Vancomycin

• A bactericidal drug which acts by inhibiting cellwall synthesis.

• Active only against gram-positive bacteria,particularly staphylococci.

• Used IV in treating endocarditis caused bymethicillin-resistant staphylococci and resistantenterococci.

• Also used orally in Pseudomembraneous Colitiscaused by Clostridium difficile .

S viridansnot absorbed

GI tract waterydiarrheUsual normal flora bacteria fever

Vancomycin

• Valuable in severe staphylococcalinfections in patients allergic topenicillins and cephalosporins.

• Resistance can be caused by changingthe permeability to the drug and bydecreasing the binding of Vancomycin toreceptors.

Usual normal flora

MRSA

MRSA B lactamase formation resistance

Vancomycin

• Unwanted effects include fever, rashes and localphlebitis.

• Ototoxicity and nephrotoxicity can occur andhypersensitivity reactions are occasionally encountered.

• Vancomycin must be administered in a dilute solutionslowly, over at least 60 minutes to avoid an infusionreaction known as the Red Man Syndrome or Red NeckSyndrome.

inflammation of vein due to IV

toxic to the ear5

it IV is givenquickly 9

flushingerythemapruritus

myalgia dyspnea

stopinfusiond ia

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 fromeukaryotic cells, enabling antibiotics to exhibit selectivetoxicity.

❖ Interfere with the main ribosomal processes:Binding of aminoacyl-tRNANormal codon:anticodon recognitionTranspeptidation

Tetracyclines

• Tetracycline, Methacycline, Moxycycline, doxycyclineminocycline, and Tigecycline.

• Bind to both mRNA and the ribosomal 30S subunit wherethey prevent the binding of aminoacyl-tRNA.

• Bacteriostatic.

• Wide spectrum of activity and includes some spirochaetesand even some protozoa like amoebae.

orally

no longerused

newest

not bacteria

severe diarrhea

Mycoplasma and chlamydia infections

Brucellosis: usually in combination with an aminoglycoside.

Acne

Occasionally used in dentistry to treat bacterial infections.

Syphilis

Clinical Uses of Tetracyclines

usually a mixture of bacteriaso youneed a broadspectrumdrug

doxycycline

• Resistance is common and mainly due to a plasmid-mediated energy-dependent efflux pump(typical of themultiple drug resistance type). Mutations in thetetracycline target site are also found.

• Usually administered orally but can be givenparenterally.

• Absorption from the gut is irregular and better in theabsence of food, but they are gastric irritants, so usuallygiven after meals.

• Since Tetracyclines are chelated by di- and trivalent metalions, forming insoluble complexes, absorption isdecreased in the presence of milk, certain antacids andiron preparations.

Tetracyclines

doesntcause anyallergies

onlinedefinition

pbindingto metal so that metal

loses its toxic effect

• The most Common side-effects are GI disturbances,essentially due to direct irritation and later tomodification of gut flora.

• Deposit in growing bones and teeth, so caused stainingand 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 pregnantwomen (may causes hepatotoxicity in pregnant women).

Tetracyclines

Macrolides• Erythromycin• Clarithromycin(1 tablet for 14 days)• Azithromycin( 1 tablet for 5 days)• Telithromycin.

• These bind to the 50S ribosomal subunit and inhibitprotein synthesis.

• Erythromycin is active against Gram-positive bacteria andspirochaetes but not against most Gram-negativeorganisms( the same spectrum of Penicillins).

• Azithromycin is far more active against respiratoryinfections due to Haemophilus influenzae and E.coli.

substitute forpenicillinin allergicpatients

• Because antibacterial spectrum is very similar to that ofpenicillins, they are considered as a very useful substitutesin penicillin-sensitive patients.

• Drugs of choice in corynebacterial infections (diphtheria,corynebacterial sepsis);

Clinical Uses of Macrolides

Clarithromycin• Clarithromycin is effective against Mycobacterium avium

cellulare which can cause chronic lung disease in elderlyor immunologically compromised individuals.

• Clarithromycin is an aadjuvant in the treatment of pepticulcer to eradicate H. pylori ( 1 tablet for 14 days).

difficultto treatg

Azithromycin• Penetrates well into most tissues (except cerebrospinal

fluid), with tissue concentrations exceeding serumconcentrations 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, orgenital chlamydial infections because the spectrum ofactivity includes pneumococcus, mycoplasma, andlegionella.

• Azithromycin shows particularly good activity againstchlamydial urethritis.

avoids mostly in better than themasking

of Kids infections restmeningitis

• Macrolides are administered orally, although they can begiven parenterally.

• Gastrointestinal disturbances are common side effects, butnot serious. The newer agents seem to have less GIeffects.

• Skin rashes, and fever.• Transient hearing disturbances have been associated with

erythromycin, especially at high dosages.

• Cholestatic jaundice especially with the estolate form oferythromycin

Side Effects of Macrolides

no anaphylaxis likepenicillin

pmetabolizesmany drugs

al

Aminoglycosides

• The only bactericidal protein synthesis inhibitors.• They bind to the ribosomal 30S subunit.• Inhibit initiation of peptide synthesis and cause mis-

reading of the genetic code.• Streptomycin is the oldest member of the group, 1947• Amikacin• Gentamicin• Tobramycin• Netilmycin• Neomycin.

• Spectrum includes many aerobic Gram-negative and someGram-positive bacteria.

otherantimicrobials 2

successful in treating TBprognosisimproved a lot

I

initiallydiscovered to cover gram vewider spectrum than penicilins

not consideredbroadspectrumeffective againststaphinfection

ay H

Clinical Uses of Aminoglycosides Widely used in the empirical treatment of infections

suspected of being due to aerobic gram-negativebacilli.

Gram –ve bacillary infection, septicemia, pelvic &abdominal sepsis

Bacterial endocarditisEnterococcal, streptococcal or staphylococcal pneumonia.TuberculosisPlague, BrucellosisTo sterilize the bowel of patients who receive

immunosuppressive therapy, before surgery & inhepatic coma

enteroccoci

streptomycin is theonly one effective againsTB then resistance formedbecame a second line defense

liver failure toxinsbuildup ammonia in

• Aminoglycosides are poorly absorbed fromall sites of administration including the GItract.

• They are usually administeredintramuscularly or intravenously, ortopically. They can be given orally to actlocally in sterilizing the GIT.

• Serious dose-related side-effects occurwith the aminoglycosides,

• The main hazards are Nephrotoxicity andOtotoxicity, may also cause n.m. blockade

Aminoglycosidesbloodmight lead to brain damage coma

orally is notabsorbed so itsIV stays in circulation used for GIT

septicemia infections

works locallyOystemicdefats

bbalauce of ear

Clinical Uses of Aminoglycosides • Gentamycin is usually the first choice due to its low

cost, reliable activity and long experience of use.Used in infected burns, otitis externa, acutepyelonephritis.

• Tobramycin is the most active against Pseudomonasinfections

• Amikacin has the broadest antibacterial spectrum.Preferred in serious nosocomial G –ve bacillaryinfection in hospitals where Tobramycin &Gentamicin have developed resistance.

• Neomycin is reserved for topical applicationsbecause of its serious systemic toxicity.

routinelymeasured drug in hospital labs liver GENTT test

also used for septicemia endocarditispneumonia generalactivity

more toxic than gentaurycin

even more toxic

creamsmost toxic

Clindamycin• Active against Gram-positive cocci, including

penicillin-resistant staphylococci, and manyanaerobic bacteria.

• Binds to the 50S ribosomal subunit andinhibits the correct attachment of theamino acid end of aminoacyl-tRNA.

• Mainly used in infections caused byBacteroides organisms and in staphylococcalinfections of bones and joints.

• Nearly completely absorbed (90%), andpenetrates deeply into the soft tissues of thebody, as well as bone, where dental infectionsreside

widelyused because of this

verygoodpenetration

Can cause pseudomem colitis

Clinical Uses of Clindamycin

• Penetrating wounds of the abdomen and the gut.

• Female genital tract infections, like septic abortion.

• Aspiration pneumonia.• Highly effective in dental infections.

I 41side effect

googledrugs responsible for pseudomen colitismost of the time are ampicillinclindamycin fluoroquinolones cephalosporins

Side-effects of Clindamycin

• 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!

r

der mentioned that lincomycin causes this tooits generally a side effect of broad spectrumdrugs

fecal transplant bringsback florabalance

Quinolones• First oral antibiotics effective against gram-negative bacteria.

• Ciprofloxacin is the most commonly used fluoroquinolone.

• Ciprofloxacin is the most active member against gram-negatives, Pseudomonas aeruginosa in particular

• Ofloxacin• Levofloxacin• Gemifloxacin• Moxifloxacin• These have improved activity against gram-positive organisms,

particularly S. pneumoniae and some staphylococci.

I 9

aminoglycosides IVFloro cephalosporins

1st 2nd W

totter than gentamycineffective in UTI

new drugs

Quinolones

• Specific inhibitors of DNA gyrase by trapping the enzymein its cleavable complex.

• Bacterial DNA gyrase is a type II topoisomerase thatproduces transient double strand breaks in DNA.

• Inhibition of DNA gyrase prevents the relaxation ofpositively supercoiled DNA required for normal transcriptionand replication.

• Quinolones are broad spectrum antibiotics, active againstboth Gram-negative and Gram-positive bacteria.

• More active against Gram-negative species.

Tpevents proteinsynthesis but doesntact on ribosome

ve ve

Clinical Uses of QuinolonesComplicated urinary tract infections

Respiratory infections in patients with cystic fibrosisLevofloxacin,, gemifloxacin, and moxifloxacin, so-called respiratory

fluoroquinolones, have enhanced activity against gram-positive bacteriaand atypical pneumonia agents (e.g. chlamydia, mycoplasma, andlegionella), nowadays are increasingly used for treatment of upper andlower respiratory tract infections.

Infections of soft tissues, bones, and joints and intra-abdominalinfections

Bacterial prostatitis and cervicitis

Bacterial diarrhoea caused by shigella, salmonella, and E. coli.

drugmust begivenorallyrapidlyexcreted in urine

genetic diseasemostly in children

Side Effects of Quinolones

• Mainly cause GI symptoms (nausea, vomiting, anddiarrhea) and skin rashes.

• Arthropathy, may damage growing cartilage, particularly inyoung individuals.

So, contraindicated in children (under 18) except in specialcases.

A disease of joints

risk benefit ratio

Sulphonamides

• Sulphonamides have a similar structure to p-aminobenzioc acid(PAPA), which is a precursor of Folic acid.

• Compete with PAPA for the bacterial enzyme, dihydropteroatesynthetase. Thus, they inhibit the synthesis of bacterial folicacid, and the end result is interference with nucleic acidsynthesis

• The sulphonamides are bacteriostatic.

• Resistance is common, mainly via up-regulation of thesynthesis of PABA and by mutations in dihydropteroatesynthetase.

limited use nowadaysnazis discovered it

forhumansmust begiven exogenously

Sulphonamides

Orally Absorbable Agents:Sulfisoxazole and sulfamethoxazole are almost

exclusively used in urinary tract infections.Orally Nonabsorbable Agents:Sulfasalazine, and salicylazosulfapyridine are

widely used in ulcerative colitis, enteritis, andother inflammatory bowel disease

-Topical Agents:Silver sulfadiazine is used for burn wound

infections.

if its thepatientsfirst timehaving a UTgivesulfonamideveryeffective cheapcompared to quinolonest

expensive

salicylacidprecursorinaspirinres has also anti inflammatorypropent

• Sulphonamides have mild to moderateside-effects including, nausea, vomiting,headache, and depression.

• More serious side-effects include hepatitis,hypersensitivity reactions, bone marrowdepression, and aplastic anemia.

• Sulfonamides may provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency.

Sulphonamides

thats why use of sulphonamide declined

Chloramphenicol

• Isolated from Streptomyces venezuelae in 1947.• 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.• Cost in the developing world of an intravenous dose is about

$0.40–1.90.

proteinsyn inhibitor not bactericidalotherantimicrobials3

veryeffective can senetrateBBBtissues

very toxic

its an importantdrug innep.la

very cheap likepenicilin

Chloramphenicol

• Chloramphenicol has a broad spectrum of activity(including Stap. aureus, Strep. pneumoniae, and E. coliand Salmonella . It is not effective against Ps. Aeruginosa ).

• Extremely lipid-soluble; unbound to protein and is a small molecule. It has a large apparent volume of distribution and penetrates effectively into all tissues of the body, including the BBB, and eye.

N oraltopical

not very favorable inmodern medicine

verdurous

grain veinfection

prostatelarge moledifficult penetration cant beabsorbed

usually fordrugs orally

Chloramphenicol

• Aplastic anaemia:• Rare and sometimes fatal.• 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).

unpredictableside effect

non dosedependantvery toxic severe

thrombocytopenia leucopenia

can also occur intopical administration bone marrow transplantneededbecause it penetratesgood even in skin eye doesnt regenerate

Chloramphenicol

• Bone marrow suppression:• Dose dependent toxicity(which occurs quite predictably

once a cumulative dose of 20 g has been given).• Fully reversible after stopping the drug.

leads to anemia leukopeniathrombocytopenia

predictable side effect i depends on the doselarger dose higher toxicity

Chloramphenicol

• Gray Baby Syndrome • 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.

sit

al meningitis is treated withchloramphenicol

Chloramphenicol• The original indication was in the treatment of

typhoid fever.• 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.

• In preventing endophthalmitis, a complication of cataract surgery.

orallywas very common serious disease

now rarelyusedhere arealternativesampicillin

cephalosporins are now used 3rd 4thgen

used because it can penetratethe whole eye tissuecornea is cut L

Linezolid• New bacteriostatic synthetic antibiotic.• Binds to the 50s ribosome, but has no cross

resistance with other antibiotics.• Active against G+ve organisms• Approved for vancomycin-resistant

Enterrococcus faecium infections; nosocomialpneumonia; community-acquired pneumonia;and skin infections.

• Reserved for treatment of infections causedby multidrug-resistant gram-positive bacteriaincluding tuberculosis and Nocardia.

cornea is cutsevere infection causesblindness if its not treated

Lm feature

VRE

qecond linetreatment

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 methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

• Daptomycin:• Active against vancomycin-resistant strains of enterococci and

S aureus.

Commonly prescribed ABX in the community setting

■ Oral infections: penicillin, clindamycin, erythromycin, amoxicillin, cephalexin

■ UTI: ciprofloxacin, SMX/TMP

■ RTI’s, sinusitis: clarithromycin, azithromycin, 2nd or 3rd 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 deebarelygavethese slidesany importanceduring thelecture read themjust incase

■ 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, 2nd genCephs

■ Patients with penicillin allergy: clindamycin or erythromycin.

■ Intraabdominal infections: ciprofloxacin, metronidazole, 3rd genCephs

■ C. difficile diarrhea: metronidazole, vancomycin

Commonly prescribed ABX in the community setting