Transcript Spectrum of Activity - Vanderbilt University Medical Center

Critical Care Antibiotics
Kelli A. Rumbaugh, PharmD, BCPS
Surgical ICU Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN
Objectives
• To define terminology used to describe antimicrobials
and bacteria
• To review the mechanism of action, pharmacodynamics,
adverse effects, and antimicrobial spectrum of commonly
used antibiotics in the intensive care unit
• To describe the incidence and treatment approach to
penicillin allergic patients
Definitions
• Minimum Inhibitory Concentration
– Antimicrobial concentration that inhibits visible
microbial growth in artificial media
• Gram Stain
– Gram positive
– Gram negative
• Acid fast
Pharmacodynamics
Time Dependent Killing
• Beta-Lactams
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–
–
–
Penicillin
Cephalosporins
Piperacillin-Tazobactam
Carbapenems
• Meropenem
• Ertapenem
Braz. J. Microbiol. 2007;38(2).
Pharmacodynamics
Concentration Dependent Killing
• Fluoroquinolones
– Levofloxacin
– Ciprofloxacin
– Moxifloxacin
• Aminoglycosides
– Amikacin
– Tobramycin
– Gentamicin
Braz. J. Microbiol. 2007;38(2).
Pharmacodynamics
AUC/MIC Dependent Killing
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•
•
•
Vancomycin
Linezolid
Clindamycin
Macrolides
– Azithromycin
– Clarithromycin
– Erythromycin
Braz. J. Microbiol. 2007;38(2).
Keys to Success
• Antibiotic covers potential infection/bacteria
• Dose of antibiotic is appropriate for treatment
of infection and adjusted for renal/hepatic
impairment
• Antibiotic penetrates site of infection
• Antibiotic is being absorbed
• Adequate treatment duration
Risk Factors for Resistance
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Antimicrobial therapy in the preceding 90 days
Current hospitalization of 5 days or more
High resistance rates in the unit
Residence in a nursing home or extended care facility
Immunocompromised
Home wound care
Chronic dialysis
Am J Respir Crit Care Med. 2005;171:388–416.
Clin Infect Dis. 2012;54(4):470–8.
Gram Positive Agents
Vancomycin
Linezolid
Daptomycin
Gram Positive Bacteria
• Cocci
– Staphylococcus
• S. aureus
• S. epidermidis
– Streptococcus
• S. pyogenes (Group A)
• S. viridians
• S. pneumoniae
– Enterococcus
• E. faecalis
• E. Faecium
• Bacilli
–
–
–
–
Listeria monocytogenes
Bacillus anthracis
Corynebacterium species
Proprionibacterium acnes
Vancomycin
• Spectrum of activity
– Staph (MRSA, MSSA), strep, enterococcus, c. difficile colitis (oral)
• Mechanism of action
– Inhibits synthesis of peptidoglycan/bacterial cell wall formation
• Dosing
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–
–
–
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Actual body weight
Loading dose = 25-30 mg/kg
Maintenance dose = 15-20 mg/kg
Usual Frequency = every 8-24h
Adjust dose for renal impairment
Am J Health-Syst Pharm. 2009; 66:82-98.
Vancomycin
• Adverse effects
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–
–
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Redman syndrome
Thrombocytopenia
Possible nephrotoxicity ??
Ototoxicity (rare)
• Monitoring
– Goal Trough = 15-20 mcg/mL
– Bacteremia, endocarditis, osteomyelitis, meningitis, pneumonia
– Initial: trough before 4th or 5th dose
– Maintenance: trough once weekly
Am J Health-Syst Pharm. 2009; 66:82-98.
Vancomycin with Dialysis
• Continuous renal replacement therapy (CRRT)
– 15mg/kg q24h
– Hold dose if CRRT stopped > 8h
– Trough before 4th or 5th dose
• Intermittent hemodialysis (iHD)
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–
–
–
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Pulse dosing with iHD
iHD removes ~25% of vancomycin
Goal Pre-iHD level < 24 mcg/mL
Initial dose = 15mg/kg x1 dose
Maintenance dose based on pre-iHD levels
Linezolid
• Spectrum of activity
– Staph (MSSA, MRSA), strep, VRE
• Mechanism of action
– Binds to bacterial ribosomes to inhibit protein synthesis
• Adverse Effects
– Myelosupression (pancytopenia, thrombocytopenia)
– GI upset
– Serotonin syndrome
• Drug interactions
– Monoamine oxidase inhibitors (MAOI’s)
– Selective serotonin reuptake inhibitors (SSRI’s)
• Dosing
– 600mg IV/PO q12h
Product Information: ZYVOX(R) Pharmacia and Upjohn Company, New York, NY, 2008.
Linezolid
• Clinical Pearls
– May be used for vancomycin failure or intolerance
– Oral & IV formulations
– Bacteriostatic
– No renal adjustment
– May have prescribing restrictions
– Expensive - $$$
Daptomycin
• Spectrum of activity
– Staph (MSSA, MRSA), strep, enterococcus (VRE)
• Mechanism of action
– Causes bacterial membranes to depolarize leading to inhibition of
protein, DNA, and RNA synthesis
• Typical Dosing
– Adjust with renal impairment
– 4-6 mg/kg (actual weight) q24-48h
• Adverse Effects
– Arthralgia
– Myalgia
– CPK elevations
Product Information: CUBICIN® Cubist Pharmaceuticals, Inc, Lexington, MA, 2010.
Clin Infect Dis 2011; 52(3):e18-e55.
Daptomycin
• Clinical Pearls
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Not for treatment of pneumonia
Can use doses of 8-10 mg/kg for severe infections
Monitor CPK at baseline and weekly
Can falsely elevate INR
May have prescribing restrictions
Takes 30-60 minutes to reconstitute
Expensive - $$$
Gram Negative Agents
Aminoglycosides
Aztreonam
Gram Negative Bacteria
Cocci
Bacilli
• Neisseria gonorrhoeae
• Neisseria meningitidis
• Moraxella catarrhalis
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•
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Pseudomonas aeruginosa
Acinetobacter species
Citrobacter species
Enterobacter species
Klebsiella pneumoniae
E. Coli
H. influenzae
Proteus mirabilis
S. maltophilia
Aminoglycosides
Medications
Gentamicin
Tobramycin
Amkicacin
• Spectrum of activity
– Only gram negative, gram positive synergy
• Mechanism of action
– Bind bacterial ribosome and inhibit protein synthesis
• Adverse effects
– Nephrotoxicity
– Ototoxicity
– Prolonged neuromuscular blockade
Aminoglycosides
• Clinical Pearls
– Used for
• Nosocomial infections
• Double gram negative coverage
• Endocarditis (synergy)
– Two dosing schemes
• Traditional dosing
• Extended interval dosing/once daily dosing
– Levels must be monitored
• Traditional = peak & trough around 3rd dose
• Extended interval = trough before 2nd dose
– Monitor Scr daily
Aztreonam
• Class
– Monobactam
• Spectrum of activity
‒ Gram positive: none
‒ Gram negative: most, except S. maltophilia
• Mechanism of action
– Inhibit cell wall synthesis
• Dosing
– Usual: 1-2g IV Q8h
– Meningitis: 2g IV Q6-8h
• Adverse effects (rare)
– Transient eosinophilia
– LFT elevations
– Thrombocytopenia
**Can be used with
penicillin allergy**
Mixed Spectrum Agents
Cephalosporins
Piperacillin-Tazobactam
Carbapenems
Cephalosporins
Spectrum of Activity
First Generation
Cefazolin (Ancef) (IV)
Cephalexin (Keflex) (PO)
•
Simple Gram (+) , simple gram (-) , no
anaerobes. No ceph gets enterococci.
Primary Use
•
Simple SSTI, surgical prophylaxis
•
Surgical prophylaxis if anaerobes,
URTI, UTI
•
PNA, meningitis
Good gram (+), nosocomial gram (-)
including pseudomonas
No anaerobes
•
Sepsis, HAP, neutropenic fever
MRSA, MSSA, E. faecalis, s.pneumoniae,
Some gram (-), NO pseudomonas
•
Pneumonia, SSTI
Second Generation
Cefotetan (Cefotan) (IV)
Cefoxitin (Mefoxin) (IV) •
Cefuroxime (Ceftin) (IV) •
Cefaclor (Ceclor) (PO)
Cefprozil (Cefzil) (PO)
Same spectrum as 1st Generation
Cefotetan and Cefoxitin cover anaerobes
Third Generation
Ceftriaxone (Rocephin) (IV)
Cefotaxime (Claforan) (IV) •
Ceftazadime (Fortaz) (IV) •
Cefpodoxime (Vantan) (PO)
Cefdinir (Omnicef) (PO)
Cefixime (Suprax) (PO)
•
Fourth Generation
Cefepime (Maxipime) (IV)
Fifth Generation
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•
Ceftaroline (Teflaro) •
Better gram (-)
Ceftazadime-pseudomonas
Cephalosporins
• Clinical Pearls
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Do not cover enterococcus (except ceftaroline)
↑ gram negative coverage with higher generations
Used for surgical prophylaxis
Anaerobic coverage
• Cefoxitin
• Cefotetan
– Pseudomonas coverage
• Ceftazidime
• Cefepime
Fluoroquinolines
Medications
Ciprofloxacin
Mechanism of
Action
Clinical Use
Moxifloxacin
Gemifloxacin
Inhibit DNA gyrase and topoisomerase IV inhibiting DNA synthesis
•
Spectrum of
Activity
Levofloxacin
Gram Negative: Enterobacteriaceae, Haemophilus spp, Neisseria spp
and M. Catarrhalis
• Atypicals
Pseudomonas
Pseudomonas
S. pneumoniae
Anaerobes
S. pneumoniae
---
Gram (-)
infections,
Bone/Joint
PNA, UTI
PNA
NOT: UTI
PNA
Jl of Antimic Chemo. 2003;51:S1, 13–20.
Piperacillin-Tazobactam
• Spectrum of activity
– Gram negative: P. aeruginosa, Enterbacteriaceae
– Gram positive: MSSA, Enterococci, Strep
– Anaerobes
• Mechanism of action
– Inhibit cell wall synthesis
• Adverse effects
– Gastrointestinal intolerance
– C. difficle colitis
– Interstitial nephritis
Piperacillin-Tazobactam
• Clinical Pearl
– Extended infusion = 3.375g Q8h
Lodise. Pharmacotherapy 2006;26:1320-32.
Lodise. Clin Infect Dis 2007;44:357-63.
Carbapenems
Meropenem
(Merem®)
Ertapenem
(Invanz®)
Mechanism of
Action
Broad Spectrum: Gram (+), Gram (-), ESBL, Anaerobes
NOT: MRSA
NOT: Pseudomonas,
Enterococcus,
Acinetobacter
--
Common Use
Doripenem
(Doribax®)
Inhibit cell wall synthesis
Spectrum of
Activity
Adverse Effects
Imipenem Cilastatin
(Primaxin®)
↓ Platelets
Drug Fever
Meningitis
Intra-abdominal
--
--
Seizure
↓ Platelets
Drug Fever
Nocardia
NOT: Pneumonia
Carbapenems
• Clinical Pearls
– First line agent for extended spectrum beta-lactamase
(ESBL) producing bacteria
– Extended infusion meropenem
• ↑ time above MIC
– Reserved for severe infections
– May have prescribing restrictions
Pharmacotherapy 2006;26(9):1320–1332.
Tigecycline
• Spectrum of activity
– Enterococcus (including VRE), MSSA, MRSA, MRSE, anaerobes
– Not pseudomonas, proteus, providencia
• Mechanism of action
– Binds to bacterial ribosomes to inhibit protein synthesis
• Dose
– 100mg IV x 1 dose
– 50mg IV q12h
• Adverse effects
– Nausea and vomiting
– Hyperbiliruminemia
Product Information: TYGACIL(R) Wyeth Pharmaceuticals, Inc, Philadelphia, PA, 2013.
Tigecycline
• Clinical Pearls
– No renal adjustment
– Hepatic dose adjustment (Child Pugh C)
• 100mg IV x 1, then 25mg IV Q12h
– Used for resistant infections
– Do not use for
• Ventilator associated pneumonia
• Bacteremia
– Can be used for
• Intra-abdominal infections
• Skin & soft tissue infections
FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and
approves new Boxed Warning. U.S. Food and Drug Administration (FDA). Rockville, MD. 2013.
Atypical Agents
Fluoroquinolones
Macrolides
Tetracyclines
Atypical Bacteria
Agents
• Fluoroquinolones
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Levofloxacin
Ciprofloxacin
Moxifloxacin
Gemifloxacin
• Macrolides
– Azithromycin
– Erythromycin
– Clarithromycin
• Tetracyclines
– Tetracycline
– Doxycycline
– Minocycline
Bacteria
• Mycoplasma
• Legionella pneumoniae
• Chlamydia pneumoniae
• Richettsia
• Actinomyces
References
Commonly Encountered
Infectious Disease Issues
Clostridium Difficile
Antimicrobials per IDSA Guidelines
Infect Control Hosp Epidemiol. 2010;31(5):000-000.
Clostridium Difficile
• IDSA Recommendations
– No probiotics - ↑ Bloodstream infections
– Stop causative antimicrobials
– Repeat testing during the same episode is
discouraged
– Vancomycin taper after second reoccurrence
– Dual antimicrobials
• Ileus = IV metronidazole + vancomycin enema
**PO vancomycin is only used to treat c. diff infection**
Infect Control Hosp Epidemiol. 2010;31(5):000-000.
Allergic Reactions
• IgE reactions
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Anaphylaxis
Bronchospasm
Angioedema
Pruritic rash
Uticaria
Hypotension
J Emerg Med. 2012;42(5):612–620.
Penicillin Allergy
Avoid Use
Incidence of
Reaction
May Use
Cephalosporins
• 1st/2nd generation
cephalosporin
2%
• Aztreonam
• 3rd/4th generation
cephalosporin
Carbapenems
• None?
J Chemother. 2008;20(2):233.
Clin Infect Dis. 2000;31(6):1512.
Clin Infect Dis. 2004;38(8):1102
0-11%
• All carbapenems?
• Aztreonam
• Graded challenge or
PCN skin test
Pharmacotherapy. 2007;27(1):137.
J Antimicrob Chemother. 2004;54(6):1155.
J Emerg Med. 2012;42(5):612–620.
Treatment Approach
Clin Infect Dis. 2002; 35:26–31.
Critical Care Antibiotics
Kelli A. Rumbaugh, PharmD, BCPS
Surgical ICU Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN