EXAM TWO COVERAGE Flashcards
Macrolides
Extended G+ Spectrum
MOA: Bind to MLSb site on subunit 50S, inhibit protein synthesis
AE: GI intolerance and QT Prolongation
Resistance Mechanism: Mutation in MLS and Efflux Pumps
Erythromycin
Macrolide
Extended G+
PO or IV
Half Life: 1.4 hr
Metabolized in Liver, CYP430 3A4
Mainly excreted through bile/feces
Clarithromycin
Macrolide
Extended G+, some activity against SOME anaerobes
PO ONLY
Half-Life: 3.7 hr
Metabolized in Liver, CYP450 3A4
60% excreted through bile/feces, 40% KIDNEY – consider renal adjustments
AE: metallic taste
Azithromycin
Macrolide
Extended G+
PO or IV
Half Life: 68 hr
NOT METABOLIZED - lowest DDIs
Mainly excreted through bile/feces
15-Membered Ring = AZOLIDES
Ketolide - Telithromycin
Substituting cladinose sugar with KETO GROUP and attaching a CYCLIC Carbamate making it EFFECTIVE against macrolide resistant bacteria due to their ability to bind at 2 SITES (Domain 5 &2)
Fidaxomicin/Dificid
Macrolide
Inhibits the bacterial enzyme RNA polymerase by binding and preventing movement of the SWITCH REGIONS resulting in the death of C.Diff
Narrow Spectrum
Rifamycins
Broad Spectrum
MOA: Inhibit bacterial RNA polymerase, inhibit RNA synthesis
Resistance Mechanism: single amino acid change in the bacterial RNA polymerase
Primarily used for tuberculosis
Rifampin
Rifamycin
Broad Spectrum
Used in combo with Isoniazid for chemo, unreliable alone
PO, Take on empty stomach
Powerful inducer of CYP3A4, increases metabolism of other drugs
AE: body fluids are red/orange, GI intolerance, hepatotoxicity
MOA: bind B-subunit of RNA Polymerase specifically in mycobacteria
Resistance: mutations in B-subunit
Rifabutin
Rifamycin
Broad Spectrum
Used in combo with Isoniazid for chemo, unreliable alone
PO, Take on empty stomach
Does not induce CYP3A4 as much, preferred for HIV positive patients
Preferred in TB because: longer half life, less CYP3A4, effect against some rifampin resistant strains
AE: same as Rifampin
Prophylaxis agent against mycobacterium in HIV Positive patients
Rifaximin
Rifamycin
Broad Spectrum
For Travelers Diarrhea caused by E.coli
PO, short term treatment, without regard to food
AE: Peripheral edema
1st MOA: interferes with transcription by binding to B-subunit of bacterial RNA Polymerase blocking translocation
NON SYSTEMIC, GI SPECIFIC, poor absorption
2nd MOA: activates the pregnane X receptor inhibits pro inflammatory transcription factor NF-kappa-B making it effective for IBD
Quinolones/Fluoroquinolones
Broad Spectrum BEST oral drugs for P.Aeruginosa
Concentration Dependent
1st-4th Generation
MOA: inhibit DNA replication by irreversibly binding to bacterial enzymes - DNA gyros and Topoisomerase IV, which uncoil DNA
Resistance Mechanism: modification of target enzyme, modification of porins, and efflux pumps
AE: tendons, cartilage rupture, CNS excitation and seizures
Ozenoxacin
NON-FLUORINATED
Effective against some resistant gram + s.aureus and s.pyrogenes that cause IMPETIGO
Ciprofloxacin
Second Gen Fluoroquinolone
(better gram - than +)
AE: QT Prolongation
PO and IV, food decreases absorption
Short half life 4 hr
Metabolized in liver, excreted in urine = dose adjust in renal insufficiency
Levofloxacin
Third Gen Fluoroquinolone
Best Activity against ANAEROBEs (better gram+ activity)
AE: QT Prolongation
PO and IV, food decreases absorption
Long half life 6-12 hr
Metabolized in liver, excreted in urine = dose adjust in renal insufficiency
Moxifloxacin
Third Gen Fluoroquinolone
Best Activity against ANAEROBEs (better gram+ activity)
AE: QT Prolongation
PO and IV, food decreases absorption
Long half life 6-12 hr
EXCRETED IN BILE = Decreased DDIs
Delafloxacin
Fourth Gen Fluoroquinolone
ACTIVE AGAINST MRSA
NO qt prolongation
PO and IV, food decreases absorption
Long half life 6-12 hr
Metabolized in liver, excreted in urine = dose adjust in renal insufficiency
For patients with what disease states should fluoroquinolone be reserved unless there are no alternative treatments options as recommended by the FDA?
- Acute sinusitis
- Acute bronchitis
- Uncomplicated UTI
Fluoroquinolone are Concentration Dependent meaning what?
Higher the Peak = Better the Killing
Ratio of peak drug concentration and MIC determine rate of killing
Kill even after plasma levels drop below MIC aka post-antibiotic effect
ADMIN ONCE DAILY
Tetracyclines
Broad
MOA: bind to 30s ribosomal subunit, inhibit protein synthesis
Resistance Mechanism: mutation of binding site, efflux pump, and production of ribosomal protective protein
NOT ACTIVE against P.Aeruginosa
AE: photosensitivity, teeth discoloration (avoid in pregnancy and children younger than 8yrs)
Tetracycline
Broad, NOT Active against MRSA
PO, decreased by food
Half Life 6-8 hrs
NOT metabolized
Eliminated in URINE = DDIs and dose adjust renal
Esophageal Irritation
Doxycycline
Broad, active against SOME MRSA
PO and IV
Half Life: LONG 18-20 hr
PARTLY Metabolized
60% bile/feces 40% urine = DDIs and dose adjust renal
Esophageal Irritation
Minocycline
Broad, active on SOME MRSA
PO and IV
Half life LONG: 18-20 hrs
FULLY metabolized by liver
Mostly bile/feces
Esophageal Irritation
Tigecycline
Broad, ACTIVE Against MRSA and Tetracycline Resist
IV ONLY
Half Life LONG: 36 hr
PARTLY metabolized
Mostly bile/feces
Slight increased risk of death
MOA: inhibits protein translocation by binding to the 30s ribosomal unit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome
Omadacycline
Broad, ACTIVE Against MRSA and Tetracycline Resist
PO and IV, only new gen with ORAL option!!
Half Life LONG: 36 hr
NOT metabolized
Mostly bile/feces
Pneumonia and Skin Infections
Eravacycline
Broad, ACTIVE Against MRSA and Tetracycline Resist
IV ONLY
Half Life LONG: 36 hr
Metabolized in the liver
Mostly bile/feces
Halogenated/Fluorinated
For complicated intra-abdominal infections
Aminoglycosides
Extended G-, INACTIVE against Anaerobes
Concentration Dependent
MOA: penetrate bacteria using oxygen dependent influx pumps w/ irreversible binding to 30S and 50S or membrane disruption
Resistance Mechanism: production of AG modifying enzyme, mutation of binding site, mutation of influx pump, and efflux pump
Aminoglycoside + Beta Lactam = BROAD, not active against MRSA but active against P. Aeruginosa
Excreted in Urine = UTI = dose adjust
AE: renal toxicity, neuromuscular junction blockade, ototoxicity
Gentamicin
Aminoglycoside
Extended G-
Amikacin
Aminoglycoside
Extended G-
Tobramycin
Aminoglycoside
Extended G-
Plazomicin
Aminoglycoside
Extended G-, ACTIVE against aminoglycoside resistant G-
Complicated UTI
Polypeptide Antibiotics
Narrow G-
Amphipathic
MOA: cationic moiety interacts with neg charged LPS on gram neg outer membrane and hydrophobic moiety inserts in membrane forming pores
Resistant Mechanism: decrease of neg charge on outer membrane (rare)
Last therapeutic option for multi drug resistant G-
IV ONLY
Excreted in urine = renal dose adjust
ACTIVE AGAINST: P.aeruginosa, A. baumannii, and Klebsiella pneumoniae
Colistin
Polypeptide
Narrow G-
Both hydrophilic and lipophilic with interact with cytoplasmic membrane like a detergent, solubilizing the membrane in an aqueous environment = bactericidal
Polymixin B
Polypeptide
Narrow G-
Binds and neutralizes endotoxin
Nitroimidazoles
Gram +/- ANAEROBES ONLY
MOA: reactive intermediates bind DNA causing DNA fragmentation
Food does not affect oral absorption
Excreted in urine but NO renal dose adjustments
Metronidazole/Flagyl
Nitroimidazole
Gram +/- ANAEROBES
PO, IV, and topical
Half Life 6-8 hr
Prodrug, reduction of 5 nitro group leads to 2-OH active metabolite
Secnidazole/Solosec
Nitroimidazole
Gram +/- ANAEROBES
PO ONLY
Half Life 17-29 hr
Single Dose ORAL treatment for bacterial vaginosis
UTI Agent Considerations
Drug should reach high concentration in the urine (excreted in the urine) and be active at a low pH
E.Coli is the most common cause, gram - activity is desired
Agents used in UTIs
Cefiderocol for complicated
Bactrim
Plazomicin for complication
Fluoroquinolone, avoid is possible
AEs = GI irritation
PO, rapidly excreted in the urine
Nitrofurantoin/Macrobid
UNCOMPLICATED UTIs
MOA: bacteria reduces it to a reactive metabolize that damages their DNA, similar to nitroimidazoles but the reduction can be performed in AEROBIC cells
Resistance NOT common
GI distress common
Take with food
Microcrystalline form better tolerated
RENALLY DOSE ADJUSTED
Fosfomycin/Moniril
BLADDER INFECTIONS
Broad Spectrum
MOA: inhibit pyruvyl transferase, required for cell wall biosynthesis, inactivates MurA aka one of the first steps of peptidoglycan biosynthesis
Resistance development is rapid
Given as single large dose
Methenamine/Hiprex
Prodrug
Depends on the liberation of formaldehyde to become active
Used in UTIs
Resistance: bacteria that creates UREASE prevents the activation of methenamine
Combat by giving Methenamine with salt to decrease resistance
Pleuromutilins
Fused 5,6, and 8 membered rings MUTILIN core
Gram +/-
Bind to bacteria 50s ribosome at the PEPTIDYL Transferase Center both at the A and P sites
Lefamulin
Pleuromutilins
Retapamulin
Pleuromutilins
Empiric Dosing
NON SERIOUS MRSA Infections
Weight Based mg/kg
Pre-Dose Trough at steady state
Goal = 10-15 mg/L
No Monitoring Dosing
NON SERIOUS Infections and SHORT TERM Therapy <5 days
Weight Based mg/kg
No serum concentration monitoring
Individualized Dosing/Peak Trough Monitoring Dosing
ALTERED VANC CLEARANCE (ex. AKI)
Dosing selected to achieve target peak and trough Cp
CP MIN GOAL = 10-15 mg/L non-serious or 15-20 mg/L serious
Pre-Dose Trough and Post-Dose Peak
AUC Based Dosing
SERIOUS MRSA Infections
Desired AUC 400-600 mg-hr/L
Post Dose Peak and Trough preferred at steady state
Vancomycin Dosing Strategy
Determined by severity of infection, renal function, and duration of treatment
Method of Sampling = impacts PK parameter accuracy
Dosing of Vanc can be determined prior to steady state acheived
Mechanisms of Resistance: Alterd Penetration
- Altered Porin Channels
- Efflux pumps
Mechanisms of Resistance: Inactivation
- B-Lactamase
- Aminoglycoside modifying enzyme
Mechanisms of Resistance: Altered Binding/Target Mods
- Altered penicillin binding proteins
- Altered ribosomes
- Topoisomerase II/IV mutations
- Altered D-Ala
Gram Positive Resistance
Thick cell wall - PBP maintains integrity
Cytoplasmic Membrane with efflux pumps
NO barrier
Create a cloud of beta lactamase on the outside of the cell wall aka drugs are inactivated outside the cell
Gram Negative Resistance
Thin cell wall
Outer Membrane w/ Polysaccharide Capsule that repels hydrophilic drugs
Plumbing System - water filled channels based on osmotic gradient
BARRIER
Beta Lactamase in the periplasmic space aka drugs are inactivated inside the cell
Porin Channels
Common in GRAM NEG
Hydrophilic antibiotic use this to gain entry to site of action
Outer membrane, water filled that exchange nutrients and waste products
Efflux Pumps
GRAM POS/NEG
Energy Dependent, expel toxic substances
Largely responsible for intrinsic resistance of P. Aeruginosa
Cytoplasmic Membrane, Outer Membrane
Tetracycline Efflux Pump Against
Enteric Gram Neg
Gram Pos
Macrolides Efflux Pump Against
S. Pneumoniae
Enterococci
Macrolides Streptogramin B Efflux Pump Against
S. Aureus
Fluoroquinolone Efflux Pump Against
S. Aureus
S. Pneumoniae
Gram Positive B-Lactamase
Hydrolyze Penicillins -beta lactamase
Primarily Produced in Staphylococci
NOT all gram pos produce beta lactamases, strep does not and enterococcus has low production
Gram Negative B-Lactamase
Hydrolyze BOTH cephalosporins and penicillins
Found in ALL gram neg organisms
Extended Spectrum B-Lactamases ESBLs: should be considered resistant to all penicillins, cephalosporins, and monobactams –> found in E.Coli and Klebsiella
Carbapenamases: found in Klebsiella Pneumoniae should be considered resistant to all penicillins, cephalosporins, monobactams, and +/- carbapenems (can cause resistance to carbapen) susceptibility may only exist to polymyxin or tigecycline
Aminoglycoside Modifying Enzyme
GRAM POS/NEG
Add functional groups into amino glycoside to decrease binding affinity
1. Acetylation AAC: gentamicin, tobramycin
2. Adenylation ANT: gentamicin, tobramycin
3. Phosphorylation APH: amikacin
Altered Binding Site PBP
Altered or Loss of PBP
Staph Aureus MRSA = altered PBP, resistance to all B-Lactams
Neisseria Gonorrhoaeae = altered PBP, resistance to THIRD gen cephalosporins
Strep Pneumoniae = mosaic PBP, resistance to penicillin and +/- cephalosporins
Altered Binding Site Ribosomes
Altered Ribosomes- decrease affinity
Tetracyclines, Macrolides, Streptogramins, Lincosamides, Linzeolid
MLS Resistance Macrolide/Lincosamide/Streptogramin = principal resistance to macrolides/clinda in gram positive organisms
Altered Binding Site Topoisomerase
DNA Gyrase (gyr A) = fluoroquinolone in gram neg organisms
Topoisomerase IV (par C,E) = fluoroquinolone in gram pos organisms
Factors Associated with INCREASED Resistance
Infection Control Practices
1. Poor Handwashing
2. Poor infection control
3. Use of antibiotics in food industry
Patient Factors
-Prior exposure to IV antibiotics (within past 90 days)
