Anti Microbials

Basic Pharmacology Antimicrobials Part 1 (Dr. Dando) ‘Twas the week b4 xmas vacation

-

Beta Lactam Compounds & Other Inhibitors of Cell Wall Synthesis • Penicillins

•

Cephalosporins & Cephamycins

•

Other Beta Lactam Drugs o Monobactams o Beta-Lactamase Inhibitors o Carbapenems

•

Other Inhibitors of Cell Wall Synthesis

•

•

A.

Units

-

o Vancomycln o Teicoplanin o Fosfomycin o Bacitracin o Cycloserine Chloramphenicols Tetracyclines Macrolides • Erythromycin • Glarithromycin • Azithromycln Clindamycin Streptogramine • Quinupristin-dalfopristin Oxazoladinones • Linezolid

-

drugs that retain the antibacterial spectrum of penicillin and have improved activity against gramnegative organIsms, but they are destroyed by betalactamases (penicllinases) Limitations: instability at acidic pH Susceptibility to destruction by bela-lactamase Relative inactivity against gram-negative bacilli

•

PenG: 1600 unlts/mg(1M unit = 0.6g)

Mechanism of Action Inhibit bacterial cell wall synthesis (Class Ill reaction) by:

1.

binding of the drug to specific receptors (penicillinbinding protelns [PBPs]) located in the bacterial cytoplasmic membrane

2.

inhibition of transpeptidase enzymes that act to cross-link linear peptidoglycan chains, which font part of the cell wall; Beta-lactams prevent the cross-linking peptides from binding to the tetrapeptide sidechains.

3.

activation of autolytic enzymes that cause lesions in the bacterial cell wall

Beta Lactam Compounds & Other Inhibitors of Cell Wall Synthesis Penicillins and Cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis. They are called beta-lactams because of the unusual 4-member ring that is common to all their members. Penicillins • All peniclllins are derivatives of 6-emmopenicillanlc acid and contain a beta-lactam ring structure that is essential for antibacterial activity Diagrams of sbucture and metabolism of a bacterial cell. A. Schematic representation of a bacterial cell. B. Flow diagram showing the synthesis of the irein types of macromolecule of a bacterial cell. Class I reactions result in the synthesis of the precursor molecules necessary for dat II reactions, which result in the synthesis of the constituent molecules; these are then anembled into macromolecules by dna Ill reactions

•

Classification:

1.

Penicillins (e.g. PenicilIin G)

2.

Antistaphylococcal penicillins (e.g. Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin, etc.)

3.

versus gram-posltive organisms, gram-negative cocci & non-beta lactamase anaerobes

versus staphytococci and streptococci

Extended-spectrum (e.g. Ampiciilin, Antipseudomonal Penicillins)

-

Amoxicillin

&

versus gram-negative organisms

MR*, Mel, Eisa (ako, ako, parati na lang ako!)

1 of 6

Basic Pharmacology – Antimicrobials 1 by Dr Dando

Page 2 of 6

B.

•

Pharmacokinetics Oral absorption differs greatly for different penicillins, depending on acid stability and protein-binding (impaired by food, so, must be taken 1 hr before or after meals)

-

-

•

•

-

Greater activity against gram-negative bacteria

-

Ampicillin is salmonellosis

-

For Pseudomonas: Carboxypenicillins + Aminoglycosides

Amoxicillin is better absorbed from the gut - preferred preparation for oral penicillin effective

for

shigellosis

but

not

for

Beta-lactamase Inhibitors (Clavulanic Acid, Sulbactam, Tazobactam): versus beta-lactamase producing strains of Staph aureus

•

Are derivatives of 7-aminocephalosporanic acid and contain

•

the beta-lactam ring structure Soluble In water

• •

Stable to pH and temperature changes unlike Penicillins

1.

First Generation Cephalosporins

Not active against enterococci and L. monocytoqenes

Widely distributed in the body fluids and tissues Rapidly excreted by the kidneys Excreted Into sputum and milk Poor penetration in the eye, prostate and CNS except with acute inflammation of meninges if given in high doses Normal half-life: approx. 30 mins

-

Cefadroxil, Cefazolin (IV), Cephalexin (oral), Cephalotin, Cephapirin, Cephradine Greater activity for gram-negative microorganisms Tubular secretory blocking agents (probenecid) may increase serum levels

-

Pen G (IV): drug of choice for infections caused by streptococci. meningococci, enterococci, pneumococci, non-beta-lactamase producing staphylococci

-

-

Pen V (oral): Indicated only for minor infections due to poor bioavailability

-

-

Benzathine/Procaine (IM): yield low but prolonged drug levels, for treatment of beta-hemolytic strep pharyngitis; IM inj every 21 days in RHD and as prophylaxis to prevent endocarditis

Cefazolln Is almost the only first generation parenteral cephalosporin: drug of choice for surgical prophylaxis alternative to an antistaphylococcal penicillin

-

Rarely the drug of choice for any Infection

2.

ADR

-

Anaphylactic reaction (most serious and may happen even in therapeutic doses)

-

Seizures (overdose) Rashes, pruritus, urticaria in oral form

-

Hypotenslon, severe shock, circulatory collapse, death in IM form

Clinical Uses of Pen Resistant to Staph β-lactamase:

-

The sole indication is infection by beta-lactamase producing staphylococci (Methicillin, Nafcillin)

-

For mild, local Infections: lsoxazoyl (Oxacillin) - 15-25 mg/kg/d For serious systemic staph infection: Oxacillin or Nafclllin 8-12 g/d (50-100 mg/kg/d)

-

•

Aminopenicillins (Amoxicillins), Carboxypenicillins (Ticarcillin), Ureidopenicillins (Piperacillin)

Cephalosporins

Clinical Uses of Penicillins:

-

•

-

Clinical Uses of Extended Spectrum Penicillins:

3.

Second Generation Cephalosporins

-

Cefaclor, Cefamandole, Cefonicid, Cefuroxime, Cefprozil, Loracarbef, Ceforanide, Cephamycins (Cefoxitin, Cefmetazole, Cefotetan)

-

Extended gram-negative coverage

-

Tx of sinusitis, otitis or lower RTI

Dose: (oral) 10-15 mg/kg/d BID versus beta.-lactamase Bhanhamella catarrhalis

producing

H.

Influenza

or

Cefuroxlme: for community-acquired pneumonia; the only second-generation drug that crosses blood-brain barrier, but less effective in treatment of meningitis, than Ceftriaxone and Cefotaxime

Third Generation Cephalosporlns

-

Cefoperazone, Cefotaxime, Ceftazidime (IV for meningitis), Ceftizoxime, Ceftriaxone (DOC: typhoid fever), Cefixime (oral), Cefpodoxime proxetil, Ceftibuten, Moxalactam

Basic Pharmacology – Antimicrobials 1 by Dr Dando

4.

Page 3 of 6

-

Expanded gram-negative Cefoperazone)

-

Some can cross blood brain barrier (Ceftriaxone and Cefotaxlme)

-

Active versus Citrobacter, Serratia & Providencia

-

Cefixime, Ceftibuten, Cefpodoxine proxetil: are oral agents with similar activity except that Cefixime and Ceftibuten are much less active against Pneumococci and have poor activity against S. aureus

coverage

(except

for

2.

Ceftazidime & Cefoperazone: vs P. aeroginosa

Beta-Lactamase InhIbItors Clavulanic acid, Sulbactam, Tazobactam

-

Treatment of mixed aerobic and anaerobic infections (lntra-abdominal infections)

-

are used in fixed combinations with certain hydrolyzable penicillins

Ceftizoxime & Moxalactam: vs B. fragilis 3.

Cefixime & Ceftriaxone: 1st line drug for tx of N. gonorrhea

-

Ceftibuten (Cedax): newest oral cephalosporin with sImilar spectrum to Cefixime and Cefpodoxime; oncedaily

-

Ceftriaxone and Cefotaxime most active vs. penicillinresistant strains of Pneumococci and are recommended for empirical therapy of serious infections caused by these strains

Carbapenems

-

-

•

Oral Cephalosporins

-

1.

Monobactam Aztreonam vs gram-negative rods

-

resistant to beta-lactamases produced by certain gramnegative rods (Klebsiella, Pseudomonas, Serratia)

-

AE: GI upset with possible superinfection, vertigo, headache, rare hepatotoxicity

-

Although skin rash may occur, there is no crossallergenicity with penicillin

AE of Imipenem-cilastatin: GI distress, skin rash,

Meropenem is similar to imipenem except that it is not metabolized by renal dehydropeptidases and is less likely to cause seizures

D.

Ertapenem has a long half-life but it is less active against Pseudomonas, and its IM injection causes pain and irritation. Other Inhibitors of Cell Wall Synthesis 1.

Vancomycin For staphylococcal infection

-

Other Beta-Lactams

Imipenem is rapidly inactivated by renal dehydropeptldase I and Is administered in fixed combination with cilastatin, an inhibitor of this enzyme. Cilastatin increases the plasma half-life of imipenem and inhibits the formation of a potentially nephrotoxic metabolite

-

-

C.

Chemically different from penicillins but retaining the beta-lactam ring structure with low susceptibility to betalactamase Wide activity against gram-positive cocci, gram-negative rods, and anaerobes

and at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). There is a partial cross-allergenicity with penicillin

• -

Choice for treatment of infection caused by enterobacter

o

Fourth Generation Cephalosporins Cepefime More resistant to hydrolysis by beta-lactamase Active versus P. aeroginosa, Enterobacter, S. aureus, and S. pneumoniae Half life: 2 hours Adverse Effects Allergy Toxicity – Renal, Hypoprothrombinemia,, severe disulfiram-like reactions Superinfection

Imipenem, Meropenem, Ertapenem

2.

-

oral form used in tx of enterocolitis due to C. difficile

-

w/ gentarnlcln: as alternative regimen for treatment of enterococcal endocarditis in patient with serious penicillin allergy

-

Adverse Reaction: chills, fever, phlebitis, ototoxicity, and nephrotoxitity; Rapid IV infusion may cause “Red man” or “red neck” syndrome (diffuse flushings)

glycopeptide with similar MOA and antibacterial spectrum as vancomycin

Daptomycin Cyclic lipopeptide

4.

parenteral form indicated for sepsis, or endocarditis due to MRSA

Telcoplanin

3.

Inhibits cell wall synthesis by binding firmly to the D-AlaD-Ma terminus of nascent peptidoglycan pentapeptide Poorly absorbed In GI

Spectrum of activity similar to vancomycin but is active against vancomycin resistant strains of S. aureus

Fosfomycin stable salt of phosphonomycin

Basic Pharmacology – Antimicrobials 1 by Dr Dando

5.

-

antimetaboiite transferase

-

tx of uncomplicated UTI

-

interferes with dephosphorylation in cycling of the lipid carrier and transfer of peptidoglycan subunits no cross-resistance

-

limited to topical use because of its marked nephrotoxicity (proteinuria, hematuria. nitrogen retention)

Cycloserine water-soluble, unstable at acid pH

•

Broad spectrum bacteriostatic

•

Inhibits protein synthesis - bind reversibly to 30S

• • • •

Chelate divalent metal Ions

•

-

antimetabohte that blocks the incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan

•

-

potentially neurotoxic (tremors, seizures. psychosis)

Chloramphenicols Soluble in alcohol, neutral, stable

 

Completely and rapidly absorbed orally Used for eye infections

Mycoplasma

GI disturbances—from mild nausea and diarrhea to severe, possibly life-threatening colitis

-

Bony structures end teeth—tooth enamel dysplasia and irregular bone growth after to fetal exposure; tx of younger children may cause enamel dysplasia and crown deformation when permanent teeth appear Liver toxicity Kidney toxicity

-

Local tissue toxicity Photosensitization Vestibular reactions—dose dependent dizziness and vertigo with doxycycline and minocycline

Macrolides Binds to 50s subunit of the ribosome Erythromycln

-

Adverse Reactions:

-

Interaction with other drugs: Inhibits hepatic microsomal CYP450 enzymes

Bone marrow disturbances: aplastic anemia

-

Toxicity with newborn infants: Gray baby syndrome (lack of effective glucoronic acid conjugation)

-

Tetracyclines

Rickettsiae,

-

1.

GI disturbances

Chlamydiae,

Adverse reactions:

-

Dose: 50-100 mg/kg/d

-

pneumoniae,

Avoid In pregnant women and children below 8 years old, to avoid

-

•

•

Doxycycline — once daily

DOC

-

Potent inhibitor of microbial protein synthesis - bind to 50S subunit inhibit peptidyl transferase Bacteriostatic, broad-spectrum

Choice for patient with renal insufficiency:

deposition In growing bones and teeth

Inactivation by B lactamase Modification of target PBPs Impaired penetration of drug to target PBPs Presence of an efflux pump

 

Cross the placenta and excreted in milk

Spirochetes. Helicobacter pylori

•

Resistance:

40-80% protein bound

-

almost exclusively used to treat tuberculosis resistant to first-line agents

-



enolpyruvate

useful for suppression of mixed bacterial flora in surface lesions

-



cytosolic

-

-

•

of

Bacltracin cyclic peptide

-

6.

inhibitor

Page 4 of 6

Poorly soluble in water Unstable at acid pH Versus gram-positive organisms Inhibitory or bactericidal Inhibit protein synthesis via binding to 50S rRNA Destroyed by stomach acid (needs enteric coating) DOC: corynebactedal infection, respiratory, neonatal, ocular/genital chlamydial infection, community-acquired pneumonia, alternative for penicillin-allergic individuals

2.

Prophylaxis against endocarditis procedures with valvular heart disease Clarithromycin

-

during

Derived from erythromycih by methyl group addition Identical antibacterial activity with erythromycin More active against Mycobacterium avium complex 250-500 mg BID Longer half-life: 6 hours

dental

Basic Pharmacology – Antimicrobials 1 by Dr Dando

3.

4.

Laser frequency of GI intolerance Less frequent dosing

Azithromycin

-

15-atom lactone ring derived from erythromycin by addition of methylated nitrogen

-

Highly active against chlamydia Once-daily dosing and short duration of tx (3 days) Given 1 hour before or after meals Does not Inactivate cytochrome P450 enzymes

Ketolides Telithromycin Semisynthetic 14-membered ring macrolide Oral bioavailability: 57%

•

Bactericidal antibiotics obtained from Streptomyces sp

-

•

Water-soluble, stable, more active at alkali pH

•

Irreversible inhibitors of protein synthesis — binds to specific 30S

Once daily dose of 800 mg Clindamycin

•

Chlorine-substituted lincomycin

•

VS strep, staph, pneumococd

• •

Inhibits protein synthesis by binding on the 50S subunit

10-20 mg/kg/d (0.15-0.3g every 8 hrs) Newer Agents

A.

Streptogramins Quinupristin-daltopristin

B.

•

Absorbed poorly in GI tract

•

Ototoxic and nephrotoxic

•

ADR: ototoxicity and nephrotoxicity; In high doses: curare-like effect with neuromuscular blockade

•

versus gram-negative enteric bacteria especially in bacteremia and

•

sepsis (in neonates), in combination with vancomycin or with penicillin for endocarditis, and for TB treatment No oral preparation

• •

Streptomycln - oldest aminoglycoside

•

Mechanism of Action:

Gentamycin, Tobramycin, Amikacin—only differ In side chain

Bactericidal except Entrococcus faecium lV 7.5 mg/kg every 8-12hrs AE pain at infusion site, athrelgla-myalgia syndrome

Oxazoladinones LinezoIid

-

•

subunit ribosomal proteins

For prophylaxis of endocarditis with valvular heart disease undergoing dental procedures

•

Aminoglycosides

For severe anaerobic infection due to bacteroides & other anaerobes

•

Page 5 of 6

Bacteriostatic except for strep Inhibits protein synthesis by binding on 23S ribosomal RNA of the 5OS subunit High oral bioavailability – 100% Half-life: 4-6 hours

For vancomycin-resistant E. faecium Toxicity: thrombocytopenia and neutropenia Mechanism of Action 1.

2.

Streptomycin

-

Second line agent for tuberculosis tx

-

If given during pregnancy may cause deafness in newborn

With penicillin: for enterococcal endocarditis With tetracycline: tularemia, plague, brucellosis Most serious toxic effect: vestibular disturbance — vertigo arid loss of balance

Gentamicin

Basic Pharmacology – Antimicrobials 1 by Dr Dando

3.

Siguro naman this time papasa na kau ng pharma =p

No activity against anaerobes

Brim, print mo 2, may kulang sa old trans

For severe infections (sepsis and pneumonia) 5-6 mg4cgd

More active against pseudomonas

4.

Amikacin For resistant organisms 500mg BID IV

5.

Netilmicin 5-7 mg/kg/d

6.

Kanamycin & Neomycin

-

7.

•

vs gram-positive and gram-negative

Tobramycin

-

Page 6 of 6

Bowel preparation for elective surgery For topical and oral use only

Spectinomycin

-

Alternative treatment for gonorrhea for peniciilin-aIIergic patients

-

2 g IM (40 mg/kg)

Mechanisms of Resistance: -

Alteration of target Modification to insensitivity to Inhibitor Reduction in physiologic Importance of target Synthesis of new target enzyme that duplicates function of inhibited target

-

Prevention of access to target Efflux of more drug than enters cell Failure of modified drug to enter cell

-

Inactivation of scent Destruction of the agent Modification of the agent so It fails to bind target

-

Failure to convert an inactive precursor agent to its active form

Quiz (2C): 1. MOA of penicillin: inhibit cell wall synthesis 2. MOA of chloramphenicol: inhibit protein synthesis by 50s 3. MOA of aminoglycoside: inhibit protein synthesis by 30s 4. ADR of aminoglycoside: ototoxicity 5. ADR of aminoglycoside: nephrotoxicity 6. Inflamed meninges: ceftriazone, penicillin 7. DOC for typhoid: chlroramphenicol 8. Most impt mode of inactivation: beta lactamases 9. ADR of vancomycin: red man 10. Prophylaxis for RHD with valvular churva: clinda/erythromycin

Haay, full effort tong trans na to….