Vancomycin. A bactericidal drug which acts by inhibiting cell wall synthesis. Active only against gram-positive bacteria, particularly staphylococci.

Transcription

1 Vancomycin A bactericidal drug which acts by inhibiting cell wall synthesis. Active only against gram-positive bacteria, particularly staphylococci. Used IV in treating endocarditis caused by methicillin-resistant staphylococci and resistant S viridans enterococci. not absorbed Also used orally in Pseudomembraneous Colitis caused by Clostridium difficile. GI tract waterydiarrhe

2 Vancomycin Valuable in severe staphylococcal infections in patients allergic to penicillins and cephalosporins. MRSA Usual normal flora B lactamase formation resistance MRSA Resistance can be caused by changing the permeability to the drug and by decreasing the binding of Vancomycin to receptors.

3 Vancomycin Unwanted effects include fever, rashes and local phlebitis. inflammation of vein due to IV toxic to the ear Ototoxicity 5 and nephrotoxicity can occur and hypersensitivity reactions are occasionally encountered. Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes to avoid an infusion reaction known as the Red Man Syndrome or Red Neck Syndrome. it IV is givenquickly 9

4 flushing erythema pruritus myalgia dyspnea stopinfusion ad i

5 Protein Synthesis Inhibitors Active against a wide variety of organisms (broad spectrum). Most are bacteriostatic but a few are bactericidal against certain organisms. Because of overuse, resistance is common. Bacterial ribosomes differ in molecular detail from eukaryotic cells, enabling antibiotics to exhibit selective toxicity. Interfere with the main ribosomal processes: Binding of aminoacyl-trna Normal codon:anticodon recognition Transpeptidation

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7 Tetracyclines no longerused Tetracycline, Methacycline, Moxycycline, doxycycline minocycline, and Tigecycline. newest orally Bind to both mrna and the ribosomal 30S subunit where they prevent the binding of aminoacyl-trna. Bacteriostatic. Wide spectrum of activity and includes some spirochaetes and even some protozoa likeamoebae. not bacteria

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9 Mycoplasma and chlamydia infections Brucellosis: usually in combination with an aminoglycoside. Acne doxycycline Occasionally used in dentistry to treat bacterial infections. Syphilis Clinical Uses of Tetracyclines usually a mixture so you need a of bacteria broad spectrumdrug

10 Tetracyclines Resistance is common and mainly due to a plasmidmediated energy-dependent efflux pump(typical of the multiple drug resistance type). Mutations in the tetracycline target site are also found. Usually administered orally but can be given parenterally. doesntcause any allergies Absorption from the gut is irregular and better in the absence of food, but they are gastric irritants, so usually given after meals. onlinedefinition to pbinding metal so that metal loses its toxic effect Since Tetracyclines are chelated by di- and trivalent metal ions, forming insoluble complexes, absorption is decreased in the presence of milk, certain antacids and iron preparations.

11 Tetracyclines The most Common side-effects are GI disturbances, essentially due to direct irritation and later to modification of gut flora. Deposit in growing bones and teeth, so caused staining and dental hypoplasia and bone deformities in children. Phototoxicity: for example, severe sunburn, after exposure to sun or ultra-violet rays. Contraindicated in children, nursing mothers and pregnant women (may causes hepatotoxicity in pregnant women).

12 Macrolides Erythromycin Clarithromycin(1 tablet for 14 days) Azithromycin( 1 tablet for 5 days) Telithromycin. substitute forpenicillin in allergic patients These bind to the 50S ribosomal subunit and inhibit protein synthesis. Erythromycin is active against Gram-positive bacteria and spirochaetes but not against most Gram-negative organisms( the same spectrum of Penicillins). Azithromycin is far more active against respiratory infections due to Haemophilus influenzae and E.coli.

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15 Clinical Uses of Macrolides Because antibacterial spectrum is very similar to that of penicillins, they are considered as a very useful substitutes in penicillin-sensitive patients. Drugs of choice in corynebacterial infections (diphtheria, corynebacterial sepsis);

16 Clarithromycin difficultto treat Clarithromycin is effective against Mycobacterium avium g cellulare which can cause chronic lung disease in elderly or immunologically compromised individuals. Clarithromycin is an aadjuvant in the treatment of peptic ulcer to eradicate H. pylori ( 1 tablet for 14 days).

17 avoids mostly in better than the asking of Kids infections rest meningitis Azithromycin Penetrates well into most tissues (except cerebrospinal fluid), with tissue concentrations exceeding serum concentrations by 10- to 100-fold. Short treatment course, 1 tablet for 5 days. Slowly released from tissues (tissue half-life of 2 4 days) to produce an elimination half-life approaching 3 days. Azithromtcin is the drug of choice in respiratory( Community Aquired Pneumonia), neonatal, ocular, or genital chlamydial infections because the spectrum of activity includes pneumococcus, mycoplasma, and legionella. Azithromycin shows particularly good activity against chlamydial urethritis.

18 Side Effects of Macrolides Macrolides are administered orally, although they can be given parenterally. Gastrointestinal disturbances are common side effects, but not serious. The newer agents seem to have less GI effects. Skin rashes, and fever. no anaphylaxis like penicillin Transient hearing disturbances have been associated with erythromycin, especially at high dosages. Cholestatic jaundice especially with the estolate form of erythromycin

19 p metabolizes many drugs

20 Aminoglycosides other antimicrobials 2 The only bactericidal protein synthesis inhibitors. They bind to the ribosomal 30S subunit. Inhibit initiation of peptide synthesis and cause misreading of the genetic code. Streptomycin is the oldest member of the group, 1947 Amikacin successful in treating TB Gentamicin Tobramycin prognosisimproved alot I Netilmycin Neomycin. initially discovered to cover gram ve wider spectrum Spectrum includes many aerobic Gram-negative than penicilins and some Gram-positive bacteria. not considered broad spectrum effective against

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22 Clinical Uses of Aminoglycosides Widely used in the empirical treatment of infections suspected of being due to aerobic gram-negative bacilli. Gram ve bacillary infection, septicemia, pelvic & abdominal sepsis Bacterial endocarditis enteroccoci Enterococcal, streptococcal or staphylococcal pneumonia. Tuberculosis streptomycin is the only one effective agains Plague, Brucellosis TB then resistance formed became a second line defense To sterilize the bowel of patients who receive immunosuppressive therapy, before surgery & in hepatic coma liver failure toxins buildup ammonia in

23 bloodmight lead to brain damage Aminoglycosides coma orally absorbed so IV stays in circulation used for GIT septicemia infections O is not Aminoglycosides are poorly absorbed from all sites of administration including the GI tract. works locally They are usually administered intramuscularly or intravenously, or topically. They can be given orally to act locally in sterilizing the GIT. Serious dose-related side-effects occur with the aminoglycosides, The main hazards are Nephrotoxicity and Ototoxicity, may also cause n.m. blockade ystemic de fats bbalauce of ear its

24 Clinical Uses of Aminoglycosides routinely measured drug in hospital labs liver GENTT test Gentamycin is usually the first choice due to its low cost, reliable activity and long experience of use. Used in infected burns, otitis externa, acute pyelonephritis. also used for septicemia endocarditis pneumonia generalactivity Tobramycin is the most active against Pseudomonas infections more toxic than gentaurycin Amikacin has the broadest antibacterial spectrum. Preferred in serious nosocomial G ve bacillary infection in hospitals where Tobramycin & Gentamicin have developed resistance. even more toxic Neomycin is reserved for topical applications because of its serious systemic toxicity. creams most toxic

25 Clindamycin Active against Gram-positive cocci, including penicillin-resistant staphylococci, and many anaerobic bacteria. widelyused because of this Binds to the 50S ribosomal subunit and inhibits the correct attachment of the amino acid end of aminoacyl-trna. Mainly used in infections caused by Bacteroides organisms and in staphylococcal infections of bones and joints. very goodpenetration Nearly completely absorbed (90%), and penetrates deeply into the soft tissues of the body, as well as bone, where dental infections

26 Clinical Uses of Clindamycin Penetrating wounds of the abdomen and the gut. Female genital tract infections, like septic abortion. Aspiration pneumonia. I 41 side effect Highly effective in dental infections. google drugs responsible for pseudomen colitis most of the time are ampicillin clindamycin fluoroquinolones cephalosporins

27 r Side-effects of Clindamycin der mentioned that lincomycin causes this too its generally a side effect of broad spectrumdrugs Pseudomembranous colitis: This is a very serious condition. Clostridium difficile outbreak can spreadin hospital patients within a week. With weakened intestinal flora due to antibiotics, C. difficile could be fatal. Immediately upon finishing a course of clindamycin, or any antibiotic, one should take probiotics(beneficial bacteria) to repopulate the intestines. Eat your yogurt! fecal back balance

28 I 9 Floro Quinolones aminoglycosides cephalosporins 1st 2nd First oral antibiotics effective against gram-negative bacteria. W IV Ciprofloxacin is the most commonly used fluoroquinolone. Ciprofloxacin is the most active member against gramnegatives, Pseudomonas aeruginosa in particular Ofloxacin Levofloxacin totter effective in UTI than gentamycin Gemifloxacin Moxifloxacin new drugs These have improved activity against gram-positive organisms, particularly S. pneumoniae and some staphylococci.

29 Quinolones Specific inhibitors of DNA gyrase by trapping the enzyme in its cleavable complex. Tpevents proteinsynthesis but doesnt act on ribosome Bacterial DNA gyrase is a type II topoisomerase that produces transient double strand breaks in DNA. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA required for normal transcription and replication. Quinolones are broad spectrum antibiotics, active against both Gram-negative and Gram-positive bacteria. More active against Gram-negative species. ve ve

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31 Clinical Uses of Quinolones Complicated urinary tract infections drug must be givenorally rapidly excreted in urine Respiratory infections in patients with cystic fibrosis Levofloxacin,, gemifloxacin, and moxifloxacin, so-called respiratory fluoroquinolones, have enhanced activity against gram-positive bacteria and atypical pneumonia agents (e.g. chlamydia, mycoplasma, and legionella), nowadays are increasingly used for treatment of upper and lower respiratory tract infections. mostly in children Infections of soft tissues, bones, and joints and intra-abdominal infections Bacterial prostatitis and cervicitis genetic disease Bacterial diarrhoea caused by shigella, salmonella, and E. coli.

32 Side Effects of Quinolones Mainly cause GI symptoms (nausea, vomiting, and diarrhea) and skin rashes. A disease of joints Arthropathy, may damage growing cartilage, particularly in young individuals. So, contraindicated in children (under 18) except in special cases. risk benefit ratio

33 Sulphonamides limited use nowadays nazis discovered it Sulphonamides have a similar structure to p-aminobenzioc acid (PAPA), which is a precursor of Folic acid. Compete with PAPA for the bacterial enzyme, dihydropteroate synthetase. Thus, they inhibit the synthesis of bacterial folic acid, and the end result is interference with nucleic acid synthesis The sulphonamides are bacteriostatic. forhumans must be given exogenously Resistance is common, mainly via up-regulation of the synthesis of PABA and by mutations in dihydropteroate synthetase.

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35 Sulphonamides Orally Absorbable Agents: Sulfisoxazole and sulfamethoxazole are almost exclusively used in urinary tract infections. Orally Nonabsorbable Agents: if its thepatients first timehaving a UT give sulfonamide very effective cheap compared to quinolones t expensive salicylacidprecursorinaspirin res has also anti inflammatory pro pent Sulfasalazine, and salicylazosulfapyridine are widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease -Topical Agents: Silver sulfadiazine is used for burn wound infections.

36 Sulphonamides Sulphonamides have mild to moderate side-effects including, nausea, vomiting, headache, and depression. thats why use of sulphonamide declined More serious side-effects include hepatitis, hypersensitivity reactions, bone marrow depression, and aplastic anemia. Sulfonamides may provoke hemolytic reactions in patients with glucose-6- phosphate dehydrogenase deficiency.

37 proteinsyn inhibitor not bactericidal very effective Chloramphenicol Isolated from Streptomyces venezuelae in otherantimicrobials3 can senetratebbb tissues very toxic Binds the 50S ribosomal subunit, preventing peptide bond formation. First antibiotic to be synthesized instead of extracted from a micro-organism. It is on the World Health Organization's List of Essential Medicines. its an importantdrug innep.la Cost in the developing world of an intravenous dose is about $ very cheap like penicilin

38 N oral topical Chloramphenicol favorable in not very Chloramphenicol has a broad spectrum of modern medicine activity(including Stap. aureus, Strep. pneumoniae, and E. coli and Salmonella. It is not effective against Ps. Aeruginosa ). verdurous Extremely lipid-soluble; unbound to protein and is a small grain ve infection molecule. It has a large apparent volume of distribution and penetrates effectively into all tissues of the body, including the BBB, and eye. prostate difficult penetration large mole cant be absorbed usually for drugs orally

39 Chloramphenicol very Aplastic toxic severe anaemia: thrombocytopenia Rare and sometimes fatal. unpredictable side effect Occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved. The highest risk is with oral chloramphenicol (affecting 1 in 24,000 40,000)[17] and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions). can also occur in non leucopenia dosedependant topical administration bone marrow transplant needed because it penetrates good even in skin eye doesnt regenerate

40 Chloramphenicol Bone marrow suppression: leads to anemia leukopenia thrombocytopenia Dose dependent toxicity(which occurs quite predictably once a cumulative dose of 20 g has been given). Fully reversible after stopping the drug. predictable side effect i depends on larger dose highertoxicity the dose

41 sit Gray Baby Syndrome Chloramphenicol Occurs after intravenous use in newborn infants due to immaturity of liver enzymes (UDP-glucuronyl transferase), This causes several adverse effects, including hypotension and cyanosis. al meningitis is treated with chloramphenicol

42 orally now rarely used here are lternatives ampicillin Chloramphenicol The original indication was in the treatment of typhoid fever. was very common serious disease Due to the presence of multiple drug-resistant Salmonella typhi, it is seldom used for this indication except when the organism is known to be sensitive. Was considered as first-line drug for meningitis, it may be used with caution if there are no available alternatives. cephalosporins are now used 3rd 4th gen In preventing endophthalmitis, a complication of cataract surgery. used because it can penetrate the whole eye tissue

43 cornea is cut severe infection causes blindness if its not treated Linezolid New bacteriostatic synthetic antibiotic. Binds to the 50s ribosome, but has no cross resistance with other antibiotics. Lm Active against G+ve organisms Approved for vancomycin-resistant Enterrococcus faecium infections; nosocomial pneumonia; community-acquired pneumonia; and skin infections. Reserved for treatment of infections caused by multidrug-resistant gram-positive bacteria including tuberculosis and Nocardia. qecond line feature VRE

44 VRE and more Teicoplanin: A glycopeptide like vancomycin with similar mechanism and spectrum of activity. Long half life. Used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillinresistant Staphylococcus aureus and Enterococcus faecalis. Daptomycin: Active against vancomycin-resistant strains of enterococci and S aureus.

45 Commonly prescribed ABX in the community setting Oral infections: penicillin, clindamycin, erythromycin, amoxicillin, cephalexin UTI: ciprofloxacin, SMX/TMP RTI s, sinusitis: clarithromycin, azithromycin, 2 nd or 3 rd gen Cephs, amoxi/clav, levo-/moxifloxacin Skin/nail/bites: cephalexin, cloxacillin, amoxi/clav Travellers diarrhea: azithromycin, ciprofloxacin, norfloxacin H. pylori: amoxi+clarithromycin, metronidazole+clarithromycin, tetracycline+metronidazole the dee barelygave these slides any importanceduring the lecture read themjust in case

46 Commonly prescribed ABX in the community setting Bacterial vaginosis: metronidazole, clindamycin Chlamydia: single dose azithromycin, 7-day course doxycycline, ofloxacin Gonorrhea: cefixime, ceftriaxone Acne: tetracyclines, erythromycin Acute otitis media: Macrolides, amoxicillin, amoxi/clav, 2 nd Cephs Patients with penicillin allergy: clindamycin or erythromycin. Intraabdominal infections: ciprofloxacin, metronidazole, 3 rd Cephs C. difficile diarrhea: metronidazole, vancomycin gen gen