Antibiotics and Antifungal Agents Lecture Flashcards
Classification by MOA
Inhibitors of cell wall synthesis
Protein synthesis inhibitors
Inhibitors of nucleic acid function or synthesis
Inhibitors of cell membrane permeability/function
Factors affecting drug choice and drug activity
ID and drug sensitivity of the organism Status of host defenses/immune function Bacteriocidal vs bacteriostatic MOA Antimicrobial resistance Site of infection Absorption, Distribution and pharmacokinetics issues Metabolism and elimination pathways Pharmacogenetics of the host Drug interactions Pregnancy or nursing infants
ID and drug sensitivity of the organism
Best educated guess, based on history and clinical exams
Empiric therapy
Decision based on population parameters and statistics
Definitive therapy
Decision based on ID and lab study of specific organisms in the patients
Status of host defenses/immune function
Good host immune system function is critical in synergy with the antibiotic agent for successful therapy
Bacteriocidal vs bacteriostatic MOA
Some antibiotics kill the bug, some only inhibit its active growth
Antimicrobial resistance
Creates a selective survival advantage for certain individual organisms present
Resistance may be aquired or intrinisic
Transfer can be vertically or horizontally
May develop rapidly
Site of infection
Reduced drug deliviery relative to plasma
Local factors: pH, low oxygen levels
Foreign Bodies: catheters, artificial joints
Absorption, distribution and pharmacokinetics issues
Desire prompts delivery
Reach peak plasma concentration 1-2 hours after PO administration
Metabolism and elimination pathways
May accumulate to toxic levels if elimination pathways are compromised
- Renal disease: lower excretion
- Hepatic disease: lower metabolism
Pharmacogenetics of the host
Population differences in metabolism are due to genetic variation
Pregnancy and nursing infants
Potential for toxic or teratogenic effects of fetus
Alter normal flora of newborns or create allergies
Six P’s of Resistance
Penetration Porins Pumps PBP's Penicillinase Pathway/Process
Penetration
Cannot pass into human cells, then it cannot cause a reaction and get rid of the infection
- Atypical organisms move into the cell and live there
Porins
Channels
Drugs must make its way through these in order to get rid of the infections
Pumps
Efflux pumps
Push a drug into the bug and is pumped straight back out –> Never achieves effect concentration (MIC)
PBP’s
Altered receptors –> Less effective
Penicillinase
Can be upregulated so it will chew up the penicillin
- Microorganism is making an enzyme that is rendering the drug in effective (chew it up)
- Enhanced inactivation of drug
Pathway/Process
Get around the affect of the organisms, it diverts to another pathway to accomplish the same thing
Complications of treatment?
Development or emergence of resistance
Therapy fails from outset (not sensitive to the drug)
Drug interactions/antagonism or PK (patient genetics)
Hypersensitivity
Direct toxicity to the host
Superinfections (overgrowth)
What is superinfection?
Appearance of a new infection by different organisms
Dangerous bc organisms is difficult to eradicate
Caused by a removal of inhibition by normal flora
Frequent with prolonged antibiotic use
Tetracycline, Minocycline, Doxycycline, Gentamycin, Neomycin
30S Inhibition
Macrolides: Erythromycin, Clarithromycin, Chloramphenicol
50S Inhibition
Clindamycin
More active than tetracyclines –> 50S inhibition
Amplicillin, Amoxacillin
Cell wall inhibition
Quinolones (ciprofloxacin)
Inhibition of topoisomerases to interrupt DNA functions
Cephalosporins (cephalexin), Bacitracin
Cell wall inhibition
Sulfamethoxazole/Trimethoprim (Bactrim)
Antifolate
Metronidazole
Reactive intermediate that damages DNA/enzymes
Metronidazole
Produces reactive intermediate that damage DNA and other sensitive molecules
Mupirocin
Binds and inhibits tRNA-synthetase for leucine
Polymixin B
Cationic detergent; interacts as surfactant with negatively charged membrane phospholipids
Povidone-Iodine
Topical antiseptic/antibacterial
Mafenide
Acts on G- and G+ bacteria
Silver Sulfadiazine
Active against bacteria and fungi (burns)
Fungi
Eukaryotes
Rigid cell walls
Contain ergosterol instead of cholesterol
Derm conditions with fungal infections
Common members of normal flora
Growth is normally well-constrained
Overgrowth normally only occurs if immune is compromised
- Antibacterial agents do not work against fungi
Antifungal Agents
Topical: azoles, naftifine, ciclopirox, and the polyene agents amphotericin B and nystatin
Oral: Used for drugs to reach site of infection
Griseofulvin
Act on microtuble system to disrupt mitosis in certain fungal cells
Not used systemically, common dosing issues, questioning efficacy, + adverse effects and drug interactions
Terbinafine
PO but 40% loss due to first-pass
Accumulates in skin, nails and fat
Topically too
Inhibits conversion of squalene to alnosterol by squalene epoxidase –> squalene accumulates and ergosterol is decreased
- Rifampin decreases and Cimetidine increases plasma concentration of terbinafine
- ADR with antidepressants, hepatoxicity can occur
Azoles- Imidazoles and Triazoles
Im: 2 N in 5 membered azole ring - used in OTC/Topical situations
Tri: 3 N in a 5 membered azole ring - used in more serious situations
Azole MOA
Block fungal P450 dependent synthesis of ergosterol
Disrupts cell membranes –> decrease in ATPase and electron transport enzymes
Inhibits gonadal and adrenal steroids synthesis –> decreases T and cortisol formations
Tri: less effect on human P450 dependent steroid synthetic pathways
Itraconazole
Potent 3A4 inhibitor
Fluconazole
Inhibits 3A4 and 2C9 –> raises plasma levels of cyclosporine, phenytoin, tacrolimus, theophylline, warfarin
Voriconazole
Inhibits 2C19, 2C9, 3A4
Posaconazole
No CYP inhibition
Azole ADR
Hepatotoxicity is rare but lead to hepatic failure and deaht
GI distress with nausea, vomiting & diarrhea
Skin irritation, rash, alopecia seen
QT prolongation (except posa)
Visual distrubances and hallucinations (Vor)
NOT IN PREGNANT WOMEN
