Lecture 2: Antimicrobials CB Flashcards
(104 cards)
1
Q
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:
A
- 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)
2
Q
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:
A
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
3
Q
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?
A
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
4
Q
Risk for development of Surgical Site Infections(SSI)
SURGICAL RISK:
A
Procedure Type Skill of surgeon Use of foreign material or implantable device - no blood supply for abx Degree of tissue trauma
5
Q
Risk for development of Surgical Site Infections(SSI)
PATIENT RISKS:
A
- 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
6
Q
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
A
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
7
Q
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
A
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
8
Q
Review slide 8!
A
Review slide 8!
9
Q
Review slide 9!
A
Review slide 9!
10
Q
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
A
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
11
Q
CDC “Campaign to Prevent Microbial Resistance”
What can we do?
A
- 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
12
Q
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
A
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
13
Q
Bactericidal
A
kill the susceptible bacteria
14
Q
Bacteriostatic
A
reversibly inhibit the growth of bacteria
15
Q
- 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.
A
- 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.
16
Q
Types of antibiotics Bactericidal ~ most SSIs • Penicillin's & Cephalosporin's • Isoniazid • Metronidazole • Polymyxins • Rifampin • Vancomycin • Aminoglycosides • Bacitracin • Quinolones
A
Types of antibiotics Bactericidal ~ most SSIs • Penicillin's & Cephalosporin's • Isoniazid • Metronidazole • Polymyxins • Rifampin • Vancomycin • Aminoglycosides • Bacitracin • Quinolones
17
Q
Types of antibiotics Bacteriostatic • Chloramphenicol • Clindamycin • Macrolides • Sulfonamides • Tetracyclines • Trimethoprim
A
Types of antibiotics Bacteriostatic • Chloramphenicol • Clindamycin • Macrolides • Sulfonamides • Tetracyclines • Trimethoprim
18
Q
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
A
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
19
Q
Antimicrobials: Selective toxicity
Exploit cellular biological differences between microbes and mammals……
A
- Bacterial cell wall
- Bacterial enzyme inhibition
- Bacterial ribosome
20
Q
Beta-Lactam Antibiotics:
A
Penicillins
Cephalosporins
Carbapenems
21
Q
Beta Lactams: Mechanism of Action
A
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
22
Q
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_____
A
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
23
Q
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 ?
A
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
24
Q
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
A
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
25
Broad Spectrum Penicillin: Second generation
* Amoxicillin
| * Ampicillin - 50% excreted unchanged by the kidney 6 hours after admin
26
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
27
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)
28
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
29
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!
30
Cephalosporins: Class
• Beta-lactam antibiotics
31
Cephalosporins
| • Favorable or unfavorable therapeutic index?
• Favorable therapeutic index
32
Cephalosporins
| • Bacteri_____
• Bactericidal
33
Cephalosporins: MOA
Same as pcns!
Bind to penicillin binding proteins
• Activate autolysins
• Inhibit (transpeptidases) enzyme needed for cell wall synthesis and integrity
34
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
35
Cephalosporins: Examples From Each Generation
| First generation =
• Cephalexin, cefazolin
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Cephalosporins: Examples From Each Generation
| Second generation =
• Cefuroxime, cefoxitin, cefotetan
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Cephalosporins: Examples From Each Generation
| Third generation =
• Ceftazidime, ceftriaxone, cefotaxime (BBB)
38
Cephalosporins: Examples From Each Generation
| Fourth generation – (broadest) =
• Cefepime
39
```
Cephalosporins: Examples From Each Generation
Fifth generation (or 3rd generation depending on the source) =
```
• Ceftaroline (MRSA coverage)
40
Broadest Cephalosporin =
• Cefepime
41
Cephalosporin MRSA coverage =
• Ceftaroline (MRSA coverage)
42
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)
43
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
44
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
45
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)
46
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)
47
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))
48
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
49
Macrolides: Mechanism of Action
• Bind to 50S subunit of the ribosome to block protein synthesis in bacterial cells
50
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.)
51
Macrolides: Adverse effects
```
N/V/D
abd px
liver toxicity (estolate related)
inhibit P-450 (drug interactions)
increased QTc
```
52
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
53
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
```
54
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
55
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
56
Clindamycin: Class
Linomycins
57
Clindamycin: Mechanism of Action
* Blocks protein synthesis by binding to 50S ribosomal subunit
* Usually bacteriostatic agent
58
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
59
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
60
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
61
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
62
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.
63
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
64
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
65
Vancomycin: Interactions
* Other nephrotoxic drugs
| * Return of neuromuscular blockade?
66
Vancomycin: Broad or Narrow Therapeutic Index
| • Monitor serum __________ level, _____ level, etc
Vancomycin: Narrow Therapeutic Index
| • Monitor serum creatinine level, vanc level, etc
67
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
68
```
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
69
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
70
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
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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)
72
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**
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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.
74
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.
75
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
76
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)
77
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
78
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
79
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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
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• 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
80
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)
81
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
82
Sulfonamides: Sulfamethoxazole and trimethoprim
| Clinical uses
⚫ Urinary tract infections
⚫ Inflammatory bowel disease
⚫ Burns
83
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
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84
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
85
Antifungals: Amphotericin B
MOA:
MOA: Binds to ergosterol in fungal membranes to form pores
| • Altered membrane permeability causes leakage of cellular contents
86
Antifungals: Amphotericin B
| • Given for ?
yeasts and fungi
87
Antifungals: Amphotericin B
| • ______ po absorption – given __
• Poor po absorption – given IV
88
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
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Antifungals: Amphotericin B
| Side effects
* Fever, chills, dyspnea, hypotension can occur during infusion
* Impaired hepatic function
* Hypokalemia
* Allergic reactions
* Seizure
* Anemia
* Thrombocytopenia
90
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
91
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Antiviral Drugs: Acyclovir
Used to treat ?
May cause ? damage if infused rapidly
Thrombo?
Patients may complain of ? during IV infusion
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Antiviral Drugs: Acyclovir
Used to treat herpes
May cause renal damage if infused rapidly Thrombophlebitis
Patients may complain of headaches during IV infusion
92
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
93
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
94
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
95
HIV/AIDS: Review of Current Treatments = Many Side Effects Influencing Anesthetic:
• 6 categories (2 more in clinical trials) –always on combination therapy (HAART)
1. 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).
2. Protease inhibitors (ritonavir)–
Hyperlipidemia, glucose intolerance, abnormal fat distribution, altered LFTs, inhibition of cytochrome P-450 3A4 (decreased fentanyl clearance ~ 67%)
96
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%!
97
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.
98
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
99
Ritonavir (Protease inhibitor) and Interactions with Anesthetic Drugs
Avoid (pronounced effects – life threatening) ?
* Meperidine
* Amiodarone (arrhythmias)
* Diazepam
*long half times potentiated!
100
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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
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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
101
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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
```
102
Special Population Considerations
| PREGNANCY = ?
always double check
103
Special Population Considerations
| Tetracyclines (tooth dis-coloration in baby) =
just do not give to mom or children
104
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
