Anti Microbials

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

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.

A. Penicillins

• All peniclllins are derivatives of 6-emmopenicillanlc acid and contain a beta-lactam ring structure that is essential for antibacterial activity

•

Classification :

1.

Penicillins (e.g. PenicilIin G)

-

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

2.

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

-

versus staphytococci and streptococci

3.

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

-

versus gram-negative organisms

-

drugs that retain the antibacterial spectrum of penicillin and have improved activity against gram-negative organIsms, but they are destroyed by beta-lactamases (penicllinases)

• Limitations:

- instability at acidic pH

- Susceptibility to destruction by bela-lactamase - Relative inactivity against gram-negative bacilli

• Units

-

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 (penicillin-

binding 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

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

• 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)

-

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

•

Clinical Uses of Penicillins :

-

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

• 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)

•

Clinical Uses of Extended Spectrum Penicillins:

-

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

-

Greater activity against gram-negative bacteria

-

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

-

Ampicillin is effective for shigellosis but not for salmonellosis

-

For Pseudomonas: Carboxypenicillins + Aminoglycosides

-

Beta-lactamase Inhibitors (Clavulanic Acid, Sulbactam,

Tazobactam): versus beta-lactamase producing strains of Staph aureus

B. Cephalosporins

•

Are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure

• Soluble In water

•

Stable to pH and temperature changes unlike Penicillins

•

Not active against enterococci and L. monocytoqenes

1.

First Generation Cephalosporins

-

Cefadroxil, Cefazolin (IV), Cephalexin (oral), Cephalotin, Cephapirin, Cephradine

- Greater activity for gram-negative microorganisms - Tubular secretory blocking agents (probenecid) may

increase serum levels

-

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. Second Generation Cephalosporins

-

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

-

Extended gram-negative coverage

-

Dose: (oral) 10-15 mg/kg/d BID

-

versus beta.-lactamase producing H. Influenza or Bhanhamella catarrhalis

-

Tx of sinusitis, otitis or lower RTI

-

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

3.

Third Generation Cephalosporlns

-

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

-

Expanded gram-negative coverage (except for Cefoperazone)

-

Some can cross blood brain barrier (Ceftriaxone and Cefotaxlme)

-

Active versus Citrobacter, Serratia & Providencia

-

Ceftazidime & Cefoperazone: vs P. aeroginosa

-

Ceftizoxime & Moxalactam: vs B. fragilis

-

Cefixime & Ceftriaxone: 1st _{line drug for tx of N.}

gonorrhea

-

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

-

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

-

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

4. 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

• Oral Cephalosporins

C.

Other Beta-Lactams

1. Monobactam

Aztreonam vs gram-negative rods

-

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

-

AE: GI upset with possible superinfection, vertigo,

headache, rare hepatotoxicity

-

Although skin rash may occur, there is no cross-allergenicity with penicillin

2. 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

3. Carbapenems

-

Imipenem, Meropenem, Ertapenem

-

Choice for treatment of infection caused by enterobacter

-

Chemically different from penicillins but retaining the

lactam ring structure with low susceptibility to beta-lactamase

- Wide activity against gram-positive cocci, gram-negative rods, and anaerobes

-

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

o

AE of Imipenem-cilastatin: GI distress, skin rash, and at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). There is a partial cross-allergenicity with penicillin

-

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

-

Ertapenem has a long half-life but it is less active against Pseudomonas, and its IM injection causes pain and irritation.

D. Other Inhibitors of Cell Wall Synthesis

1. Vancomycin

- For staphylococcal infection

-

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

-

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

-

parenteral form indicated for sepsis, or endocarditis due

to MRSA

-

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)

2. Telcoplanin

-

glycopeptide with similar MOA and antibacterial spectrum as vancomycin

3. Daptomycin

- Cyclic lipopeptide

-

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

4. Fosfomycin

-

antimetaboiite inhibitor of cytosolic enolpyruvate transferase

-

tx of uncomplicated UTI

5. Bacltracin

- cyclic peptide

-

interferes with dephosphorylation in cycling of the lipid carrier and transfer of peptidoglycan subunits

- no cross-resistance

-

useful for suppression of mixed bacterial flora in surface lesions

-

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

6. Cycloserine

- water-soluble, unstable at acid pH

-

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

-

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

-

potentially neurotoxic (tremors, seizures. psychosis)

•

Resistance :

-

Inactivation by B lactamase - Modification of target PBPs

- Impaired penetration of drug to target PBPs - Presence of an efflux pump

Chloramphenicols

 Soluble in alcohol, neutral, stable



Potent inhibitor of microbial protein synthesis - bind to 50S subunit - inhibit peptidyl transferase



Bacteriostatic, broad-spectrum



Dose: 50-100 mg/kg/d

 Completely and rapidly absorbed orally  Used for eye infections

• Adverse Reactions:

-

GI disturbances

-

Bone marrow disturbances: aplastic anemia

-

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

-

Interaction with other drugs: Inhibits hepatic microsomal CYP450 enzymes

Tetracyclines

•

Broad spectrum bacteriostatic

• Inhibits protein synthesis - bind reversibly to 30S

•

Chelate divalent metal Ions

•

40-80% protein bound

•

Cross the placenta and excreted in milk

•

Choice for patient with renal insufficiency:

-

Doxycycline — once daily

•

DOC Mycoplasma pneumoniae, Chlamydiae, Rickettsiae, Spirochetes. Helicobacter pylori

•

Avoid In pregnant women and children below 8 years old, to avoid deposition In growing bones and teeth

•

Adverse reactions :

-

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

1. Erythromycln

-

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

-

Prophylaxis against endocarditis during dental

procedures with valvular heart disease

2. Clarithromycin

-

Derived from erythromycih by methyl group addition

-

Identical antibacterial activity with erythromycin

-

More active against Mycobacterium avium complex

-

250-500 mg BID

-

Laser frequency of GI intolerance

-

Less frequent dosing

3. 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

4. Ketolides

Telithromycin

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

-

Once daily dose of 800 mg

Clindamycin

•

Chlorine-substituted lincomycin

• VS strep, staph, pneumococd

•

Inhibits protein synthesis by binding on the 50S subunit

•

For severe anaerobic infection due to bacteroides & other anaerobes

•

For prophylaxis of endocarditis with valvular heart disease undergoing dental procedures

•

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

Newer Agents A. Streptogramins

Quinupristin-daltopristin

-

Bactericidal except Entrococcus faecium

-

lV 7.5 mg/kg every 8-12hrs

- AE pain at infusion site, athrelgla-myalgia syndrome

B. Oxazoladinones

LinezoIid

-

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

Aminoglycosides

•

Bactericidal antibiotics obtained from Streptomyces sp

• Water-soluble, stable, more active at alkali pH

•

Irreversible inhibitors of protein synthesis — binds to specific 30S subunit ribosomal proteins

•

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

•

Gentamycin, Tobramycin, Amikacin—only differ In side chain

• Mechanism of Action:

1. Streptomycin

-

Second line agent for tuberculosis tx

-

With penicillin: for enterococcal endocarditis

-

With tetracycline: tularemia, plague, brucellosis

-

Most serious toxic effect: vestibular disturbance — vertigo arid loss of balance

-

If given during pregnancy may cause deafness in newborn

-

vs gram-positive and gram-negative

-

No activity against anaerobes

-

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

3. Tobramycin

-

More active against pseudomonas

4. Amikacin

- For resistant organisms - 500mg BID IV

5. Netilmicin

- 5-7 mg/kg/d

6. Kanamycin & Neomycin

-

Bowel preparation for elective surgery

-

For topical and oral use only

7.

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….

Siguro naman this time papasa na kau ng pharma =p Brim, print mo 2, may kulang sa old trans