Chemotherapy of Microbial Disease (Antibacterial agents).pptx

Chemotherapy of Microbial Disease
Antimicrobial
Antibiotic
Selective toxicity
Bactericidal
Bacteriostatic
Gram-negative Vs Gram-positive
Susceptibility testing?
Resistance
Empirical Vs definitive therapy

1. Chemotherapy of Microbial Disease 1

2. Key Words 2 Antimicrobial Antibiotic Selective toxicity Bactericidal Bacteriostatic Gram-negative Vs Gram-positive Susceptibility testing? Resistance Empirical Vs definitive therapy

3. Chemotherapy Use of chemical agents (either natural or synthetic) used to destroy infective agents and also to inhibit the growth of malignant or cancerous cells . Antibiotics: are substances produced by micro organisms which suppress the growth and multiplication or kill other micro organisms at very low concentration. Note: at present many antibiotics are synthesized in the laboratory. Antibiotics do not kill viruses -not effective in treating viral infections. 3

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5. History of antibiotics Germ theory of disease: Louis Pasteur and Robert Koch, linked specific microorganisms to specific diseases (Koch, 1876; Pasteur, 1861) 5

6. History of antibiotics 1906: Paul Ehrlich discovered Salvarsan 1930s: sulfa drugs discovered 6

7. Penicillins First antibiotic to be used clinically, 1941 Originally obtained from fungus Penicillium notatum Present source is a high yielding mutant of P. chrysogenum 7

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10. Selection of Antimicrobial Agent Empiric therapy - prior to identification of organism – critically ill patients Organism’s susceptibility to the antibiotic Patient factors - immune system, renal/hepatic function Effect of site of infection on therapy –blood brain barrier Safety of the agent Cost of therapy 10

11. Properties Influencing Frequency of Dosing Concentration dependent killing : significant increase in rate of bacterial killing as the drug concentration increases. E.g., aminoglycosides Time-dependent killing – dependent on the % of time that blood concentrations remain above minimum inhibitory concentration (MIC ). E.g., β- lactams , macrolides, and clindamycin 11

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13. Properties Influencing Frequency of Dosing… Post-antibiotic effect (PAE)– persistent suppression of microbial growth after levels of antibiotic have fallen below MIC Antibiotics with a long PAE: aminoglycosides and fluroquinolones Minimum bactericidal concentration (MBC ): the lowest concentration of antibiotic that kills 99.9% of bacteria Minimum inhibitory concentration 13

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17. Chemotherapeutic Spectra of antibiotics Narrow-spectrum Antibiotics: Act on a single/limited group of micro-organisms; e.g ., isoniazid given for mycobacterium Extended-spectrum Antibiotics: Effective against gram-positive organisms and a significant number of gram-negative organisms; e.g., ampicillin Broad-spectrum Antibiotics: Effective against a wide variety of microbial species; e.g ., tetracycline & chloramphenicol. Can alter the nature of intestinal flora = superinfection 17

18. Chemotherapeutic Spectra… 18

19. Complications of Antibiotic Therapy Resistance – inappropriate use of antibiotics Hypersensitivity : e.g., penicillin Direct toxicity : e.g., aminoglycosides = ototoxicity Super infections – broad spectrum antimicrobials cause alteration of the normal flora ; often difficult to treat 19

20. Drug Resistance Alteration of the target site of the antibiotic One of the most problematic antibiotic resistances worldwide, methicillin resistance among Staphylococcus aureus . Enzyme inactivation of the antibiotic β-lactam antibiotics ( penicillins & cephalosporins) can be inactivated by β-lactamases. 20

21. Drug Resistance…. 3 . Active transport of the antibiotic out of the bacterial cell ( efflux pumps) Removal of some antibiotics (i.e. tetracyclines , macrolides, & quinolones ) 4. Decreased permeability of the bacterial cell wall to the antibiotic Alteration in the porin proteins that form channels in the cell membrane – Resistance of Pseudomonas aeruginosa to a variety of penicillins and cephalosporins 21

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23. Classifying Antimicrobial Agents Mode of action Bactericidal Bacteriostatic Spectrum of activity Broad (e.g. effective against variety of gram-VE & gram+ve ) Narrow (e.g. effective only against gram- ve or gram+ve ) Mechanism of action / site of action Inhibitors of cell metabolism ; (Sulfonamides, Trimethoprim) Cell wall inhibitors ; ( β- Lactam, Vancomycin ) Protein synthesis inhibitors ; ( Tetrecyclines , Aminiglycosides , Macrolides, Clindamycin, CAF) Nucleic acid inhibitors ; ( Floroquinolones , Rifampin) Cell membrane inhibitors ; (Isoniazid, Amphotericin B) 23

24. Classification of Antimicrobials by Site of Action 24

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26. Classification of antibacterials … Bacteriostatic: inhibits the growth of bacteria: e.g. sulphonamides, tetracyclines Minimum inhibitory concentration (MIC) The lowest concentration that inhibits the growth of bacterial population Bactericidal: kill the microorganism directly e.g. Penicillins, cephalosporins, aminoglycocides etc. Minimum bactericidal concentration (MBC) The lowest concentration that kills 99.9% of the bacterial population 26

27. Note!!! Bactericidal agents are less dependent on body defense mechanism for final eradication of Microorganisms DOC when body defense mechanism is deficient. Concomitant administration of bacteriostatic and bactericidal agents decreases the action of bactericidal agents Bactericidal agents kill MOs effectively when bacteria is actively dividing or synthesizing 27

28. According to spectrum of antimicrobial activity Narrow spectrum- when effective against narrow range of microorganisms.(Gm +/Gm-) eg. Benzyl penicillins , streptomycin, penicillin G, 1st -2nd generation cephalosporins. Broad spectrum- Antibiotic that can inhibit wide range of G-positive and G-negative bacteria e.g. Tetracycline, chloramphenicol, Carbapenem , 3rd -4th generation cephalosporins, quinolones 28

29. According to mechanism of action Agents inhibiting bacterial cell wall synthesis Eg- penicillins , cephalosporins. Agents altering cell membrane function: Eg . Polymyxin Protein synthesis inhibitors Eg-Tetracycline, CAF, erythromycin, aminoglycosides Agents that affect bacterial nucleic acid metabolism: Eg - Floroquinolones Antimetabolites-block essential enzymes of folate metabolism Eg : Trimetoprim+Sulphoamides 29

30. Mechanisms of Antimicrobial Action 30

31. Combinations of antimicrobial drugs Advantages For empirical therapy of an infection in which the cause is unknown Rx of poly-microbial infections To enhance antimicrobial activity (i.e., synergism) for a specific infection To prevent emergence of drug resistant microorganism. Disadvantages Increased risk of toxicity from two or more agents Selection of multiple-drug-resistant microorganisms Eradication of normal host flora with subsequent super infection Increased cost to the patient. 31

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33. 1. Inhibitors of cell wall synthesis 33

34. Inhibitors of cell wall synthesis… Interfere with the synthesis of the bacterial cell wall Little or no effect on bacteria that are not growing and dividing 34

35. Inhibitors of Cell Wall Synthesis 35

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37. Penicillin units and formulations A ctivity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg 1 unit = 0.6 mcg 1 million units of penicillin = 0.6 g Semisynthetic penicillins are prescribed by weight rather than units 37

38. β -lactam antibiotics Inhibit synthesis of bacterial cell wall by binding to proteins (penicillin binding proteins) in bacterial cell membranes This binding produces a defective cell wall that allows intracellular contents to leak out , destroying the micro-organism. Differ in anti-bacterial spectrum, route of administration, susceptibility to β -lactamase and adverse effects. 38

39. Resistance Resistance to penicillins and other β - lactams is due to one of four general mechanisms: I nactivation of antibiotic by B –lactamase most common M odification of target PBPs I mpaired penetration of drug to target PBPs E fflux 39

40. Resistance…. β -lactamase produced by S . aureus , Haemophilus sp, and E . C oli N arrow in substrate specificity P referring penicillins to cephalosporins. β -lactamases produced by P . aeruginosa and Enterobacter sp H ydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases 40

41. Resistance…. Altered target PBPs M ethicillin resistance in staphylococci (MRSA) and penicillin resistance in pneumococci and enterococci. PBPs that have low affinity for binding B -lactam antibiotics Resistance due to impaired penetration of antibiotic occurs only in G- ve species cross the outer via porins. Absence of the porins or down-regulation of its production can greatly impair drug entry into the cell 41

42. Resistance…. Efflux pump C onsists of cytoplasmic and periplasmic protein in G - ve organisms E fficiently transport some B -lactam antibiotics from the periplasm back across the outer membrane. 42

43. 1. Penicillins First antibiotic When first developed, Had to be given parentrally because it was destroyed by gastric acid After absorption, penicillins are widely distributed and achieve TC in most body fluids. Unless inflammation present, therapeutic levels can not be achieved in CSF Except naficillin , all penicillins are excreted in high concentration through kidney. 43

44. Note: Intact b-lactam ring is essential for activity. 44

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46. Mechanism of action like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis . The cell wall is composed of a complex, cross-linked polymer of polysaccharides and polypeptides , peptidoglycan. Penicillin binding protein (PBP, an enzyme) catalyzes the cross-link to give the cell wall its structural rigidity. Beta-lactam antibiotics, covalently bind to the active site of PBPs and inhibit the transpeptidation reaction, halting peptidoglycan synthesis → cell dies. 46

47. The  - lactam antibiotics structurally resemble the terminal D- alanyl -D- alanine (D-Ala-D-Ala) in the pentapeptides on peptidoglycan (murein). Bacterial transpeptidases covalently bind - lactam antibiotics at the enzyme active site, and the resultant acyl enzyme molecule is stable and inactive. The  - lactam ring modifies the active serine site on transpeptidases and blocks further enzyme function. Mechanism of action 47

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49. In addition, penicillins bind to penicillin-binding proteins (PBPs), which function as transglycosylases and carboxypeptidases . PBPs are involved with assembly, maintenance, or regulation of peptidoglycan cell wall synthesis. 49

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51. Classification of penicillins Currently penicillins are divided in to 4 groups based on the spectra of activity Natural penicillins Penicillin G, Penicillin V Penicillinase -resistant penicillins Cloxacillin , dicloxacillin , Nafcillin , Oxacillin , Methicillin Aminopenicillins Amoxicillin, Ampicillin Extended-spectrum penicillins Carbenicillin , Piperacillin , Ticarcilllin 51

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53. i . Natural penicillins Natural penicillins : penicillin G and penicillin V Penicillin V is more acid stable than penicillin G and is often employed orally in the treatment of infections . 53

54. ii. Antistaphylococcal penicillins : Methicillin, nafcillin , oxacillin , and dicloxacillin are β-lactamase ( penicillinase )-resistant penicillins . Their use is restricted to the treatment of infections caused by penicillinase -producing staphylococci, including methicillin sensitive Staphylococcus aureus ( MSSA). The penicillinase -resistant penicillins have minimal to no activity against gram-negative infections. 54

55. iii. Extended-spectrum penicillins Ampicillin and amoxicillin have an antibacterial spectrum similar to that of penicillin G but are more effective against gram negative bacilli. Ampicillin (with or without the addition of gentamicin) is the drug of choice for the gram- positive bacillus Listeria monocytogenes and susceptible enterococcal species . These extended-spectrum agents are also widely used in the treatment of respiratory infections, and amoxicillin is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis. 55

56. Extended-spectrum penicillins … Resistance to these antibiotics is now a major clinical problem because of inactivation by plasmid-mediated penicillinases . [Note: Escherichia coli and Haemophilus influenza are frequently resistant.] Formulation with a β-lactamase inhibitor, such as clavulanic acid or sulbactam , protects amoxicillin or ampicillin , respectively , from enzymatic hydrolysis and extends their antimicrobial spectra. For example, without the β-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin 56

57. iV . Antipseudomonal penicillins : Piperacillin and Ticarcillin are called antipseudomonal penicillins because of their activity against Pseudomonas aeruginosa . These agents are available in parenteral formulations only. Piperacillin is the most potent of these antibiotics. They are effective against many gram-negative bacilli, but not against Klebsiella because of its constitutive penicillinase . Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam , respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase -producing organisms (for example, most Enterobacteriaceae and Bacteroides species ). 57

58. A. Natural Penicillins Produced by fermentation of of Penicillium chrysogenium . Different side chains at R are produced by altering the composition of the culture media of Penicillium Penicillins F, G , N, O, V , X Are acid labile and - lactamase sensitive Active against most Gm(+) and Gm(-) aerobic cocci , some Gm (+) aerobic and anaerobic bacilli , and most spirochetes . Many bacteria have developed resistance. Most streptococci are susceptible More than 90% of staphylococcal strains are now resistant 58

59. Penicilin G Non-suitable for oral administration (IM or IV) The drug distributes to most tissues Excreted by the kidneys (90% of renal elimination occurs via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to prolong the half-life of penicillins ). Depot IM formulations of penicillin G ( procaine penicillin and benzathine penicillin) have decreased solubility, delayed absorption, and a prolonged t ½ IV penicillin G is among the antibiotics of first choice in meningitis caused by susceptible Streptococcus pneumoniae 59

60. Penicillin G potassium and Penicillin G sodium Aqueous, crystalline Pen G is used IV Used when rapid and high serum concentrations are required Septicemia , meningitis , pericarditis , endocarditis , severe pneumonia Penicillin G procaine and penicillin G benzathine Used only For treatment of moderately severe infections susceptible to low concentrations Prophylaxis of infections caused by these organisms Or maintenance therapy to IM or IV Penicillin G 60

61. Penicillin V Phenoxymethyl congener of penicillin G More stable in acidic media and is better absorbed from the GIT Have similar antibacterial spectrum as penicillin G. Used to treat streptococcal infections when oral therapy is appropriate and desirable. 61

62. Fig: Typical therapeutic applications of penicillin G. 62

63. Uses for penicillin g and penicillin v…. 63

64. Uses for penicillin g and penicillin v…. 64

65. B. β -lactamase resistant penicillin: Oxacillin , Naficillin and Cloxacillin Cloxacillin Acid and penicillinase resistant- effective against penicillinase producing S.aureus ( gram + ve ) Adequately absorbed orally Less active when compared to penicillin G. May cause Nausea and vomiting Food affects absorption: Should be given 1 hr before and 2 hr after food Use - Pneumonia due to S.aureus , osteomyelitis, septic arthritis, mastitis 65

66. C. Broad spectrum penicillins : Amino penicillins B actericidal for gram + ve and gram – ve bacteria Ineffective against B-lactamase producing staphylococci and gonococci 66

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68. Amino penicillins …… Amoxacillin - similar to ampicillin except More rapidly and completely absorbed from the GIT Absorption is less affected by food Ampicillin has low oral absorption and food decrease the absorption Has less incidence of diarrhea. Has longer duration of action But amoxicillin is less active against shigella 68

69. Amino penicillins … Therapeutic uses - Bronchitis, tonsilitis , UTI, otitis media, pneumonia, sinusitis Amoxacillin PUD ( H. pylori) Endocarditis prophylaxis A mpicillin Meningitis (listeria monocytogenes ) Pneumonia (gram – ve ) with gentamicin Bile (biliary tract infection) 69

70. Therapeutic uses -… Otitis Media Bronchitis/Pneumonia – may be used, but resistance is a problem . Enterococcal endocarditis (ampicillin or PenG + aminoglycoside is DOC) Meningitis – Ampicillin - alternative choice to 2nd gen. cephalosporins (+chloramphenicol). Urinary Tract Infections - Covers three most common organisms E . coli, Proteus mirabilis, & Staph. Saprophyticus but resistance is common in E. coli. Prophylaxis for bacterial endocarditis - prior to dental procedures - DOC Lyme Disease ( Borrelia burgdorferi ) and Erlichiosis ( Erlichia chaffeinsis ) - alternate to doxycycline (1 g amoxicillin + 0.5 g probenicid q 8 h) Alternate for susceptible strains of N. gonorrheae (3.5 g oral ampicillin or amoxicillin + 1 g probenecid .) 70

71. Extended spectrum penicillins Carpenicillin , ticarcillin For gram + ve & gram – ve like pseudomonas and proteus species and E. coli. Pseudomonas- combined with aminoglycosides or fluoroquinolones . Carpenicillin - used for UTI and prostatitis caused by susceptible pathogens, burn resistant to aminopenicillins . 71

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73. Beta lactamase inhibitors β- Lactamase is family of enzyme produced by bacteria ( E. coli, S. aureus , H. infleuenza , N. gonorrhea, klebsella , enterobacter ) that inactivate β- lactam antibiotics. β- lactamase inhibitors are drugs with β - lactam structure but little antibacterial activity Clavulanic acid Vs amoxacillin , sulbactam Vs ampicillin/ amoxacillin and tazobactam Vs piperacillin Amoxacillin+clavulanic acid (Augmentin ®) 73

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78. Penicillins: Adverse Effects Allergic reactions occur in 0.7% – 8% of treatments urticaria , pruritus , angioedema , bronchoconstriction 10% of allergic reactions are life-threatening and 10% of these are fatal Hepatotoxcity with naficillin and oxacillin Bleeding tendency with carpenicillin , piperacillin 78

79. Penicillins: Adverse effects…. Nausea, vomiting, diarrhea, abdominal pain Super infection with broad spectrum Irritation at the site of injection Can cause seizure in higher doses CI- hypersensitive patients 79

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81. 2. Cephalosporins 81

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85. Cephalosporins Similar to penicillins in terms of mechanism of action , chemical structure and toxicities . When compared to penicillins Less active against gram + ve More active against gram – ve Individual cephalosporins differ in their Anti bacterial spectrum and relative effectiveness against specific organisms. Susceptibility to β- lactamase Pharmacokinetic property Local irritation at the site of injection. 85

86. Cephalosporins……. Cephalosporins are widely distributed Some- cephalosporins are orally bioavailabe Often used in mild infections and UTI Many cephalosporins do not cross BBB, exceptions are cefuroxime, a 2 nd generation drug, and 3 rd generation agents. IM administration cause irritation Cefazolin can be given with less irritation 86

87. Indications Septicemia (e.g. cefuroxime , cefotaxime ) Surgical prophylaxis Pneumonia caused by susceptible organisms Meningitis (e.g. cefriaxone , cefotaxime ) Neisseria gonorrhea- ceftriaxone Biliary tract infection Urinary tract infection (especially in pregnancy, or in patients unresponsive to other drugs) Sinusitis (e.g. cefadroxil ). 87

88. Classification of the cephalosporins 4 th generation : Cefepime (IM,IV) 88

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92. Cephalosporins …. Classified in to 4 generations based on Chronological sequence of development Spectrum First generation cephalosporins Cephalexin - given orally Cause irritation if given parentrally Cefazolin , cefalotin - parentral Good activity against G+ and modest activity against G-(except MRSA ) 92

93. 1 st generation cephalosporins Not effective against enterobacter , pseudomonas, and serratia species Cefazolin is a drug of choice for surgical prophylaxis Cephalothin –resistant to B- lactamase Excellent in the treatment of soft tissue and skin infection ( s. aureus , s. pyrogens ) 93

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95. First Generation Cephalosporins - Uses Upper respiratory tract infections due to Staph. and Strep. Lower respiratory tract infections due to susceptible bacteria e.g. Strep. Pneumoniae in penicillin-allergic patient (previous rash) ???? Uncomplicated urinary tract infections (Cephalexin) Surgical prophylaxis for orthopedic and cardiovascular operations ( cefazolin preferred because of longer half-life) Staphylococcal infections of skin and skin structure 95

96. Second generation cephalosporins Cefuroxime ( PO, parentral ) Cefaclor , cefprozil -PO Cefotetan , cefamandole , cefoxitin ( IV), Spectrum - very good activity for gram – ve and anaerobic organisms and less activity for gram + ve . More activity against H. infleuenzae and E. coli by cefaclor Cefoxitin has activity for B. fragilis , anaerobic organism resistant to most antimicrobial drug. Ceftzidime effective against gram + ve and gram – ve including P. aeruginosa . 96

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98. Second Generation Cephalosporins – Uses Community-acquired pneumonia - Cefuroxime is widely used for empiric therapy. Skin and soft tissue infection Urinary tract infections Upper respiratory tract infections (otitis media, sinusitis). Mixed aerobic & anaerobic infections - Cefoxitin & Cefotetan . Surgical prophylaxis - Cefoxitin or cefotetan are widely used in cases where mixed aerobic & anaerobic infections may occur, esp. intra-abdominal, colorectal, and gynecologic operations. For cardiovascular and orthopedic procedures , cefuroxime and others may be used, but cefazolin is cheaper and appears to work well. 98

99. Third generation cephalosporins Ceftriaxone ( parentral ) Cefdinir , cefixime , cefpodoxime - PO Useful for meningial infections Penetrate inflammed meninges to reach CSF Has activity against H. infleuenzae , N. meningitidis and S. pneumoniae Gain gram – ve and lose gram + ve activity as they move from 1st to 3rd generations Enhanced activity g- ve organisms ( serratia , providencia , citrobacter ) Active against P. aeruginosa - should be used in combination due to resistance Preferable drugs in bone infections 99

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101. Third Generation Cephalosporins - Uses Gram negative septicemia & other serious Gm – infections Pseudomonas aeruginosa infections ( Ceftazidime ) Gram negative meningitis - Cefotaxime , Ceftriaxone, Cefepime . For empiric therapy add vancomycin ± rifampin to cover resistant Strep. Pneumoniae Gonorrhea - Single shot of Ceftriaxone is drug of choice. Oral cefixime and ceftibuten are also OK. V. Complicated urinary tract infections, pyelonephritis VI. Osteomyelitis – Ceftriaxone VII. Lyme disease - ceftriaxone 101

102. Ceftriaxone Usual dose: 1-2gm every 12-24hrs depending on the type and severity of infection. Bacillary dysentery (250 mg Stat) Pneumonia (1gm for 5-7days) Typhoid fever (1gm for 5-7days) Bacterial septicemia (1gm for 5-7days) Pelvic inflammatory disease - 250mg stat Meningitis (2gm for 5-7days) complicated gonococcal conjunctivitis 1gm stat Uncomplicated gonococcal infection -125-250mg stat Surgical prophylaxis - 1gm IV 30min to 2 hr before surgery 102

103. 4 th generation cephalosporins cefepime , cefepirome Active against G + ve and – ve Highly resistant to penicillinase Active against streptococci and staphylococci (but not against MRSA) Used for P. aeruginosa and enterobacter infection Dosage must be reduced with renal impairment ( cefepime ) 103

104. Fourth generation….. Cefepime : Parenterally : IM/IV It has a wide antibacterial spectrum, with activity against streptococci and staphylococci (but only those that are methicillin susceptible ). It is also effective against aerobic gram-negative organisms, such as Enterobacter species , E. coli, K . pneumoniae , P. mirabilis, and P. aeruginosa . 104

105. Therapeutic use UTI- E. coli or klebsella pneumoniae Skin and soft tissue infection- streptococci or staphylococci Pneumonia- S. pnemoniae , P. aeruginosa Complicated intra abdominal infection 105

106. Advanced generation-cephalosporin Ceftaroline : IV Active against MRSA and is indicated for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. It has similar gram negative activity to the third-generation cephalosporin ceftriaxone. Not active against P . Aeruginosa 106

107. Adverse effect of cephalosporins Hypersensitivity reaction (1-7 %): Some cross-sensitivity with penicillins Diarrhea- cefoperazone , cefixime , cefdinir Bleeding tendency ( Hypoprothombinemia ): Common with cefoperazone , cefamandole , cefotetan Disulfiram -like reaction: cefoperazone , cefamandole , cefotetan Phlebitis, Pain on IM injection Most common with cephalothin and cephapirin . Cefotaxime also. 107

108. Contraindication Previous severe anaphylactic reaction to a penicillin (cross reactivity) Cephalosporin allergy 108

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110. 3. Carbapenems : imipenem Other drugs in this group include: meropenem , doripenem , Imipenem and ertapenem Are broad spectrum, bactericidal, B-lactam antibiotics Given parentrally and distributed widely Active against B-lactamase producing species Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase . Indication - infection caused by resistant organisms Adverse effect- NVD and seizure 110

111. Carbapenems Used for Severe Life Threatening Infections Intra-Abdominal & Pelvic Infections Urinary Tract Infections (UTI ) Complicated Skin & Soft Tissue Infections (SSTI ) Bone & Joint Infections (including diabetic foot infections ) Meningitis Sepsis Endocarditis Ventilator-Associated Pneumonia 111

112. 4. Monobactams : Aztreonam Active against gram- ve bacteria including enterobacteriaceae and P. aeruginosa and many strains resistant to multiple antibiotics Active against B- lactamase producing gram – ve species Gram + ve and anaerobic bacteria are resistant Indications – UTI, LRTI, systemic/skin infection safe alternative for treating patients who are allergic to other penicillins , cephalosporins , or carbapenems 112

113. B-lactam use Generally safe in children Caution neonates-immature kidney function Dose of pen G should be decreased in renal impairment In renal failure ( CrCl <20-30ml/min) dosage of all cephalosporins should be reduced Augmentin -should be used in caution with hepatic impairment Contraindicated in hepatic dysfunction and cholestatic jaundice Hepatotoxicity attributed to clavulanic acid 113

114. 5. Vancomycin Inhibitor of bacterial cell wall synthesis Used for treatment of multiple drug resistant organisms. Poorly absorbed from the intestinal tract Should be administered IV Irritates the tissue surrounding injection site 114

115. Use of vancomycin M RSA Endocarditis due to Strep. viridans or enterococci Pseudomembranous enterocolitis due to Clostridium difficile (administered orally). Adverse effects irritates tissue at injection site, chills and fever. Ototoxicity and nephrotoxicity (rare) Increased risk when administered along with Aminoglycosides . 115

116. 6. Bacitracin Active against Gm+ microorganisms Inhibit bacterial cell wall synthesis It is markedly nephrotoxic if administered systemically, thus limited to topical use. Major Clinical Use Alone or in combination with polymyxin or neomycin: treatment of mixed skin, wound or mucous membrane infections. Adverse Effects Significant nephrotoxicity with systemic administration, skin sensitization may occur on topical use. 116

117. Polymyxins The polymyxins are cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria →disrupts cell membrane integrity →leakage Have activity against P . aeruginosa , E. coli, K. pneumoniae , Acinetobacter species , and Enterobacter species . Polymyxin B and colistin ( polymyxin E ) are currently used clinically Polymyxin B: available in parenteral, ophthalmic, otic , and topical preparations. Colistin : administered IV or inhaled via a nebulizer. Limited use : nephrotoxicity and neurotoxicity (for example, slurred speech, muscle weakness) when used systemically . However , with the increase in gram-negative resistance, they have seen a resurgence in use and are now commonly used as salvage therapy for patients with multidrug-resistant infections. 117

118. Antimetabolites 118

119. Sulphonamides First antibacterial (bacteriostatic) drug MOA Competitively inhibit dihydropteroate synthase that antagonise para- aminobenzoic acid (PABA) Required for synthesis of folic acid essential for synthesis of nucleic acid and protein. Some bacteria develop metabolic pathway to synthesize NA from precursor molecules Use - less useful due to Increased resistance UTI caused by certain bacteria such as E. coli, S. aureus , and Klebsiella-Enterobacter . 119

120. Mode of action of Sulfonamides 120

121. Adverse effect Hematologic changes Agranulocytosis (decrease in/lack of granulocytes) Thrombocytopenia (decrease in platelet number) Aplastic anemia (deficient RBC production) and Leucopenia (decrease in the number of WBC) Anorexia, nausea, vomiting, diarrhea, abdominal pain, chills, fever, and stomatitis . Crystalluria (crystals in the urine) prevented by increasing fluid intake during sulfonamide therapy. 121

122. Trimethoprim A potent inhibitor of bacteria dihydrofolate reductase Trimethoprim exhibit antimicrobial spectrum similar to the sulfonamides Usually compounded with sulfamethoxazole (Co- trimoxazole ) Combination has synergistic effect (bactericidal) 122

123. Cotrimoxazole ( sulfamethoxazole & trimethoprim ) Uses UTI due to enterobactericiae Chronic bronchitis due to pneumococci and H. infleuenzae Shigellosis Pneumocystis carnii pneumonia ( P x and R x) Acute otitis media Traveler's diarrhea due to E. coli Dose 160 mg TMP/800 mg SMZ PO q12h 8–10 mg/kg/d (based on TMP) IV in 2–4 divided doses 123

124. Adverse effect Gastrointestinal disturbances Allergic skin reactions hematologic changes Headache Crystaluria 124

125. Contraindications Renal failure patients Late stages of pregnancy, lactation, children younger than two months Hypersensitive reaction 125

126. Protein synthesis inhibitors 126

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128. Protein synthesis inhibitors Bacteria have two ribosomal subunits; 30 S and 50 S whereas in the mammalian ribosome the subunits are 60 S and 40 S . The 30 S subunits bind mRNA in initiation and holds growing peptide chains. The 50 S subunit accepts / translocates charged tRNAs . Divided in to two groups Bacteriostatic: Chloramphenicol, Macrolides, Clindamycin and tetracyclines Bactericidal: Aminoglycosides 128

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130. 1. Tetracyclines Tetracycline , Chlortetracycline , Doxycycline , Oxytetracycline and Minocycline Spectrum: Broad spectrum bacteriostatic Active against G+ and G- Ricketsial , Chylamydia , mycoplasma, protozoa e.g . malaria, amoeba Many gram – ve and P. aeruginosa develop resistance MOA : inhibit protein synthesis by binding 30 S 130

131. Resistance Three mechanisms of resistance to tetracycline analogs have been described: ( 1) impaired influx or increased efflux by an active transport protein pump Most common (2 ) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome (3 ) enzymatic inactivation. 131

132. Tetracyclines …. Absorption is low (30%) with chlor TTC, intermediate(60-80%) with TTC and oxyTTC , high (90-100%) with doxycycline Absorption will decrease when they are taken with antacid and diary products Short acting (6-8hr)- TTC and OxyTTC Long acting (18hr)- Doxycycline and minocycline 132

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134. Use To avoid NVD take with foods except diary products Cholera Doxycycline 100mg po bid for 03 days Tetracycline 500mg po Qid for 3-5 days Malaria Severe and complicated P. falciparum: Doxycycline 200mg po Qid for 7 days + Quinine Prophylaxis for chloroquine resistant: Doxycycline 100mg po daily + chloroquine 300mg once weekly Acne -TTC 250mg po bid 134

135. Use……. Mycoplasma infection Relapsing fever TTC 500mg po stat, the same dose can be repeated the following days Trachoma - chlamidia trachomatis TTC eye oint , 1% twice daily for 6-8 week Doxycycline 100mg twice daily for 7 days Typhus TTC 250mg Qid for 7 days Doxycycline 100mg po bid for 7 days 135

136. Use… STD Genital ulcer syndrome and syphilis Benz, penicillin 2.4 M, IM stat In penicillin allergy Doxycycline 100mg po bid for 7 days Pelvic inflammatory disease Doxycycline 100mg po bid for 14 days Urethral or vaginal discharge syndrome Doxycline 100mg po bid for 7 days 136

137. Adverse Effect of tetracyclines GI effect – NVD Avoided by taking it with food FOOD decrease the rate not the extent If it form insoluble complexes, it is not advisable Bone and Teeth TTC strongly bind to Ca ++ deposit in bone and teeth Bone - growth inhibition Teeth - discoloration Hepatotoxicity Renal toxicity (except doxycycline) Photosensitivity 137

138. Contraindication Pregnancy breast feeding mothers and children under 8yrs 138

139. 2. Amphenicols - Chloramphenicol (CAF) Are broad spectrum, bacteriostatic antibiotic Active against aerobic and anaerobic G+ and G- Active against Mycoplasma , Ricketssial , Chylamydia Distribute to most tissue and body fluid (readily cross the placenta and breast milk) MOA: Inhibit protein synthesis by binding to 50S. 139

140. Use Meningitis Best for H. influenza Trachoma CAF eye drop 0.5% 4-6hrly for 7 days Thyphoid fever- CAF 500mg po Qid for 14days Thyphus - CAF 500mg po Qid for 7 days Anaerobic infection Lung abscess - inflammation of lung parenchyma which results in tissue necrosis Usual dosage: 50-100mg/kg/day in 4 divided doses 140

141. Adverse Effect Hematologic toxicity Dose related i.e. when serum concentration is greater than 25ug/ml. Anemia, Leukopenia Idiosyncratic Aplastic anemia (incidence 1:300,000) in most cases they are fatal When CAF is given orally - aplastic anemia but not parentral Hyphothesis - nitro group will be oxidized by normal flora to produce toxic metabolite 141

142. Adverse effect…… N/V Superinfection Toxicity in infants Dose greater than 50mg/kg - Gray baby syndrome (vomiting, hypothermia, shock, circulatory collapse, acidosis, abdominal distention, coma and death) 142

143. 3. Macrolides : Erythromycin, Clarithromycin and Azithromycin Spectrum - G+(Streptococcus, staphylococcus), G- (Neisseria, H. influenza), Mycoplasma , chylamidia Clarithromycin and Azithromycin - Require less frequent administration Cause less NVD Have enhanced antimicrobial activity (atypical Mycobacteria and H. pylori) 143

144. 144

145. MOA Macrolide bind to 50-s subunit and inhibit peptide translocation. elongation of protein will be blocked. Note: - Macrolide should not be given together with CAF, since they compete for the same site. Absorption from GI tract is incomplete Erythromycin- is acid labile hence administered as enteric coated product in empty stomach Clarithromycin - rapid absorption from GIT Not affected by gastric acidity 145

146. Use Respiratory and skin infection Tetanus due to Clostridium tetani ERM 500mg po Qid for 10 days + diazepam, cpz Tonsilitis - for penicillin allergy ERM 250mg po Qid for 5 days Clarithromycin 250mg po bid for 10 days 146

147. Uses…… Sinusitis Clarithromycin 500mg bid for 14days H. pylori infection Clarithlormycin 500mg bid Uncomplicated skin and skin structure infection Clari 250mg po bid for 7-14days 147

148. Uses…. Pneumonia (S. pneumonia, M. pneumonia, C. pneumonia, H. influenza) Clarithromycin 250mg po bid for 7-14days C. trachomatis Azithromycin 1gm as single dose N. gonorrhea Azithromycin 1gm as single dose 148

149. AE GI intolerance Hepatotoxicity Cardiac arrhythmia 149

150. 150

151. 4. Aminoglycosides Gentamicin , Neomycin, Amikacin , Streptomycin, Kenamycin , Tobramycin MOA Enter the outer P. membrane by passive diffusion through porins . Bind to the 30-S ribosomal subunit Decrease initiation of protein synthesis. Cause misreading of genetic code Incorporation of wrong amino-acid, leading to altered protein. Protein is some times toxic to the bacteria 151

152. Spectrum G- bacilli, staphylococci, Mycobacteria Poorly absorbed from GIT Well absorbed IM ( peak in 30-60 min) Accumulate in proximal convoluted tubule: nephrotoxicity Accumulate in inner ear result in damage to cochlea: ototoxcity With cell wall active agent - synergism. Due to facilitation of entrance of Aminoglycosids into cell. 152

153. Adverse Effect Ototoxicity Auditory damage -tinnitus ( amikacin , Kenamycin ) Vestibular damage -STM, Gentamicin Nephrotoxicity Amphotericin , Vancomicin , cephalosporin -  toxicity Neuromuscular blockage In high conc , produce a curare like effect such as Respiratory paralysis Dysfunction of optic nerve, pain at site of injection 153

154. Gentamicin Pseudomonal infection Aminoglycoside and anti- pseudomonal penicillin UTI Topical – to the eye or skin Pneumonia Gentamicin 5-7mg/kg Iv daily for 7 days + Benz. Penicillin 1.2mg/kg IM daily for 7 days Bacterial endocarditis - strep. virdans Genta 1mg/kg Iv tid for 2wk + PenG 12-18M iv/day in divided dose 4hrly for 4 wk 154

155. Streptomycin Bacterial endocarditis (for gentamicin resistant) Tuberculosis (second line drug due to drug resistance and toxcity ) Contraindication Renal impairment Myasthenia gravis (caution) Pregnancy (can cause deafness in the new born) 155

156. 156

157. Spectinomycin Related to aminoglycoside in structure and mode of action Use - treatment of gonorrhea in patient allergic to penicillin and those infection caused by penicillin resistant gonococci Side effects- nausea, dizziness, urticaria , pain at the site of injection 2 gm IM injection(stat) 157

158. NA synthesis inhibitors: Fluoroquinolones (FQs) Highly concentrated in the kidney used for lower urinary tract infection (30-60% excreted unchanged). Most are orally available MOA: inhibit DNA Gyrase and Topoisomerase IV bactericidal Note : In G- ve organisms, there is high resistance of entry due to the outer membrane. But there is transportation process through the porins . Agent that passes through the porins will exhibit activity against G- ve . 158

159. Spectrum least effect against G+ and G- Norfloxacin Excellent G+ and moderate to good G- Ciprofloxacin , pefloxacin , lemofloxacin Improved activity against G+ and good activity against anaerobes Gatifloxacin , cinfloxacin , Enhanced G+ activity and good action on anaerobes Moxifloxacin and Trovafloxacin 159

160. Fluroquinolones … After oral administration, FQs are well absorbed, distributed widely in body fluids and tissues Absorption is impaired by divalent cations including those in antacids Adverse effect GI disturbances (NVD) CNS toxicity (hallucination, seizure) Liver toxicity Photosensitivity Arthropathy – as they inhibit development of bone growth by complexing with calcium. 160

161. Use UTI ( E.coli , klebsiella , enterobacteria , serratia , pseudomonas) Norfloxacin 400mg po bid 3-21 days or Naldixic acid 12mg po Qid for 15days Sexual transmitted disease – Gonorrhea ( no longer use due to resistance), chylamydia Norfloxacin 800mg as a single dose (but CDC recommend ciprofloxacin) or Ciprofloxacin 250 - 500mg as a single dose (best with doxycycline ) Prostatitis Norfloxacin 400mg po bid for 4 weeks Ciprofloxacin 500mg po bid for 28 days 161