Pogue: Antimicrobials IIb Flashcards
Macrolides
MOA:
Bacteriostatic or Bactericidal?
Bind to the 50S subunit of the ribosome
Bacteriostatic
Macrolides
Agents (of clinical relevance)
Erythromycin (IV/PO)
Clarithromycin (PO)
Azithromycin (IV/PO)
Macrolides
Spectrum of activity
The respiratory pathogens
C.trachomatis: causes Chlamydia
Mycobacterium avium complex (MAC)
H.pylori: clarithromycin
The respiratory pathogens:
Streptococcus H.influenzae M.catarrhalis Mycoplasma pneumonia Chlamydia pneumonia Legionella pneumophilia
What treats against MAC?
Mycobacterium avium complex (MAC): clarithromycin and azithromycin
What treats H.pylori?
Clarithromycin
Macrolides
Side effects
Biggest class concern:
Worst with what? Why?
Much less with what?
Biggest class concern: nausea/vomiting/diarrhea
–Worst with erythromycin as it binds to the motolin receptor in the GI tract
•Pearl: erythromycin actually used as promotility agent in hospital for severe constipation
–Much less with azithromycin
Macrolides
Other side effects:
QT prolongation (pro-arrhythmia) Rare hepatotoxicity
Macrolides
Clinical Uses:
Respiratory Tract Infections: azithromycin first line for CAP (also used in traceobronchitis, COPD exacerbations)
H.pylori: clarithomycin part of standard therapy
Mycobacterial regimens: clarithromycin and azithromycin
Macrolide Resistance:
Target-Site Modification: change in the 50S subunit binding site
Decreased Concentration in the Cell: efflux pumps
Macrolide
IV dose = Azithromycin half life: Metabolism DDIs Renal dosing
IV dose = PO dose
Azithromycin long half-life
–~ 72 hours; allows shorter course of the drug
Metabolism
–Inhibitors and substrates of CYP3A4
Many drug interactions
No renal dose adjustment needed
Macrolide
DDIs:
Erythromycin and clarithromycin are the big players here
Azithromycin much less
Why azithromycin is the workhorse for this class
What is first line medication for CAP?
Azithromycin
What are ketolides?
What is Telithromycin?
Ketolides are antibiotics belonging to the macrolide group
Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek.
Ketolides: Telithromycin
General:
Spectrum of Activity:
Clinical Use:
Derivative of macrolides
Spectrum of Activity:
- Similar to azithromycin, with enhanced activity against S.pneumo
Clinical Use:
- Originally thought to be a niche drug for CAP
- High rates of hepatotoxicity has limited use clinically
TETRACYCLINES:
MOA:
Bacteriostatic or Bactericidal?
MOA: ribosomal antibiotic that works on the 30S subunit of the ribosome
Bacteriostatic
TETRACYCLINES:
Pharmacokinetics:
Highly lipophilic: penetrates tissues well
Not highly renally eliminated: but still sufficient for UTI
Tetracycline Agents (3):
What is used for SIADH?
Tetracycline (PO)
Doxycycline and Minocycline (IV/PO): most often used
Demeclocycline (PO): used for SIADH
Doxycylin and Minocycline
Spectrum of activity: G+ G- Anaerobic activity Miscellaneous: has activity against (2)
Gram (+) Activity:
S.pneumo
S.aureus (including MRSA)
enterococcus
Gram (-) Activity:
H.influenzae
M.catarrhalis
may also have activity against enterobacteraciae (including MDRO)
Anaerobe Activity: variable
Miscellaneous: has activity against
o Atypical pneumonia pathogens
o Organisms associated with animal bites (Lyme disease)
Clinical Use (Doxycyclin and Minocyclin) (3):
Respiratory tract infections (including CAP)
UTIs
Skin and soft tissue infections (particularly when community acquired-MRSA is a concern)
Tetracycline Adverse Effects (3):
N/V/D: lessened with food
Binding to growing teeth and bones: avoid if less than 8 years old
Photosensitization
Tetracycline
Drug Interactions:
Chelate with divalent and trivalent cations
Do not take with multivitamins!
What are Glycylcyclines?
What is Tigecycline?
Glycylcyclines are a new class of antibiotics derived from tetracycline.
Tigecycline is a glycylcycline antibiotic
Tigecycline:
MOA:
Pharmacokinetics:
First in this new class that is a derivative of the tetracyclines
MOA: same as tetracycline (bind 30S subunit of ribosome); also bacteriostatic (?)
o However, has a different structure and has the ability to overcome some of the tetracycline-resistance mechanisms (efflux pumps, target-site alterations)
Pharmacokinetics:
- Same as tetracycline
Tigecycline
Spectrum of Activity: G+ G- Anaerobic Notable holes
Gram (+) Activity: broad (includes MRSA and VRE)
Gram (-) Activity: similar to tetracyclines, but also includes resistant organisms (ESBL, Acinetobacter)
Anaerobic Activity: some coverage
Notable Holes: pseudomonas and proteus (and providencia)
Tigecycline
Clinical use (3):
Adverse reactions:
Clinical Use:
Last line option for many nasty Gram (-) bugs:
o Carbapenem-resistant acinetobacter
o Klebsiella
Polymicrobial wounds: including MRSA or VRE
2nd line therapy for pts with penicillin allergies for multiple disease states
Adverse Reactions:
- Nausea and vomiting: 20% of patients
- Pancreatitis: few cases noted in post marketing analysis
LINCOSAMIDES
MOA:
Bacteriostatic or Bactericidal?
Agents (2):
Acts on 50S subunit of the ribosome to prevent protein synthesis
Bacteriostatic
Lincosamide Agents:
- Lincomycin: been completely replaced by clindamycin (increased activity)
- Clindamycin
Spectrum of Activity (Clindamycin):
G+
G-
Anaerobes
Gram (+) Activity: S.aureus (including MRSA), Streptococcus (usually)
o Note: has toxin suppression activity and necrotizing Gram (+) infections
Gram (-) Activity: NONE
Anaerobes: good (better for oral anaerobes than lower GI anaerobes)
Clinical Uses (Clindamycin) (3):
Skin infections: because of staphylococcus (including MRSA) and streptococcus coverage
Aspiration pneumonia: since anaerobes are thought to play a role (but NO Gram (-) coverage)
Alternative for anaerobic coverage
Side Effects (Clindamycin):
Diarrhea: in both PO and IV formulations
Nausea
C.difficile Diarrhea: used to be the number one antibiotic associated with C.diff (now FQ and other broad spectrum agents)
Macrolide-Lincosamide-Streptogramin (MLS) resistance seen in what?
S.aureus can posses:
Can lead to:
How do you detect presence of erm gene?
Macrolide-Lincosamide-Streptogramin (MLS) Resistance in S.aureus:
S.aureus can posses an erm gene that can encode resistance to all 3 classes (all bind 50S subunit)
Can lead to inducible clindamycin resistance when isolate says “erythromycin resistant and clindamycin susceptible”
Can use a special D test to detect presence of the erm gene
Sulfonamides:
MOA
What does PABA do?
Bacteriostatic or Bactericidal?
Most commonly used agent:
MOA: structural analog of PABA, which blocks the production of dihydrofolic acid
Folic acid –> DHF –> THF –> Thymidines, purines
Bacteriostatic
Most commonly used agent: sulfamethoxazole (combined with trimethoprin= BACTRIM)
Bactrim (TMP/SMX): together, the two become bactericidal (synergy)
What is Trimethoprin?
Inhibitor of dihydrofolic acid reductase (next step in the production of purines and DNA); also bacteriostatic
Spectrum of Activity (TMP/SMX):
G+
Anaerobic
Miscellaneous:
Gram (+): staphylococcus (including MRSA), some streptococcus (notably lacks group B strep), no enterococcus
Anaerobic: minimal
Miscellaneous:
o Listeria and Nocardia
o DOC for Stenotrophomonas maltophilia
What is the DOC for Stenotrophomonas maltophilia?
TMP/SMX
Spectrum of Activity (TMP/SMX):
G-
Pseudomonas
Gram (-):
Enteric Gram negatives (variable; Klebsiella, Proteus, E.coli)
SPICE organisms (limited clinical use for these)
No pseudomonas coverage
Clinical Applications (TMP/SMX):
Outpatient UTIs: most commonly used agent for these
Skin infections when MRSA is a concern: but remember, no coverage of group B strep
DOC for many nasty infections:
o PCP (pneumocystis) pneumonia
o Stenotrophomonas maltophilia
o Nocardia
Treatment of multi-drug resistant Gram-negatives: role still debated
What is the most commonly used agent for outpatient UTIs?
TMP/SMX
What is the DOC of Nocardia and PCP Pneumonia?
TMP/SMX
TMP/SMX
Side Effects:
Hypersensitivity Reactions: most common agents that cause these (~3% of patients)
- Simple rash –> Severe skin reactions (SJS/TEN)
High concentrations can crystallize in the urine (Rare)
TMP SEs:
o Bone marrow suppression: anemia, leucopenia, and granulocytopenia
o Hyperkalemia
TMP/SMX
DDIs:
Increased INR (How thin blood is) when given with warfarin: INR is the measurement that indicates if warfarin is at therapeutic levels or not
NITROIMIDAZOLES:
MOA
Pharmacokinetics:
Agents:
MOA: not clearly defined; interaction with DNA that causes a loss of the helical structure and strand breaking, leading to cell death
Pharmacokinetics:
- ~100% bioavailability
- Minimal renal elimination
Agents:
- Metronidazole
- Tinidazole
Spectrum of Activity (Metronidazole):
ANAEROBES ONLY: better for lower GI anaerobes vs. mouth anaerobes (opposite of clindamycin)
o DOC for C.difficile**
- Some parasitic activity: T.vaginalis
What is the DOC of C.difficile?
Metronidazole - Mild
Vanco - Severe
Clinical Applications (Metronidazole):
Side Effects:
Drug Interactions:
Clinical Applications (Metronidazole):
- Anaerobic coverage for nosocomial patients
- DOC for C.diff
- T.vaginalis
Side Effects:
- N/V
- Metallic taste
- Disulfuram reaction with ethanol
- Peripheral neuropathies (rare)
Drug Interactions:
- Increased INR when given with warfarin
Drugs with anaerobic coverage (8)
Metronidazole Penicillin B-lactam/B-lactamase inhibitors –Piperacillin/tazobactam, ampicillin/sulbactam Clindamycin Cephamycins Carbapenems Moxifloxacin Tetracyclines (some)
RIFAMPIN
MOA:
Pharmacokinetics:
Spectrum of Activity:
G+:
G-:
Miscellaneous:
MOA: binds to b-subunit of DNA-dependent RNA polymerase, blocking RNA synthesis
Pharmacokinetics:
- ~100% bioavailability (IV dose=PO dose, but food may delay absorption)
- No renal dosing necessary
Spectrum of Activity:
Gram (+): S.aureus (including MRSA) and streptococcus; not used as monotherapy
Gram (-): used in combination with cell wall agent for synergy; minimal activity alone
Miscellaneous: standard therapy for mycobaterial infections
RIFAMPIN
Clinical Application:
Side Effects:
Clinical Application: - Synergy: o Severe staph infections o Multi-drug resistant gram (-) bacilli - Mycobacterial infections: part of standard TB regimen
Side Effects:
- Hepatotoxicty (HIGHLY)**
- Discolored fluids
RIFAMPIN
Drug Interactions:
STRONG inducer of multiple CYP450 isoenzymes**
Contraindicated with many HIV meds
Significant interactions with:
o Antifungals
o Anti-hypertensives
o Statins
What is part of the standard therapy for mycobaterial infections?
Rifampin
POLYMIXINS:
MOA:
Bacteriostatic or Bactericidal?
Why was use abandoned? What lead to re-emergence?
MOA: Cationic detergent that damages the cytoplasmic membrane, leading to leakage of intracellular substances and rapid cell death
Electrostatically interacts with the LPS outer membrane of G- organisms
Bactericidal
Originally utilized in the 1950s
Associated with high rates of nephrotoxicity and neurotoxicity, so use abandoned;
Multi-drug resistance Gram negatives in the 1990s lead to re-emergence
POLYMIXINS
Agents:
Pharmacokinetics:
Agents:
- Colistin (IV)
- Polymixin B (IV,PO,topical)
Pharmacokinetics:
- Poorly understood
POLYMIXINS
Spectrum of Activity:
G+
G-
Anaerobic
Gram (+): NONE
Gram (-):
Pseudomonas, A.baumannii, K.pneumoniae, E.coli;
No activity against serratia and proteus
Anaerobic: NONE
Clinical use
Adverse events
DDIs
Clinical Use:
- Mulit-drug resistant gram (-) organisms in the hospital: when there are no other options!
o Usually pseudomonas, A.baumannii, and K.pneumoniae (KPC- carbapenamase producing organism)
Adverse Events:
- Nephrotoxicity: up to 40% of patients; dose dependent and reversible
- Neurotoxicity: parasthesias
Drug Interactions:
- Additive toxicities
Antipseudomonal Agents (Full List)
Piperacillin, Piperacillin/Tazobactam Cefepime, Ceftazadime Meropenem, Imipenem, Doripenem Aztreonam Gentamicin, Tobramycin, Amikacin Ciprofloxacin, Levofloxacin Polymixins
CHLORAMPHENICOL:
MOA:
Clinical Use:
Side Effects:
MOA: ribosomal 50S inhibitor
Clinical Use: not clinically used any more due to toxicity
Side Effects:
- Bone Marrow Suppression: dose-dependent
- Aplastic Anemia: non-dose dependent
- Gray-Baby Syndrome
Gray-Baby Syndrome:
SE of Chloramphenicol
Lack of an enzyme in phase II metabolism of the drug; leads to accumulation of a toxic metabolite (causes graying of the skin and cyanosis, among other symptoms)
NITROFURANTOIN:
MOA: Spectrum of Activity: Clinical Use: Side Effects: Contraindications:
MOA: inhibition of a variety of bacterial enzyme systems interfering with metabolism
Spectrum of Activity: organisms causing UTIs
Clinical Use: only to treat lower UTIs (First line)
Side Effects: rare inflammatory lung process
Contraindications: cannot use if GFR <60mL/min (completely filtered by the kidney)
DAPSONE:
MOA:
Clinical Use:
Side Effects:
MOA: antagonist of PABA (similar to sulfa drugs)
Clinical Use: prevention/treatment of PCP pneumonia when TMP/SMX cannot be used (ie. allergy)
Side Effects: hemolysis; generally infrequent but more common in patients with G6P deficiency
