Transcript Empiric Therapy

Terapia empirica o mirata?
L’importanza del timing
terapeutico
Marco Falcone
Department of Public Health and Infectious Diseases
Scuola Superiore Studi Avanzati Sapienza (SSAS)
“Sapienza” University of Rome
Principles of Antibiotic Therapy
Empiric Therapy (85%)
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Infection not well defined
(“best guess”)
Etiology unknown
Broad spectrum
Multiple drugs
Evidence usually only 2
randomized controlled trials
More adverse reactions
More expensive
Directed Therapy (15%)
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Infection well defined
Narrow spectrum
One, seldom two drugs
Evidence usually stronger
Less adverse reactions
Less expensive
Why So Much Empiric Therapy?
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Need for prompt therapy with certain infections
– Life or limb threatening infection
– Mortality increases with delay in these cases
Cultures difficult to do to provide microbiologic
definition (i.e. pneumonia, sinusitis, cellulitis)
Negative cultures
Provider Beliefs
– Fear of error or missing something
– Not believing culture data available
– “Patient is really sick, they should have ‘more’
antibiotics”
– Myth of “double coverage” for certain infections
– “They got better on drug X, Y, and Z so I will just
continue those”
Untoward Effects of Antibiotics
• Antibiotic resistance
• Adverse drug events (ADEs)
– Hypersensitivity/allergy
– Drug side effects
– Clostridium difficile infection
– Antibiotic associated diarrhea/colitis
• Increased health-care costs
Ohl CA, Luther VP. J. Hosp. Med. 2011;6:S4
Empirical therapy: decisional process
EMPIRICAL THERAPY
TIMING
-Spectrum of
coverage
- Patterns of
resistance
Severity
Allergy/Toxicity
Formulation (IV vs. PO); if
PO assess bioavailability
Achievable serum,
tissue, or body fluid
concentration (e.g.
cerebrospinal fluid,
urine)
Fraction of total patients
Effect of timing on survival
Time from hypotension onset (hours)
Crit Care Med 2006;34:1589-96
Case report
• 81-year-old woman, diabetic, previous AMI, admitted to
Emergency Department for dyspnea, confusion, cough and
productive sputum
• No fever
• Resident in a nursing home, acute mental deterioration.
Urinary tract infection treated with ciprofloxacin 1 month
earlier.
• WBC 21.000, marked hypoxemia, C-reactive protein +++,
procalcitonin ++
• Chest radiograph…
Chest radiograph
Start therapy with levofloxacin 750 MG every 24 hours
Patient characteristics
• Comorbidities
• Mental status deterioration
• No fever
• Recent antibiotic therapy with quinolones
• Residence in a nursing home
Evolution of clinical case
• Worsening of respiratory function, ICU
transfer, tracheal aspirate Gram stain:
gram-positive cocci.
• Culture: methicillin-resistant S. aureus
(MRSA) > 105
• Start Vancomicin 1 g loading dose then 1 g
every 24 ore
• Renal failure (creatinine 2.5), shift to
linezolid 600 mg every 12 hours.
• The patient die.
Epidemiological classification of pneumonia
Communityacquired pneumonia
Common infecting pathohens
- Streptococcus pneumoniae
- Mycoplasma pneumoniae
- Chlamydia pneumoniae
- Haemophilus influenzae
- Legionella species
- Respiratory viruses
- Antibiotic-susceptible
Enterobacteriaceae
Potential treatment regimen
- Respiratory fluoroquinolone
or
- beta-lactam + macrolide
Hospital-acquired
pneumonia
Possible infecting pathogens:
•Pseudomonas aeruginosa
•MRSA
•Acinetobacter spp
•Enterobacteriaceae (ESBL+)
•Legionella pneumophila
Start empirical treatment
- Third or fourth generation cephalosporin
(ceftazidime or cefepime) or Carbapenem
(imipenem,
meropenem)
or
Piperacillin/tazobactam
plus
- Quinolone (levofloxacin or ciprofloxacin) or
Aminoglycoside
plus
- Linezolid or vancomycin
CAP: relationship between severity and
etiologies
PATHOGEN
ADULTS
(mild to moderate)
ADULTS
(severe)
S. pneumoniae
M. pneumoniae
H. influenzae
S. aureus
M. catharralis
L. pneumophila
50%
15- 25%
20-30%
5%
20%
<1%
S. pneumoniae
30%
L. pneumophila
15%
S. aureus
10-20%
Enterobacteriaceae 10-20%
P.aeruginosa
5-10%
Mycobacteria
1-3%
PLoS One 2015;10:e0119528.
Distributions of MDR bacteria
PLoS One 2015;10:e0119528.
Factors associated with isolation of MDR bacteria
PLoS One 2015;10:e0119528.
PLoS One 2015;10:e0119528.
PLoS One 2015;10:e0119528.
Empirical therapy: decisional process
EMPIRICAL THERAPY
-Spectrum of
coverage
- Patterns of
resistance
Severity
Allergy/Toxicity
Formulation (IV vs. PO); if
PO assess bioavailability
Achievable serum,
tissue, or body fluid
concentration (e.g.
cerebrospinal fluid,
urine)
Clin Infect Dis 2012; 54:1739-46
Diagn Microbiol Infect Dis 2009; 64: 402-407
T2 Magnetic Resonance Assay for
the Rapid Diagnosis of
Candidemia in Whole Blood
T2MR and T2 Candida:
time to detection!
Pfaller MA et al. Future Microbiol. 2016;11:103-17
Clinical case, 2
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Diabetic patient undergone urgent cardiothoracic surgery, ICU
admission.
CVC, TPN, multiple drainages, secretion from sternal wound
infection
7th post-operative day fever, hypotension, chest radiograph no
new infiltrates, urine microscopy: no leukocytes
Redness around CVC insertion, removal of CVC, blood cultures and
start daptomycin 8 mg/Kg/day plus pip/taz 4.5 g 3 times daily
Blood cultures positive for MRSA,
No improvement, persistance of hypothension evolution in septic
shock
Persistence of MRSA bacteremia
No response death
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Check for daptomycin level……AUC 24 h 188…..
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≥ 1.36 L/min
(≥ 75° percentile)
Clin Infect Dis 2013; 57:1568-76
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Clin Infect Dis 2013; 57:1568-76
Clinical features of patients
with augmented daptomycin
clearance
Clin Infect Dis 2013; 57:1568-76
Probability of target attainment (PTA) and toxicity in patients
with severe sepsis or septic shock at Monte Carlo simulation
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Clin Infect Dis 2013; 57:1568-76
Fraction of total patients
Effect of timing on survival
Time from hypotension onset (hours)
Crit Care Med 2006;34:1589-96
Pharmacokinetics of Antimicrobial Therapy
Dosing
regimen
Concentration
versus time in
serum
Concentration
Cmax
AUC
ABSORPTION
DISTRIBUTION
METABOLISM
ELIMINATION
Pharmacokinetics
“PK”
Elimination half-life (T1/2, k10)
Cmin
0
Time (hours)
Plasma pharmacokinetics of antimicrobial
agents in critically ill patients
Federico Pea, Current Clinical Pharmacology 2013; 8: 5-12
High-Dose Micafungin for Preterm Neonates and Infants
with Invasive and Central Nervous System Candidiasis
18 pre-term newborns with invasive candidasis
Auriti C, Falcone M….Pai MH. Antimicrob Agents Chemother 2016 Oct 3
High-Dose Micafungin for Preterm Neonates and Infants
with Invasive and Central Nervous System Candidiasis
0
200
400
600
800
- Suggested EMEA dosage of micafungin in neonates 2 mg/kg/day
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9
10
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12
Dose (mg/kg)
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5th-95th Percentile (observed)
Median (observed)
5th-95th Percentile (model predicted)
Median (model predicted)
Individual Bayesian Estimated (external validation)
Auriti C, Falcone M….Pai MH. Antimicrob Agents Chemother 2016 Oct 3
The last consideration….
THE RIGHT CHOICE AT THE RIGHT TIME
Induction of resistance among Gram-negative
bacilli
abuse 3rd gen cephalo + fluoroquinolones
Cef -R P.aeruginosa
Klebsiella ESBL+
E.coli ESBL+
Enterobacter
Citrobacter
Increased use of carbapenems
Carba-R P.aeruginosa
KPC Klebsiella
S.maltophilia
Carba-R Acinetobater
Considerations About Antimicrobial Stewardship in Settings with
Epidemic Extended-Spectrum b-Lactamase-Producing or CarbapenemResistant Enterobacteriaceae
Viale P et al. Infect Dis Ther 2015; 4 (Suppl 1):S65–S83
Conclusions
• Appropriateness of antibiotic therapy: the right drug at
the right time
• Switch therapy if appropriate
• Knowledge of bio-availability of drugs and potential
side effects
• Final decision: ….the clinician