Details of Penicillins:

Structure?

SOA?

Chemical Stability?

Beta-Lactamase Stability?

Plasma protein binding?

MOA?

Resistance?

- All active drugs must have intact beta-lacam ring to be effective

- Penicillins differ on their R group.  R group is claved by Amidase

- Postive/Negative/Broad spectrum determined by charge.  Charged Penicillins will be broad spectrum so they can penetrate porins.

- Electron withdrawing groups increases stability in acid (GI absorption)

- Aromatic ring with ortho sub. gives increased resistance to beta lactamase.

- The more hydrophobic the R group, the more it will bind to plasma proteins.  Only free drug has effect.

- Binds to PBP as a suicide inhibitor, prevents cross-linking of wall, and activates autolysins at wrong time, leads to lysis of cell. 

- Genes and plasmid acquisition can lead to Beta lactamase resistance.  Altered PBP can lead to resistance 

Details of Natural Penicillins:

Structure?

MOA?

SOA?

PK?

Adverse Rxns?

Benzylpenicillin (Penn G)

- Unstable in acid

- Poor BA

- Given IV

- Gram Positive, broken down by Beta-Lactamase

- Penetrates BBB and can treat Meningitis

Phenoxymethylpenicillin (Penn V)

- Stable in acid

- Given orally

- Gram Positive activity, broken down by B-L

- Good for syphillis, pneumococcal + streptococcal infections, and other gram (+)

Details of Beta-Lactamse Resistant Penicillins: Nafcillin and Methicillin

MOA?

SOA?

Targets?

Methicillin

- Causes kidney toxicity and nephritis so not used much anymore

- MRSA are gram (+) that secrete B-L that can resist this molecule

- Must be given IV

- Main target is Staph Aureus

Nafcillin

- Organisms also becoming resistant to this

- Have to revert to Vancomycin

- Not useful in treatment of gram (-)

- Must be given IV

- Main target is Staph Aureus

- Resistant to B-L cleavage (orth-substituted aromatic ring)

- Semisynthetic derivates

- Orally effective

- Primarily for gram (+) including Staph Aureus

Examples of Broad Spectrum Penicillins?

Amoxicillin, Ampicillin, Carbenicillin, Ticarcillin, Mezlocillin, Azlocillin, Piperacillin

- Both orally effective

- Useful against wide variety of gram (+) and (-)

- Food doesn't change absorption of Amoxicillin

- Good for ear aches, upper resp. tract infections, etc.

Carbenicillin

- By itself is used very much

- Ester derivative carbenicillin indanyl useful orally

- Susceptible to B-L activity

- Broad spectrum not good against Staph

Ticarcillin

- Given IV because not well absorbed

- Works well against gram (-) pseudonomas infections

- Susceptible to B-L activity

- All must be given IV

- Active against gram (-) pseudonomas infections

- Tend to be good against gram (-) infections from hospitals

- Good for gram (-) Pneumonia, UTI

- Susceptible to B-L digestion

- Few are orally effective

- Food decreases absorption, Amox. is exception

- Non emergency situations

- Parenteral is IV because IM is too painful

- Plasma binding varies dramatically, PennG being the least, Cloxacillin being the most

- Therapeutic [ ] achieved in most tissues

- Can't penetrate macrophage, sub therapeutic [ ] in intraocular fluid

- Probenicid inhibits secretion

- In kidneys, 10% filtrate and 90% secreted

- Naficillin is biliary excretion

- Oxacillin, Dicloxacillin, Cloxacillin are combo of billiary sec. and kidney clearance.

- Considered safe, biggest problem is allergies

- High dose with renal failure leads to seizures

- High dose will irritate GI (nausea and vomit)

- Superinfection risk for broad spectrum oral admin.

- Anaphylactic shock

- Angioedema

- Skin Rashes

- Might see elevated body temp

- Itching

- Hapten, although inactive, acts as Hapten .  IgE mediates the rxn, and incidence is lower than it should be because people think they have allergy, when they don't.  Immediate response within 30 min. or 24 hours is treated with epinephrine/glucocorticoid.  Also a rxn when treatment is finished, not serious.  Sometimes rxn is one-time only (if mild).

 General Details of Cephalosporins:

Structure?

MOA?

Resistance?

- Like Penicillins, also contain a beta-lactram ring

- Also has a dihydrothiazide ring attached to it, makes B-L ring less sensitive to breakdown or degradation

- Inhibits transpeptidation, activates autolysins, does this by binding to PBP (aka CBP).

- Poor penetration of bacteria by the drug

- Alterations in the CBP/PBP

- Degradation by B-L is most important resistance

- Modification of R1 side chain modifies SOA, R2 modifies PK properties, electron wihdrawing increases acid stability.

What are some examples of First Generation Cephalosporins?

- Cefazolin often used for surgical prophylaxis

- Cephalexin, Cefadroxil, Cephadine orally effective

- Others are IV only

- Effective vs. gram (+), except for high B-L activity like MRSA

- Excreted by kidneys through filtration + secretion

- Reach high enough kidney [ ] for UTI use

- NOT useful for CNS infections

- Used similar to Amoxicillin for Respiratory, urinary, and skin infections

What are examples of Second Generation Cephalosporins?

- Less active than first generation against gram (+)

- More active than first generation against gram (-)

- Not useful against Staph Aureus that produce high B-L

- Cefuroxime is only one to penetrate CNS (Meningitis treatment)

- Excreted via the kidneys

- Expanded gram (-) coverage, more so than 2nd gen.

- All can penetrate CNS, except Cefoperazone

- Associated with potential for superinfection

- Ceftazidime/Cefoperazone are good against pseudonomas infections

- Cefoperazone is excreted by bile, all others by kidneys. 

- Good CNS penetration

- Extended SOA against gram positive and gram negative

- 100% excreted by the kidneys, dose adjust for renal failure

- More resistant to B-L activity

- Given IV

- Cefamandole, Cefotetan, Cefoperazone; the R2 ring connected to six-membered methothiotetrazole, causes interaction with disulfram resulting in vomiting, and inhibits clotting by interfering with Vitamin K. 

- Same allergies as Penicillin. 

- Alternative if rxn, is had with Penicllin, but not if rxn was serious. 

- Possibility of having reaction with both is 10%

- Nephrotoxicity in those with problems + on aminoglycosides

- Superinfection in 2nd and 3rd generation associated with GI tract problems

Imipenem

*Structurally related to Beta-Lactam antibiotics

Details of Carbapenems: Imipenem

- Mechanism is the same as Penicillins and Cephalosporins (anti cross-linking and activation of autolysins)

- Stable in B-L's

- Given with Cilastrin to inhibt the enzyme that breaks it down, dehydropeptidase I (kidney tubules)

- Not absorbed orally, so given IM or IV

- One of the broadest SOA's

- Excreted primarily by kidneys

- Able tp penetrate all fluids + CNS

- Adverse effects include GI problems, seizures at high [ ], cross-sensitization to penicillin and cephalosporin

- Meropemem is not susceptible to dehydropeptidase I

- Lacks a second ring structure (hence name)

- Has beta lactram ring

- Good activity vs. gram (-)

- NOT good against gram (+) or anaerobic organisms

- Little cross-sensitization with penicillin or cephalosporin

- Not absorbed orally, given IM or IV

- Excreted by the kidneys

Clavulanic Acid, Sulbactam, Tazobactam

* Structure resembles Beta-Lactam molecules

- Suicide inhibitors

- Bind to serine

- Clavulanic acid given with ABX to inhibit breakdown

- Given orally with oral agents (Clav. Acid + Amoxicillin)

- Used against Staph. Aureus (gram positive)

- Used to treat routine infection (Ear ache, sinusitis, respiratory tract infections, UTI)

Vancomycin 

- Isolated from streptococcus

- Glycopeptide

- Inhibitor of cell wall synthesis

- Binds to D-Ala-D-Ala portion of side chains and inhibits transpeptidase

- NOT suicide inhibitor

- Slower effects than Penicillin

- Effective vs. Gram (+) organisms

- Reserved for serious infections (endocarditis, sepsis, MRSA)

- Not absorbed well, given IV

- Slow infusion over 30-60 min.

- Does penetrate CNS and bile

- Given ORALLY to treat Pseudomembranous colitis because we don't want it to attack clostridium.

- Adverse effects include Redman syndrome, tachycardia, hypotension.

- 90% cleared by glomerular filtration

Bacitracin

- Bacteprenol is a carrier of phosphates that are needed for cell wall synthesis.  

- Bacteprenol must be dephosphorylated before it can come back through to the inside of the cytoplasm; Bacitracin inhibits this.

- Nephrotoxic

- Topical use only

- No beta-lactam ring

- Give in combination of bacitracin-neomycin-polymycin