Lecture 2: Antimicrobials CB Flashcards
Prevention Guidelines for Surgical Site Infections(SSI)
• SSI are second most common healthcare associated infection
• SSIs develop in 2-4% of 30 million surgical patients
• Represent approximately 14-16% of all hospital acquired infections annually in the U.S. and cost 9.8 billion dollars/year
• SSIs account for 3% of surgical mortality and lead to:
- SSI are second most common healthcare associated infection
- SSIs develop in 2-4% of 30 million surgical patients
- Represent approximately 14-16% of all hospital acquired infections annually in the U.S. and cost 9.8 billion dollars/year
- SSIs account for 3% of surgical mortality and lead to:
- Increased re-admissions
- increased length of stay (7-10 days)
- Increased hospital costs (additional $3000-29,000/per SSI diagnosis)
Surgical Site Infections(SSI)
• SSI defined as an infection related to a operative procedure that occurs at or near the surgical incision within X days of the procedure
• Purulent exudate draining from a surgical site
• A positive culture obtained from a surgical site that was closed initially
• A surgeon’s diagnosis of infection
• A surgical site that requires reopening due to at least one of the following signs or symptoms:
Surgical Site Infections(SSI)
• SSI defined as an infection related to a operative procedure that occurs at or near the surgical incision within 30 days of the procedure
• Purulent exudate draining from a surgical site
• A positive culture obtained from a surgical site that was closed initially
• A surgeon’s diagnosis of infection
• A surgical site that requires reopening due to at least one of the following signs or symptoms: tenderness, swelling, redness or heat
Surgical Site Infections(SSI) Prevention
• According to the literature most SSIs are ?
• Anesthesia providers can make an impact on prevention through:
• Timely and appropriate use of ?
• Maintenance of ?
• Proper syringe/med administration practices
• Perioperative ___________ control?
Surgical Site Infections(SSI) Prevention
• According to the literature most SSIs are preventable
• Anesthesia providers can make an impact on prevention through:
• Timely and appropriate use of antibiotics
• Maintenance of normothermia
• Proper syringe/med administration practices
• Perioperative glucose control
Risk for development of Surgical Site Infections(SSI)
SURGICAL RISK:
Procedure Type Skill of surgeon Use of foreign material or implantable device - no blood supply for abx Degree of tissue trauma
Risk for development of Surgical Site Infections(SSI)
PATIENT RISKS:
- Diabetes
- Smoking use
- Obesity
- Malnutrition
- Systemic steroid use (not proven)
- Immunosuppressive therapy
- Intraoperative hypothermia
- Trauma
- Prosthetic heart valves
- Extremes of age
- Hair removal
- Preoperative hospitalization
Surgical Site Infections(SSI) Prevention
Antibiotic Timing:
Antibiotic prophylaxis X hour(s) before ______ had the lowest rate of SSI
30-60 minutes before ______ is the ideal window for drug administration
Antibiotic Timing:
Antibiotic prophylaxis 1 hour before incision had the lowest rate of SSI
30-60 minutes before incision is the ideal window for drug administration
Surgical Site Infections(SSI) Prevention:
Normothermia – consider ____________ measures
Hypothermia is associated with adverse outcomes which include:
Compromised Neutrophil function→ vasoconstriction → tissue ________ and increased incidence of SSI
Normothermia – consider pre-warming measures
Hypothermia is associated with adverse outcomes which include: ⚫Increased blood loss ⚫Increased transfusion requirements ⚫Prolonged PACU stay ⚫Post-op pain ⚫Impaired immune function
Compromised Neutrophil function→ vasoconstriction → tissue hypoxia and increased incidence of SSI
Review slide 8!
Review slide 8!
Review slide 9!
Review slide 9!
Microbial resistance to anti-microbials
Major threat to public health:
• New Delhi Metallo-Beta Lactamase 1 _____
Mechanisms:
• Inc/dec active transport out of the bacterial cell and/or decrease the active transport into the cell?
• Structural changes in the drug _____
• Production of a drug antibiotic __________
• Enzymatic drug __________
• The more antibiotics are used the more __________ develops (in target bacteria and normal flora)
• Antibiotics are used extensively in hospitals
• 1.7 million patients acquire nosocomial infections almost 100,000 die
Major threat to public health:
• New Delhi Metallo-Beta Lactamase 1 Gene
- resists all abx but 2?
Mechanisms:
• Increase active transport out of the bacterial cell and/or decrease the active transport into the cell
• Structural changes in the drug target
• Production of a drug antibiotic antagonist
• Enzymatic drug destruction
• The more antibiotics are used the more resistance develops (in target bacteria and normal flora)
• Antibiotics are used extensively in hospitals
• 1.7 million patients acquire nosocomial infections almost 100,000 die
CDC “Campaign to Prevent Microbial Resistance”
What can we do?
- Encourage vaccination
- Limit invasive catheter use/vigilant infection control with placement
- Involve infectious disease experts
- Identify and target the specific microbe
- Quality control mechanisms for abx use
- Use local information about pathogen & sensitivity “antibiogram”
- Treat infection, not contamination or colonization
- Limit vancomycin use
- Avoid using when infection is cured or not likely present
- Isolation/infectious control procedures
- Hand washing
Antimicrobial Therapy and Anesthesia Practice: Signficance
⚫Prophylaxis before surgery:
Anesthesia plays important role in timely administration of ?
Reimbursement for quality care
⚫Potential for adverse reactions
Hypersensitivity Reaction (dose dependent/independent)
Direct organ toxicity (dose related/unrelated)
Potential for superinfections
Identify patients at risk for complications
⚫Cross-reactions with other medications we give
Signficance
⚫Prophylaxis before surgery:
Anesthesia plays important role in timely administration of ABXs
Reimbursement for quality care
⚫Potential for adverse reactions
Hypersensitivity Reaction (dose independent)
Direct organ toxicity (dose related)
Potential for superinfections
Identify patients at risk for complications
⚫Cross-reactions with other medications we give
Bactericidal
kill the susceptible bacteria
Bacteriostatic
reversibly inhibit the growth of bacteria
- In general the use of bacteri______ antibiotics is preferred but many factors may dictate the use of a bacteriostatic antibiotic.
- When a bacteri______ antibiotic is used the duration of therapy must be sufficient to allow cellular and humoral defense mechanisms to eradicate the bacteria.
- In general the use of bactericidal antibiotics is preferred but many factors may dictate the use of a bacteriostatic antibiotic.
- When a bacteriostatic antibiotic is used the duration of therapy must be sufficient to allow cellular and humoral defense mechanisms to eradicate the bacteria.
Types of antibiotics Bactericidal ~ most SSIs • Penicillin's & Cephalosporin's • Isoniazid • Metronidazole • Polymyxins • Rifampin • Vancomycin • Aminoglycosides • Bacitracin • Quinolones
Types of antibiotics Bactericidal ~ most SSIs • Penicillin's & Cephalosporin's • Isoniazid • Metronidazole • Polymyxins • Rifampin • Vancomycin • Aminoglycosides • Bacitracin • Quinolones
Types of antibiotics Bacteriostatic • Chloramphenicol • Clindamycin • Macrolides • Sulfonamides • Tetracyclines • Trimethoprim
Types of antibiotics Bacteriostatic • Chloramphenicol • Clindamycin • Macrolides • Sulfonamides • Tetracyclines • Trimethoprim
Antimicrobials and Anesthesiology
⚫Goals and General Rules
1. Inhibit microorganisms at concentrations that are tolerated by the?
2. MIC= ?
3. Seriously ill/ immunocompromised select bacteri____
4. Narrow spectrum before or after broad spectrum or combination therapy to preserve normal flora
Antimicrobials and Anesthesiology
⚫Goals and General Rules
1. Inhibit microorganisms at concentrations that are tolerated by the host
2. MIC= Minimum Inhibitory concentration to be effective
3. Seriously ill/ immunocompromised select bactericidal 4. Narrow spectrum before broad spectrum or combination therapy to preserve normal flora
Antimicrobials: Selective toxicity
Exploit cellular biological differences between microbes and mammals……
- Bacterial cell wall
- Bacterial enzyme inhibition
- Bacterial ribosome
Beta-Lactam Antibiotics:
Penicillins
Cephalosporins
Carbapenems
Beta Lactams: Mechanism of Action
Weaken bacterial cell wall
• Bind to penicillin binding proteins (only expressed during bacterial proliferation~atively dividing)
- Activate autolysins (decrease inhibition of murein hydrolase – enzymatic destruction of cell wall)
- Inhibit (transpeptidases) enzyme needed for cell wall synthesis and integrity
Penicillin
• Basic structure is a dicyclic nucleus that consists of a thiazolidine ring connected to a _________ ring
• Several subtypes based on structure, B-lactamase activity, and spectrum ?
• Bacteri_____
Penicillin
• Basic structure is a dicyclic nucleus that consists of a thiazolidine ring connected to a B-lactam ring
• Several subtypes based on structure, B-lactamase activity, and spectrum
• Bactericidal
Penicillin
• Allergic reactions are the principle concern- most common cause of drug allergy (Allergy incidence is 1-10% of patients)
• ___________ (.004-.04% with 10% mortality)
- Laryngeal edema, bronchoconstriction, severe hypotension
• May occur on 1st _________ (PCN contamination in food supply)
• ** patients with documented IgE mediated anaphylactic reactions the Beta lactam antibiotics can be substituted with ?
Penicillin
• Allergic reactions are the principle concern- most common cause of drug allergy (Allergy incidence is 1-10% of patients)
• Anaphylaxis (.004-.04% with 10% mortality)
• Laryngeal edema, bronchoconstriction, severe hypotension
• May occur on 1st exposure (PCN contamination in food supply)
• ** patients with documented IgE mediated anaphylactic reactions the Blactam antibiotics can be substituted with Clindamycin or Vancomycin
Penicillin - G (NOT Ampicillin): Excretion
• Renal excretion is rapid/slow: plasma concentration inc/dec 50% in 1st hour
• X% glomerular filtration
• X% renal tubular secretion
• _______ increases elimination half-time by 10 fold
• Adjust ______ in renal failure
• Administration of _________ will reduce renal excretion and ________ action
Penicillin - G (NOT Ampicillin): Excretion
• Renal excretion is rapid: plasma concentration decreases 50% in 1st hour
• 10% glomerular filtration
• 90% renal tubular secretion
• Anuria increases elimination half-time by 10 fold
• Adjust dose in renal failure
• Administration of probenecid will reduce renal excretion and prolong action
Broad Spectrum Penicillin: Second generation
- Amoxicillin
* Ampicillin - 50% excreted unchanged by the kidney 6 hours after admin
Even more Broad Spectrum Penicillin: Third generation
Organisms
• Same as second generation + ?
Carbenicillin
• Elimination half time is ?
• X% excreted unchanged by the kidney
• High/low sodium load (30—40 mg/caution in ___)
• Hypo_______
• Metabolic ________
• _________ bleeding time despite nml plt count
Broad Spectrum Penicillin: Third generation
Organisms
• Same as second generation + ?
• Pseudomonas aeruginosa and Proteus
Carbenicillin
• Elimination half time is 1 hour (2 hours renal disease)
• 85% excreted unchanged by the kidney
• High sodium load (30—40 mg/caution in CHF)
• Hypokalemia
• Metabolic alkalosis
• Prolonged bleeding time despite nml plt count
Beta-Lactamase Resistant Penicillins
Agents:
Spectrum of Activity:
• Broad/Narrow spectrum agents = ?
• Binds irreversibly to ____________ enzymes (large side group sterically hinders ____________ from cleaving ____________ ring
Beta-Lactamase Resistant Penicillins
Agents:
• Dicloxacillin
• Nafcillin (penetrates CNS; 80% secreted in the bile/good for pts w/renal dysfunction)
• Oxacillin
Spectrum of Activity:
• Narrow spectrum agents (Staph & Strep)
• Binds irreversibly to B-lactamase enzymes (large side group sterically hinders B-lactamase from cleaving B-lactam ring)
Beta-Lactamase Resistant Penicillins
• Nafcillin
- penetrates ?
- X% secreted in the bile/good for pts w/ _____ dysfunction
• Nafcillin
- penetrates CNS
- 80% secreted in the bile/good for pts w/renal dysfunction
B-Lactam/B-Lactamase inhibitor combinations:
- Ampicillin/Sulbactam (Unasyn®)
- Amoxicillin/Clavulanic Acid (Augmentin ®)
- Ticarcillin/Clavulanic Acid (Timentin ®)
- Pipercillin/Tazobactam (Zosyn ®)
- pt will end up with diarrhea
- *we want to preserve these from resistance!
Cephalosporins: Class
• Beta-lactam antibiotics
Cephalosporins
• Favorable or unfavorable therapeutic index?
• Favorable therapeutic index
Cephalosporins
• Bacteri_____
• Bactericidal
Cephalosporins: MOA
Same as pcns!
Bind to penicillin binding proteins
• Activate autolysins
• Inhibit (transpeptidases) enzyme needed for cell wall synthesis and integrity
Cephalosporins
1st & 2nd generation cephalosporins:
3rd & 4th generation cephalosporins:
4th generation cephalosporins:
*Beta lactimase susceptibility inc/dec as you move from the 1st to 4th generation
Cephalosporins
1st & 2nd generation cephalosporins:
Gram positive activity
3rd & 4th generation cephalosporins:
Gram negative activity & activity against anaerobes & ability to penetrate the BBB into CSF
4th generation cephalosporins: (EXPENSIVE)- maintain good gram neg. activity (including pseudomonas)
Retains gram positive activity of earlier generation cephalosporins
*Beta lactimase susceptibility also decreases as you move from the 1st to 4th generation
Cephalosporins: Examples From Each Generation
First generation =
• Cephalexin, cefazolin
Cephalosporins: Examples From Each Generation
Second generation =
• Cefuroxime, cefoxitin, cefotetan
Cephalosporins: Examples From Each Generation
Third generation =
• Ceftazidime, ceftriaxone, cefotaxime (BBB)
Cephalosporins: Examples From Each Generation
Fourth generation – (broadest) =
• Cefepime
Cephalosporins: Examples From Each Generation Fifth generation (or 3rd generation depending on the source) =
• Ceftaroline (MRSA coverage)
Broadest Cephalosporin =
• Cefepime
Cephalosporin MRSA coverage =
• Ceftaroline (MRSA coverage)
Cephalosporins: Elimination
Cephalosporins: Elimination
• Primarily renal (dose reduction in renal disease)
• Ceftriaxone the exception only 33-67% excreted unchanged + significant hepatic metabolism (also longest E1/2t of 3rd generation)
Cephalosporins: Routes of Administration
• ? generation have both IV and oral formulations
• ? cephalosporins are generally administered IV
Cephalosporins: Routes of Administration
• 1st and 2nd generation have both IV and oral formulations
• Broadest spectrum cephalosporins are generally administered IV
Cephalosporin Antibiotics: Cefazolin (First generation)
• Very common for ?
• Crosses the ?
• Allergy incidence is X-X%
• Life threatening anaphylaxis = X% (_________ edema, _______constriction, severe ____________)
• _______________ with other cephalosporins
• ___________ and Cephalosporin cross reactivity only X% (but when it happens it is ?)
• ________ excretion
Cephalosporin Antibiotics: Cefazolin (First generation)
• Very common for SSI prophylaxis (CV, ortho, biliary, pelvic, intraabdominal)
• Crosses the placenta
• Allergy incidence is 1-10%
• Life threatening anaphylaxis = 0.02% (Laryngeal edema, bronchoconstriction, severe hypotension)
• Cross reactivity with other cephalosporins
• Penicillin and Cephalosporin cross reactivity only 1% (but when it happens it is life threatening)
• Renal excretion
Cephalosporins: Adverse Effects
• Hypersensitivity: Cross-reactivity in patients with _________ allergy ~ X%
• Bleeding: ______, ______, _______ inhibit conversion of ____________ to active form
• ______________ (IV site)
• __________ anemia
• _______________ (C.diff)
Cephalosporins: Adverse Effects
• Hypersensitivity: Cross-reactivity in patients with PCN allergy ~ 1%
• Bleeding (cefoperazone, cefotetan, cetriaxone) inhibit conversion of vitamin K to active form
• Thrombophlebitis (IV site)
• Hemolytic anemia
• Superinfection (C.diff)
Cephalosporins: Drug Interactions
• __________ (prolong DOA by delaying elimination)
• ETOH ______, ______, ______, _______ disulfiram like reaction
• Anticoagulants/anti-plt drugs w/ 4 mentioned above
• Calcium + ____________ = fatal precipitates (especially neonates)
Cephalosporins: Drug Interactions
• Probenecid (prolong DOA by delaying elimination)
• ETOH (cefazolin, cefmetazole, cefoperazone,cefotetan) disulfiram like reaction
• Anticoagulants/anti-plt drugs w/ 4 mentioned above
• Calcium + Ceftriaxone = fatal precipitates (especially neonates)
Monobactams: Aztreonam (Azactam ®)
Cell wall agent
• Inhibits ?
• Has a high affinity to a specific ___________ in gram negative bacteria only
• Highly resistant to ?
Broad/Narrow spectrum of activity?
• Excellent activity against gram negative organisms,
• No activity against gram positive organisms
• Penetrates ?
Few/many adverse effects ?
Excreted /changed/unchanged by the kidney (E1/2 t X hrs) ?
Expensive
Most significant risk is superinfections where?
Good substitute for patients with a _________ allergy- cross reactivity is unlikely (Lacks thiazolidine ring (PCN) and the dihydrothiazine ring (cephalosporins))
Monobactams: Aztreonam (Azactam ®)
Cell wall agent
• Inhibits cell wall synthesis = cell lysis and death occur
• Has a high affinity to a specific PBP (PBP3) in gram negative bacteria only
• Highly resistant to beta-lactimases
Narrow spectrum of activity
• Excellent activity against gram negative organisms,
• No activity against gram positive organisms
• Penetrates CSF
Few adverse effects
Excreted unchanged by the kidney (E1/2 t 1.5 hrs)
Expensive
Most significant risk is GI superinfections
Good substitute for patients with a penicillin allergy- cross reactivity is unlikely (Lacks thiazolidine ring (PCN) and the dihydrothiazine ring (cephalosporins))
Macrolides
? Spectrum Agents usually bacteri? (bacteri?/high concentrations):
Compounds characterized by a macrolytic lactone ring containing 14-16 atoms with a deoxy sugar attached
Macrolides
Broad Spectrum Agents usually bacteriostatic (bacteriocidal/high concentrations)
• Erythromycin
• Clarithromycin (Biaxin ®)
• Azithromycin (Zithromax ®)
Compounds characterized by a macrolytic lactone ring containing 14-16 atoms with a deoxy sugar attached
Macrolides: Mechanism of Action
• Bind to 50S subunit of the ribosome to block protein synthesis in bacterial cells
Macrolides: Spectrum of Activity (relatively broad- similar to PCN/useful w/PCN allergy)
• Activity against common gram positive and negative pathogens
• Limited activity against anaerobes
• Very good activity against _________ pathogens:
Macrolides: Spectrum of Activity (relatively broad- similar to PCN/useful w/PCN allergy)
• Activity against common gram positive and negative pathogens
• Limited activity against anaerobes
• Very good activity against atypical pathogens:
**(Commonly used for community acquired pneumonia (CAP), Legionella pneumophila (legionnaire’s disease), pertussis, acute diphtheria, chlamydial infections, bacterial endocarditis, etc.)
Macrolides: Adverse effects
N/V/D abd px liver toxicity (estolate related) inhibit P-450 (drug interactions) increased QTc
Macrolides (Erythromycin): Metabolism & Elimination
Metabolized by the ________________ system and thus increase serum concentration of ?
Excreted mostly in ?
No need to alter dose in ______ disease
Metabolized by the cytochrome P-450 system and thus increase serum concentration of theophylline, warfarin, cyclosporine, methylprednisone and digoxin
Excreted mostly in bile
No need to alter dose in renal disease
Macrolides (Erythromycin): Side Effects
• GI intolerance - Most common side effect - Severe N/V can occur with IV infusion • May slow gastric emptying (asp. risk) • Cholestasic hepatitis
Macrolides (Erythromycin): QT effects
• Prolongs ?
• Reports of ?
• CYP3A inhibitors (_________, ________, ________ inhibitors, ________ antifungals) can increase plasma concentrations and increase risk of fatal ventricular dysrhythmias
• _X increase in sudden cardiac death when erythromycin and CYP3A4 inhibitor are prescribed together
Macrolides (Erythromycin): QT effects
• Prolongs cardiac repolarization
• Reports of torsades de pointes
• CYP3A inhibitors (Verapamil, diltiazem, protease inhibitors, azole antifungals) can increase plasma concentrations and increase risk of fatal ventricular dysrhythmias
• 5X increase in sudden cardiac death when erythromycin and CYP3A4 inhibitor are prescribed together
Macrolides (Erythromycin):
• __ formulation associated with tinnitus hearing loss
• Thrombo_________ (Common with prolonged __ use)
- IV formulation associated with tinnitus hearing loss
- Thrombophlebitis
- Common with prolonged IV use
Clindamycin: Class
Linomycins
Clindamycin: Mechanism of Action
- Blocks protein synthesis by binding to 50S ribosomal subunit
- Usually bacteriostatic agent
Clindamycin:
⚫Similar to Erythromycin in antimicrobial activity
⚫More active with anaerobes
⚫Pseudomembranous colitis→ severe diarrhea should indicate ?
⚫Most commonly used in ?
⚫What limit its use to infections that are difficult to treat?
⚫Similar to Erythromycin in antimicrobial activity
⚫More active with anaerobes
⚫Pseudomembranous colitis→ severe diarrhea should indicate discontinuation of therapy
⚫Most commonly used in female GU surgeries ⚫Severe complications limit its use to infections that are difficult to treat
Clindamycin: DOSING
Only 10% of administered dose is excreted unchanged in ?
Decrease dose in severe _____ disease
Only 10% of administered dose is excreted unchanged in urine
*Decrease dose-severe liver disease
Clindamycin: SIDE EFFECTS
⚫_______ (related or unrelated to Pseudomembranous colitis due to C.diff infection~6%)
⚫_____ Rash/Hypersensitivity, _____
⚫_____ dyscrasias (eosinophilia, leukopenia, thrombocytopenia)
⚫Prolonged pre and post junctional effects at NMJ in the absences of ____
⚫Not antagonized with anticholinesterases or calcium *Concurrent administration with ____ can produce long lasting, profound neuromuscular blockade
Clindamycin: SIDE EFFECTS
⚫N/V/D (related or unrelated to Pseudomembranous colitis due to C.diff infection~6%)
⚫Skin Rash/Hypersensitivity, fever
⚫Blood dyscrasias (eosinophilia, leukopenia, thrombocytopenia)
⚫Prolonged pre and post junctional effects at NMJ in the absences of NDMR
⚫Not antagonized with anticholinesterases or calcium *Concurrent administration with NDMR can produce long lasting, profound neuromuscular blockade
Vancomycin (Glycopepetide): Mechanism of Action
• Inhibits ?
• Binds and inactivates ?
• Bacteri?
- Inhibits bacterial cell wall synthesis= cell lysis & death
- Binds and inactivates cell wall precursors
- Bactericidal – “slowly” cidal
Vancomycin (Glycopepetide): Spectrum of Activity
**Gram ________ activity only*
**Synergistic action with ?
Narrow Spectrum → but….
• **“Activity against ?
• Severe ? infection
• Good choice in severe ? allergy patients
• Severe ? infections
• ______coccal, ______coccal endocarditis
• Cardiac/Orthopedic procedures using ?
• ___ and _____ related infections
***Reserve use for severe infections and these indications only to prevent development of ? If bacteria become _________ to vancomycin, there are only a few other drugs that may be effective in treating the patient.
Vancomycin (Glycopepetide): Spectrum of Activity
Gram positive activity only
Synergistic action with aminoglycosides *allows access through cell wall?
Narrow Spectrum → but….
• “Activity against MRSA (methicillin resistant staph aureus)
• Severe C-difficile infection
• Good choice in severe PCN allergy patients
• Severe staph infections
• Streptococcal, enterococcal endocarditis
• Cardiac/Orthopedic procedures using prosthetic devices
• CSF and shunt related infections
***Reserve use for severe infections and these indications only to prevent development of resistance If bacteria become resistant to vancomycin, there are only a few other drugs that may be effective in treating the patient.
Vancomycin: Administration
• Dose: 10-15 mg/Kg over X minutes (**can start up to X hours pre-op)
• X hours of therapeutic plasma concentration
• 1 Gram mixed in 250ml.
• **__ administration (slowly over X hour)
• Rapid infusion → ?
• Very poor absorption upon oral administration (PO only for ________ infection)
• Slow CSF penetration unless there is ?
- Dose: 10-15 mg/Kg over 60 minutes (can start up to 2 hours pre-op)
- 12 hours of therapeutic plasma concentration
- 1 Gram mixed in 250ml.
- IV administration (slowly over 1 hour)
- Rapid infusion → PROFOUND HYPOTENSION/cardiac arrest (massive histamine release)
- Very poor absorption upon oral administration (PO only for intestinal infection)
- Slow CSF penetration unless there is meningeal inflammation
Vancomycin
• Dose adjust for ? → increased monitoring in this population
• **Renal excretion X% unchanged in the urine
• **Elimination ½ time is X hrs and can be prolonged (up to X days) with _____ failure patients
- Dose adjust for renal insufficiency → increased monitoring in this population
- Renal excretion 90% unchanged in the urine
- Elimination ½ time is 6 hrs. and can be prolonged (up to 9 days) with renal failure patients
Vancomycin: Interactions
- Other nephrotoxic drugs
* Return of neuromuscular blockade?
Vancomycin: Broad or Narrow Therapeutic Index
• Monitor serum __________ level, _____ level, etc
Vancomycin: Narrow Therapeutic Index
• Monitor serum creatinine level, vanc level, etc
Vancomycin: Side Effects
• Thrombophlebitis/Phlebosclerotic ( irritating to tissue)
• _______toxicity (renal failure)
- RARE unless concomitant treatment with other _______toxic drugs such as ?
• _______toxicity when concentrations are >30mcg/ml (increased risk if giving with ?)
• Hypersensitivity (maculopapular ____ rash)
• Severe _______tension & “_______ Syndrome” if given IV in less than 30 minutes
• Administration of ? 1mg/kg and ? 4mg/kg 1 hour before induction limits histamine related effects
• Rare: Immune mediated ? & ? (ab develops against plt + vanco complex)
Vancomycin: Side Effects
• Thrombophlebitis/Phlebosclerotic ( irritating to tissue)
• Nephrotoxicity (renal failure)
- RARE unless concomitant treatment with other nephrotoxic drugs such as aminoglycosides
• Ototoxicity when concentrations are >30mcg/ml (increased risk if giving with aminoglycosides)
• Hypersensitivity (maculopapular skin rash)
• Severe Hypotension & “Red Man Syndrome” (flushing due to histamine release) if given IV in less than 30 minutes
- Intense facial and truncal erythema from histamine release
• Administration of diphenhydramine 1mg/kg and Cimetidine 4mg/kg 1 hour before induction limits histamine related effects
• Rare: Immune mediated thrombocytopenia & bleeding (ab develops against plt + vanco complex)~long term use
Aminoglycosides Bacteri\_\_\_\_ Agents Mechanism of Action • Block the initiation of ? • Effective for aerobic gram negative & positive bacteria • such as ?
Aminoglycosides
Bactericidal Agents
Mechanism of Action
• Block the initiation of protein synthesis in bacterial cells (30S ribosomal subunit)
• Effective for aerobic gram negative & positive bacteria
• Mycobacterium Tuberculosis
Aminoglycosides
⚫Extensive renal excretion through glomerular filtration (almost 100%) ~> ?
⚫Highly ?
⚫Vd= ______cellular volume
⚫2-3 hour elimination half time that is increased X fold with renal failure
⚫Extensive renal excretion through glomerular filtration (almost 100%) ~>very polar
⚫Highly water soluble
⚫Vd= extracellular volume
⚫2-3 hour elimination half time that is increased 20-40 fold with renal failure
Aminoglycosides: Side effects
• Limited by their toxicity
• Ototoxicity
• Esp. w/diuretics such as furosemide, mannitol
• Nephrotoxicity
• Esp. w/ Amphotericin B, cyclosporine, etacrynic acid, vancomycin, NSAIDS
• Skeletal Muscle weakness: inhibit the prejunctional release of Ach and decreases postsynaptic sensitivity to the neurotransmitter (impact on patients with neuromuscular pathology ie.. Myasthenia gravis)
Aminoglycosides: Side effects
• Limited by their toxicity
• Ototoxicity
• Esp. w/diuretics such as furosemide, mannitol
• Nephrotoxicity
• Esp. w/ Amphotericin B, cyclosporine, etacrynic acid, vancomycin, NSAIDS
Aminoglycosides: CIs
• _________: Cross the ________ could cause harm
• ***Skeletal Muscle weakness: inhibit the prejunctional release of Ach and decreases postsynaptic sensitivity to the neurotransmitter (impact on patients with neuromuscular pathology ie.. ?)
- Pregnancy: Cross the placenta could cause harm
- ***Skeletal Muscle weakness: inhibit the prejunctional release of Ach and decreases postsynaptic sensitivity to the neurotransmitter (impact on patients with neuromuscular pathology ie.. Myasthenia gravis)
Aminoglycosides
Gentamicin
• _______ spectrum (______, ______, ______ infections)
• Toxic level – (> Xmcg/ml)/levels should be monitored
Amikacin***
• Derivative of ? with very little antibiotic ________ (yet)
• Useful in gentamicin or tobramycin ________ gram negative bacilli
• Similar side effects as gentamicin
• Do NOT use with ?
Neomycin**
• Topical treatment for ? infections (X% allergy risk)
• Adjunct therapy to ? coma (decreases ammonia concentrations)
• Administered to decrease bacteria in ? before ? Surgery
• Most ________toxic**
Gentamicin
• Broader spectrum (pleural, ascitic, synovial infections)
• Toxic level – (> 9mcg/ml)/levels should be monitored
Amikacin***
• Derivative of kanamycin with very little antibiotic resistance (yet)
• Useful in gentamicin or tobramycin resistant gram negative bacilli
• Similar side effects as gentamicin
• Do not use with PCN (may antagonize PCN effects)
Neomycin**
• Topical treatment for skin, eye and mucous membrane infections (6-8% allergy risk)
• Adjunct therapy to hepatic coma (decreases ammonia concentrations)
• Administered to decrease bacteria in intestine before GI Surgery
• Most nephrotoxic**
Aminoglycosides and Potentiation of muscle relaxants:***
• IV Administration of aminoglycosides associated with potentiation of ?
• This _________ is usually reversible with ?
Aminoglycosides and Potentiation of muscle relaxants:***
• IV Administration of aminoglycosides associated with potentiation of Non-depolarizing neuromuscular-blocking drugs.
• This paralysis is usually reversible with calcium gluconate or neostigmine.
Linezolid (Zyvox): MOA
Bacteriostatic - Inhibits bacterial protein synthesis by preventing the formation of a functional ribosomal subunit initiation complex that is essential for the bacterial translation process.
Linezolid (Zyvox): Spectrum of Activity
- **Very important because active against resistant bacteria such as ?
- **$$ + should reserve to avoid the development of ?
- Gram positive pathogens
- Not active against gram negative bacteria
- **Very important because active against resistant bacteria such as MRSA & VRE (vancomycin resistant enterococci)
• **$$ + should reserve to avoid the development of resistance
Linezolid (Zyvox): Adverse Effects
• _____________, _____________, ____________, _____________ (especially >2 wks of tx) -> CBC check
• ? effects (? 5%, ? 3.5%)
• **Rare: ? and ? neuropathy ->?
• Formulated with phenylalanine (Avoid in patients with ?)
• Weak monoamine oxidase inhibitor- watch for additive norepinephrine and serotonergic effects when used with other serotonergic agents and/or indirect sympathomimetics → risk of ? (? and ? contraindicated)
Thrombocytopenia, anemia, leukopenia, pancytopenia (especially >2 wks of tx) -> CBC check
• GI effects (diarrhea 5%, nausea 3.5%)
• **Rare: optic and peripheral neuropathy ->document!
• Formulated with phenylalanine (Avoid in patients with phenylketonuria….PKU)
• Weak monoamine oxidase inhibitor- watch for additive norepinephrine and serotonergic effects when used with other serotonergic agents and/or indirect sympathomimetics → risk of serotonin syndrome & hypertensive crisis (Ephedrine and SSRIs contraindicated)
Fluoroquinolones:
Bactericidal broad Spectrum Agents
Effective for enteric Gram negative bacilli and *?
**Useful in treatment of complicated GI and GU infections:
Bactericidal broad Spectrum Agents
Effective for enteric Gram negative bacilli and *mycobacterium
**Useful in treatment of complicated GI and GU infections
• Ciprofloxacin (Cipro ®) (PO or IV)
• Levofloxacin (Levaquin ®)
• Moxifloxacin (Avelox ®) – higher risk of adverse effects
Fluoroquinolones: Mechanism of Action
• Inhibits DNA gyrase (super qoiler) and topoisomerase (separator in replication), which are critical bacterial enzymes used in DNA replication & cell division
Fluoroquinolones: Adverse effects • Class warning for ? • Nausea, CNS disturbances, opportunistic candida, rashes, phototoxicity(severe sunburn) • ? superinfection • Muscle weakness in ? patients • ? and ? rupture due to extracellular ? matrix weakening (1:10,000) - Highest risk ? - Avoid IV form
• Class warning for QT prolongation
• Nausea, CNS disturbances, opportunistic candida, rashes, phototoxicity(severe sunburn)
• C. Diff superinfection
• Muscle weakness in myasthenia gravis patients
• Tendinitis and Achilles tendon rupture due to extracellular cartilage matrix weakening (1:10,000)
- Highest risk >65 years and older, corticosteroid use, s/p transplant
- Avoid IV form <18 years old
Fluoroquinolones: Interactions & Elimination Considerations
• CYP450 interactions ->increases levels of ?
• ______ excretion, through ? (Decrease dose in ? dysfunction)
theophylline, warfarin, and tinidazole
Renal excretion, through glomerular filtration and renal tubular secretion (Decrease dose in renal dysfunction)
Sulfonamides: Sulfamethoxazole and trimethoprim
⚫Bacterio?
Antimicrobial activity is due to the ability of these drugs to prevent normal use of ? by bacteria to synthesize ?
Inhibit microbial synthesis of ? production
⚫Met and excretion = ?
⚫? disease = ?
⚫Bacteriostatic
Antimicrobial activity is due to the ability of these drugs to prevent normal use of PABA by bacteria to synthesize folic acid.
Inhibit microbial synthesis of folate production ⚫Portion of drug is acetylated in the liver and other is renally excreted
⚫Renal disease-dose is reduced
Sulfonamides: Sulfamethoxazole and trimethoprim
Clinical uses
⚫ Urinary tract infections
⚫ Inflammatory bowel disease
⚫ Burns
Sulfonamides: Sulfamethoxazole and trimethoprim
Side Effects
Skin rash to anaphylaxis Photosensitivity Allergic nephritis Drug fever Hepatotoxicity Acute hemolytic anemia Thrombocytopenia Increase effect of po anticoagulant *coag issues ~ CBC
Metronidazole (Flagyl)
**⚫Bacteri?
**Aerobic or Anaerobic Gram + or - bacilli & clostridium?
⚫Useful for wide variety of infections:
- Well absorbed orally and widely distributed in tissue including ?
- ** recommended for ?
- PO or IV
Side effects:
⚫Bactericidal
Anaerobic Gram negative bacilli & clostridium
CNS infections
Abdominal and pelvic sepsis
Pseudomembranous colitis (C-diff)
Endocarditis
CNS
pre-op prophylaxis for colorectoal surgery
- Dry mouth
- Metallic taste
- Nausea
- Avoid Alcohol
- Rare: neuropathy and pancreatitits
Antifungals: Amphotericin B
MOA:
MOA: Binds to ergosterol in fungal membranes to form pores
• Altered membrane permeability causes leakage of cellular contents
Antifungals: Amphotericin B
• Given for ?
yeasts and fungi
Antifungals: Amphotericin B
• ______ po absorption – given __
• Poor po absorption – given IV
Antifungals: Amphotericin B
• Fast or Slow renal excretion?
• ***_____ function is impaired in X% of patients treated with this drug. Most recover after drug is stopped but some resulting permanent decrease in ?
• Monitor plasma ___________ levels
- Slow renal excretion
- renal function is impaired in 80% of patients treated with this drug. Most recover after drug is stopped but some resulting permanent decrease in glomerular filtration rate may remain.
- Monitor plasma creatinine levels
Antifungals: Amphotericin B
Side effects
- Fever, chills, dyspnea, hypotension can occur during infusion
- Impaired hepatic function
- Hypokalemia
- Allergic reactions
- Seizure
- Anemia
- Thrombocytopenia
Antiviral Drugs
⚫Viruses are obligate intracellular parasites:
Difficult to kill virus and not ____ cell
Some cell surface receptors are unique for viruses and this gives a location for ?
⚫Viruses are obligate intracellular parasites:
Difficult to kill virus and not host cell
Some cell surface receptors are unique for viruses and this gives a location for potential drug therapy
Antiviral Drugs: Acyclovir Used to treat ? May cause ? damage if infused rapidly Thrombo? Patients may complain of ? during IV infusion
Antiviral Drugs: Acyclovir
Used to treat herpes
May cause renal damage if infused rapidly Thrombophlebitis
Patients may complain of headaches during IV infusion
Antivirals: Interferons
Term used to designate ___________ produced in response to viral infections
Bind to receptors on host cell membranes and induce the production of enzymes that inhibit ?, resulting in ? of viral mRNA
Enhance tumoricidal activities of ?
Treatment for chronic ?
Nasal sprays
Term used to designate glycoproteins produced in response to viral infections
Bind to receptors on host cell membranes and induce the production of enzymes that inhibit viral replication-degradation of viral mRNA
Enhance tumoricidal activities of macrophages (oncology)
Treatment for chronic hepatitis B and C
Nasal sprays
Antivirals: Interferons
Side Effects
- Flu like symptoms
- Hematologic toxicity
- Decreased mental concentration
- Development of autoimmune conditions
- Depression, irritability
- Rashes, alopecia
- Changes in CV, thyroid, hepatic function
- check for goider
Antiretroviral Drugs: Steps in the HIV Replication Cycle
1. Fusion of the HIV cell to the host cell surface *CCR5/CXCR4 proteins
Antiretroviral Drug MOA = ?
2. HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
Antiretroviral Drug MOA = ?
3. Viral DNA is formed by reverse transcription.
4. Viral DNA is transported across the nucleus and integrates into the host DNA.
Antiretroviral Drug MOA = ?
5. New viral RNA is used as genomic RNA and to make viral proteins.
6. New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
7. The virus matures by protease releasing individual HIV proteins.
Antiretroviral Drug MOA = ?
Antiretroviral Drugs: Steps in the HIV Replication Cycle
1. Fusion of the HIV cell to the host cell surface *CCR5/CXCR4 proteins
Antiretroviral Drug MOA = Fusion entry inhibitors
2. HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
Antiretroviral Drug MOA = RTI, NRTI, NNRTI
3. Viral DNA is formed by reverse transcription.
4. Viral DNA is transported across the nucleus and integrates into the host DNA.
Antiretroviral Drug MOA = Integrase inhibitors
5. New viral RNA is used as genomic RNA and to make viral proteins.
6. New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
7. The virus matures by protease releasing individual HIV proteins.
Antiretroviral Drug MOA = Protease inhibitors
HIV/AIDS: Review of Current Treatments = Many Side Effects Influencing Anesthetic:
• 6 categories (2 more in clinical trials) –always on combination therapy (HAART)
- Nucleoside reverse transcriptase inhibitors
Nausea, diarrhea, myalgia (avoid succs), increased LFTS, pancreatitis, peripheral neuropathy (preop doc), renal toxicity, marrow suppression, anemia, lactic acidosis, inhibition cytochrome P450 (zidovudine + corticosteroids can = severe myopathy including respiratory muscle dysfunction). - Protease inhibitors (ritonavir)–
Hyperlipidemia, glucose intolerance, abnormal fat distribution, altered LFTs, inhibition of cytochrome P-450 3A4 (decreased fentanyl clearance ~ 67%)
HIV/AIDS: Review of Current Treatments = Many Side Effects Influencing Anesthetic:
Nonnucleoside analog reverse transcriptase inhibitors
• ? inhibits cytochrome P450 may increase concentrations sedatives, antiarrhythmics, warfarin, Ca-channel blockers
• ? induces cytochrome P450 by 98%!
Nonnucleoside analog reverse transcriptase inhibitors
• Delavirdine inhibits cytochrome P450 may increase concentrations sedatives, antiarrhythmics, warfarin, Ca-channel blockers
• Nevirapine induces cytochrome P450 by 98%!
Ritonavir (Protease inhibitor) and Interactions with Anesthetic Drugs
• Midazolam - Increased/decreased effects (sedation, confusion, respiratory depression) ~ ? dosing O.K.
• Midazolam - Increased effects (sedation, confusion, respiratory depression) small carefully titrated IV dosing O.K.
Ritonavir (Protease inhibitor) and Interactions with Anesthetic Drugs
• Fentanyl – Increased effects (sedation, confusion, respiratory depression) ~ Start with ? dose and titrate to ?
• Fentanyl – Increased effects (sedation, confusion, respiratory depression) Start with low dose and titrate to pain
Ritonavir (Protease inhibitor) and Interactions with Anesthetic Drugs
Avoid (pronounced effects – life threatening) ?
- Meperidine
- Amiodarone (arrhythmias)
- Diazepam
*long half times potentiated!
Special Population Considerations Parturient Most antimicrobials ? Plasma concentrations could be 10-50% higher/lower than predicted ? Increased/decreased maternal blood volume, GFR, metabolism ? Teratogenicity -Concern with any drug -Immature hepatic and renal clearance
Parturient
Most antimicrobials cross the placenta and enter maternal milk
Plasma concentrations could be 1050% lower than predicted
Increased maternal blood volume, GFR, metabolism
Teratogenicity
-Concern with any drug
-Immature hepatic and renal clearance
Special Population Considerations Elderly ? impairment Increased/Decreased plasma protein Reduced gastric ? and ? -Altered distribution Increased total body fat -Decreased plasma albumin concentration -Decreased hepatic blood flow -Decreased GFR
Elderly Renal impairment Decreased plasma protein Reduced gastric motility and acidity -Altered distribution Increased total body fat -Decreased plasma albumin concentration -Decreased hepatic blood flow -Decreased GFR
Special Population Considerations
PREGNANCY = ?
always double check
Special Population Considerations
Tetracyclines (tooth dis-coloration in baby) =
just do not give to mom or children
During labor and delivery, the mother should receive intravenous (IV) ? and the baby should take ? (in liquid form) every 6 hours for 6 weeks after birth
AZT
