Protein Synthesis Inhibitors Dr Rajendra Nath Professor Protein

Protein Synthesis Inhibitors Dr. Rajendra Nath Professor

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

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

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

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

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 , Anaerobes & Chlamydia , they are known as Broad spectrum antibiotics.

Protein Synthesis Inhibitors Tetracyclines

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

Protein Synthesis Inhibitors Tetracyclines polycyclic naphthocemecarboxamide having fusion of four cyclohexane rad. hence the name. OH O CO – NH 2 OH CH 3 OH N(CH 3)2

Protein Synthesis Inhibitors Tetracyclines 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

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

Protein Synthesis Inhibitors Tetracyclines ( 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 effective ( It causes Rocky mountain spotted fever , Typhus, scrub typhus & Q – fever) .

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 ).

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. )

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

Protein Synthesis Inhibitors Tetracyclines Effect on Intestinal Flora : 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.

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

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

Protein Synthesis Inhibitors Tetracyclines

Protein Synthesis Inhibitors Tetracyclines

Protein Synthesis Inhibitors Tetracyclines

Protein Synthesis Inhibitors Tetracyclines - 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 : Plasmid mediated & is inducible.

Protein Synthesis Inhibitors Tetracyclines Mech. of action of resistance: 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 displaces Tetracyc. from its target ( may occur by mutation ). 3. Enzymatic inactivation of Tetracyclines

Protein Synthesis Inhibitors Tetracyclines Classification : 1. Incompletely absorbed ( 60 -80% ) Natural- Oxytetra & Demeclocyc. Semi- synth. – Tetracyclines 2. Almost completely absorbed (90100%) – Semi synthetic Doxycyclines & Minocyclines

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%)

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 Doxy & Minocycline ) Doxy & Minocycline

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

Protein Synthesis Inhibitors Tetracyclines 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.

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

Protein Synthesis Inhibitors Tetracyclines 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.

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.

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

Protein Synthesis Inhibitors Tetracyclines - 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 – 200 mg I. V. infusion on 1 st day then 100 mg once or twice subsequently -Tetracycline – in acute infections – 1 gm ( 2 gm in Tetracycline severe inf. ) div. in equal doses. inf. (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 & poor absorption occurs.

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

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.

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 x 14 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 ).

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

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. In non pregnant Penicillin resist. Pts can be treated with Tetracycline.

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 ). -Tularemia- Although Streptomycin is preferred but Tetracyclines also are effective.

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 )

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 -250 mg orally twice a day ).

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

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

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 Gastrointestinal (GI) tract and is only available for parenteral administration ) parenteral administration

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

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

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

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) Tetracyclines.

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. )

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

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

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

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

Mnemonic: ( Side effects ) KAPIL DEV • • • K – Kidney failure ( All are contra-indicated except Doxycycline ) Doxycycline A - Antianabolic effect P - Photosensitivity ( maximum with Demeclocycline ) Demeclocycline I - Insipidus ( Diabetes Insipidus : maximum with Demeclocycline ) 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 V - Vestibular dysfunction ( maximum with Minocycline ) Minocycline

Protein Synthesis Inhibitors Tetracyclines 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.

Protein Synthesis Inhibitors Chloramphenicol 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. -

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

Protein Synthesis Inhibitors Chloramphenicol Chemistry : The antbiotic is unique among natural comp. s in that it has nitrobenzene moiety (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

Protein Synthesis Inhibitors Chloramphenicol diffusion. - It acts primarily by binding reversibly to the 50 S 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 30 S ribosomal subunit is undisturbed,

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 ribosome –m RNA complex ( by preventing the interaction between peptidyl transferase & its aminoacid substrate → ↓↓ of peptide bond formation and transfer of elongated peptide chain from ‘P’ to ‘A ‘site , therefore inhibits Transpeptidation reaction ) inhibits Transpeptidation reaction

Protein Synthesis Inhibitors Chloramphenicol

Protein Synthesis Inhibitors Chloramphenicol

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

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.

Protein Synthesis Inhibitors Chloramphenicol It is active against the same range of organisms as Tetracyclines but notable differences are – differences - 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.

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.

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)

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. .

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 )

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.

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

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

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

Protein Synthesis Inhibitors Chloramphenicol 1. Typhoid fever – ( 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) 2. Bact. Meningitis- 3 Meningitis rdgen. Cephalosporin have replaced CAP (but CAP remain an alternative drug for the Tt. of meningitis caused by

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

Protein Synthesis Inhibitors Chloramphenicol. 4. Rikettsial inf. – Preferred agents are inf. 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).

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

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

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.

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

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

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: 1. ) Deficiency of glucoronyl transferase , transferase hepatic enzyme that metabolize CAP in first 3 -4 wks of life.

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

Protein Synthesis Inhibitors Chloramphenicol D/I – CAP ↓ hepatic C-P 450 isozyme & D/I prolong the half life of drugs that are metabolized by this system e. g. - Warferin Dicoumarol Phenytoin Chlorpopamide etc.

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

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

Protein Synthesis Inhibitors Macrolides - Clarithromycin & Clarithromycin Azithromycin are Azithromycin semi-synthetic derivative of Erythromycin (Roxithromycin is also semi- synth. , long acting, acid Roxithromycin 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. )

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.

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.

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 mechanism affect all macrolide antibiotics so cross resist. is complete. ) is complete -Staphylococci are not reliably sensitive to Erythromycin.

Protein Synthesis Inhibitors Macrolides -G+ve bacilli are sensitive to Erythromycin (e. g. Clostridium perfringes , Coryne - bacterium diphtheriae & L. monocytogenes) -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. )

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

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

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

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

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.

Protein Synthesis Inhibitors Macrolides Mechanism of action : ↓ protein synthesis by binding reversibly to 50 S ribosomal subunit at or very near the site that binds CAP. It does not ↓ peptide bond formation phase 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).

Protein Synthesis Inhibitors Macrolides

Protein Synthesis Inhibitors Macrolides

Protein Synthesis Inhibitors Macrolides -G +ve bacteria accumulates about 100 times more Erythromycin than do G –ve bacteria. -Have ↑antimicrobial activity at alkaline p. H.

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.

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

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 it is given as enteric coated tabs /caps ( contain enteric coated pellets) or an ester.

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

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

Protein Synthesis Inhibitors Macrolides 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.

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.

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.

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.

Protein Synthesis Inhibitors Macrolides Doses : Erythromycin- 1 -2 gm orally in 6 hrly div. doses. ( child – 30 -50 gm / 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).

Protein Synthesis Inhibitors Macrolides Clarythromycin– 250 mg BD for adult & children above 12 y (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.

Protein Synthesis Inhibitors Macrolides 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 -500 mg daily in combination with other agents or 1200 mg once a wk. - used for STD during pregnancy when Tetracycline is C/I).

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 )

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

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

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

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

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

Protein Synthesis Inhibitors Macrolides 11. Mycobacterial inf. – Clarythromycin & Mycobacterial inf. Azithromycin for therapy & prophylaxis of Mycobacterium avium intracellulare in AIDS pts. ( Clarythromycin 500 mg 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.

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

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- MAC T- Toxoplasma

Protein Synthesis Inhibitors Macrolides Side Effect : : Serious S/E are rarely present. - Fever , Eosinophilia & skin eruption (disappear after stoppage of therapy) - Cholestatic hepatitis , most sig. S/E ( by Cholestatic hepatitis 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. )

Protein Synthesis Inhibitors Macrolides -Large doses orally associated with epigastric pain. -Cardiac arrhythmia ( ↑QT interval with Cardiac arrhythmia ventricular tachycardia ). -Transient auditory impairment ( by I. V. Transient auditory impairment 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 )

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 – Erythromycin & Clarythromycin→ – ↓CYP 3 A 4 microsomal enzyme & therefore potentiate the effect of Carbamazepine Cyclosporin Valproate Corticosteroid Digoxin Ergot alkaloids Theophylline & Warferin when given simultaneously

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 : 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).

Miscellaneous & Newer Antibiotics Ketolides: Telithromycin It is a macrolide with keto gp. that binds with ribosome with greater affinity & resists efflux mediated & methylase mediated 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.

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

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

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 the D- Ala –D-Ala terminus of nascent peptidoglycan pentapeptide. This ↓ the Transglycolase

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

Miscellaneous & Newer Antibiotics S/E : -Fever , chills , phlebitis. - 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 ) Tubocurarine , Polymixin B -Nephrotoxicity -Ototoxicity -H/S reactions.

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

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

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

Miscellaneous & Newer Antibiotics Fusidic Acid: 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.

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 as a reserved drug for osteomyelitis.

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

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.

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 – Local infections of skin , eyes Indication ears & mucous membrane.

Miscellaneous & Newer Antibiotics -Colistin is used orally for infective Colistin 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 and/or Polymixin. ( Nebasulf – Neomycin + Bacitracin + Sulfacetamide , powder / ointment )

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

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.

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

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) They are indicated for serious MDR staphylococcus, streptococcus & pneumococcus infections.

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

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 not against G –ve org. s. -Indicated as a last resort for MDR Staphylococcal, Streptococcal & Pneumococcal infections.

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. ) S/ES/E GI upset Skin rashes Headache ↓platelet count hence ↑risk of bleeding Week MAO ↓ that may lead to the cheese reaction.

Miscellaneous & Newer Antibiotics Fosfomycin: -It ↓ cell wall synthesis & transported by G 6 PD transport system. -Used for selective cases of UTI. -It is safe in pregnancy.

Miscellaneous & Newer Antibiotics Spectinomycin: -It is similar to Aminoglycosides , binds to 30 S 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.

Miscellaneous & Newer Antibiotics 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. -Indicated for resistant Staphylococcal & Streptococcal infections

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

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

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.

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

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

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 G –ve rods ( aer. ) E. Coli , Proteus , Cephsp. I / II g. , TMP- Quinol. s & Aminog. s Klebsiella SMZ.

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. 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. Vibrio sp. Tetracyc. , TMP-SMZ Quinol. s

ANTIMICROBIAL THERAPY P. aeruginosa Antipseudomonal Penicil. Antipseud. Penicil. + P. aeruginosa + 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, Eryth. , Imipenem/ Mero S. pyog. ( gp -A) Penicil. , Clindamy. Eryth. , Cephsp. ( I g ) Penicil. , Clindamy. S. agalact. (gp. B) Penicil. ( + Aminog. ) Vancomycin Viridans Strept. Penicil. Vancomy. , Cephsp.

ANTIMICROBIAL THERAPY Staphyl. aureus Penicil. Vancomy. , Cephsp. ( I g ) Penicil. Vancomy. , (Beta- lactamase - ve) Beta-lactamase +ve Penicillinase resist. Vancomy. , Cephsp. ( I g ) Penicil. Methicil. – resist. Vancomycin TMP-SMZ , Minocyc. 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

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

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

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

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

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.

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 m. RNA

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

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

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

MCQs • • • • • 16. Mechanism of action of Chloramphenicol is through : a) Nucleus b) 30 S ribosome c) Mitochondria d) 50 S 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

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

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.

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)

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