ANTIBACTERIAL DRUGS.pptx

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1. ANTIBACTERIAL DRUGS YOHANA makeja

2. INTRODUCTION Sir Alexander fleming Discovered first antibiotic (1928) in his culture plate of staphylococci and named it penicillin.

3. Major divisions of bacteria-Gram + and – Reflect the important differences in the structure of their cell wall for action of many antibiotics Gram positive cell wall Simple in structure (15-50nm thick) Has peptidoglycan (50%), acidic polymer (40-45%)-makes the wall polar with negative charge and ‘protein and polysaccharides’ (5-10%) The polymer favors penetration of ionized molecules and positively charged molecules eg streptomycin

4. Gram negative cell wall Is much more complex. It comprises of Periplasmic space-contains enzymes and other components Peptidoglycan layer (2nm, 5%). Linked to outwardly projecting lipoprotein molecules Outer membrane-has lipid bilayer that contains protein molecules (outside) and lipoprotein (inside) linked to peptidoglycan layer. Other proteins form water filled trans membrane channels ( porins ) through which hydrophilic antibiotics can move freely.

5. Complex polysaccharides-forms important components of the outer surface. They differ between bacteria and responsible for their antigenicity. They are the source of endotoxin which activates the complement system in inflammation. Difficulty in penetrating this complex is the reason why some antibiotics are ineffective against gram negative bacteria. Eg P. Auroginosa has extraordinary resistance against antibiotics The wall also hinders penetration of benzylpenicillin , fucidic acid, bacitracin, vancomycin , meticilin , novobiocin and rifampicin

6. ANTIMICROBIAL AGENTS AND THEIR SITES OF ACTION

7. β- LACTAM ANTIBIOTICS

8. PENICILLINS They are effective and widely used antibiotics However they can be destroyed by bacterial amidases and beta-lactamases. Penicillins combined with other antibiotics remain crucially important in antibacterial chemotherapy.

9. Mechanism of action Work by interfering with synthesis of bacterial wall peptidoglycan After attaching to the penicillin binding protein on the bacteria they inhibit transpeptidation enzymes which cross-link peptide chain attached to peptidoglycan backbone. Final bactericidal effect is due to inactivation of inhibitor of autolytic enzymes in the cell wall. This leads to lysis of the bacterium.

10. Types of penicillins and their action Naturally occurring penicillins- benzylpenicillin (PG) and its congener including phenoxymethylpenicillin (PV). PG is the choice for many infections. Its disadvantages are poor absorption through the gut and its susceptibility to lactamases. Semisynthetic penicillin- They have side chains attached to penicillin nucleus. They include beta-lactamase resistant penicillin eg meticillin , temocillin , flucloxacillin Broad spectrum penicillin- eg . Ampicillin and amoxicillin

11. Extended spectrum penicillin- example ticarcillin and piperacillin which have antipseudomonal activity. Amoxicillin and ticarcillin are sometimes given in combination with beta-lactamase inhibitor as clavulanic acid.

12. Pharmacokinetics Absorption varies depending on stability in acidic environment and adsorption on the food substances. Parenteral preparations are also available They have wide distribution in tissues. They reach the joints, pleural and pericardial cavities, saliva, milk and across the placenta. They cross BBB when the meninges are inflamed eg in meningitis Elimination is mainly by kidneys through secretion

13. Clinical uses of penicillin Clinical uses

14. Unwanted side effects The main unwanted effects are hypersensitivity reactions caused by the degradation products of penicillin, which combine with host protein and become antigenic. Skin rashes and fever are common; a delayed type of serum sickness occurs infrequently. Much more serious is acute anaphylactic shock which, although rare, may be fatal. When given orally, penicillins , particularly the broadspectrum type , alter the bacterial flora in the gut. This can be associated with gastrointestinal disturbances and in some cases with suprainfection by other, penicillin insensitive, microorganisms leading to problems such as pseudomembranous colitis (caused by C. difficile

15. CEPHALOSPORINS AND CEPHAMYCINS Cephalosporins N and C, which are chemically related to penicillin, and cephalosporin P, a steroidal antibiotic that resembles fusidic acid, were first isolated from Cephalosporium fungus . Cephamycins are beta-lactam antibiotics produced by Streptomyces and are closely related to cephalosporins They have similar mechanism of action as penicillin. Semi-synthetic broad spectrum cepharosporins have been produced by addition of side chains to cepharosporin c nucleus.

16. Original members of the group such as cefradine , cefalexin and cefadroxil have largely been replaced with ‘second-generation’ drugs such as cefuroxime and cefaclor , or ‘third-generation’ drugs such as cefotaxime , ceftazidime , cefixime , cefpodoxime and ceftriaxone. Resistance to this group of drugs has increased because of plasmid-encoded or chromosomal beta-lactamase . Nearly all Gram-negative bacteria have a chromosomal gene coding for a beta-lactamase that is more active in hydrolyzing cephalosporins than penicillins Resistance also occurs when there is decreased penetration of the drug as a result of alterations to outer membrane proteins, or mutations of the binding-site proteins.

17. Pharmacokinetics Some cephalosporins may be given orally, but most are given parenterally , intramuscularly (which may be painful) or intravenously. After absorption, they are widely distributed in the body and some, such as cefotaxime , cefuroxime and ceftriaxone, cross the blood–brain barrier. Excretion is mostly via the kidney, largely by tubular secretion, but 40% of ceftriaxone is eliminated in the bile . Side effects Hypersensitivity reactions, very similar to those seen with penicillin , may occur, and there may be some cross sensitivity; about 10% of penicillin-sensitive individuals will have allergic reactions to cephalosporins . Nephrotoxicity has been reported (especially with cefradine ), as has drug-induced alcohol intolerance. Diarrhoea is common and can be due to C. difficile

18. Clinical uses

19. Other beta-lactam antibiotics They were produced to deal with beta-lactamase producing microorganisms resistant to penicillins . Carbapenems- imepenem is an example. Has very broad spectrum of action and acts the same way as the b-lactams. Active against many aerobic and anaerobic G-and G + organisms. However, many of the meticillin -resistant ’ staphylococci are less susceptible, and resistant strains of P. aeruginosa have emerged during therapy. Other drugs in the grou are meropenem and etarpenem .

20. Monobactams - The main monobactam is aztreonam which is resistant to most b-lactamases . It is given by injection. Aztreonam has an unusual spectrum of activity and is effective only against Gram negative aerobic bacilli such as pseudomonads, Neisseria meningitidis and Haemophilus influenzae . It has no action against Gram-positive organisms or anaerobes. Unwanted effects are, in general, similar to those of other b-lactam antibiotics, but this agent does not necessarily cross-react immunologically with penicillin and its products, and so does not usually cause allergic reactions in penicillin-sensitive individuals.

21. Glycopeptides . Vancomycin is a glycopeptide antibiotic, and teicoplanin is similar but longer lasting. Vancomycin acts by inhibiting cell wall synthesis It is effective mainly against Gram-positive bacteria and has been used against MRSA . Vancomycin is not absorbed from the gut and is only given by the oral route for treatment of gastrointestinal infection with C. difficile . For parenteral use, it is given intravenously. The clinical use of vancomycin is limited mainly to pseudomembranous colitis (a clostridial infection sometimes associated with antibiotic therapy) and the treatment of some multiresistant staphylococcal infections. It is also valuable in severe staphylococcal infections in patients allergic to both penicillins and cephalosporins , and in some forms of endocarditis.

22. Unwanted effects include fever, rashes and local phlebitis at the site of injection. Ototoxicity and nephrotoxicity can occur, and hypersensitivity reactions are occasionally seen. Daptomycin is a new lipopeptide antibacterial with a similar spectrum of actions to vancomycin . It is usually used, in combination with other drugs, for the treatment of MRSA.

23. ANTIMICROBIAL AGENTS THAT INTERFERE WITH FOLATE SYNTHESIS OR ACTION

24. SULFONAMIDES Their discovery dates back to 1930s Discovered from prontosil ( prodrug ) which was metabolized to sulfanilamide (active product) Since then many sulfonamides were developed but most lost their usefulness due to resistance. The remaining commonly used are sulfamethoxazole (usually combined with trimethoprim as co- trimoxazole ), sulfasalazine and sulfadiazine.

25. Mechanism of action Sulfanilamide is a structural analogue of p- aminobenzoic acid (PABA) which is the precursor for synthesis of folic acid needed for DNA and RNA synthesis in bacteria. Sulfonamides compete with PABA for the enzyme dihydropteroate synthetase . Increasing [PABA] overcomes the effect of sulfonamides. PABA esters used as local anaesthetics ( eg . Procaine) antagonize the effect of sulfonamides

26. Sulfonamides are in action bacteriostatic Their action is lost in pus and products of tissue breakdown due to presence of thymidine and purine which are directly utilized by bacteria to form DNA and RNA Resistance to drug is plasmid mediated resulting in forming enzymes insensitive to the drug

27. Pharmacokinetics They have good oral absorption except for sulfasalazine Have risk of sensitization or allergic reaction when given topically Metabolized in the liver to form acetylated product (inactive) Have wide distribution in the body. Can cross inflammatory exudates, BBB and placenta.

28. Unwanted side effects Serious side effects which necessitate stopping the drug are hepatitis, hypersensitivity reactions (SJS, TEN, fever, anaphylactoid reactions), bone marrow depression and AKI due to IN or crystalluria . Mild to moderate side effects include nausea, vomiting, headache and mental depression

29. Clinical uses Co- trimoxazole for P. Carinii Combined with pyrimethamine for drug resistant malaria and toxoplasmosis. Sulfasalazine for IBD ( sulfapyridine and aminosalicylate comb) Silver sulfadiazine for infected burn Sexually transmitted infections (trachoma, chancroid and chlamydia) Rarely used for RTI and UTI

30. TRIMETHOPRIM Mechanism of action Is related to anti-malaria pyrimethamine both being folate antagonists. It resembles pteridine moiety of folate and therefore inhibiting dihydrofolate reductase . Bacterial enzyme is highly sensitive to trimethoprim than the equivalent human enzyme. It is bacteriostatic and is active against many bacteria and protozoa. Usually combined with sulfonamides for potentiation of activity

31. Pharmacokinetics Is well absorbed from the GIT and widely distributed in tissues in body fluids Reaches high concentration in lungs, kidney and CSF Is a weak base hence elimination increased in low urine PH.

32. Unwanted side effects Nausea Vomiting Rashes Megaloblastic anemia ( due to deficiency of folic acid, hence prevented by giving folinic acid)

33. ANTIMICROBIAL AGENTS AFFECTING BACTERIAL PROTEIN SYNTHESIS

34. TETRACYCLINES Is the broad acting antibiotic The group includes tetracycline, demeclocycline , minocycline, doxycycline, oxytetracycline , tigelcycline They are taken by active transport by susceptible bacteria They are bacteriostatic by inhibiting formation of proteins

35. Antibacteria spectrum Have very wide antimicrobial activity. They act against gram+, gram-, mycoplasma, rickettsia, chlamydia, protozoa (amoeba). Minocycline is active against N-meningitides Their usefulness has been decreased by development of resistance transmitted through plasmids

36. Pharmacokinetics Are given orally, but can also be given parenterally Minocycline and doxycycline are virtually completely absorbed Absorption of others is irregular and incomplete. It is improved by food Tetracycline chelates with metals (aluminum, calcium, iron and magnesium) to form non-absorbable complexes. Hence their absorption is decreased when taken with milk, iron preparations and some antacids.

37. Clinical uses Chlamydia, rickettsial , lyme , anthrax and brucellosis Second choice for leptospira and mycoplasma RTI eg . Exacerbation of chronic bronchitis and community acquired pneumonia Acne Demeclocycline has activity against ISADH Doxycycline can be used in renal impairment due to its once daily dosing

38. Unwanted side effects Commonest is GIT disturbance due to direct irritation and later by modification of gut flora. Vitamin B complex deficiency Dental hypoplasia and bone deformity. Also staining. Should not be given to pregnant and breasting women as well as children. Demeclocycline-phototoxicity , minocycline-vestibular disturbance High dose-reduced protein synthesis to cause renal damage Long term use may lead to bone marrow disturbance.

39. AMPHENICOLS Principal agent in the group is chloramphenicol It inhibits protein synthesis by binding to 50s ribosome Has wide spectrum of activity (G+, G-, Rickettsiae ) Mostly bacteriostatic, but kills H-influenza Resistance is to due to formation of chloramphenicol acetyltransferase which is plasmid mediated.

40. Pharmacokinetics Is rapidly and completely absorbed in the GIT Reaches peak plasma concentration in 2 hours Widely distributed in tissues in the CSF 10% excreted in the kidneys unchanged, the rest deactivated in the liver.

41. Clinical uses Reserved for serious infections due to its serious adverse effects. The infections include H-influenza resistant to other drugs, meningitis in whom penicillin can be used etc Topically for bacterial conjunctivitis. Is safe and effective For typhoid fever.

42. Side effects Pancytopenia due to bone marrow depression (most important and unwanted side effect) Should be used with great care in newborns closely monitoring plasma concentration (fear of grey-baby syndrome) hypersensitivity GIT disturbance

43. AMINOGLYCOSIDES They have a complex chemical structure. Include gentamycin, amikacin , tobramycin, streptomycin They are similar in properties and toxicity Penetration into the cell is by the oxygen dependent active transport by a polyamine carrier system. Have minimal action against anaerobes It is bactericidal and its activity is enhanced by agents which interfere with cell wall synthesis

44. Mechanism of action

45. Resistance Is mainly due to formation of inactivating microbial enzymes. Sometimes resistance is due to failure of penetration which is overcome by concomitant use of penicillins Antibacterial spectrum Active against most aerobic G- and some G+. Mostly used for enteric G- organisms and in sepsis. May be given with penicillin in streptococcal infections as well as Listeria and P.Aeruginosa Amikacin has the widest antimicrobial activity.

46. Pharmacokinetics They are highly polar and only given IM or IV Can cross placenta but cannot cross the BBB More than 50% excreted unchanged by kidneys hence rapid accumulation to toxic level in renal impairment situations

47. Side effects Serious, dose related toxic effects, include ototoxicity and nephrotoxicity. Ototoxicity is due to progressive damage and eventually destruction of sensory cells in the cochlea especially for neomycin and amikacin (auditory disturbance and deafness) and vestibular, especially for gentamycin and streptomycin (ataxia, vertigo and loss of balance) Ototoxicity is potentiated by simultaneous use of other ototoxic agents such as loop diurets Nephrotoxicity is due to damage of the tubules and is reversible upon stopping the drug. Rare but serious side effect is paralysis due to neuromuscular block. Occurs especially when administered together with neuromuscular blocking agent

48. MACROLIDES The main macrolide and related antibiotics are erythromycin, clarithromycin and azithromycin. Spiramycin and telithromycin are of minor utility . They inhibit protein synthesis by effecting translocation They bind to the 50S ribosome

49. Antimicrobial spectrum Erythromycin-spectrum like that of penicillin and hence used as alternative in sensitive patients. Is active against G+ and spirochaetes but not G- with few exceptions. Resistance develops due to alteration of erythromycin binding site controlled by plasmid. Azithromycin is less active against G+ but more active against legionella, H-influenza and toxoplasma gondii . Clarithromycin is also active against H-influenza, MAI, leprosy and H-Pylori.

50. Pharmacokinetics They are given orally. Erythromycin can be given IV Diffuse readily in tissues except for BBB and have poor penetration into the synovial fluid They enter and get concentrated in phagocytes. Erythromycin is partly inactivated in the liver, azithromycin resist inactivation and clarithromycin is converted to active metabolites. They inhibit P450 increasing availability of some drugs such as theophylline Main route of excretion is bile

51. Unwanted side effects Gastrointestinal disturbance With erythromycin, the following have also been reported: H ypersensitivity reactions such as rashes and fever, transient hearing disturbances and, rarely , following treatment for longer than 2 weeks, cholestatic jaundice . Opportunistic infections of the gastrointestinal tract or vagina can occur.

52. ANTIMICROBIAL AGENTS AFFECTING TOPOISOMERASE

53. QUINOLONES Include broad spectrum agents; ciprofloxacin, levofloxacin , ofloxacin , norfloxacin and moxifloxacin as well as a narrow-spectrum drug used in urinary tract infections— nalidixic acid . These agents inhibit topoisomerase II (a bacterial DNA gyrase ), the enzyme that produces a negative supercoil in DNA and thus permits transcription or replication

54. Antibacterial spectrum and clinical use The fluoroquinolone ciprofloxacin is the most commonly used and typical of the group It is a broad-spectrum antibiotic, effective against both Gram-positive and Gram-negative organisms , and also against the Enterobacteriaceae (the enteric Gram-negative bacilli), including many organisms resistant to penicillins , cephalosporins and aminoglycosides. And also against H. influenzae , penicillinase -producing N . gonorrhoeae , Campylobacter spp. and pseudomonads . Of the Gram-positive organisms, streptococci and pneumococci are only weakly inhibited, and there is a high incidence of staphylococcal resistance. Ciprofloxacin should be avoided in MRSA infections.

55. Clinically, the fluoroquinolones are best reserved for infections with facultative and aerobic Gram-negative bacilli and cocci . Resistant strains of S. aureus and P. aeruginosa have emerged Clinical use Norfloxacin and ofloxacin - for complicated UTI and gonorrhoea P. aeruginosa respiratory infection in patients with cystic fibrosis Invasive external otitis due to P. aeruginosa Eradication of salmonella typhi Cervicitis ( ofloxacin ) and prostatitis ( norfloxacin )

56. Pharmacokinetics Well absorbed orally Accumulate in certain tissues; kidney, lungs and prostate All quinolones are concentrated in phagocytes. Most fail to cross the blood–brain barrier, but ofloxacin does so. Aluminium and magnesium antacids interfere with the absorption of the quinolones. Elimination of ciprofloxacin and norfloxacin is partly by hepatic metabolism by P450 enzymes (which they can inhibit, giving rise to interactions with other drugs) and partly by renal excretion. Ofloxacin is excreted in the urine.

57. Unwanted side effects In hospitals, infection with C. difficile may prove hazardous but otherwise unwanted effects are infrequent, usually mild and reversible. The most frequent manifestations are Gastrointestinal disorders and skin rashes. Arthropathy has been reported in young individuals. Central nervous system symptoms (headache and dizziness) have occurred, as have, less frequently, convulsions associated with central nervous system pathology or concurrent use of theophylline or a non-steroidal anti-inflammatory drug .

58. MISCELLANEOUS AND LESS COMMON ANTIBACTERIAL AGENTS

59. Metronidazole It was introduced as antiprotozoa It is also active against anaerobic bacteria such as bacteroides and clostridia species and some streptococci It is effective in the treatment of pseudomembranous colitis and serious anaerobic infection It has disulfiram like action and so should not be taken with alcohol.

60. Streptogramins Quinupristin and dalfopristin are cyclic peptides , They inhibit protein synthesis by binding to 50S ribosome For most effect they are used in combination and are active against most gram positive bacteria Dalfopristin changes the structure of ribosome facilitating binding of quinupristin . Used in the treatment of serious bacterial infection where no other antibiotic is suitable. They are active against MRSA and vancomycin resistant enterococcus faeceum . Must be given IV due to high fast pass effect. Unwanted side effects include anthragia , myagia , nausea, vomiting and diarrhea Resistance against streptogramins does not seem to be a problem

61. Clindamycin Is the lincosamide active against gram positive cocci including penicillin resistant staphylococcus and many anaerobes such as bacteriodes . It is used in treatment of staphylococcal infection in bones and joints Also given topically for staphylococcal conjunctivitis Acts in the same way as chloramphenicol and macrolides Unwanted side effects include GI disturbance and pseudomembranous colitis due C.dificile ( treated by metronidazole and vancomycin )

62. Oxazolidinones It is the true new antibacterial by the novel MOA It acts by inhibiting protein synthesis by inhibiting binding of N- formylmethionyl - tRNA to 70S ribosome. Linezolid is the first member of this class and is active against many gram positive bacteria and particularly important in treatment of MRSA, penicillin resistant streptococcus pneumonia and vancomycin resistant enterococci. Most gram negative organisms are not susceptible Unwanted effects include thrombocytopenia, diarrhoea , nausea and, rarely , rash and dizziness. Linezolid is a non-selective inhibitor of monoamine oxidase, and appropriate precautions need to be observed

63. Fusidic acid Is a narrow spectrum steroid antibiotic active mainly against gram positive bacteria. Is well absorbed in the gut and widely distributed in tissues. Some is excreted in bile and some is metabolized Can be combined with other antistaphylococcal agents against sepsis and topical infections eg . Eyes Unwanted effects such as gastrointestinal disturbances are fairly common . Skin eruptions and jaundice can occur. Resistance occurs if it is used systemically as a single agent.

64. Nitrofurantoin Is synthetic and active against a range of G+ and G-s Development of resistance and cross-resistance is rare Unknown mechanism of action and its rapidly and completely absorbed from the gut. Is rapidly excreted by the kidneys. Its use is confined to treatment of UTI Unwanted effects such as gastrointestinal disturbances are relatively common , and hypersensitivity reactions involving the skin and the bone marrow (e.g. leukopenia) can occur. Hepatotoxicity and peripheral neuropathy have also been reported.

65. Polymixins Polymixin antibiotics in use are polymixin B and colistin ( polymixin E). They have cationic detergent properties and exert their antibacterial action by disrupting the outer cell membrane They have a selective, rapidly bactericidal action on Gram-negative bacilli , especially pseudomonads and coliform organisms. They are not absorbed from the gastrointestinal tract. Clinical use of these drugs is limited by their toxicity and is confined largely to gut sterilization and topical treatment of ear, eye or skin infections caused by susceptible organisms. Unwanted effects may be serious and include neurotoxicity and nephrotoxicity