Action of Penicillin

bind to PBPs, inactivates:

• transpeptidase for cell wall synthesis

• inhibitors of autolytic enzymes so cell lysis and die

Methicillin is highly resistant to beta-lactamase

if the bug is meticillin resistant, then another cause the resistance.

Fight Resistance

1, Clavulanic Acid

bind to Beta lactamase and inactivate it.

2,Beta-lactam Analogs

(not recognized by B-lactamase)

eg: Cephalosporin, monobactam, carbapenem

Cephalosporins:

Resistant to B-lactamase. 3 generations

1st generation like penicillin mostly for gram +

3rd generation works mostly for gram -, highly penetrant into CSF, good for meningitis.

Cephalosporins Resistance

inability to reach site of action due to mutation

Alteration in PBPs

Vancomycin, last resort agent

large ampiphilic molecule.

cell wall inhibitor like penicillin, but diff mechanism

B-lactamase resistant due to lack of B-lactam ring,

works by binding covalently to glycopeptide polymer to disrupt cell wall.

Vancomycin Resistance

conversion from D-alanine to D-lactate by evolution

thus vancomycin can't

Absorption of Vancomycin

poor absorption after oral. IV

Antimicrobial activity of Vancomycin:

against gram +

synergism with aminoglycoside against S. aureus and Enterococcus

Metabolic Inhibitors in Synergistic Combination

1, Sulfonamides block first step, inhibit production of DHFA from PABA, it's bac-specific coz we don't use PABA to make DHFA, we eat folic acid instead.

2, Trimethoprim

inhibits DHFR enzyme which reduce DHFR to make Tetrahydrofolic acid (critical for thymidine production)

Trimethoprim has high affinity to bacterial DHFR

Sulfonamide

rarely used as single agent

treat UTI as single agent

topical ophthalmic ointment or solution

topical ointment for burn

Adverse RXN of Sulfonamides

cross-allergenic with thiazide

precipitate in urin

hemolytic/aplastic anemia

hemolytic rxn in G6PD deficient patient

Resistance to Trimethoprim

reduced permeability

amplification of DHFR, bac makes more DHFR enzyme

mutations reducing DHFR binding

Co-trimoxazole (combination of trimethoprin and sulfamethoxazole)

Reduced toxicity & resistance

lower dose to reach MIC when combined

Anti-fungal Targets

cell walls

cell membrane

enzyme in cell membrane produce ergosterol that is fungal specific.

nucleic acid synthesis

Amphotericin

target yeast specific membrane steroid ergostrol

Pharmacokinetics of Amphotericin

poor absorption from GI

90% bound by serum proteins

Slow excretion in urine

lipophilic nature, widely ditributed in tissues

2-3% in CNS, not good for meningitis

Resistance to Amphotericin

occurs when..

1, reduced ergosterol

or

2, modified ergosterol, reduced affinity

Adverse Effect of Amphotericin

Immediate toxicity: fever, chills, muscle spasm, vom, H/A, HTN

Slower toxicity: renal damage, abnormality of liver fxn

CNS effect such as seizures

Clinical use of Amphotericin

induction therapy follow by Azole as maintenance

life threatening mycotic infection

topical administration due to poor absorption

Azole

broad spectrum antifungal agents

eg: Fluconazole: high oral bioavailability

Prophylaxix in AID & immunocompromised ppl

good for cryptococcal meningitis

Flucytosine

inhibits thymidylate synthetase

methylation of dUMP to dTMP for thymidine

Flucytosine

pro-drug : cytosine deaminase (fungal specific)  convert flucytosine to 5-FU (anti-cancer drug)

↓

5-FU → 5-FUMP→5-FdUMP

5-FdUMP is the active drug that inhibit thymidylate synthetase. Works like trimethoprim for antibac.

Resistanct to Flucytosine

altered metabolism of flucytosine

occur when used alone.

Adverse Effect

bacteria in GI die, toxic to human cell

bone marrow toxicity

derangement of liver fxn

narrow therapeutic window

Clinical Use of Flucytosine

not used as single agent due to fast resistance

in combination with amphotericin B or itraconazole.

Azoles inhibit sterol 14-a-demethylase which is an enzyme that makes ergosterol

broad spectrum

prophylaxis in AIDS and transplant pt

Clotrimazole: for superficial fungal infection

Nystatin: more toxic, topical use only