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Page 1: Beta lactams, protein sythesis inhibitors, other antibiotics 1-suman nizam.iiuc .pharmacy.b.pharm.

BETA LACTAM ANTIBIOTICS AND OTHER

CELL WALL SYNTHESIS INHIBITORS

Ma. Shiela Cano-Guiking, M.D.

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PENICILLINS I. CLASSIFICATION

A. Penicillinase Resistant ( Antistaphylococcal Penicillins)

1. Methicillin ( Staphcillin)2. Nafcillin (Unipen, Nafcil, Nallpen)3. Isoxazolyl penicillins

a. Oxacillin b. Cloxacillin c. Dicloxacillin d. Flucloxacillin

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B. Penicillinase-Susceptible 1. Narrow-Spectrum a. Benzylpenicillin – Penicillin G

b. Phenoxymethyl penicillin – Penicillin V

2. Extended Spectrum

A. Aminopenicillins

a.1 Ampicillina.2 Esters

a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin

a.3. Amoxicillin

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B. Carboxypenicillins

a.1 Carbenicillin

a.1.1. Indanyl carbenicillin e.g Geopen

a.1.2. Disodium carbenicillin e.g. Pyopen

a.2. Ticarcillina.3. Temocillin

C. Ureido-penicillinsc.1. Mezlocillinc.2. Azlocillinc.3. Piperacillinc.4. Apalcillin

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II. GENERAL PROPERTIES

A. Chemical Properties

Penicillins are derivatives of benzylpenicillin, from which

the methyl benzene radical is split

off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins

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The compound consists of 2 basic structures:

1 Thiazolidine Ring (A)

2.Beta-Lactam Ring (B)

- Site of action of Beta-lactamase

- Site of action of Amidase

- Site of attachment of side chain ®, which determines many of the antibacterial and pharmacologic characteristics of a derivative

( spectrum and penicillin-resistance)

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Mechanisms of Action:

Specific:

inhibit the last step in the peptidoglycan synthesis of

the cell wall

Underlying:

1. inhibition of transpeptidase enzymes

2. activation of penicillin binding proteins (PBPs)

3. activation of autolysins (murein hydrolases)

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C. Mechanisms of Resistance

1. inactivation of antibiotic by Beta lactamases 2. modification of PBPs 3. impaired penetration of drug to target PBPs 4. presence of an efflux pump Kinetics: - absorption vary with the preparation

depending on their acid stability and protein binding

- absorption of most oral penicillins (except amoxicillin) impaired by food and drugs should be given 1-2 hours before or after meal; parenteral – complete and rapid

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- cannot penetrate the blood-brain barrier; but 50% of the plasma concentration can pass through in the presence of inflammation:

Probenecid and certain organic acids can inhibit transfer from cerebrospinal fluid (CSF) to blood stream; may lead to increase CSF level.

- Metabolized by the liver to penicillanic/penicillenic acid; penicillamine, penicilloic acid and other penicilloyl derivatives (allergenic metabolites)

- Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration) small amount through bile and feces, sputum and milk; renal excretion inhibited by probenecid

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E. Adverse Effects:

1. Hypersensitivity reactions

most common adverse effects - cause the highest incidence of antibiotic allergy

a. major antigenic determinant- penicilloyl metabolite skin testing( penicilloyl polylysine (PPL) )

b. Signs and symptoms: - varied skin rashes and purpuric

reactions - angioedema and anyaphylactic

reactions - fever - eosinophilia - interstitial nephritis

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2.Gastrointestinal disturbances after oral administration

3.Convulsions following rapid IV administration

4. Accidental injection into the sciatic nerve – severe pain and nerve

dysfunction persisting for weeks

5. Chronic use may cause: hepatitisovergrowth of minor/atypical organisms following use of broad spectrum preparations

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6. Specific toxicities:

a. Procaine Penicillin G after accidental IV injection: pulmonary embolism

acute psychotic reactionsb. Oxacillin and Nafcillin

hepatitisgranulocytopenia, bone marrow depression

c. Disodium Carbenicillin and high dose Penicillin G Na

-hypernatermiad. Penicillin G Potassium

hyperkalemia with high doses

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e. Penicillin G Sodium Jarisch_herxheimer reaction with high

doses

in secondary syphilis f. Carbenicillin and Ticarcillin

bleeding diathesis

g. Methicillin interstitial nephritis

h. Ampicillin

associated with pseudomembranous colitis

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III. INDIVIDUAL AGENTS

A. Penicillin G

1. Antimicrobial Spectrum- Streptococci, meningococci,

enterococci, pen. susceptible pneumococci, non-B lactamase producing staph, Treponema, spirochetes, B. anthracis, Clostridium, Actinomyces, G(+) rods and non B lactamase producing G (-)anaerobic organisms

2.Kinetics - 1/3 of oral dose absorbed from

intestinal tract rapidly; food impair absorption

- maximal concentration: 30-60 min.

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- intravenous a. Aqueous Penicillin G - peak in 15-30 min -T ½ - 0.5-2 hrs.

- intramuscular B. Procaine Penicillin G

peak in 1-3 hrs. T1/2 – 12 hrs.

C. Benzathine Penicillin G

mean duration of antimicrobial activity - 26 days - 60% albumin bound

- widely distributed to the tissues and body fluids - does not readily enter the cerebrospinal fluid when meninges are not inflamed

- probenecid and uremia inhibits active transport secretion into the blood stream

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Preparations: “ International Units “ – measure of strength Oral Preparations: Penicillin G Sodium

Penicillin G Potassium Parenteral Preparations 1.short acting

a. aqueous Penicillin G Potassium – 1.7 meq K/1M “u” b. aqueous Penicillin G Sodium – 2.4. meq Na/1M “u”

2. long acting a. Procaine Penicillin G – 300,000 – 600,000 “u” 120 mg procaine/vial b. Benzathine Penicillin G – 600,000 “u” 1.2 M “u”/vial

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4. Doses and Therapeutic Uses

a. Aqueous Penicillin G Child: mild infections – 50,000 “u” – 100,000 “u”/kg/day in

equally divided Doses every 4-6 hrs. for 7

days Severe infections – 200,000 “u” – 600,000 “u”/kg/day

in equally divided Doses every 2-6 hrs.

for 14 days.

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a. Procaine Penicillin G – 300,000 – 600,000 “u” IM OD or BID for 7 days for Adults b. Benzathine Penicillin G – 1.2 million – 2.4 “u” IM monthly

Syphilis – less than 1 year duration – 2.4 M “u” IM + Probenicid 1 gm/day for 10 days or 2.4 M “u” Benzathine Penicillin G IM

single dose

late latent, complicated – 20 M “u” aqueous Penicillin G/day for 10 days

congenital syphilis – 50,000 “u”/kg/day aqueous Penicillin G for 10 days

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Staphylococcal infectionsGram (+) anaerobesMeningococcal infectionsGonococcal infectionsCarrier state diphtheria

Other unusual infections – actinomycosis, Anthrax, rat bite fever, listeria, pasteurella, lyme disease, erysipeloid

Prophylaxis – recurrences of streptococcal, rheumatic fever, gonorrhea, syphilis, bacterial endocarditis

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D . Penicillin V

Oral form indicated only in minor infections Relative poor bioavailability; need for

dosing 4x a day

Gram (+) aerobic activities similar to Penicillin G

5-10x less active against gram(-) microbes, esp. Neisseria and certain anaerobes

better absorbed from the gastrointestinal tract because of better acidic stability

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D. Ampicillin

1. Microbial SpectrumSomewhat less active than Penicillin G

against gram (+) cocci Enterococcal grp. D and viridans grp. Of streptococci

- Listeria monocytogenes - H. influenza

Effective for Shigellosis

Should not be used for uncomplicated salmonella gastroenteritis – may prolong the carrier state

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2. Kinetics: Gastric acid stable and well absorbed

from the gastrointestinal tractOrally absorbed drug peaks in 2 hrs.

Intramuscular administered drug peaks in 1 hour

Mainly excreted by the kidneys; also thru the bile and feces

Undergoes enterohepatic circulation

Other kinetic properties similar to Penicillin G Sodium

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3. Adverse Effects: “Ampicillin skin rash” – occurs in 7-8%

others similar to Pen G

4. Preparations a. Oral

Capsules – 250-500 mgSuspension – 125 mg, 250 mg/5

mlDrops – 100 mg/ml

b. parenteral250 mg; 500 mg/ml vial

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5. Doses a. mild infections

Newborn – 25-50 mg every 12 hrs. Child – 50-100 mg/kg/d in 4-6 divided

doses Adult – 1-4 gm/day

b. severe infectionsChild – 200-600 mg/kg/dayAdult – 6-12 gm/day

E. Esters of Ampicillin No inherent antimicrobial activity as esters, but

pharmacologically active following hydrolysis to Ampicillin

50% higher blood concentration than Ampicillin and Amoxicillin

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F. Amoxicillin

Closely related to Ampicillin in chemical

and pharmacologic properties

More rapidly and completely absorbed

from gastrointestinal tractAttains higher serum levels than

ampicillin

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G. CARBOXYPENICILLINS AND UREIDOPENICILLINS

1. Antimicrobial SpectrumGram (-) aerobesPseudomonas aeroginosaBacteroides fragilis; but in higher

amount/dose

Carboxypenicillins – certain indole (-)

ProteusUreidopenicillins – KlebsiellaAzlocillin – 10x more active than

carbenicillin against Pseudomonas

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2.Preparations

a. Carbenicillin Disodium salt – contains approximately 5 meq sodium/gm

for parenteral administration

Indanyl esters – 500 mg tablets

b.UreidopenicillinsParenteral preparations

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H. Penicillinase-Resistant

1. Methicillin -15-80x more active against penicillinase producing microbes than Penicillin G; only parenterally available; currently many resistant strains of Staph. Aureus have emerged, no longer

used because of nephrotoxicity

2. Nafcillin – slightly more active than Cloxacillin against penicillinase producing Staph. Aureus, available in oral and parenteral preparations: GIT absorption is erratic

3. Isoxazolyl PenicillinsStable in gastric acid and adequately

absorbed after oral administrationDicloxacillin is most active against

penicillinase producing Staph. Aureus

Available in oral and parenteral preparations

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CEPHALOSPORINS

I. CLASSIFICATION A. First Generation

1. Cephaloridine-Loridine, Ceporan 2. Cephalothin-Keflin 3. Cephalexin-Keflex, Ceporex 4. Cefazolin-Cefacidal 5. Cephradine-Velosef 6. Cepharpirin-Cefadyl 7. Cephadroxil-Doricef, Cefamox

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– B. Second Generation

1. Cefaclor-Ceclor 2. Cefoxitin – Mefoxin 3. Cefuroxime – Zinacef, Zinnat 4. Cefonicid – Monocid 5. Cefotetan - Cefotan 6. Cefamdandole – Mandol 7. Cefprozil – Cefzil 8. Loracarbef – Lorabid 9. Cefmetazole – Zefazone 10. Ceforanide

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C. Third Generation 1. Cefotaxime – Claforan 2. Cefoperazone – Cefobid 3. Moxolactam – Moxam 4. Ceftizoxime – Cefizox 5. Ceftriaxone – Rocephin 6. Ceftazidime – Fortum 7. Cefotiam – Ceradolan 8. Cefixime – Suprax 9. Cefetamet – Globocef 10. Cefpodoxime – Vantin 11. Ceftibuten – Cedax 12. Cefdinir –Omnicef 13. Cefditoren

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D. Fourth Generation1. Cefepime – Maxipime2. Cefpirome – Cefrom

II. BASIS FOR CLASSIFICATIONA. Antimicrobial SpectrumB. Pharmacokinetic Properties

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III. GENERAL PROPERTIES

A. Chemistry

7-amino cephalosporanic acid – parent

compound contains an R2 that makes the compound stable in dilute acid and highly penicillinase resistant

* MW – 400-450 *Soluble to water and relatively stable to

ph and temperature changes

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C7 modifications alter antibacterial activity

C3 substitutes change metabolism and kinetic properties

B. MECHANISM OF ACTION AND RESISTANCESimilar to penicillins

C. Antimicrobial SpectrumGenerally broader spectrum than

PenicillinsGenerally more effective than Penicillins

against B- lactamase-producing microbes

(except enterococci, Methicillin-resistant Staph. aureus and Staph. epidermis)

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D. SPECIFIC GROUPS/INDIVIDUAL AGENTS

1. FIRST GENERATION Good activity against gram (+) and modest

against gram (-) microbes

Penetration of the cerebrospinal fluid (CSF) is

inadequate

UTI, minor staph lesions, minor polymicrobial

infections – cellulitis, soft tissue abscessNot used in serious systemic infections

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2. SECOND GENERATION

Better activity against anaerobes and gram (-) aerobes

Only Cefuroxime can produce sufficient

CSF level

Sinusitis, otitis, LRTI, mixed anaerobic

infections such as peritonitis/diverticulitis

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3. THIRD GENERATION

Generally less active than the first generation against gram (+) cocci but most active against gram (-)

including B-lactamase- producing strains

Cefoperazone, Ceftazidime – (more active) against

Pseudomonas

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Active against anaerobes – Cefoperazone,

Cefotaxime

Ceftizoxime, Moxolactam – B. fragilis

Cefoperazone & Ceftriaxone -excreted primarily in the bile; Probenecid does not affect

renal excretion

Cross BBB except Cefoperazone, Cefixime, Ceftibuten and Cefpodoxime proxetil

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Ceftriaxone, 125 mg inj., Cefixime, single 400 mg oral dose -N. gonorrhea

Cefoperazone –(T1/2 – 2 hrs. ) 25-100 mg/kg/d injected q 8-12 hrs Cefixime 200 mg orally twice a day or 400 mg

ODCefpodoxime proxetil & Ceftibuten –

200 mg 2x/dayMeningitis caused by pneumococci,

meningococci, H. influenza & susceptible enteric gram (-) rods but not by L. monocytogenes; should be used in combination with

aminoglycoside for the treatment of meningitis caused by P. aeruginosa.

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4. FOURTH GENERATION

More resistant to hydrolysis by chromosomal

beta lactamases (eg. Those produced by enterobacter)

Good activity against P. aeruginosa, enterobacteriaceae, staph. aureus,

S. pneumoniaeHighly active against Haemophilus &

Neisseria

Penetrates well into CSFCleared by kidneysT1/2 – 2 hrsGood activity against most penicillin

resistant strains of streptococci

Useful in the treatment of enterobacter infections

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E. ADVERSE EFFECTS1. Allergy2. Toxicity:3. Renal toxicity – interstitial nephritis and even tubular

necrosis Cephalosporin that contains a methyl thiotetrazole

group ( Cefamandole, Cefmetazole, Cefotetan, Cefoperazone)

– cause disulfiram like reactions, hypoprothrombinemia and bleeding disorders- Antidote: Vit K, 10 mg 2x/week Moxolactam – interferes with platelet function, severe bleeding

4. Superinfection

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MONOBACTAMS

Monocyclic beta lactam ringResistant to B-lactamaseActive against gram (-) rods including

Pseudomonas and SerratiaAztreonam – resembles aminoglycosides

in spectrum of activity

Given 1-2 g IV q 8 hrs.; T1/2 – 1-2 hrs

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BETA LACTAMASE INHIBITORS ( CLAVULANIC ACID, SULBACTAM & TAZOBACTAM)

Resemble B- lactam moleculesBind to Beta-lactamase, inactivate them and

prevent the destruction Synergistic with other beta-lactams A. Clavulanic Acid – produced by S. Clavuligerul

potentnt inhibitor of beta-lactamases (plasmid encoded)

weak antibacterial action combined with Amoxicillin (Augmentin) or Ticarcillin( Timentin):

the combination widens the antimicrobial spectrum

B. Sulbactam Pivoxil and Ampicillin ( Unasyn)C. Tazobactam and Piperacillin (Tazocin)

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CARBAPENEMS - structurally related to Beta lactam

antibiotics 1. Imipenem – gram (-) rods, gram (+) org. &

anaerobes inactivated by dehydropeptidases in renal tubules resulting in low urinary concentration

combined with Cilastatin ( dehydropeptidase

inhibitor ) to reduce inactivation penetrates body tissues and fluids well including

the CSF.25-0.5 g IV q 6-8 hrsAdverse effects include nausea, vomiting,

diarrhea, reactions to infusion site; excessive in renal failure – seizures 2. Meropenem – slightly greater activity

against gram (-) aerobesdoes not require an inhibitorpenetrates CSF 1 g q 8 hrs.

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ERTAPENEM

-Less active than meropenem or imipenem

against Pseudomonas aeruginosa and

acinetobacter species

- It is not degraded by renal dehydropeptidase

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OTHER CELL WALL SYNTHESIS INHIBITORS

1. VANCOMYCIN

Gram (+) staphWater soluble and quite stable

MOA - Inhibits cell wall synthesis by binding firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide

Resistance – modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate resulting to loss of a critical H bond that facilitates high affinity binding of vancomycin to its target and loss of activity

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Synergistic with gentamicin and Streptomycin against E. faecium and E. faecalis strains that do not exhibit high levels of aminoglycoside resistance

Poorly abosorbed from the GITAdministered orally for the treatment of antibiotic associated enterocolitis caused by C. difficile; 0.125 – 0.25 g q 6 hrs

99% excreted by glomerular filtrationT1/2 6-10 days – not removed by dialysis

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- Sepsis or endocarditits caused by Methicillin resistant staph

Combined with Cefotaxime, Ceftriaxone or Rifampicin for the treatment of meningitis suspected or known to be caused by a highly penicillin resistant strain of pneumococcus.

- Recommended dosage is 30 mg/kg/day in two

or three divided doses - Adults with normal renal function – 1 g

every 12 hrs

Children – 40 mg/kg/d in 3 to 4 divided dose -

Causes phlebitis, chills and fever, ototoxicity, nephrotoxicity, red man or red neck syndrome

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2. FOSFOMYCIN

- inhibits a very early stage of bacterial cell

wall synthesis- inhibits cytoplasmic enzyme enol

pyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the phosphoenolpyruvate to UDP-N-acetylglucosamine – 1st step in the formation

of UDP-N- acetylmuramic acid, the

precursor of acetylmuramic acid – found

only in bacterial cell walls.

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- Drug is transported into the cell by glycerophosphate or glucose 6 phosphate transport systems

- Resistance is due to inadequate transport of drug into the cell

- Active against both Gram (+) and Gram (-)- In vitro synergism with beta lactams,

aminoglycosides or fluoroquinolones- Available orally ( 2-4 g, single dose

in uncomplicated UTI) and parenterally- Excreted through the kidneys - Safe in pregnancy

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4. BACITRACIN- cyclic peptide mixture- active against Gram (+) organisms- inhibits cell wall formation by interfering

with dephosphorylation

- in cycling of the lipid carrier that transfers peptidoclycan subunits to the growing cell wall

nephrotoxic- poorly absorbed; limited to topical use 500 units/g ointment + Polymyxin B or

Neomycin

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5. CYCLOSERINE

- water soluble; very unstable at acid ph treat tuberculosis caused by M. tuberculosis resistant to first line agents- structural analogs of D-alanine and inhibits incorporation of D-alanine into peptidoglycan

pentapeptide by inhibiting alanine racemase

which converts L alanine to D alanine and D- alanyl- D-alanine ligase

- widely distributed into tissues- excreted through the urine- 0.5 – 1 g /d in 2 – 3 divided doses- causes dose related CNS toxicity,

headaches, tremors, acute psychocis, convulsions

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THANK YOU VERY MUCH

AND

STUDY WELL!

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PROTEIN SYNTHESIS INHIBITORS

Ma. Shiela Cano-Guiking, M.D.

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The 30 S Inhibitors:

I. AMINOGLYCOSIDES

Older Aminoglycosides:StreptomycinKanamycin

Newer Aminoglycosides:GentamicinTobramycinNeomycinAmikacinNetilmicinSisomicin

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Antimicrobial Spectrum:1. Gram (-) Aerobic Bacilli2. Beta-lactamase producers:

Staph. aureus N. gonorrhea

3. Mycobacteria Mechanism of Action:

- interferes with initiation complex of peptide formation

- induces misreading of mRNA causing incorporation of incorrect AA

causes breakup of polysomes into nonfunctional monosomes

- Requires oxygen uptake, therefore ineffective against anaerobes.

- Bactericidal

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Microbial Resistance:1. enzyme inactivation2. Cell surface alteration3. receptor protein alteration4. oxygen requirement related

Kinetics:minimally absorbed from the GIT, well absorbed thru

IM, IVpoorly penetrate the BBBnot significantly metabolizedprimarily executed unchanged through GF

Clinical Uses:severe gram (-) rod infectionsMycobacterial infections

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Toxicity:Ototoxicity (esp. with loop diuretics)Auditory damage – Neomycin, Kanamycin

and AmikacinVestibular Damage – Streptomycin,

GentamicinNephrotoxicity (esp. with cephalosporins)Neomycin, Tobramycin, Gentamicin- most

nephrotoxic

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STREPTOMYCIN - ribosomal resistance to this agent develops readily, limiting its role as a single agent- mainly used as a second line agent for treatment of

tuberculosis- given at 0.5-1 g/d (7.5-15 mg/kg/day for children) IM or IV should be used only in combination with other agents to

prevent emergence of resistance- In plague, tularemia and sometimes brucellosis, 1 g/d

(15 mg/kg/day for children) IM or IV + oral tetracycline +Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis- Can cause fever, skin rashes and other allergic reactions, pain at injection site, vestibular dysfunction – most serious toxic

effectIf given during pregnancy, can cause deafness in the newborn

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GENTAMICINemployed mainly in severe infections (sepsis and

pneumonia) caused by gram (-) bacteria in combination with a cephalosporin or a penicillin may be life saving

given at 5-6 mg/kg/day IV in three equal doses+ Penicillin G for bactericidal activity in endocarditis

due to viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis

Serum concentrations and renal function should be monitored if administered for more than a few days

or if renal function is changing (eg. Sepsis; often complicated by acute renal failure)

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Gentamicin sulfate 0.1% -0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infectionsTopical gentamicin is partly inactivated by purulent exudatesTen milligrams can be injected subconjunctivally for treatment of ocular infections.Nephrotoxicity is reversible and usually mild; Irreversible ototoxicity manifested as vestibular dysfunction, hypersensitivity reactions are uncommon

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TOBRAMYCIN

Antimicrobial spectrum and pharmacokinetic properties virtually identical to gentamicin

Given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours

Blood levels should be monitored in renal insufficiency

Slightly more active against pseudomonas but not E. faecium

Ototoxic and nephrotoxic

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AMIKACIN

semisynthetic derivative of kanamycinresistant to many inactivating enzymesfor tuberculosis; given at 7.5 – 15 mg/kg/d as a once

daily or 2- 3x weeklySerum concentrations should be monitoredNephrotoxic and ototoxic

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NETILMICIN

shares many characteristics with gentamicin and tobramycin

dosage and the routes of administration are the same, completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities

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KANAMYCIN AND NEOMYCIN

Paromomycin is also a member of this group and all have similar properties

Used for bowel preparation for elective surgery

There is complete cross-resistance between kanamycin and neomycin

Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine

Too toxic for parenteral use, now limited to topical and oral use

Solutions 1-5 mg/ml – used on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where

infection is present (15 mg/kg/day)

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Ointments (Neomycin-Polymyxin-Bacitracin combination) applied to infected skin lesions or in the nares for suppression of staphylococci

In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base;

Paromomycin, 1 g q 6 hours orally for 2 weeks; effective in intestinal amoebiasis

Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like

neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes)

Prolonged application to skin and eyes-severe allergic reactions

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SPECTINOMYCIN

chemically related to the aminoglycosides

binds at the 30 S subunit (bacteriostatic)

Dispensed as the dihydrochloride pentahydrate for IM

injection

Used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs

Single dose of 2 g ( 40 mg/kg )

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II.TETRACYCLINES: Short Acting: Tetracyline, Oxytetracycline, ChlortetracyclineIntermediate Acting: Demeclocycline, MethacyclineLong Acting: Doxycycline, MinocyclineAntimicrobial Spectrum: Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P. pseudomallei, Brucella, Psittacosis, BorreliaMinocycline – carrier state of Meningococcal infections, N. asteroides N. gonorrhea

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Mechanism of Action: - enter microorganisms in part by passive diffusion and in part by an energy dependent process of active transport

binds to 30 S and prevents attachment of aminoacyl tRNA, prevents the addition of amino acids to the growing peptide

Bacteriostatic

Resistance:decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pumpribosome protection due to production of proteins that interfere with tetracycline binding to the ribosomeenzymatic inactivation

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Kinetics:limited CNS penetrationabsorption occurs mainly in the upper small intestine and is impaired by food ( except Doxycycline and

Minocycline) Must not be taken with milk or antacidsCross placenta, excreted in milkCarbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half life of

doxycyclineExcreted mainly in bile and urine ( Doxycycline

fecally eliminated; can be used in renal failure

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Clinical Uses:Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, M. pneumonia, Rickettsia, Acne, Tularemia, Cholera,

Leptospirosis, Protozoal infectionsMinocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier stateDemeclocycline – inhibits the action of ADH in the renal tubule and has

been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors

Tetracycline – 250-500 mg 4x/day adults20-40 mg/kg/d – children above 8 y/0

600 mg daily dose for Demeclocycline and Methacycline100 mg 1-2x/d for Doxycycline and Minocycline

Toxicity: Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogencic, hepatotoxicity, vestibular toxicity

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Page 106: Beta lactams, protein sythesis inhibitors, other antibiotics 1-suman nizam.iiuc .pharmacy.b.pharm.

THE 50 S INHIBITORS:

CHLORAMPHENICOL

MACROLIDES

CLINDAMYCIN/LINCOMYCIN

STREPTOGRAMINS

OXAZOLADINONES

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I CHLORAMPHENICOL Bactericidal – H. influenzae, N. meningitides, B. fragilis Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes,ineffective for chlamydial infections

Mechanism of Action:

attaches at P sites of 50 S subunit of microbial ribosomes and inhibits functional attachment of amino-acyl end of AA-t-RNA to 50 S subunit

inhibits peptidyl transferase step

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Spectrum:broad spectrum antibioticmore effective than Tetracyclines against Typhoid Fever and

other Salmonella infections Kinetics:

well absorbed after oral administrationChloramphenicol succinate used for parenteral administration

is highly water solubledistributed into total body waterexcellent penetration into CSF, ocular and joint fluidsrapidly excreted in urine, 10% as chloramphenicol; 90% as

glucuronide conjugatesystemic dosage need not be altered in renal insufficiency but

must be reduced markedly in hepatic failureNewborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25

mg/kg/d

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Uses: meningitis, rickettsia, Salmonella and anaerobic infections

ineffective against chlamydial infectionsoccasionally used topically in the treatment of eye

infections for its well penetration to ocular tissues and the aqeous humor

Adverse Effects: GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome

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II. MACROLIDES: Old Generation: Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin New Generation: Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin

Mechanism of Action:binds to the P site of the 50 S bacterial ribosomal subunit.Aminoacyl translocation and formation of initiation complex are blockedInhibitory or bactericidal

RESISTANCE:reduced permeability of the cell membrane or active effluxproduction (by Enterobacteriaceae) of esterases that hydrolyze macrolidesmodification of the ribosomal binding site by chromosomal

mutation

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Spectrum: Erythromycin has a narrow Gram (+) spectrum similar to Pen. G.Also active against Chlamydia and Legionella organisms1. Erythromycin:

prototypedistributed into total body waterpoor CSF penetrationfood interferes with absorptionserum half life is app. 1.5 h normally and 5 hours in patients with anurianot removed by dialysismetabolized in the livertraverses the placenta and reaches the fetus

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Commercial Preparations:Oral-stearate, ethyl succinate, estolate salts – 250-500 mg q 6 h adults40 mg/kg/d - children

Parenteral- lactobionate, gluceptate – 0.5-1 g q 6 hours for adults 20-40 mg/kg/d for children

Adverse Effects: GIT dysfunction, intrahepatic cholestatic jaundice- Erythromycin metabolites can inhibit cytochrome p450

enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone;also oral digoxin by increasing its bioavailability

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2. Clarithromycin- hydroxylated derivative of erythromycin- more active against Gram (+) pathogens, Legionella

and Chlamydia than Erythromycin- lower frequency of GIT effects, less frequent dosing- Half life of 6 hours- given at 250-500 mg twice daily

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3.Azithromycin- more active than erythromycin against several Gram (-)

pathogens- maintains high concentrations for prolonged periods into a

number of tissues (lungs, tonsil, cervix)- tissue half life – 2-4 days- long half-life allows once daily oral administration and

shortening of treatment in many cases ( a single 1 g dose of azithromycin is as effective as a 7 day course of doxycycline for chlamydial cervicitis and urethritis)

-Community acquired pneumonia – 500 mg loading dose, followed by a 250 mg

- single daily dose for the next 4 days-Should be administered 1 hour before or 2 hours after meals;

aluminum and magnesium delay absorption and reduce peak serum concentrations

Does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin

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AZITHROMYCIN

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KETOLIDES

- semisynthetic 14 membered ring macrolides

Telithromycin – active in vitro against S pyogenes, S.

penumoniae, S. aureus, H. influenzae, Moraxella catarrhalis, mycopasmas, legionella sp, chlamydia sp, Helicobacter pylori, N. gonorrhoaea, B. fragilis, T gondii and nontuberculosis mycobacteria

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-Oral bioavailability – 57%- good tissue and intracellular penetration- metabolized in the liver- eliminated by a combination of biliary and urinary routes of excretion- administered as a once daily dose of 800 mg- indicated for treatment of respiratory tract infections, including community acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis- a reversible inhibitor of the CYP3A4 enzyme system

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TELITHROMYCIN

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III. CLINDAMYCIN/LINCOMYCINMechanism of Action: attach to 50

S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction

Spectrum: Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci

Resistance: mutation of the ribosomal receptor

sitemodification of the receptor by a

constitutively expressed methylase enzymatic inactivation

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Clindamycin is more clinically used than Lincomycin:excellent absorptiongiven at 150-300 mg q 6 hrs – adults; 10-20 mg/kg/d

for childrenlow concentration in CSFwell bone penetrationexcreted mainly via the liver, bile and urinehalf life is 2.5 hours normally and 6 hours in patients

with anuriamore toxic than erythromycinprophylaxis of endocarditis in patients with valvular

heart disease for dental procedures

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most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections

+ aminoglycoside or cephalosporin used to treat penetrating wounds of the abdomen and the gut

Septic abortion, pelvic abscesses, aspiration pneumonia

+ primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients+ Pyrimethamine for AIDS – related toxoplasmosis

of the brain

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ADVERSE EFFECTS:

Diarrhea, nausea, skin rashes, impaired liver function and neutropenia; Antibiotic associated colitis caused by toxigenic C. difficile

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NEWER AGENTS:

STREPTOGRAMINS:Quinuprisitn-Dalfopristin (Synercid)action is similar to macrolides except bactericidal for staph and most organisms except Enterococcus faeciumprolonged postantibiotic effect up to 10 h for Staph. aureusadministered IV at 7.5 mg/kg q 8-12 heliminated through fecal route, < 20% urineinhibits CYP 3A4, which metabolizes warfarin, diazepam,

astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine.Clinical Uses: infections caused by Vancomycin resistant strains of E faecium but not E. faecalis, bacteremis or respiratory tract infections caused by methicillin-resistant staphylococci and penicllin susceptibe and resistant strains of S. pheumoniaToxicities: infusion related events, pain at the injection site, arthralgia, myalgia synd

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STREPTOGRAMIN A

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STREPTOGRAMIN B

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OXAZOLADINONES: Linezolid (Zyvox)inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein

synthesis.Its unique binding site located on 23 S ribosomal

RNA of the 50 S subunit, results in no cross resistance with other drug classes

Has high oral bioavailability, half life of 4-6 hUses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, L. monocytogenes

- treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple

drug resistant organisms

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METABOLIC INHIBITORS:

SULFONAMIDES

- structurally similar to p-aminobenzoic acid (PABA) that competitively inhibits dihydropteroate synthase

- inhibits growth by reversibly blocking folic acid synthesis - mammalian cells do not make folic acid and are not affected- cross the placenta and secreted in breast milk and should not be given to pregnant Women- highly bound to plasma proteins esp, albumin- penetrates CNS well

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SPECTRUM: - Gram (+) & Gram (-) Bacteria - Nocardia - C. trachomatis - Enteric bacteria (E. coli, Klebsiella, Salmonella, Shigella Enterobacter)

Ricketssia – sulfonamides do not inhibit these organisms but stimulate its growth Resistance: - occurs as a result of mutations that: 1. cause overproduction of PABA 2. cause production of a folic acid synthesizing enzyme that has a low

affinity for Sulfonamides 3. cause a loss of permeability to the sulfonamides

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Pharmacokinetics:

- 3 MAJOR GROUPS: 1. ORAL, ABSORBABLE 2. ORAL, NON-ABSORBABLE 3. TOPICALIntravenous Preparation: - Na salts of sulfonamides in D5W

Oral, absorbable sulfonamides:

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DRUGS HALF LIFE ORAL ABS

1.short actingSulfacytine

Sulfisoxazole

Sulfamethizole

Short

Short (6 h)

Short (9 h)

Prompt (peaks in

1-4h)

Prompt

Prompt

2. Medium acting

Sulfadiazine

Sulfamethoxazole

Sulfapyridine

Intermediate(10-17h)

Intermediate (10-12h)

No data

Slow (peak in 4-8h)

Slow

Slow

Long ActingSulfadoxine Long (7-9 days) Intermediate

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absorbed from stomach and small intestine- distributed widely to tissues and body fluids

(CSF), placenta and fetus- protein binding 20% to over 90%- therapeutic concentration – 40-100 ug/ml of

blood- peak blood levels – 2h to 6 h after oral

ingestion- metabolism: glucoronidation or acetylation

in liver- eliminated in urine-mainly by glomerular

filtration

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CLINICAL USES:1. Urinary tract infectionSulfisoxazole – 1 gm 4x daily }combined with PHENAZOPYRIDINESulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic)2. Respiratory infections3. Sinusitis, bronchitis, pneumonia4. Otitis media5. Dysentery6. Acute Toxoplasmosis

Sulfadiazine + Pyrimethamine – SynergisticBlock sequential steps in folate synthesis:Sulfadizine- inhibits dihydropteroate synthasePyrimethamine – inhibits dihydrofolate reductase

Dosage – Sulfadiazine – 1 g 4x daily Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD

Folinic Acid – administered to minimize bone marrow

suppression7. Malaria

- sulfadoxine + pyrimethamine – 2nd line agent in the treatment for malaria

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ORAL, NONABSORBABLE AGENTS

Sulfasalazine (Salicylazosulfapyridine)more effective than soluble sulfonamides or other antimicrobials taken orally in inflammatory bowel diseaseulcerative colitisenteritisother inflammatory bowel diseasesplit by intestinal microflora to yield:

Sulfapyridine – absorbed and may lead to toxic symptomsIf more than 4 g of sulfasalazine is taken per day esp. in persons who are slow acetylators5-aminosalicylate (5-ASA) – released in the colon in high

concentrations and is responsible for an anti-inflammatory effect

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TOPICAL AGENTS:

Sodium Sulfacetamide ophthalmic solution or ointment effective for bacterial conjunctivitisadjunct therapy for trachoma

Mafenide acetateused topically to prevent bacterial colonization and infection of burn woundsinhibits also carbonic anhydrase – cause metabolic acidosis

Silver Sulfadiazineless toxic topical sulfonamidepreferred to mafenide for prevention of infection of burn woulds

ADVERSE REACTIONS:Cross allergy with the ffg.carbonic anhydrase inhibitors, thiazides, furosemide,

bumetanide, furosemide, diazoxide, sulfonylureas, hypoglycemicsMost common adverse effects:

Fever, skin rashes, exfoliative dermatitis, nausea, vomiting,

urticaria, photosensitivity

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Urinary tract disturbances:sulfas may ppt. in urine at neutral or acid ph-Crystalluria – treated with sod. Bicarbonate to alkalinize urine and fluids to maintain adequate hydrationHematuriaObstruction

implicated in nephrosis and allergic nephritisOTHER SIDE EFFECTS:

Stevens-Johnson Syndrome – uncommon but serious and potentially fatal type of skin & mucous membrane eruptions

Hematopoietic disturbances:hemolytic or aplastic anemia, thrombocytopenia, granulocytopenia, leukemoid reaction, provoke hemolytic reactions in patients with deficient rbc glucose 6 phosphate dehydrogenaseincreased risk of kernicterus in newborns when sulfonamides were taken near the end of pregnancyStomatitis, Conjunctivitis, Arthritis, HepatitisPolyarteritis nodosa – rarePsychosis – rare

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STEVENS JOHNSON SYNDROME

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TOXIC EPIDERMAL NECROLYSIS

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TRIMETHOPRIMwell absorbed from the gutwidely distributed in body fluids and tissues incldg. CSFfound in high concentrations in prostatic & vaginal fluidsEven if given orally alone or in combination with sulfonamides, it will have the same half-lifeMore lipid soluble – larger volume of distribution than

sulfonamidesRESISTANCE TO TM:

due to reduced cell permeabilitydue to overproduction of dihydrofolate reductasedue to production of an altered reductase & reduced drug

bindingCLINICAL USES: Oral TM:

acute UTI 100 mg BIDcommunity acquired organisms – 200 ug to 600 ug/ml

concentration of TM in urineADVERSE EFFECTS:megaloblastic anemia, leucopenia, granulocytopeniaPrevention of adverse effects:simultaneous administration of folinic acid 6 mg-8 mg/day

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TRIMETHOPRIM-SULFAMETHOXAZOLE (CO-TRIMOXAZOLE)

synergistically active antimicrobial agent which blocks two sequential steps in the obligate enzymatic reaction in bacteria preventing the formation of nucleotides:

Sulfamethoxazole – competitively inhibits the incorporation of PABA into folic acid

Trimethoprim inhibits dihydrofolate reductase preventing the reduction of dihydrofolate to tetrahydrofolate

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ADVANTAGES OF THE COMBINATION:increased potencyincreases spectrumdecreased incidence of resistanceexhibits selective toxicity for bacteria which must

synthesize their own folic acidTrimethoprim is more potent, more lipid soluble and has a greater volume of distribution than sulfa drugsPenetrates CSF well

65-70% of each drug is protein boundEliminated in the urine within 24 h – reduce dose by half if creatinine clearance is 15-30 ml/min

CLINICAL USES:Oral TMP-SMX

urinary tract infection:

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complicated UTI – 2 double strength tabs (TM-160 mg+SM 800 mg) q 12 hoursRecurrent UTI prophylaxis – ½ of regular size (single strength) 3x weekly

Prostatitis – 2 double strength tabs (TM 160 mg + SM 800 mg) q 12 hSusceptible strains of shigella and salmonella

2 double strength tabs q 12 hChildren with shigellosis, UTI, otitis media-8mg/kg TM and 40 mg/kg SM q 12 hoursP. carinii and other pathogens – orally 15-20 mg/kg

in immunosuppressed patients – one double strength tab daily or 3x weekly

Nontuberculous mycobacterial infectionRespiratory tract pathogens – useful alternative to B lactamase for community acquired bacterial pneumonia

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CLINICAL USES:Inravenous TMP-SMX:

drug of choice for moderately severe to severe pneumocystis pneumonia esp. patients with AIDSTM 80 mgs + SM 400mg/5 ml diluted in 125 ml of D5WFolinic acid increases morbidity and treatment failures so not usedUsed for Gram (-) bacterial sepsis – incldg. Those caused by some multiple drug resistant species such as Enterobacter and SerratiaShigellosisTyphoid feverUTI caused by susceptible organisms if patient is unable to take drug orallyDosage- 10-20 mg/kg/day of TM componentOral Pyrimethamine + Sulfadiazine= used in the treatment of leishmaniasis and toxoplasmosisPyrimethamine + Sulfadoxine = used in the treatment of Falciparum malaria

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ADVERSE EFFECTS:mostly due to untoward reactions to SMXdermatological effectsGI effects: glossitis, stomatitis, nausea and vomitingCNS disturbances: headache, depression, hallucinationsHematologic reactions- aplastic, hemolytic and macrocytic

anemia, coagulation disordersVasculitisRenal impairment or damage

AIDS PATIENTSmore sensitive to increased frequency of reactions toward TMP-SMX drug:-rashes, hemtologic effects-leukopenia, fever, diarrhea, elevated hepatic aminotransterases, hyperkalemia, hyponatremia

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FLUOROQUINOLONESQUINOLONES

synthetic fluorinated analogs of nalidixic acidblock bacterial DNA synthesis by inhibiting bacterial

topoisomerase II (DNA Gyrase) and topoisomerase IV

INHIBITION OF DNA GYRASEprevents relaxation of positively supercoiled DNA that is

required for normal transcription and replication

INHIBITION OF TOPOISOMERASE IVinterferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division

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EARLY QUINOLONES (Nalidixic Acid, Oxolinic acid, Cinoxacin)did not achieve systemic antibacterial levelsuseful only for treatment of lower UTI

ANTIBACTERIAL ACTIVITY:Gram (-) aerobic bacteria- excellent activityGram (+) organism – limited activity

NORFLOXACIN – least active against gm (+) and Gm (-)SECOND GROUP

excellent gm (-) activity, moderate gm (+) activityCiprofloxacin (prototype), Enoxacin, Lomefloxacin,

Levofloxacin, Ofloxacin, PefloxacinMethicillin susceptible S. aureus – susceptible to

fluoroquinolonesMethicillin resistant S. aureus – resistant to fluoroquinolonesCiprofloxacin – most active against gm (-) expecially P.

aeroginosaLevofloxacin – 2x more potent than ofloxacinsuperior activity against gm (+) org. incldg S. pneumoniae

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THIRD GROUP:improved activity against gm (+) organism particularly S.

pneumoniae and some staphClinafloxacin – best activity against gm (+) activityGatifloxacinSparfloxacin – some activity against anaerobesnot as active as ciprofloxacin against gm (-)

FOURTH GROUPenhanced gm (+) activitygood activity against anaerobic bacteriaMoxifloxacin, Trovafloxacin

Other activities:Atypical pneumoniae ( Mycoplasma, ChlamydiaIntracellular pathoges (Legionella, Mycobacteria tb, and M.

avium complex)RESISTANCE:

Due to one or more point mutations in the quinolone binding region of the target enzyme

Due to a change in the permeability of the organism

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DNA GYRASE – primary target in E. coli with single step mutants exhibiting amino acid substitution in the alpha subunit of the gyraseTOPOISOMERASE IV – secondary target in E. coli that is alerted in mutants expressing higher levels of resistanceIN STAPH AND STREP

Topoisomase IV – primary targetDNA gyrase – secondary targetcross resistance to other members

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PHARMACOKINTEICS:well absorbed after oral intakebioavailability 80-95%distributed widely in body fluids and tissues

Half life3 hrs- norfloxacin and ciprofloxacin10 hrs. – pefloxacin & Fleroxacin> 10 hrs. – sparfloxacin

Long half life : Levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin

Ofloxacin and Levofloxacin – identical pharmacokineticsOral absorption impaired by divalent cations including those

antacindsAlatrovafloxacin – inactive prodrug of trovafloxacin for

parenteral administrationConcentration is higher in prostate, kidney, neutrophiles and

macrophages than in serum

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ELIMINATION: Renal – tubular secretion, Glomerular filtration- If creatinine clearance < 50%ml/min – adjust dosageSparfloxacin – a50 % fecal, 50% renalIf creatinine clearance <50 ml/min -400 mg LD followed by 200 mg q other dayNon renal – trovafloxacin and moxifloxacin_ CI in patients with hepatic failureCLINICAL USES:UTI – even when caused by multi drug resistant bacteria like pseudomonasNorfloxacin 400 mg BidCiprofloxacin 500 mg BIDOfloxacin 400 mg BIDProstatitis – 4-6 wksNorfloxacin, Ciprofloxacin, Ofloxacin

Bacterial Diarrhea

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Shigella, Salmonella, toxigenic E. coli, campylobacterInfection of soft tissues, bones, joints, intraabdomina and respiratory tract infection even caused by Pseudomonas and EnterobacterGonococcal infection, including disseminated diseaseCiprofloxacin, ofloxacin oral single doseChlamydia urethritis or cervicitisofloxacin x 7 daysLegionellosisCiprobay – 2nd line agentTB and atypical mycobacteria infectionEradication of meningococci carrierProphylaxis in neutropenic patientUpper and lower RTINewer fluoroquinolones enhanced gm (+) activity and atypical pneumonia

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ADVERSE EFFECTS:most common – nausea, vomiting and diarrheaOthers – headache, dizziness, insomnia, skin rash, abn liver function testTrovafloxacin – associated rarely with acute hepatitis and hepatic failurePhotosensitivity – lomefloxacin, pefloxacinCV toxicity – GrepafloxacinDamage growing cartilage and cause arthrpathy- not recommended < 18 y/oTendinitis – may rupture

DRUG INTERACTION:

Theophylline – increase metabolism of theophylline – elevated concentration-seizuresCONTRAINDICATIONS:Nursing mothers, children, pregnancy

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NALIDIXIC ACIDFirst antibacterial quinolone introduced in 1963Not fluorinatedVery rapid elimination, no systemic bacterial effectsUsed only for UTIOxolinic Acid and Cinoxacin – similar structure

NOVOBIOCIN:Acidic antibiotic prod. By Streptococcus niveiusInhibitor of B subunit of DNA gyraseActive mainly against gm (+) bacteriaRapid emergence of resistance; inc. incidence of adverse

effectsNo clear indication

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URINARY ANTISEPTICS:

Methenamine Mandelate and Hippuratereleases mandelic acid, hippuric acid or formaldehyde in sufficiently acidic urinebactericidal or bacteriostatic to most organisms causing UTI except ProteusNalidixic Acid and Cinoxacin:interferes with DNA polymerization by binding to DNA gyrasecauses nausea, vomiting, skin rashes and CNS effects

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Nitrofurantoinwell absorbed after ingestionexcreted into the urine100 mg q 6 h with food or milkcontraindicated in severe renal insufficiencybactericidal or bacteriostatic for many gram (+) and gram (-)antagonizes the action of nalidixic acidcauses hypersensitivity, nausea, vomiting, neuropathies and hemolytic anemia in G6PD

Trimethoprimselective inhibition of bacterial dihydrofolate reductasemay be bacteriostatic or bacteridial+ Sulfamethoxazole – P. carinii, shigellosis, prostatitis, some nontuberculous mycobacterial infections, systemic salmonella infections, complicated UTI

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MISCELLANEOUS ANTIBACTERIAL DRUGS:

Metronidazolepenetrates CSF, metabolism-livertreatment of amoebic infections, intraabdominal infections, vaginitis, antibiotic associate enterocolitis, brain abscessoral, IV, rectal suppositorycauses metallic taste, glossitis and anorexia

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Polymyxin B

group of basic peptides active against Gram (-), bactericidaltreatment of serious enteric infections(Pathogenic E. coli, Shigella, Enterobacter, Klebsiella and Pseudomonas , not Proteus)poor tissue distributionattach to and disrupt bacterial cell membrane, bind and inactivate endotoxintoxicity includes neurological and renal effectstopical (+Bacitracin+Neomycin)

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Mupirocin

ointment for topical applicationactive against staph aureus; inh. Isoleucyl tRNA synthetaseindicated for impetigo, intranasal application for elimination of methicillin resistant S. aureus carriage by patient or health care workers

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