antiupdate

Report
Antibiotics:
Novel and Rediscovered
Stephen Swanson, MD, DTM&H
Pediatric Infectious Diseases, Travel Medicine
Department of Pediatrics
Hennepin County Medical Center
Antibiotic Groups
•
•
•
•
•
•
•
•
•
•
•
•
•
PENICILLINS
CEPHALOSPORINS
Monobactams, Carbapenems
Vancomycin (Glycopeptide)
Linezolid (Oxazolidinone)
Aminoglycosides
Macrolides
Clindamycin
Tetracyclines
Sulfonamides plus trimethoprim
Rifamycins
Quinolones
Metronidazole
β – lactams
Truth in Advertising
Objectives
• MRSA Epi Trends
• Old Antibiotics used for Gram-positive
Infections
• Newer Antibiotics: on Horizon and Approved
Evolution of Drug Resistance
in S. aureus
Penicillin
Methicillin
Penicillin-resistant
MethicillinS. aureus
resistant
[1950s]
S. aureus
[1960s] S. aureus (MRSA)
[ 1998 ]
[ 1981 ]
[ 1999 ]
4 Pediatric
Deaths in
MN and ND
- MMWR
“Community Acquired
MRSA in Children
With No Identified
Predisposing Risk”
-JAMA
CA-MRSA among
IV Drug Users)
Minnesota Population Distribution
and Sentinel Hospital Laboratories
.
.
.
.
.
.....
.
CA-MRSA in MN: a shift from
USA400 to USA300 lineage
CA-MRSA in MN: a shift from
USA400 to USA300 lineage
USA300 MRSA
(predominant lineage)
is more susceptible to
clindamycin
CA-MRSA Antibiotic Susceptibilities
in MN, 2006 (N=492)
Antibiotic
% Susceptible
Erythromycin
17 %
Clindamycin
95 %
Ciprofloxacin
72 %
Tetracycline
96 %
TMP/SMX
100 %
Gentamicin
100 %
Vancomycin
100 %
Linezolid
100 %
Rifampin
99 %
Mupirocin
97 %
Source: MDH
CA-MRSA Antibiotic Susceptibilities
in MN, 2006 (N=492)
Antibiotic
% Susceptible
Erythromycin
17 %
Clindamycin
95 %
Ciprofloxacin
72 %
Tetracycline
96 %
TMP/SMX
100 %
Gentamicin
100 %
Vancomycin
100 %
Linezolid
100 %
Rifampin
99 %
Mupirocin
97 %
Source: MDH
Epidemiologic Trends of MRSA:
USA300 and USA100
•
USA300 strain more common among:
– Patients < 20 years
– ~92% susceptible to clindamycin
– Wound/abscess
•
USA100
– Blood, lower respiratory tract
– Elderly (age > 65)
– 95% resistance to clindamycin
Activity of Ceftaroline and Epidemiologic Trends of Staphlyococcus aureus collected
from 43 Medical Center in the United States in 2009; Richter et al., Antimicrob Agents
Chemother. 2011
CA-MRSA Antibiotic Susceptibilities
in MN, 2006 (N=492)
Antibiotic
% Susceptible
Erythromycin
17 %
Clindamycin
95 %
Ciprofloxacin
72 %
Tetracycline
96 %
TMP/SMX
100 %
Gentamicin
100 %
Vancomycin
100 %
Linezolid
100 %
Rifampin
99 %
Mupirocin
97 %
Source: MDH
CA-MRSA Antibiotic Susceptibilities
in MN, 2006 (N=492)
Antibiotic
% Susceptible
Erythromycin
17 %
Clindamycin
95 %
What about
rifampin and
72 %
Tetracycline
96
%
gentamicin?
Ciprofloxacin
TMP/SMX
100 %
Gentamicin
100 %
Vancomycin
100 %
Linezolid
100 %
Rifampin
99 %
Mupirocin
97 %
Source: MDH
Clinical Practice Guidelines by
IDSA for MRSA - 2011
• Addition of gentamicin or rifampin
for bacteremia or native valve infective
endocarditis not recommended in adults
(A-II, A-1 evidence)
• Data in children insufficient to support
routine use of combination therapy.
• Osteomyelitis – maybe helpful
• Pneumonia – not likely helpful
• Eradication – never rifampin monotherapy
BACTRIM:
Why Bactrim Might Fail with ca-MRSA
infections…
Why Bactrim Might Fail with MRSA
infections…
Why Bactrim Might Fail with MRSA
infections…
Take-home:
Avoid TMP-SMX monotherapy if significant
amount of tissue damage/necrosis
MRSA necrotizing pneumonia
following influenza
Vancomycin Limitations:
Newer Gram-positive Antibiotics Needed
• Burden of MRSA increasing
• USA300 entering hospital system
• Treatment failures and poor outcomes with
Vancomycin
– Variable dosing/levels
– Limited penetration of bone, lung epithelial
fluid, CSF
– Slow killing time, especially higher inocula
• MIC creep (> 2 μg/mL) requires higher dosing
Linezolid
• Oxazolidinone-class antibiotic
– Inhibits protein synthesis
– Excellent bioavailability
– Excellent CSF penetration
• Covers GAS, S. pneumoniae, MSSA/MRSA,
enterococcus, Listeria, oral anaerobes
– Uses:
• Pneumonia
• Complicated SSTI
• Osteomyelitis
• Meningitis*
– Failures: endocarditis (static)
• Major side effect: reversible myelosuppression
– Follow weekly CBC if using > 2 weeks
Minocycline – the forgotten child
•
•
•
•
Oral and IV
Can be used in MRSA SSTI
Data lacking for more invasive infections
Very active against MRSA and CONS embedded in
biofilms on catheters
Raad I., et al.
Antimicrob. Agents
Chemother,
May 2007
Ceftaroline fosamil (Teflaro)
•
•
•
•
5th generation cephalosporin
Low propensity for inducing resistance
Excellent safety profile
Gram-positive bacteria (CONS, MRSA, VISA,
VRSA, resistant pneumococcus, resp gram negs)
– 4-fold greater activity against MRSA than Vanc
– 16-fold greater activity against MSSA than Ceftr
– Active against daptomycin- and linezolidresistant staph
• Avoid in ESBLs, Pseudomonas, Acinetobacter
• FDA approved in 2010 for CAP and cSSTI (adults)
Ceftobiprole - another 5th gen ceph
• Active against MRSA
• Approved in Canada
• FDA approval pending further evaluation
The newer antibiotics…
never to be approved for children?
Daptomycin
Activity of Nafcillin, Vancomycin
and Daptomycin
 Rapid killing of almost
all clinically relevant
gram-positive bacteria
 Effective all stages of
bacterial growth
10
Log10 CFU S aureus per thigh
 An old drug, that
did not receive
FDA approval until
2003
Vanco
Nafcillin
Dapto
1
0
6
12 18 24 48
Time (hours)
T. Greenhow, MD
Daptomycin
 Clinical trials in complicated SSTIs showed it
was equivalent to nafcillin / vancomycin
 Cure rate >96%
 Currently indicated for complicated SSTIs (adult)
 Drug was found to be less effective than
ceftriaxone in treating community-acquired
pneumonia
– Binds to surfactant which reduces its activity in the alveolar
spaces of the lung
Carpenter, CF and HF Chambers CID 2004
Hancock, RE Lancet 2005
Daptomycin
 Approved for right-sided endocarditis, S. aureus
bacteremia (6mg/kg)
 Prolonged half-life (once daily dosing)
 Monitor weekly CPK levels (dose-dependent,
reversible)
 Not FDA approved in 2 – 17 year olds, but literature
increasingly supportive
 Pregnancy B category
Carpenter, CF and HF Chambers CID 2004
Hancock, RE Lancet 2005
N Engl J Med 2006; 355:653-665
Adura M, et. al. “Daptomycin therapy for invasive Gram-positive bacterial
infections in children.” PIDJ 2007: 1128-1132
Daptomycin Pediatric Dosing
 Dosing under study. Recommended starting doses:
 Complicated SSTI
 9 mg/k IV QD (ages 2-6)
 7 mg/kg IV QD (ages 7-11)
 5 mg/kg IV QD (ages 12-17)
 Osteomyelitis, Septic Arthritis, Bacteremia
 6-10 mg/kg IV daily
 Failures more likely in patients with prior vancomycin
exposure or elevated vancomycin MICs (adult data)
Final notes
• Azithromycin resistance rates
– >20% for S. pneumoniae
– 5-10+% for GAS
• Clindamycin
– S. pneumoniae (~88% susceptible)
– Group A streptococcus (~10% inducible
resistance)
– Group B streptococcus (~70% susceptible)
Thank you.

similar documents