The Scarlet Gospels

Susan Fryters
Susan Fryters, BScPharm., ACPR
NPAA Conference
June 2013
Objectives
To review key changes in the Bugs & Drugs book with
a focus on:
antimicrobial resistance and how it is affecting the
treatment of common infections
principles of antimicrobial stewardship in treating
infections and preventing antimicrobial resistance.
Bugs & Drugs 2012
Authors
Dr. Edith Blondel-Hill, MMID
Susan Fryters, BScPharm, ACPR
> 40 editorial contributors and reviewers
Literature search from 2005-August 2011 → Almost
1900 references (1/3 new)
Key references/guidelines cited throughout
Supported by:
Alberta Health Services (AHS)
Alberta Health (AH)
BC Ministry of Health
Do Bugs Need Drugs? program
Bugs and Drugs 2012
Sections
Antibiotics
Treatment Recommendations
Prophylaxis Recommendations
Dental
Pregnancy/Lactation
Organisms
References – available on-line only
Susan Fryters
Vancomycin
Dosing/Monitoring Guidelines
Antibiotics
Antimicrobial Spectrum of Activity
Pharmacodynamics
Dosing Guide and Daily Costs
Adult
Paediatric
Aminoglycosides - Dosing/Monitoring Guidelines
High-Dose Extended Interval
Conventional
Vancomycin Dosing/Monitoring Guidelines
Adult Dosing Guidelines in Renal/Hepatic Impairment
Loading Dose:
25-30mg/kg (ABW; no maximum) single dose followed by
MD at appropriate dosing interval, e.g. q8h, q12h, etc.
Severe infections - where rapid attainment of target
g of 15-20mg/L
g needed,, e.g.:
g
trough
Vertebral osteomyelitis
Epidural abscess
MRSA pneumonia
Septic shock
Patients with significant renal dysfunction - to
decrease time to target trough level
Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of ASHP,
IDSA, SIDP) Am J Health Syst Pharm 2009;66:82-98..
Vancomycin
Dosing/Monitoring Guidelines
Maintenance Dose (MD):
15mg/kg (ABW; empiric max of 2g/dose) at dosing
interval based on Clcr and target trough
q8h dosing in patients with good renal function
Calculated Clcr
(mL/min)
Dosing Interval for trough
10-20mg/L
Dosing Interval for trough
15-20mg/L
≥ 80
q12h
q8h
40 - 79
q24h
q12h
20 - 39
q36h
q24h
10 - 19
q48h
q48h
< 10
Consider loading dose.
Obtain pharmacist consult.
Consider loading dose. Obtain
pharmacist consult.
Vancomycin
Dosing/Monitoring Guidelines
Desired trough levels:
Serious MRSA infection
CNS infections
Endocarditis
Osteomyelitis
Pneumonia
Bacteremia
All other infections
15 20 mg/L
15-20
10-20 mg/L
Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of ASHP,
IDSA, SIDP) Am J Health Syst Pharm 2009;66:82-98..
Antibiotics
Antimicrobial Generic/Trade Name Listing
IV to PO Switch Recommendations
CSF Penetration of Antimicrobials
β-lactam Allergy
Susan Fryters
β-Lactam Allergy
Accurate allergy history important:
to determine nature of reaction
to decrease use of broad spectrum alternatives
Cross-reactivityy between p
penicillin &:
cephalosporins 1% (2.55% if confirmed pen
allergy)
negligible between penicillin &:
2nd generation cephs (except cefaclor &
cefprozil)
3rd and 4th generation cephs
carbapenems ~1%
Frumin J, Gallagher JC. Allergic cross-sensitivity btwn pen, carbapenem, monobactam abx. AnnPharmacother 2009;43:304-15
Management of
β-Lactam Allergy
If documented severe non-lgE-mediated reaction
to penicillin, such as:
interstitial nephritis
Avoid all β-lactams (penicillins,
hepatitis
cephalosporins, carbapenems)
hemolytic anemia
serum sickness
severe cutaneous reactions
If documented severe lgE-mediated reaction
to penicillin, such as:
Avoid penicillins, firstgeneration and secondurticaria (hives)
laryngeal edema, angioedema generation cephalosporins
Solensky R, Khan DA, eds. Drug allergy: an updated practice parameter. Ann Allergy, Asthma & Immunol 2010;105:273.e1-78.
Frumin J, Gallagher JC. Allergic cross-sensitivity btwn pen, carbapenem, monobactam abx. AnnPharmacother 2009;43:304-15
Management of
β-Lactam Allergy
TREATMENT
RECOMMENDATIONS
Treatment options for pts with severe IgEmediated pen allergy include:
Non-β-lactam
β
antibiotic
or
3rd or 4th -generation cephalosporin or
carbapenem via graded challenge*
or
3rd or 4th -generation cephalosporin or
carbapenem after drug desensitization*
Recommended Empiric Therapy of Selected Infections
Neonates/Paediatrics
Adults
Ophthalmic
Fungal
Enteric Parasitic
Solensky R, Khan DA, eds. Drug allergy: an updated practice parameter. Ann Allergy, Asthma & Immunol 2010;105:273.e1-78.
TREATMENT RECOMMENDATIONS
Recommended Therapy of Culture-Directed Infections
Pneumonia
CAPD Peritonitis
Adult - ISPD 2010 Guidelines
Pediatrics - ISPD 2012 Guidelines
Meningitis
Endocarditis - gent synergy for native valve
MSSA/MRSA endocarditis no longer recommended
due to increased nephrotoxicity, and no difference in
cure, mortality, or relapse
Culture- negative Endocarditis
MRSA
Methicillin-resistant S. aureus
resistant to all β-lactams (cloxacillin, cefazolin,
other cephs, carbapenems)
Community-associated MRSA (CA-MRSA)
56% of MRSA isolates in Edmonton
may be susceptible (S) to TMP/SMX,
doxycycline, clindamycin
all S to vancomycin
Healthcare/hospital associated MRSA (HA-MRSA)
usually only susceptible to vancomycin,
[linezolid, daptomycin]
Susan Fryters
MRSA
MRSA
Significant M&M in both CA & HA infections - SSTI,
pneumonia, bacteremia
20-25% of S. aureus clinical isolates in western Canada
are MRSA
Edmonton – 13%, UAH ~20%
Calgary – 19%
Resistance to clindamycin (and quinolones) very
% Susceptible
common
Clindamycin
Tetra/Doxy
TMP/SMX
Vancomycin
63
vs. MSSA 76%
96
97
100
Calgary –
S. aureus
62-77
97
96-97
100
Central –
MSSA
80
97
99
100
Edmonton –
MRSA
Empiric therapy of serious infections – vancomycin
or linezolid
Switch to β-lactam if appropriate and susceptible
(MSSA) as better outcome – next slide
Increased vancomycin MICs → clinical failure
Linezolid preferred over vancomycin if:
vancomycin MIC ≥ 1.5µg/mL
concurrent nephrotoxins
pre-existing renal dysfunction
Drugs for Serious MRSA Infections
cSSSI
Drug
Daptomycin
Bactericidal vs. (MR)SA
•
Once daily
•
Potential for cross-resistance with
vancomycin
•
Not for use in lower RTIs
•
ADRs: dose-dependent
dose dependent ↑ CK,
CK
rhabdomyolysis
Vancomycin
•
Slowly bactericidal vs (MR)SA
•
Twice-thrice daily, IV only
Linezolid IV/PO
•
Bacteriostatic vs. (MR)SA
•
ADRs
•
Twice daily
•
Oral formulation
Bacteremia/IE
Dosage
Dosage
4mg/kg IV Q24h
6mg/kg IV Q24ha
15mg/kg IV Q12H
15mg/kg IV Q8-12H
600 mg Q12H
600 mg Q12Hb
•
a. Although daptomycin is approved at this dosage, higher doses (up to 12 mg/kg/day) are being used due to its concentration dependent
activity to increase its antibacterial activity and potentially prevent the development of resistance.
b. Linezolid is not indicated for bacteremia or infective endocarditis specifically although there are limited clinical data on its use in
bacteremia & infective endocarditis.
Skin/Soft Tissue Infections
Skin/Soft Tissue Infections
MRSA
Superficial – when to use systemic therapy vs. topical
Impetigo
Folliculitis/furunculosis
Carbuncles
Cellulitis – differential diagnosis
Clindamycin – significant Strep/Staph resistance
– use only if β-lactam allergy
– monitor clinical response
Empiric therapy:
Carbuncles – unresponsive to clox or cephalexin
I&D +/TMP/SMX
or
Doxycycline
Purulent cellulitis
Mild: I&D if abscess +/Cephalexin (for MSSA/Strep) +
[TMP/SMX or Doxycycline (for MRSA/MSSA)]
Moderate-severe: I&D if abscess +
Vancomycin
Susan Fryters
Bone & Joint Infections
Diabetic Foot Infections
Added section on Vertebral OM:
Most common type of OM in adults
S. aureus most common; MRSA especially if:
preceding trauma
multifocal lesions
disease in adjacent muscle
Empiric coverage of P. aeruginosa IF:
tropical/warm climates
soaking of feet
failed nonpseudomonal therapy
limb threatening infection
limb-threatening
Rx: Cloxacillin 2g IV q4h
MRSA/β-lactam allergy
Vancomycin 25-30mg/kg once
then 15mg/kg IV q8-12h
Empiric coverage of MRSA IF:
previous (prior 12 months)/current
colonization/infection with MRSA
recent antibiotic use
recent hospitalization
Alternative
Linezolid or
TMP/SMX
Lipsky BA, et al. IDSA clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73.
Zimmerli W. Vertebral osteomyelitis. N Engl J Med 2010;362:1022-9.
Sinusitis
S. pneumoniae
Penicillin resistance has stabilized – still very low rates of pen R in
Western Canada justifying:
continued use of oral amoxicillin (best activity of any oral β-lactam
agent) for mild-moderate infections &
Ceftriaxone for more serious infections
Pen IV can be used if penicillin S confirmed
Significant resistance to macrolides (21-29%), clindamycin (14%), and
(6-32%)
TMP/SMX (6-32%).
Empiric therapy with these agents no longer recommended for
majority of RTIs
New IDSA guidelines:
Chow AW, et al. IDSA clinical practice guideline for
acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012:x:e1-41.
70% spontaneous resolution; only treat IF:
Symptoms >10 days
Worsening after 5-7 days
Severe - ≥ 39 C and purulent nasal discharge or facial pain x
3-4 consecutive days
Immunocompromised
% Susceptible
Pen
PO*
Pen IV
NM*
Pen IV
M**
Amox
*
Cefuroxime
Ceftriax
one**
Clindamycin
Erythromycin
Tetracycline
TMP/
SMX
Levofloxacin
Edmonton
87
91
85
100
91
100
86
76
83
83
99
Calgary
NA
NA
82-96
NA
NA
91-98
NA
71
86
68
100
Central
NA
NA
NA
NA
NA
100
NA
79
NA
94
NA
Local S. pneumoniae resistance
⇒ Macrolides, TMP/SMX and second generation cephalosporins
no longer recommended empirically
Rx: Amoxicillin – high dose if antibiotic use in past 3 months
Alternative: Doxycycline
*NM = nonmeningeal breakpoint
**M = meningeal breakpoint
AECB
First line:
Amoxicillin or
Doxycycline or
TMP/SMX
Second line:
Amoxicillin-clavulanate or
Cefuroxime axetil or
Levofloxacin
NB: Macrolides only as alternative to these due to
poor Haemophilus coverage and significant S.
pneumoniae resistance
Outpatient CAP
Imperative to adequately cover S. pneumoniae - add
Amoxicillin to Doxycycline if:
lobar pneumonia with fever or rigors
recent antibiotic therapy
tetracycline
y
resistance > 15%
Cover MRSA (Doxycycline or TMP/SMX) IF:
S. aureus/GPC clusters on Gram stain
diabetes
recent influenza
Duration: minimum of 5 days and until afebrile 4872h
Mandell LA, et al. IDSA/ATS consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:27-72.
Susan Fryters
Hospitalized &
Severe/ICU CAP
HAP/VAP
Cover MRSA IF:
coma
DM
head injury
recent influenza
IVDU
antibiotics in past 3 months
lung disease (bronchiectasis/CF)
immunosuppression
Cover MRSA (Vancomycin or Linezolid) IF:
rapid onset
necrotizing process on CXR
recent influenza
colonization/recent infection with MRSA
S. aureus/GPC clusters on Gram stain
Duration:
7 days
14 days if MRSA, Pseudomonas, Acinetobacter
NHAP
Gram Negative Resistance
Imperative to adequately cover S. pneumoniae –
Amoxicillin 1g PO tid
COPD or post-influenza – use Amoxicillin(plus Doxycycline
y y
or Azithromycin
y
or
clavulanate (p
Clarithromycin if underlying pulmonary disease) as
better coverage of :
M. catarrhalis/H. influenzae
S. aureus
Duration: 7 days
FQ and TMP/SMX resistance in enteric GNB (E. coli,
Proteus mirabilis, Morganella morganii, Serratia
marcescens) > 20% → empiric therapy with FQs &
TMP/SMX no longer recommended for infections where
GNs are predominant pathogens – GI, UTI
% Susceptible
Amp/
Amox
Amox
clav
Cefixime
Ceftria
xone
TMP/
SMX
Cipro
NTF
(urine)
Gent
38
68
92
94
76
77
99
92
Calgary
39-44
NA
NA
86-89
71-78
71-77
93-96
83-91
Central
63
NA
NA
99
80
83
98
94
E. coli
Edmonton
Gram Negative Resistance
ESBL & AmpC
Increased β-lactam (pen/ceph) resistance due to ESBL (3.5% of
Enterobacteriaceae) and Amp C β-lactamases
Typically associated with multi-resistance to other antibiotic classes
including TMP/SMX, FQs, tetracyclines, aminoglycosides
ESBL increasingly seen in community-acquired infections,
especially UTIs (90% of ESBLs are seen in urine)
C b
Carbapenems
often
ft only
l class
l
lleft
ft tto ttreatt serious
i
ESBL and
d Amp
A
C infections, and NTF or fosfomycin for uncomplicated UTIs
But now carbapenemase–producing organisms (KPC)
UTI
Increased FQ, TMP/SMX and amoxicillinclavulanate resistance of E. coli
first line empiric therapy with these no longer
recommended
if used, confirm S by culture
% Susceptible
E. coli
Amp/
Amox
Amox
clav
Cefixime
Ceftria
xone
TMP/
SMX
Cipro
NTF
(urine)
Gent
% Susceptible
ESBL E. coli
TMP/
SMX
Cipro
NTF
(urine)
Gent
Erta
Mero
Imip
Edmonton
40
11
96
63
100
100
100
Central*
40
12
89
78
NA
100
NA
* Piperacillin-tazobactam susceptibility listed but shouldn’t be used even if documented S as clinical failures have
been reported. Carbapenem best option.
Edmonton
38
68
92
94
76
77
99
92
Calgary
39-44
NA
NA
86-89
71-78
71-77
93-96
83-91
Central
63
NA
NA
99
80
83
98
94
Susan Fryters
UTI
Fosfomycin (Monurol)
Monurol)
Use cefixime, nitrofurantoin*†, fosfomycin*†
* For uncomplicated UTI only; not for complicated,
pyelonephritis, or urosepsis as poor renal tissue and
serum concentrations / lack of clinical data
†
Effective against majority of ESBL E. coli
Once only drug for uncomplicated UTI
Spectrum of activity:
E coli
E.
coli*
* including ESBL
P. mirabilis*
Citrobacter spp*
E. faecalis
NOT S. saprophyticus
Back on the market through Triton
Under consideration for listing on AH DBL
Gupta K, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a
2010 update by the IDSA and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103-20.
Complicated or catheter
catheter-associated UTI
Add gentamicin if:
Septic shock
Recent antibiotic use
Suspected
p
ESBL,, AmpC
p or carbapenemase
p
producing organism
Duration:
If prompt response (48-72h): 7 days
If delayed response or structural abnormality:
14 days
Hooton TM, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical
practice guidelines from the IDSA. Clin Infect Dis 2010;50:625-63.
Clostridium difficile
infection (CDI)
Anaerobe Resistance
Increased resistance and clinical failures
Clindamycin R common in both GP and especially GN
anaerobes
Increased R to moxifloxacin, especially Bacteroides and
Prevotella
M t id
Metronidazole
l and
d carbapenem
b
R still
till relatively
l ti l rare b
butt
have been found with increasing frequency
% Susceptible
Edmonton
Pen
Clinda
Anaerobic GPC
100
49
Metro
99
B. fragilis /
B. fragilis group
3
51
100
Clostridium spp
94
78
100
Fidaxomicin (Dificid)
Dificid)
New class of drug for CDI
2 RCTs: Noninferior to vancomycin PO for cure; superior
in reducing CDI recurrences
200mg PO bid x 10 days
$231.00/day
Common Drug Review recommendation: DO NOT LIST
at submitted price
Cohen SH, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by SHEA and IDSA. Infect Control Hosp
Epidemiol 2010;31:431-55.
Susan Fryters
GI infections
Intra--abdominal infections
Intra
Updated H. pylori to include sequential therapy
Increased FQ and cefazolin resistance:
Empiric therapy for peritonitis and cholecystitis now
ceftriaxone + metronidazole,
metronidazole not cefazolin*
* If cefazolin is reported as S, can use but at 2g/dose
Ciprofloxacin only if severe β-lactam allergy
STI/Genital
STI/Genital
Updated as per 2010 Canadian PHAC guidelines
Neisseria gonorrhoeae
Increased FQ R → quinolones no longer
recommended
d d [PHAC D
Dec 2011]
Increased ceph R:
⇒ higher doses of cephalosporins recommended
⇒ Ceftriaxone recommended in:
MSM or
pharyngeal infection
Genital Ulcers
Table on Clinical Features and Diagnosis
Central Nervous System
Added section on Recurrent/chronic meningitis
Empiric coverage of MRSA IF:
Post-trauma or postop meningitis
Shunt/EVD meningitis/ventriculitis
B il skull
Basilar
k ll ffracture
t
and
d prolonged
l
dh
hospitalization
it li ti
Colonized with MRSA and brain abscess 2 to IE or
epidural abscess
Greatly expanded section on Encephalitis including:
Epidemiology
Investigations
Etiology
Susan Fryters
Fungal Infections
Cardiovascular
Candida
[Pappas PG, et al. Clinical practice guidelines for the management of
candidiasis: 2009 update by the IDSA. Clin Infect Dis 2009;48:503-35.]
Added section on Cardiac device related
infections/ endocarditis (CDRIE)
Empiric coverage of MRSA recommended in:
Purulent pericarditis
Endocarditis
CDRIE
Fungal Infections
Prophylaxis
Recommendations
C. albicans and C. glabrata - > 80% of all
Candida from sterile sites:
% Susceptible
Oropharyngeal
Esophageal
y p
g risk
Candiduria – onlyy treat symptomatic
or high
patients
Invasive candidasis/Candidemia:
Hemodynamically stable, no azoles past 3
months – fluconazole
Hemodynamically unstable or azoles in past 3
months – echinocandin (micafungin) or ampho B
Hepatosplenic Candidiasis/Chronic disseminated
candidiasis
Ampho B
Fluc
Vori
Mica
C. albicans
100
93
92
100
C. glabrata
100
NA
90
96
Source: UAH 2011 Antibiogram
PCP now in Fungal section as re-classified as a fungus
Prevention of
Perinatal Infection
Intrapartum Antimicrobial Prophylaxis of Group B Strep
Penicillin/Ampicillin 1st line
Non severe β-lactam allergy: Cefazolin
Increased erythromycin and clindamycin resistance of
Group B Strep
⇒ Erythromycin no longer recommended
⇒ Clindamycin only if susceptibility confirmed
Vancomycin now recommended if severe pen allergy
and clindamycin resistance or susceptibility unknown
Centers for Disease Control and Prevention. Prevention of perinatal Group B streptococcal disease. Revised guidelines from CDC, 2010.
MMWR 2010;59(No. RR-10):1-31.
Surgical Prophylaxis → iPhone, AHS on-line
Endocarditis Prophylaxis – AHA 2007 guidelines
Blood/Body Fluid Exposure
Sexual Assault
Prophylaxis for Contacts of Communicable Diseases
Infection Prevention and Control
MRSA/VISA/VRSA
VRE
CDI
ESBL
AmpC
Carbapenemases
ORGANISMS
Antibiograms (no longer in book)
Calgary Zone
Antibiograms 2012 (CLS)
p
g y
http://www.calgarylabservices.com/files/LabTests/Micro
biologyNewsletters/2012_Antibiogram.pdf
Edmonton Zone
Antibiograms 2011 – UAH & Stollery Children’s Hospital
Antibiograms 2011 – Edmonton Hospitals (DynaLIFE)
Central Zone 2011
South Zone 2010
http://www.albertahealthservices.ca/3294.asp
Susan Fryters
Antimicrobial Stewardship
Appropriate use of antibiotics is critical since:
Antimicrobial resistance is increasing, leading not only
to increased costs of patient care but also to increased
morbidity and mortality
In the hospital setting:
Over 50% of patients in hospital receive antibiotics
during their stay – at least 50% unneeded in most
studies
Antimicrobials comprise the single largest category of
drug expenditures in AHS hospitals at approximately
20% of the drug budget
Antimicrobial Stewardship
Appropriate:
1. Selection:
Empiric – B&D
Definitive – B&D and C&S results
Streamlining or de-escalation
2. Dosing – PK/PD
3. Route – IV to PO
4 Duration
4.
D ti – reduces
d
selective
l ti pressure on b
bacteria
t i
preventing emergence of resistance
of antimicrobial therapy to:
optimize clinical outcomes
minimize:
toxicity
superinfections, e.g. CDI
resistance
reduce health care costs – drug, HCAI, resistance
www.bugsanddrugs.ca
Antimicrobial Stewardship
Appropriate Duration
Louis Rice: “reduction in length of antibiotic therapy is
the antibiotic strategy most likely to be effective in
reducing antibiotic resistance.” [Rice LB, Maxwell Finland
ICAAC lecture. Clin Infect Dis 2008;46;491-6]
Clin Infect Dis 2011;52:1232-40.
J Antimicrob Chemother 2012;67:2570-5.
Bugs and Drugs
For more information:
[email protected]
Susan Fryters, BScPharm., ACPR
Edmonton Oliver PCN
April 2013
Susan Fryters
THANK YOU
`