrimidine analogues cause base mispairing .

112. Synergy and Antagonism Synergy ; If two antibiotics used in combination have an antibacterial effect much greater than either drug alone Ex.; beta- lactams and aminoglycosides Antagonism ; When two drugs in combination have activity less than the better of the two Ex.; bactericidal and bacteriostatic

113. Antibiotic Susceptibility Testing Dilution Method Disc Diffusion Method E-test High-Tech Methods