1. Protein Synthesis Inhibitors Dr. Rajendra Nath Dr. Rajendra Nath Professor

2. Protein Synthesis Inhibitors & Other Newer Antibiotics Protein Synth. Inhibitors 1) Protein Synth. Inhibitors that target the ribosome that target the ribosome e.g.- - Tetracyclines - Chloramphenicol - Macrolide antb.s (Erythromycin) - Ketolide, Clindamycin (Lincosamides)

3. Protein Synthesis Inhibitors & Other Newer Antibiotics Streptogramins - Quinupristin / Dalfopristin Oxazolidinones – Linezolid Comps. acting on cell membrane /cell wall 2 ) Comps. acting on cell membrane /cell wall : - Polymixin & Glycopeptides Glycopeptides – e.g.- Vancomycin & Teicoplanin - Vancomycin & Teicoplanin

4. Protein Synthesis Inhibitors Lipopeptides Lipopeptides – e.g. –Daptomycin. Miscellaneous 3) Miscellaneous : Compds. acting by direct mech. e.g.- - Bacitracin - Mupirocin Newer AM 4) Newer AM : Raptamulin Fidaxomycin

5. Protein Synthesis Inhibitors Tetracyclines HISTORY HISTORY : soil specimens The development of the Tetracycline antibiotics was the result of a systemic screening of soil specimens collected from many parts of the world for antibiotic- producing micro-organism

6. Protein Synthesis Inhibitors Tetracyclines -Chlortetracycline (prototype) is introduced in 1948.( by S. aureofaciens ), followed by Oxy- tetracyclines & Tetracyclines in 1950 & 1952 respectively - Because of their action against G +ve, G- ve bact.s, Rikettsia,Aerobes, An- aerobes & Chlamydia,they are known as Broad spectrum antibiotics.

7. Protein Synthesis Inhibitors Tetracyclines

8. Source & Chemistry Source & Chemistry : - Oxytetracycline a natural product isolated from Streptomyces rimosus. - Tetracycline is semi synthetic derivative of Chlortetracycline ( isolated from Streptomyces aureofaciens ). DoxycyclineMinocycline - Others are Doxycycline & Minocycline - Tetracyclines are close cong.s of

9. Protein Synthesis Inhibitors Tetracyclines polycyclic naphthocemecarboxamide having fusion of four cyclohexane rad. hence the name. OH O OH O CO – NH2 OH CH3 OH N(CH3)2

10. Protein Synthesis Inhibitors Tetracyclines Susceptibility to micro-organisms (Spectrum) Susceptibility to micro-organisms (Spectrum) : Tetracyclines - more active against G +ve than G -ve micro- org.s. -G +ve: Staphylococci, Enterococi, & hemolytic Streptococi having variable susceptibility

11. Protein Synthesis Inhibitors Tetracyclines G –ve: Enterobacters have acquired resistance ) -B. anthracis & L. monocytogenes & H. influenzae are susceptible ( Enterobacters have acquired resistance ) -Other Sensitive G –ve org.s are -Brucella - Helicobacter pylori Chancroid -,H. ducreyi ( Chancroid ), - Yersinia pestis ( Plague) - V. cholerae - Enterocolitica - Legionella pnemophilla, - Tularemia -Campylobacter jejuni, - Pasteurella multocida

12. Protein Synthesis Inhibitors Tetracyclines strains of N. gonorrhea are no longer sensitive) ( strains of N. gonorrhea are no longer sensitive). - Various anaerobes are also susceptible (e.g. – Bacterioides species, Propiono - bacterium & Pepcococcus ) - Tetracycline is active against Actinomyces & is DOC. - Rikettsia – All Tetracyclines are highly It causes Rocky mountain spotted fever,Typhus, scrub typhus & Q – fever) effective ( It causes Rocky mountain spotted fever,Typhus, scrub typhus & Q – fever).

13. Protein Synthesis Inhibitors Tetracyclines Miscellaneous Miscellaneous : - Spirochetes including Borrelia recurrentis, Treponema pallidum ( Syphilis), Chlamydia, - Mycoplasma - Non T.B. strains of Mycobacterium( e.g.-M.murium) - Amoeba & some atypical mycobacteria & Plasmodium species (but not active against Fungi ).

14. Protein Synthesis Inhibitors Tetracyclines Various Tetracyclines Used : -Tetracycline & Oxytetracycline -Chlortetracycline ( obsolete in US ) - Minocycline & Doxycycline -Demeclocycline are available. ( Chlortetracyclines & Oxytetracyclines are used only in ophthalmic solution/ oint.)

15. Protein Synthesis Inhibitors Tetracyclines -The more lipophylic drugs e.g.- DoxycyclinesMinocyclines Doxycyclines & Minocyclines usually are the most active followed by Tetracyclines. -Resistance to any one can cause cross resistance to others.

16. Protein Synthesis Inhibitors Tetracyclines Effect on Intestinal Flora Effect on Intestinal Flora : Many of the Tetracyclines are incompletely absorbed from the GIT. & ↑ conc. in the bowel can markedly alter enteric flora. - Sensitive aerobic & anaerobic coliform micro-org. & G- ve spore forming bacteria are suppressed markedly.

17. Protein Synthesis Inhibitors Tetracyclines As the fecal coliform count declines – overgrowth of Tetracyc. resist. micro-org.s occurs particularly- Yeasts (esp. Candida sp.) - Yeasts (esp. Candida sp.) - Enterococci - Enterococci - Proteus & - Proteus & - Pseudomonas - Pseudomonas

18. Protein Synthesis Inhibitors Tetracyclines It occasionally produce Pseudomembranous Colitis ( caused by Clostridium difficile. ) Mechanism of Action Mechanism of Action : Tetracyclines ↓ bact. protein synth. by binding to the 30s bact. ribosomes &prevent access of aminoacyl t-RNA – ribosome complex ( by ↓its attachment to ‘A’ site)

19. Protein Synthesis Inhibitors Tetracyclines

22. -They enter G -ve bact.by passive diff. through the hydrophilic channels formed by Porin protein of the outer cell memb. via the active transport energy dependent system. Resistance to Tetracycline Resistance to Tetracycline : Plasmid mediated & is inducible.

23. Protein Synthesis Inhibitors Tetracyclines Mech. of action of resistance Mech. of action of resistance: 1.↓ Accumul. of Tetracyc. as a result of either decreased antb. influx or acquisition of an energy dependant efflux pathway. 2. Prod. of ribosomal protective protein that may occur by mutation ). displaces Tetracyc. from its target ( may occur by mutation ). 3. Enzymatic inactivation of Tetracyclines

24. Protein Synthesis Inhibitors Tetracyclines Classification Classification : 1. Incompletely absorbed ( 60-80% ) Oxytetra & Demeclocyc. Natural- Oxytetra & Demeclocyc. Tetracyclines Semi- synth. – Tetracyclines 2. Almost completely absorbed (90- 100%) – Semi synthetic Doxycyclines & Minocyclines

25. Protein Synthesis Inhibitors Tetracyclines Pharmacokinetics (Absorption, Distribution &Excretion) -Abs. of most Tetracyclines is incomplete. -% of oral dose that is absorb with empty stomach is : - Lowest for Chlortetracycline - Intermediate for Oxytetracyclines, Demeclocyclines & Tetracyclines - High for Doxycyclines (95%) & Minocyclines(100%)

26. Protein Synthesis Inhibitors Tetracyclines Absorption of Tetracyc. is impaired by the concurrent ingestion of - Dairy prod. (milk & milk products ) - Aluminum hydroxide gel - Ca, Mg, iron & Zn salts and - Bismuth subsalicylate. ( food & dairy products do not interfere with the abs. of ( food & dairy products do not interfere with the abs. of Doxy & Minocycline Doxy & Minocycline )

27. Protein Synthesis Inhibitors Tetracyclines Half life ( t½ ) Half life ( t½ ) – Oxytetracyc. & Tetracyc. -6-12 hrs. Demeclocycline – 16 hrs. Doxycyc. & Minocyc. – 16-18 hrs.

28. Protein Synthesis Inhibitors Tetracyclines Distribution Distribution : Widely distributed through out the body and into tissues & secretions including urine & prostate. They accumulate in RE cells of liver & spleen, bone marrow,dentine & enamel of unerupted teeth.

29. Protein Synthesis Inhibitors Tetracyclines -Penetration into most of the tissues & fluid is excellent e.g.- CSF. -It crosses the placenta & also secreted in milk.

30. Protein Synthesis Inhibitors Tetracyclines Excretion Excretion : - Except Doxycycline the primary route of elimination for most of the Tetracyclines is the kidney,also conc. in liver & excreted in bile ( partly goes into enterohepatic circulation). - Excretion also occurs through feces even after the parenteral administration - Minocycline is metabolized in liver.

31. Protein Synthesis Inhibitors Tetracyclines (Because of enterohepatic circulation these drugs may remain in the body for a long time after cessation of therapy). - Doxycycline at recommended doses does not accumulate significantly in pts with renal failure & thus is one of the safest of the Tetracyclines for use in patient with renal impairment.

32. Protein Synthesis Inhibitors Tetracyclines Dose Dose - Tetracyclines wide variety of Tetracyclines are available for oral, parenteral & topical administration. Tetracycline- Tetracycline- oral – 1-2 gm /day in adult ( children -25 - 50 mg/kg daily) in two-four div. doses. Demeclocycline -Demeclocycline – 150 mg every 6 hrs used rarely as AM agent because it causes photosensitivity react. & nephrogenic diabetes insipidus.

33. Protein Synthesis Inhibitors Tetracyclines Doxycycline- - Doxycycline- 100 mg 12 hrly on 1 st day then 100 mg OD (Child- 4-5 mg/kg/d on 1 st day then 2-2.5 mg /kg OD. ) Parenteral : Doxycycline - Doxycycline – 200 mg I.V. infusion on 1 st day then 100 mg once or twice subsequently Tetracycline2gm in severe inf. -Tetracycline – in acute infections – 1 gm ( 2gm in severe inf. ) div. in equal doses. Generally Tetracyclines should be given 2 hr. before or after meals ( Generally Tetracyclines should be given 2 hr. before or after meals ) Tetracyclines should not be given I.M. as local irritation & Tetracyclines should not be given I.M. as local irritation & poor absorption occurs. poor absorption occurs.

34. Protein Synthesis Inhibitors Tetracyclines Local – except for local use in the eye topical use of Tetracycline is not recommended.

35. Protein Synthesis Inhibitors Tetracyclines USES USES: 1. Rikettsial inf. ( DOC is Doxy ) Caused by obligate intracellular organism resembling viruses & bact. Maintained in nature by a cycle of animal reservoir & arthropod vector. They multiply in vas, endothelial cells & causes perivascular infiltr.& Leads to thrombosis, gangrene etc. Types are -Rocky mountain spotted fever -Epidemic & Scrub typhus -Q fever Tetracyclines are life saving & clinical improvement occurs in 24 hrs Others effective are Chloramphenicol.

36. Protein Synthesis Inhibitors Tetracyclines 2. Mycoplasma inf. ( M. pneumonia) Mycoplasma is smallest living org., lacks cell wall, do not synthesize Folic acid so naturally resist. to Sulfonamides.Erythromycin also effect. 3. Chlamydia – Lymphogranuloma –venereum (Doxy.- 100 mg BD x 21 days ) -Psittacosis & Trachoma –Doxy -100 mg BD x14 d. ( Trachoma is a type of follicular conjunctivitis & cause of blindness). or Tetracycline in Trachoma – 250 mg QID x 14 days ( because it occurs in early childhood before complete calcification of the permanent teeth so is C/I ).

37. Protein Synthesis Inhibitors Tetracyclines Non specific urethritis 4. Non specific urethritis – Doxycycline – 100 mg BD. x 7 days. Sexuallytransmitted diseases 5. Sexually transmitted diseases (STD): Not a DOC because of resistance. -C. Trachomatis is often a co-existent pathogen in acute endometritis PID including endometritis,salpingitis & for peritonitis Doxy – 100 mg I.V. BD. followed by oral therapy x 7 days usually combine with Cefoxitin to cover anaerobes ( usually combine with Cefoxitin to cover anaerobes )

38. Protein Synthesis Inhibitors Tetracyclines -Acute Epididymitis – single inj. of Ceftriaxone + Doxy 100 mg orally BD x 10 days ( Sexual partner with any of these diseases shall also be treated ) - Primary/ Secondary Syphilis- - Primary/ Secondary Syphilis- In In non pregnant Penicillin resist. Pts can be treated with Tetracycline.

39. Protein Synthesis Inhibitors Tetracyclines 6. Anthrax – Doxycycline – 100 mg 12 hrly ( 2.2 mg/kg in children ) x 60 days 7. Bacillary infections – -Brucellosis - Tetracycline + Rifampicin / Streptomycin is effective (caused by inf. milk of goat, cow or sheep & occurs in farmers ). (caused by inf. milk of goat, cow or sheep & occurs in farmers ). -Tularemia- Although Streptomycin is preferred but Tetracyclines also are effective.

40. Protein Synthesis Inhibitors Tetracyclines - Cholera – Doxy -300 mg single dose is effective in reducing stool volume & eradicating V. cholerae from stools with in 48 hrs., but it is not a substitute for I.V. electrolytes & fluid replacement. - Shigellosis / Salmonella infection: The Tetracyclines are not effective because of resistance. but can be given in Traveller’s diarrhoea by E. coli ) ( but can be given in Traveller’s diarrhoea by E. coli )

41. Protein Synthesis Inhibitors Tetracyclines 8. UTI – no longer recommended. 9. Other- Actinomycosis, Leptospirosis & infection by Borellia species (acute & prophylactic treatment of infections ) 10. Acne – Tetracyclines have been used to treat acne by inhibiting Propioni -bact. which reside in sebaceous follicles (low doses are used -250mg orally twice a day ).

42. Protein Synthesis Inhibitors Tetracyclines 11. Amoebiasis – effective with other drugs. 12. Helicobacter pylori inf. of GIT ( peptic ulcer ) 13. Malaria caused by plasmodium.

43. Protein Synthesis Inhibitors Tetracyclines Glycylcyclines The Glycylcyclines are synthetic analogs of the Tetracyclines; the Glycylcycline currently approved is Tigecycline Tigecycline, the 9-tert-butyl glycylamido derivative of Minocycline. - They display activity like older Tetracyc. & targets Tetracycline resistant org.s.

44. Protein Synthesis Inhibitors Tetracyclines They are also active against - Methicillin Resist. S. aureus (MRSA) & S. epidermidis. - Penicillin resist. S. pneumoniae & - Vancomycin resist. enterococci (VRE). Tigecycline is not appreciably absorbed from the (Tigecycline is not appreciably absorbed from the Gastrointestinal (GI) tract and is only available for Gastrointestinal (GI) tract and is only available for parenteral administration parenteral administration )

45. Mnemonic : ( Uses) T Tetracyclines are used for E T R - Rickettsia,Relapsing fever A - Atypical pneumonia C - Cholera Y - LYme’s disease C - Chlamydia L - LGV I - Inguinale ( granuloma ) N E - Epidemics of Plague

46. Protein Synthesis Inhibitors Tetracyclines Side/ effects Side/ effects: 1.GIT -GI irritation most common after oral administration - Epigastric burning, - Nausea, Vomiting & Diarrhea - Esophagitis ( give drug with food ). - Pseudomembranous colitis byClostridia difficle.

47. Protein Synthesis Inhibitors Tetracyclines 2. Photosensitivity – esp. by Doxy, & Demeclocycline 3. Hepatic toxicity :- ( esp. during preg. on prolong use ) ↑ blood urea 4. Renal toxicity : Tetracyc. have catabolic effect so aggravate azotemia ( ↑ blood urea). Doxycycline is least nephro - toxic. ( Demeclocycline often produce nephrogenic diabetes insipidus.)

48. Protein Synthesis Inhibitors Tetracyclines Fanconi syndrome – characterized by nausea,vomiting, polyuria, polydipsia, proteinuria, acidosis & glycosuria,azotemia & kidney damage due to formation of toxic metabolites e.g.- Epianhydrotetracycline & Epitetracycline which has been observed in pts ingesting outdated & degraded Tetracyclines (due to formation of toxic metabolites e.g.- Epianhydrotetracycline & Epitetracycline which has been observed in pts ingesting outdated & degraded Tetracyclines).

49. Protein Synthesis Inhibitors Tetracyclines 5.Effects on teeth : Children may develop permanent brown discoloration of teeth ( the larger is the dose more intense the discolor.) ( Total dose is more important & risk is more when given to neonates or babies before 1 st dentition. )

50. Protein Synthesis Inhibitors Tetracyclines the deposition of drug in teeth & bones is due to its chelating prop. & the formation of Tetra-calcium-orthophosphate complex. Misce. 6. Misce. : Tetracyclines are deposited in the skeleton during gestation & throughout childhood & may depress bone growth in Premature Infants.

51. Protein Synthesis Inhibitors Tetracyclines - Thrombophlebitis following I.V. administ. -↑ Intracranial pressure in some young infants. ( causes bulging fontanelles & pseudotumor cerebri in adults ) -Thromcytopenic purpura,leukocytosis

52. Protein Synthesis Inhibitors Tetracyclines -Vestibular toxicity (especially by Minocycycline ) -Hypersens. react. may occur. Superinfection - Superinfection -caused by strains of bacteria, fungi resistant to Tetracyclines ( vaginal, oral, systemic & intestinal inf. can occur. )

53. Protein Synthesis Inhibitors Tetracyclines -Pseudomembranous colitis. Discontinuation of Tetracycline & administration of Metronidazole is curative Characterized by fever, severe diarrhea & stools cont. shreds of mucous memb. & large no. of neutrophils. ( Discontinuation of Tetracycline & administration of Metronidazole is curative ).

54. Mnemonic: ( Side effects ) KAPIL DEV DoxycyclineK – Kidney failure ( All are contra-indicated except Doxycycline ) A - Antianabolic effect DemeclocyclineP - Photosensitivity ( maximum with Demeclocycline ) DemeclocyclineI - Insipidus ( Diabetes Insipidus : maximum with Demeclocycline ) L - Liver toxicity ( hepatic necrosis ) D - Dentition and Bone defects ( C/I in pregnancy and children ) E - Expired drugs can cause Fanconi’s syndrome MinocyclineV - Vestibular dysfunction ( maximum with Minocycline )

55. Protein Synthesis Inhibitors Tetracyclines Precautions Precautions : - Do not give Tetracyclines in pregnancy. - Do not use for common infections in children younger than 8 year. -Discard unused supply of this antibiotic.

56. Protein Synthesis Inhibitors Chloramphenicol Streptomyces venezuelae Produced by Streptomyces venezuelae -Introduced into clinical practice in 1948 -With wide use it became evident that Chloramphenicol (CAP) could cause serious & fatal blood dyscrasias. -Now CAP is reserved for Tt of life threatening infections e.g. -

57. Protein Synthesis Inhibitors Chloramphenicol Meningitis - Meningitis - Rikettsial inf. - Rikettsial inf. - Typhoid fever - Typhoid fever in pts who can not take safer alternative antibiotic due to resistance or allergy.

58. Protein Synthesis Inhibitors Chloramphenicol Chemistry : The antbiotic is unique among natura l comp.s in that it has nitrobenzene moiety responsible for antibacterial action ( responsible for antibacterial action ) & is a derivative of dichloroacetic acid. Mech. of Action : - It ↓ protein synthesis in bact. & to a lesser extent in eukaryotic cells. - It penetrates bacterial cells by facilitated

59. Protein Synthesis Inhibitors Chloramphenicol diffusion. -It acts primarily by binding reversibly to the 50S ribosomal subunit ( near the binding site for macrolide antb.s & Clindamycin which CAP↓ competitively ). Although binding of t-RNA at the codon recognition site on the 30S ribosomal subunit is undisturbed,

60. Protein Synthesis Inhibitors Chloramphenicol the drug prevents the transfer of elongated peptide chain to the newly attached aminoacyl-t RNA at the acceptor site of by preventing the ribosome –m RNA complex ( by preventing the interaction between peptidyl transferase & its aminoacid interaction between peptidyl transferase & its aminoacid substrate → ↓↓ of peptide bond formation and transfer of substrate → ↓↓ of peptide bond formation and transfer of elongated peptide chain from ‘P’ to ‘A ‘site,therefore elongated peptide chain from ‘P’ to ‘A ‘site, therefore inhibits Transpeptidation reaction inhibits Transpeptidation reaction )

61. Protein Synthesis Inhibitors Chloramphenicol

63. It can also ↓ mitochondrial protein synthesis in mammalian cells because mitochondrial ribosomes resemble bacterial ribosome (both are 70S ) more than they do the 80S cytoplasmic ribosomes of mammalian cells. Mammalian erythropoietic cells are particularly sensitive ( Mammalian erythropoietic cells are particularly sensitive to this drug to this drug )

64. Protein Synthesis Inhibitors Chloramphenicol Anti microbial action : - Broad spectrum antibiotic. - CAP is bacteriostatic against most species although it is bactericidal against N. gonorrheae S. pneumonia H. influenzae Brucella spc. & Bordetella pertusis.

65. Protein Synthesis Inhibitors Chloramphenicol It is active against the same range of notable organisms as Tetracyclines but notable differences differences are – - CAP was highly active against Salmonella including S. typhi ( but now resistant strains have developed ). -It is more active than Tetracyclines against H. influenzae ( now many are resistant ), B. pertusis Klebsiella, N. meningitidis & anaerobes e.g. Bacteria fragilis.

66. Protein Synthesis Inhibitors Chloramphenicol - It is less active against G +ve cocci, Spirochetes, some Enterobacters & Chlamydia. - Entamoeba and Plasmodia are not inhibited Like Tetracyclines, it is also not effective against Mycobacteria, many Proteus, Pseudomonas, viruses and fungi.

67. Protein Synthesis Inhibitors Chloramphenicol Resistance to CAP: -Caused by a plasmid encoded acetyl transferase that inactivates the drug. - Also by ↓ permeability & from ribosomal mutation ( acetylated derivative of CAP fail to bind to bacterial ribosome )

68. Protein Synthesis Inhibitors Chloramphenicol Pharmacokinetics :(Absorption,Distribution & Excretion ) Chloramphenicol ( Chloromycetin ) is absorbed rapidly from the GIT & peak plasma conc. occur with in 2-3 hrs after administration..

69. Protein Synthesis Inhibitors Chloramphenicol - Parenterally - water sol., inactive prodrug CAP succinate ( prep. of Chloramphenicol ) hydrolyzes by esterases in vivo. It is rapidly cleared from pl. by the kidney ( ↓renal function in neonates & in other states ↑plasma concentration )

70. Protein Synthesis Inhibitors Chloramphenicol - Widely distributed in body tissues & fluids & readily reaches therap. conc. in CSF ( values are 60 % of those in plasma ) in the presence or absence of meningitis. - Drug may accumulate in brain, it is also present in bile, milk & placental fluid and aqueous humor after sub conj. Injection.

71. Protein Synthesis Inhibitors Chloramphenicol Hepatic metabolism to the inactive gluco - - Hepatic metabolism to the inactive gluco - ronide is the major route of elimination ronide is the major route of elimination -This metabolite & CAP itself are excreted in the urine following filtration Pt with cirrhosis & impaired liver & secretion ( Pt with cirrhosis & impaired liver function have ↓↓ metab. clearance & therefore dosing function have ↓↓ metab. clearance & therefore dosing should be adjusted should be adjusted )

72. Protein Synthesis Inhibitors Chloramphenicol - Significant variability in the metabolism & pharmacokinetics of CAP in neonates,infants & children necessitates monitoring of drug concentration in plasma.

73. Protein Synthesis Inhibitors Chloramphenicol Therapeutic Uses Therapeutic Uses : Therapy with CAP must be limited to benefits of the infections for which the benefits of the drug outweigh the risk of the potential drug outweigh the risk of the potential toxicities toxicities. Other drugs are used if effective & less toxic instead of CAP.

74. Protein Synthesis Inhibitors Chloramphenicol 1.Typhoid fever Quinolones & 3 rd gen. Cephalosp.s are DOC 1.Typhoid fever – ( Quinolones & 3 rd gen. Cephalosp.s are DOC.) CAP can be used if senst. & above drugs are causing allergy. (response is more rapid with oral route) Bact.Meningitis 2. Bact. Meningitis- 3 rd gen. Cephalosporin have replaced CAP ( but CAP remain an alternative drug for the Tt. of meningitis caused by

75. Protein Synthesis Inhibitors Chloramphenicol H. influenzae,N. meningitis & S. pneumoniae in patients having allergy to β –lactams ). Anaerobic inf 3. Anaerobic inf. – effective against most anaerobic bacteria including Bacteroid species & effective for Tt. of serious intra- abdominal inf. or brain diseases.

76. Protein Synthesis Inhibitors Chloramphenicol. Rikettsial inf. 4. Rikettsial inf. – Preferred agents are Tetracyclines but if pt is allergic to Tetra - cyclines with ↓ renal func.s, in pregn. or in children younger than 8 yrs. CAP is the DOC (50 mg/kg/day).

77. Protein Synthesis Inhibitors Chloramphenicol Brucellosis 5. Brucellosis – when Tetracyclines are resistant. Side Effects: CAP inhibit the synthesis of protein of mitochondrial membrane by ↓ peptidyl - transferase. Much of the toxicity can be attributed to this.

78. Protein Synthesis Inhibitors Chloramphenicol H/S react. 1. H/S react. – relatively uncommon- may occur in Syphilis, Brucella & Typhoid fever treatment macular or vesicular skin rash, fever,angio-oedema,Jarish - Herxheimer react. ( may occur in Syphilis, Brucella & Typhoid fever treatment ). Hematological toxicity 2. Hematological toxicity – most impt. is on bone marrow & is dose related (30%)-anemia, leukopenia

79. Protein Synthesis Inhibitors Chloramphenicol or thrombocytopenia. 70% idiosyncratic – aplastic anemia → pancytopenia. ( who undergo prolonged therapy or in patients expose to drug for more than one occasion ). But this does not C/I the use of CAP in situation in which it may be life saving.

80. Protein Synthesis Inhibitors Chloramphenicol the drug however should never be used in diseases ( the drug however should never be used in diseases readily, safely & effectively treatable with other AM readily, safely & effectively treatable with other AM agents agents. ) - Some pts who develop chronic bone marrow suppression subsequently develop acute myeloblastic leukemia.

81. Protein Synthesis Inhibitors Chloramphenicol Toxic& Irritative effects 3.Toxic & Irritative effects : - Nausea, vomiting, unpleasant taste diarrhea & perineal irritation. - Rare toxic effect – blurring of vision & digital parasthesia. 4. Neonates may develop a serious illness Gray Baby Syndrome termed Gray Baby Syndrome if exposed to excessive doses of CAP,

82. Protein Synthesis Inhibitors Chloramphenicol ( begin 2-9 days after Tt is started → vomiting, refusal to suck, irregular respiration, abd. distension, cyanosis & passing of loose green stools, patient become flaccid & hypothermic). Two mechanism: Deficiency of glucoronyltransferase 1.) Deficiency of glucoronyl -transferase, hepatic enzyme that metabolize CAP in first 3-4 wks of life.

83. Protein Synthesis Inhibitors Chloramphenicol Inadequate renal excretion of unconjugated drug 2.) Inadequate renal excretion of unconjugated drug children who are younger than 2 wks of age – dose should not exceed ( children who are younger than 2 wks of age – dose should not exceed 25 mg/ kg ). It removed from the blood minimally by peritoneal / hemodialysis.

84. Protein Synthesis Inhibitors Chloramphenicol D/I D/I – CAP ↓ hepatic C-P450 isozyme & prolong the half life of drugs that are metabolized by this system e.g.- Warferin Dicoumarol Phenytoin Chlorpopamide etc.

85. Protein Synthesis Inhibitors Chloramphenicol Because of serious bone marrow toxicity: 1.Never use Chloramphenicol for minor infections 2.Do not use Chloramphenicol for inf.s treatable by safe alternatives. 3.Avoid repeated courses 4.Daily dose should not exceed 2-3 gms. & duration of therapy should be less than 2 wks

86. Protein Synthesis Inhibitors Macrolides It includes : Erythromycin Roxithromycin, Clarithromycin & Azithromycin. Erythromycin : -Discovered in 1952 by McGuire & co- workers in the metabolic products of a Streptomyces erythrues strain of Streptomyces erythrues.

87. Protein Synthesis Inhibitors Macrolides - ClarithromycinAzithromycin - Clarithromycin & Azithromycin are semi-synthetic derivative of Erythromycin Roxithromycin ( Roxithromycin is also semi- synth., long acting, acid stable macrolide, spectrum ≡ Erythromycin & given in BD doses ) Chemistry : - Contain a many membered lactone ring (14 memb. ring for Erythromycin & Clarithromycin & 15 memb. ring for Azth. )

88. Protein Synthesis Inhibitors Macrolides to which are attached one or more deoxy sugars. -Clarithromycin have methylation of the hydroxyl gp. at 6 th position. -Azithromycin differ in having methyl – substituted nitrogen atom into the lactone ring.

89. Protein Synthesis Inhibitors Macrolides -These structural changes improves the acid stability & tissue penetration & broadens the spectrum of activity. Anti microbial activity: - Usually bacteriostatic but may become bactericidal in high concentration against susceptible organisms.

90. Protein Synthesis Inhibitors Macrolides - Most active against aerobic G +ve cocci & bacilli e.g. S. pyogen., S. pneumoniae & viridans. bact. resist. is common against Streptococci & resistance (bact. resist. is common against Streptococci & resistance mechanism affect all macrolide antibiotics so cross resist. mechanism affect all macrolide antibiotics so cross resist. is complete is complete.) -Staphylococci are not reliably sensitive to Erythromycin.

91. Protein Synthesis Inhibitors Macrolides - G+ve bacilli are sensitive to Erythromycin ( e.g. Clostridium perfringes, Coryne - bacterium diphtheriae & L. monocytogenes) inactive against most aerobic -It is inactive against most aerobic enteric G -ve bacilli enteric G -ve bacilli. ( but some are sensitive e.g. -H. influenz., N. meningitidis & N. gonorrheae.)

92. Protein Synthesis Inhibitors Macrolides Active against Pasteurella multocida Pasteurella multocida Borrelia species Borrelia species Bordetella pertusis Bordetella pertusis Campylobacter jejuni Campylobacter jejuni M. pneumoniae. M. pneumoniae. -Some atypical mycobact. are also senst. e.g. M. scrofulaceum.

93. Protein Synthesis Inhibitors Macrolides No activity against -virus -yeast & - fungi.

94. Clarithromycin Clarithromycin: is slightly more potent against sensitive strains of Streptococci.,Staphylococci.,H. influenzae & N. gonorrhoeae. -Good action against M. catarrhalis Chlamydia spp. M. pneumoniae & Helicobacter pylori.

95. Protein Synthesis Inhibitors Macrolides Azithromycin: less sensitive against G+ve org. but more active against H. influenz. & Campylobacter. - very effective against M. catarrhalis, Chlamydia spp. P. multocida, M. – pneumoniae L. pneumophilla, Fuso-bacterium spp. N. gonorrheae.

96. Protein Synthesis Inhibitors Macrolides Clarithromycin & Azithromycin have enhanced activity against M. avium intra- cellulare Toxoplasma gondii ( protozoa ) Cryptosporidium & Plasmodium Clarithromycin have good activity against Mycobacterium leprae.

97. Protein Synthesis Inhibitors Macrolides Mechanism of action : ↓ protein synthesis by binding reversibly to 50S ribosomal subunit at or very near the site that binds CAP. It does not ↓ peptide bond formation phase inhibits thetranslocation step but rather inhibits the translocation step ( ( wherein a newly synthesized peptidyl t-RNA molecule moves from acceptor site on the ribosome to the peptidyl donor site ).

98. Protein Synthesis Inhibitors Macrolides

100. -G +ve bacteria accumulates about 100 times more Erythromycin than do G –ve bacteria. -Have ↑antimicrobial activity at alkaline pH.

101. Protein Synthesis Inhibitors Macrolides Resistance : Usually occurs from one of the four mech. 1. Drug efflux by an active pump mech. 2. Ribosome protection by inducible or constitutive prod. of methylase enzyme, which modify the ribosomal target & ↓ drug binding.

102. Protein Synthesis Inhibitors Macrolides 3. Macrolide hydrolysis by esterases produced by enterobacteriaceae. 4. Chromosomal mutation that alters a 50S ribosomal protein.

103. Protein Synthesis Inhibitors Macrolides Phamacokinetics (Absorption,Distribution & Excretion ): Abs.- Erythromycin base is incompletely but adequately absorb from the upper small intestine. -It is inactivated by gastric acid therefore enteric coated tabs /caps it is given as enteric coated tabs /caps ( contain enteric coated pellets) or an ester.

104. Protein Synthesis Inhibitors Macrolides - Food that ↑ acidity may delay absorption -Peak plasma conc. occurs 4 hrs after oral administration. Stearate -Ester of Erythromycin base ( e.g.- Stearate,Estolate & Ethyl succinate,Estolate & Ethyl succinate ) have improved acid stability & less altered by food. ( High conc. can be achieved by I.V. administration )

105. Protein Synthesis Inhibitors Macrolides Clarithromycin Clarithromycin – abs. rapidly from GI tract after oral administration. -1 st pass metabolism ↓ its bioavailability to 50 %. ( Can be given with or without food- 500mg 12 hrly or extended release form -1gm once a day ).

106. Protein Synthesis Inhibitors Macrolides Azithromycin – Azithromycin – given orally, absorb rapidly, distributed widely through out the body except to the brain & CSF. (Not to be administered with food ) -Can be given I.V.

107. Protein Synthesis Inhibitors Macrolides - Drug traverses the placenta & concentrated in breast milk are 50 % of those in serum. - Clarithromycin & Azithromycin have extensive tissue distr. & reaches in most of the cells e.g. – phagocytes & greater concentration in tissues.

108. Protein Synthesis Inhibitors Macrolides Elimination : Erythromycin : Excreted in active form in the urine ( also excreted in bile ). - Clarithromycin - Excreted unchanged in urine 20-40%, metabolize in liver into several metabolites.

109. Protein Synthesis Inhibitors Macrolides Azithromycin-hepatic metabolism into active metabolite ( & biliary exct. is the major route of elimination, only 12 % excreted unchanged in urine ). Half life -40-68 hrs because of extensive tissue sequestration & binding.

110. Protein Synthesis Inhibitors Macrolides Doses : Erythromycin- 1-2 gm orally in 6 hrly div. doses. ( child – 30-50gm / kg/day ). I.M. – not recommended because of local pain. I.V. – for severe infection -0.5 -1 gm every 6 hrly (Erythromycin lactobionate ). ( Food should not be given simultaneously ).

111. Protein Synthesis Inhibitors Macrolides Clarythromycin– 250 mg BD for adult & children above 12y (500 mg BD. for severe inf. e.g. Infection with H. influenzae. Children younger than 12 yrs- 7.5 mg/kg BD). -With Lansoprazole (30 mg) + Amoxy - (1 gm ) BD x 14 days in H. pylori inf. to reduce incidence of duodenal ulcer.

112. Protein Synthesis Inhibitors Macrolides Azithromycin - Azithromycin - Oral, suspension, powder form & I.V. injection. Loading dose – 500 mg 1 st day, 1 hr before or 2 hr after meals then 250 mg OD. x 4 days. -( M. avium in AIDS -500mg daily in combination with other agents or 1200mg once a wk.- used for STD during pregnancy when Tetracycline is C/I).

113. Protein Synthesis Inhibitors Macrolides - 1 gm single dose for Nongonococcal urethritis Chancroid & alternative Tt. to Lymphogranuloma venereum. ( Children – 10 mg /kg / day x 4 days )

114. Protein Synthesis Inhibitors Macrolides Therapeutic Uses : 1 Mycoplasma pneumonia – DOC 2.Legionnairs disease-DOC for pneumonia 3.Chlamydial infection - with any of the Azithriomycin macrolides.( Single 1gm dose of Azithriomycin is recommended in uncomp. urethritis,endocervical & epididymal inf.s( During preg. Erythromyc. 500mg QID x 7 days is the DOC.)

115. Protein Synthesis Inhibitors Macrolides 4.Diphtheria – Erythromycin -250mg QID x 7 days is very effect. in acute infection for eradicating the carrier state. Anti toxin is indicated in cases of ( Anti toxin is indicated in cases of acute infections acute infections.)

116. Protein Synthesis Inhibitors Macrolides Pertusis 5. Pertusis – DOC for Tt & post exposure prophylaxis ( 40 mg/kg day –max. 1 gm /day x 7 days ). Streptococ. Inf. 6. Streptococ. Inf. –Pharyngitis, scarlet fever, erysipelas & cellulitis – responds to macrolides ( alternative to penicillin.) Staphylococcal inf.- -Staphylococcal inf.-alternate treatment for minor infections

117. Protein Synthesis Inhibitors Macrolides Campylobacter 7. Campylobacter : in Gastroenteritis- Erythromycin-250-500mg QID x 7days ( Fluoroq.s has replaced ). Helicobacter pylori 8. Helicobacter pylori – Clarythromycin is given in comb. with Amoxycillin & Omeprazole.

118. Protein Synthesis Inhibitors Macrolides Tetanus 9. Tetanus – Erythromycin- 500mg orally 6 hrly x 10 days to eradicate Clost. alt. to Penicillin) tetani.( alt. to Penicillin) ( Debridement of wound, physiological support,Tetanus antitoxin & drug control of convulsions is the main stay of treatment) Syphilis 10.Syphilis- Early syphilis (alt. to Penicillin) but no longer recommended.

119. Protein Synthesis Inhibitors Macrolides Mycobacterial inf. 11. Mycobacterial inf. – Clarythromycin & Azithromycin for therapy & prophylaxis of Mycobacterium avium intracellulare in AIDS pts. ( Clarythromycin 500mg BD + Ethambutol-15 mg /kg once daily with or without Rifampicin is an effective combination regimen.) 12. Clarythromycin has been used with Minocycline for the Tt of M. leprae in Lepromatous leprosy.

120. Protein Synthesis Inhibitors Macrolides Prophylactic Use : Rheumatic fever 1. For recurrence of Rheumatic fever (second choice to penicillin.). Bacterial endocarditis 2. For Bacterial endocarditis. ( in Penicillin allergic pts ). ( Uses-M-C- Chancroid, Cornebacterium, Campylobacter L- Legionella infections A –Atypical pneumonia W- Whooping cough

121. Uses-Mnemonic-Erythromycin C- Chancroid, Cornebacterium, Campylobacter L- Legionella infections A –Atypical pneumonia W- Whooping cough Uses –Mnemonic- Azithromycin & Clarithromycin C- Chlamydia H- H. influenzae A A- MAC T- Toxoplasma

122. Protein Synthesis Inhibitors Macrolides Side Effect : Serious S/E are rarely present. -Fever, Eosinophilia & skin eruption (disappear after stoppage of therapy) Cholestatic hepatitis - Cholestatic hepatitis,most sig. S/E ( by Erythromyc. estolate,rarely by ethyl-succinate or stearate develop after 10-20 days of drug Tt., starts with nausea, vomiting & abdominal cramps → jaundice – ↑ transaminase level, eosinophilia & leukocytosis.)

123. Protein Synthesis Inhibitors Macrolides - Large doses orally associated with. epigastric pain. Cardiac arrhythmia -Cardiac arrhythmia ( ↑QT interval with ventricular tachycardia ). Transient auditory impairment -Transient auditory impairment ( by I.V. large doses ). (↑ GI motility by acting on Motilin recpt. to ↑ motilin secretion a harmone present in GI-tract & therefore used post operatively to ↑ peristalsis & also to improve gastric emptying in gastric paresis in diabetes ) & also to improve gastric emptying in gastric paresis in diabetes )

124. Protein Synthesis Inhibitors Macrolides -Other non chemotherapeut. role is its anti-infl. effect by↓ pro-infl. Cytokine release from the phagocytes -- may be useful in Rheumatoid arthritis,cystic fibrosis, chronic sinusitis & asthma D/I – D/I – Erythromycin & Clarythromycin→ ↓CYP3A4 microsomal enzyme & therefore potentiate the effect of - Carbamazepine Cyclosporin Valproate Corticosteroid Digoxin Ergot alkaloids Theophylline & Warferin when given simultaneously

125. Protein Synthesis Inhibitors Macrolides (Azithromycin is free of these D/I ). Adverse Effects- Mnemonic M- Motilin receptor agonists A - Allergy C- Choleastasis R - Reversible O- Ototoxicity Spiramycin : Spiramycin : A macrolide antib.& has been employed only sporadically -It resembles Erythromycin in spectrum. It has been found to limit risk. of transplacental transmission of Toxoplasma gondii infection. (Its specific utility is for Toxoplasmosis & recurrent abortion in pregnant womens).

126. Miscellaneous & Newer Antibiotics Ketolides: Ketolides: Telithromycin - It is a macrolide with keto gp. that binds with ribosome with greater affinity & resists efflux mediated & methylase mediated Thus it is effective against many macrolide resistant organisms resistance. ( Thus it is effective against many macrolide resistant organisms ) - Approved for multidrug resist. Resp. tract infections. -It is also an enzyme inhibitor so prone for similar D/I like Erythromycin.

127. Miscellaneous & Newer Antibiotics Clindamycin : Lincomycin, -It is a chlorinated derivative of Lincomycin, more effective & more safer than Lincomycin -It acts on 50S ribosomal subunit ≡ Erythromycin. -It is bacteriostatic with similar AM spectrum. Better effectiveness against anaerobic organisms e.g.- B. fragilis, - Better effectiveness against anaerobic organisms e.g.- B. fragilis, Fusobacterium, Peptostreptococci & Clostridium perfringes. Fusobacterium, Peptostreptococci & Clostridium perfringes. ( All aerobic G -ve organisms are resistant )

128. Miscellaneous & Newer Antibiotics -Good penetration in bone but does not cross BBB. S/E - S/E - Antibiotic assos.colitis (pseudom. col.) Skin rashes Neuromuscular blockade. Indication Indication- Anaerobic infections e.g.– abscess, bacteremias, empyma, reaches prostatic fluid pneumonia & prostatitis (reaches prostatic fluid) - Pneumocystis jiroveci - Toxoplasma encephalitis & Malaria

129. Miscellaneous & Newer Antibiotics GLYCOPEPTIDES : Vancomycin ( produced by Streptococcus Orientalis ) -Effective against Staphylococci (second choice due to toxicity ), Streptococci & Clostridium. - It is bactericidal by ↓cell wall synthesis It inhibits cell wall synthesis by binding firmly to ( It inhibits cell wall synthesis by binding firmly to the D- Ala –D-Ala terminus of nascent peptidoglycan the D- Ala –D-Ala terminus of nascent peptidoglycan pentapeptide. This ↓ the Transglycolase pentapeptide. This ↓ the Transglycolase

130. Miscellaneous & Newer Antibiotics, preventing further elongation of peptidoglycan &, preventing further elongation of peptidoglycan & cross linking & thus cell become susceptible to cross linking & thus cell become susceptible to lysis lysis.) - Poor oral abs. so given as I.V. infusion used orally only for local effect in GIT -More than 90% excreted by kidney.

131. Miscellaneous & Newer Antibiotics S/E S/E : -Fever, chills,phlebitis. RMS- red man/red neck syndrome, due to massive release of histamine by rapid infusion, other histamine liberators are –Morphine, Tubocurarine, Polymixin B - Extreme flushing ( RMS- red man/red neck syndrome, due to massive release of histamine by rapid infusion, other histamine liberators are –Morphine, Tubocurarine, Polymixin B ) - Nephrotoxicity -Ototoxicity -H/S reactions.

132. Miscellaneous & Newer Antibiotics Indications: MRSA -Methicillin resist. staphylococci inf. (MRSA) -Antibiotic associated colitis. - Enterococcus endocarditis -Penicillin resist. Pneumococcal infections. dose-1 gm IV 12 hrly, orally 500 mg 6 hrly in pseudm. col. ( dose-1 gm IV 12 hrly, orally 500 mg 6 hrly in pseudm. col.)

133. Miscellaneous & Newer Antibiotics Teicoplanin : Similar to Vancomycin but safe by I.M. route very expensive like Vancomycin used only in Vancomycin allergy (very expensive like Vancomycin used only in Vancomycin allergy) Cycloserine: ( produced by Streptomyces orchidaceus ) It inhibits cell wall synthesis, effective orally. -Used as a second line drug for E. coli & Tuberculosis.

134. Miscellaneous & Newer Antibiotics S/E S/E- The effects aggravated by alcohol Headache (The effects aggravated by alcohol ) Drowsiness Convulsions Psychosis

135. Miscellaneous & Newer Antibiotics Fusidic Acid Fusidic Acid: -It is a steroidal antibiotic. -Does not actually bind to ribosomes but ↓ protein synthesis by ↓a factor necessary for elongation of peptide chain. -Effective against penicillinase producing Staphylococci.

136. Miscellaneous & Newer Antibiotics -Dual interaction with penicillin i.e. in sensitive org.s there is antagonistic effect while in resistant org.s it enhances the penicillin action. -Penetration in bone is good so used reserved drug for osteomyelitis. as a reserved drug for osteomyelitis.

137. Miscellaneous & Newer Antibiotics Polypeptide Antibiotics: -They are peptides but lack antigenecity. ( molecular wt. is low). - They are- Polymixin B Polymixin E (Colistin ) Bacitracin Capreomycin

138. Miscellaneous & Newer Antibiotics Polymixin B & E: - Narrow spectrum bactericidal antibiotic - Effective against G- ve org.s ( e.g. Pseudomonas except Proteus & Neisseria ). - Not absorb orally. - Systemically they are nephrotoxic therefore used only locally.

139. Miscellaneous & Newer Antibiotics - They are surface active, cationic detergents. - They interact with phospholipid of bacterial cell membrane & alters its permeability so that vital substances leak out & cell dies. Indication Indication – Local infections of skin, eyes ears & mucous membrane.

140. Miscellaneous & Newer Antibiotics Colistin - Colistin is used orally for infective diarrhea in a child or to alter gut flora in hepatic failure. Bacitracin: - It is bactericidal by inhibiting cell wall synthesis - It is highly nephrotoxic hence used locally in combination with Neomycin Nebasulf and/or Polymixin. ( Nebasulf – Neomycin + Bacitracin + Sulfacetamide, powder / ointment )

141. Miscellaneous & Newer Antibiotics Capreomycin: Capreomycin: - - Bacteriostatic - Second line drug for Tuberculosis - High risk of nephrotoxicity & vestibular toxicity

142. Miscellaneous & Newer Antibiotics Mupirocin ( Pseudomonic acid ): -Rapidly inactivated after absorption therefore used just topically. -Staphylococci is highly sensitive so it is effective against impetigo. -Can become resistant if applied to a large surface area.

143. Miscellaneous & Newer Antibiotics Quinupristin & Dalfopristin Quinupristin & Dalfopristin : It is a combination of Streptogramin A (Dalfopristin) & Streptogramin B (Quinopristin ) in the ratio of 70 : 30. The Dalfopristin ↑ sensitivity of 50S ribosome to enhance the binding with the Quinopristin, which ↓ polypeptide elongation & terminates protein synthesis by ↓ 50S ribosome.

144. Miscellaneous & Newer Antibiotics - The combination has rapid bactericidal effect which remains for longer time period. -They are soluble semi-synthetic derivative of Pristinamycins. -Used as I.V. infusion in 5% dextrose solution for an hour. ( Inj. may lead to pain -arthralgia, myalgia & phlebitis ) indicated for serious MDR staphylococcus, -They are indicated for serious MDR staphylococcus, streptococcus & pneumococcus infections. streptococcus & pneumococcus infections.

145. Miscellaneous & Newer Antibiotics Linezolid : It is a synthetic oxazolidinone with a 23S unique site of action i.e.- 23S ribosomal subunit of 50S ribosome ribosomal subunit of 50S ribosome & its inhibition prevents formation of 70S ribosome complexes & therefore inhibits the early assembly step in protein synthesis

146. Miscellaneous & Newer Antibiotics - Due to its unique site of action there is no cross resistance. - Its oral bioavailability is 100% so the oral & I.V. doses are the same. Active against G +ve aerobic & anaerobic organisms but - Active against G +ve aerobic & anaerobic organisms but not against G –ve org.s. not against G –ve org.s. last resort for MDR Staphylococcal, -Indicated as a last resort for MDR Staphylococcal, Streptococcal & Pneumococcal infections. Streptococcal & Pneumococcal infections.

147. Miscellaneous & Newer Antibiotics ( Other latest ones are- Radezolid & Torezolid both are in phase III cl. trial. 4-6 times more active against- staphyl., enterococ.& anaerobes.) trial. 4-6 times more active against- staphyl., enterococ.& anaerobes.) S/E S/E- GI upset Skin rashes Headache ↓platelet count hence ↑risk of bleeding Week MAO ↓ that may lead to the cheese reaction.

148. Miscellaneous & Newer Antibiotics Fosfomycin: - It ↓ cell wall synthesis & transported by G6PD transport system. -Used for selective cases of UTI. -It is safe in pregnancy.

149. Miscellaneous & Newer Antibiotics Spectinomycin: -It is similar to Aminoglycosides, binds to 30S subunit of ribosome in G- ve bacteria. - It is not bactericidal. -It is a reserve drug for resist. gonorrh. used as a single dose by deep I.M. inj.

150. Miscellaneous & Newer Antibiotics Lipopeptide : Lipopeptide :- Daptomycin -Binds to bacterial membrane leading to depolarization & cell death. -Has a concentration dependent bactericidal effect. -There is no known resistance or cross resistance. resistant Staphylococcal & -Indicated for resistant Staphylococcal & Streptococcal infections Streptococcal infections.

151. Miscellaneous & Newer Antibiotics Other Glycopeptides Other Glycopeptides : Oritavancin & Dalbavancin - For GISA (glycopeptide intermediate susp. staphylococcus aureus ) & -MRSA (methicillin resistant S. aureus ).

152. Miscellaneous & Newer Antibiotics Oritavancin Oritavancin is an analog of Vancomycin effective against vancomycin resistant also effective against vancomycin resistant enterococci ( VRE ). enterococci ( VRE ). Long t½ permits once a day administration. Dalbavancin Dalbavancin is similar but not effective against VRE.It has a prolonged retention in organisms so once a week administration is sufficient.

153. Miscellaneous & Newer Antibiotics Platensimycin : - It ↓ fab F enzyme, which is required for fatty acid biosynthesis which is essential to construct cell membrane. - Effective for MRSA & VRE.

154. Miscellaneous & Newer Antibiotics Pleuromutilins : Newer class of antibiotic MOA: MOA: Bind to 50S subunit of ribosomes inhibiting protein synthesis Approved Drug Approved Drug: Retapamulin: Retapamulin: Approved in 2007 -Topical antibiotic -Treatment of skin infections such as impetigo by S. aureus (methicillin-susceptible only) or S. pyogenes

155. Miscellaneous & Newer Antibiotics Macrocyclic antibiotic drugs : Fidaxomicin ( Dificid*) -2011 -Narrow spectrum bactericidal agent -Demonstrated selective eradication of pathogenic Clostridium difficile -MOA: Inhibit bacterial enzyme RNA polymerase Awaiting FDA approval

156. ANTIMICROBIAL THERAPY Disease Drugs of First Alternative Drugs ( Pathogen) Choice G –ve cocci (aer.) Moraxella catarrh. TMP-SMZ,cephalosp Eryth., Quinol.s, Clarith. ( II / III g.) Azith. N. gonorrhoeae Ceftriaxone, Cefexime Spectinomy.& Cefoxitin Quinol.s N. Meningitidis Penicil. G Chloramph., Cephsp.III g N. Meningitidis Penicil. G Chloramph., Cephsp.III g G –ve rods ( aer.) E.Coli, Proteus, Cephsp. I / II g., TMP- Quinol.s & Aminog.s Klebsiella SMZ.

157. ANTIMICROBIAL THERAPY Enterobacter, Serrt. TMP-SMZ,Quinol.s Antipseud. Penicil., Imipenem/ Meropen. Aminog., Cefepime Shigella Quinol.s TMP-SMZ,Ampicil. Cefixime, Ceftriaxon. Salmonella TMP-SMZ, Quinol.s Chloramph., Ampicil. Cephsp. III g. Cephsp. III g. Campyl. jejuni Quinol.s, Eryth. Tetracyc., Furazolid. Brucella sp. Doxy + Rifamp./ Aminog. Chloramph.+ Aminog or TMP-SMZ Helico. pylori Bismuth + Metronid.+ Omepraz. + Amoxicil Tetracyc.or Amoxicil. or Clarith. Tetracyc.or Amoxicil. or Clarith. Vibrio sp. Tetracyc., TMP-SMZ Quinol.s

158. ANTIMICROBIAL THERAPY P.aeruginosa P.aeruginosa Antipseudomonal Penicil. Antipseud. Penicil. + + Aminogl. Quinol.s,Ceftazidime Imipenem / Meropenem or Aztreonam + Aminog. Legionella sp. Erythromycin ( + Rifamp.) Quinol.s ( + Rifamp.), Clarithromycin. G+ve cocci (aer.) Strep. pneum. Penicil. Ceftriaxone, Cefotax., Vancomy., TMP-SMZ, Vancomy., TMP-SMZ, Eryth., Imipenem/ Mero Eryth., Imipenem/ Mero. Penicil., Clindamy. S.pyog.( gp -A) Penicil., Clindamy. Eryth., Cephsp.( I g ) S. agalact. (gp. B) Penicil.( + Aminog. ) Vancomycin Viridans Strept. Penicil. Vancomy., Cephsp.

159. ANTIMICROBIAL THERAPY Penicil. Vancomy., Staphyl. aureus Penicil. Vancomy., Cephsp.( I g ) (Beta- lactamase - ve) Beta-lactamase +ve Penicillinase resist. Vancomy., Cephsp.( I g ) Penicil. Methicil. – resist. Vancomycin TMP-SMZ, Minocyc. Vancomy.+ Aminogl. Enterococ. sp. Penicil. + Aminog. Vancomy.+ Aminogl. G-+ve bacilli( aer.) Bacil.sp. ( non anth) Vancomycin Imipenem / Meropenem, Quinol.s, Clindamycin Listeria sp. Ampicil.+ Aminogl. TMP-SMZ Nocardia sp. Sulfadiazine, Minocyc., Imipenem or TMP-SMZ Meropenem, Amikacin

160. ANTIMICROBIAL THERAPY Anaerobic bact.: G +ve ( Clostridia Penicil, Clindamyc. Vancomycin, Amikacin Peptococ., Actinomyc. Imipenem / Meropenem Peptostreptococ.) Clostr. Difficile Metronidazole Vancomycin, Bacitracin Bacteroides fragilis Metronidazole Chloramph Imipenem/ Clindamyc Meropenem, beta-lactum beta-lactamase inh.comb Fusobacterium Metronid, Clindamyc. As above Penicil.Mycobacteria: Mycobact. tubercul. Isoniazid + Rifampin Streptomyc., Quinol.s

161. ANTIMICROBIAL THERAPY + Ethambutol Amikacin, Cycloser. + Ethambutol Amikacin, Cycloser. + Pyrazinamide Ethionamide, PAS. + Pyrazinamide Ethionamide, PAS. Mycobact. Leprae Multibacillary Dapsone +Rifampin + Clofazimine + Clofazimine Paucibacillary Dapsone +Rifampin Mycoplasma pneu. Tetracyc., Eryth. Azithromyc., Clarith. Chlamydia : trachomatis Tetracyc., Eryth. Azithromyc., Ofloxac. trachomatis Tetracyc., Eryth. Azithromyc., Ofloxac. Clindamyc. Clindamyc. pneumoniae Tetracyc., Eryth. Clarythromyc. & pneumoniae Tetracyc., Eryth. Clarythromyc. & Azithromyc. Azithromyc.

162. ANTIMICROBIAL THERAPY Spirochetes : Borellia recur. Doxy., Penicil. Eryth., Chloramph. Borellia recur. Doxy., Penicil. Eryth., Chloramph. Leptospira sp. Penicil. Tetracyc. Leptospira sp. Penicil. Tetracyc. Treponema sp. Penicil. Tetracyc. & Eryth. Treponema sp. Penicil. Tetracyc. & Eryth.

163. MCQs 1. All of the following antibiotics are macrolides, EXCEPT: a) Erythromycin b) Clarithromycin c) Lincomycin d) Roxythromycin 2. Tetracyclins have following unwanted effects: a) Irritation of gastrointestinal mucosa, phototoxicity b) Hepatotoxicity, anti-anabolic effect c) Dental hypoplasia, bone deformities d) All of the above 3. Chloramphenicol has the following unwanted effects: a) Nephrotoxicity b) Pancytopenia c) Hepatotoxicity d) Ototoxicity

164. MCQs 4. Lincosamides have the following unwanted effect: a) Nephrotoxicity b) Cancerogenity c) Pseudomembranous colitis d) Irritation of respiratory organs 5. Choose the characteristics of Vancomicin: a) It is a glycopeptide, inhibits cell wall synthesis active only against Gram-negative bacteria b) It is a glycopeptide, that alters permeability of cell membrane and is active against anaerobic bacteria c) It is a beta- lactam antibiotic, inhibits cell wall synthesis active only against Pseudomonas aeruginosa d) It is a glycopeptide, inhibits cell wall synthesis and is active only against Gram-positive bacteria.

165. MCQs 6. The additional anti-inflammatory & immunomodulatory activities are found in which of the following group of antibiotics : a) Fluoroquinolones b) Macrolides c) Polypeptide antibiotics d) Tetracyclines 7. Mechanism of action of Tetracyclines is by : a) Binding to 30 S subunit and inhibiting the binding of aminoacyl -t-RNA to A site b) Inhibiting peptidyl transferase activity c) Inhibiting translocation d) Inhibition of initiation and misreading of mRNA

166. MCQs 8. Tetracyclines are avoided in pregnancy because they can : (a) Cause abortions (b) Cause excessive postpartum hemorrhage (c) Affect the bones and teeth of the fetus (d) Cause excessive vomiting in the mother 9. Erythromycin is the drug of choice in : (a) Pertussis (b) Gonococcal urethritis (c) Prophylaxis of bacterial endocarditis (d) Chlamydial infections 10. Which of the following agents is not a broad spectrum antibiotic ? (a) Ampicillin (b) Tetracycline (c) Chloremphenicol (d) Gentamicin

167. MCQs 11. Vancomycin has the following unwanted effects: a) Pseudomembranous colitis b) Hepatotoxicity c) “Red neck” syndrome, phlebitis d) All of the above 12. Chloramphenicol is the drug of choice in : (a) Staphylococcal infection (b) Salmonella infection (c) Viral infection (d) Amoebic dysentery 13. In renal failure safest tetracycline is : (a) Oxytetracycline (b) Chlortetracycline (c) Doxycycline (d) Demethyl chlortetracycline

168. MCQs 14.Which of the following preparation of Erythromycin causes hepatitis with cholestatic Jaundice as an adverse effect ? a) Erythromycin ethyl succinate b) Erythromycin base c) Erythromycin stearate d) Erythromycin estolate 15. Which of the following drug interfere with translocation of protein synthesis? a) Tetracycline b) Chloramphenicol c) Penicillins d) Gentamicin e) Erythromycin

169. MCQs 16.Mechanism of action of Chloramphenicol is through : a) Nucleus b) 30S ribosome c) Mitochondria d) 50S ribosome e) Cell wall 17.Best indication of Linezolid is : a) VRSA b) K.pneumoniae c) MRSA d) E.coli e) Pseudomonas 18.Which of the following antibiotic is effective in a single dose therapy in Trachoma? a) Azithromycin b) Clarithromycin c) Erythromycin d) Doxycycline e) Chloramphenicol

170. MCQs 19. The choice of drug in Lymphogranuloma venereum is: a) Ciprofloxacin b) Tetracycline c) Penicillin d) Erythromycin e) Gentamicin 20.Which of the following is drug of choice in Mycoplasma pneumoniae infection? a) Cefotaxime b) Azithromycin c) Tetracycline d) Amoxycillin e) Gentamicin

171. Answer Key: 1-c, 2-d, 3-b, 4-c, 5-d, 6-b,7-a, 8-c, 9-a 10-d, 11-c, 12-b, 13-c, 14-d, 15-e,16-d, 17-a 18-a, 19-b, 20-b.

172. Bibliography 1.Goodman & Gilman’s,The Pharmacological Basis of Therapeutics (12 th Edition). 2. Principles of Pharmacology by H. L. Sharma & K K Sharma ( Latest Edition) 4. Essentials of Medical Pharmacology by K. D. Tripathi (7 th edition)

173. ANTIMICROBIAL THERAPY THANK YOU