Download Glenn Fennelly - Pediatric Multi-Drug Resistance Bacterial Infections

Pediatric Multi-Drug Resistant Bacterial
Infections: Can We Treat Effectively?
Glenn Fennelly, MD, MPH
Professor and Chair, Department of Pediatrics
Professor, Department of Microbiology and
Molecular Genetics
Rutgers-New Jersey Medical School
Pediatric MDR Bacterial Infections: can we treat?
Pediatric MDR Bacterial Infections: can we treat?
• Learning objectives: At the conclusion of the
presentation, the participants should be able to
– Cite emerging challenges in the management of
hospital-acquired (HAI) MDR gram-negative and
MRSA infections in children
– Select appropriate antimicrobials for treatment of HAI
or MRSA in children
– Identify opportunities to prevent HAI and MRSA in
children
Pediatric MDR Bacterial Infections: can we treat?
Pediatric MDR Bacterial Infections: can we treat?
• Emerging challenges in MDR infections
– Gram positive infections
– Gram negative infections
– Clostridium difficile
• Opportunities and novel approaches to prevent
HAI in children
– Infection Prevention
– Prudent diagnosis and antibiotic use
– Vaccination
Pediatric MDR Bacterial Infections: can we treat?
NO DRUGS FOR BAD BUGS ??
Rise in % Resistant Isolates Number of New Antibacterial Approvals
Spellberg, et. al., CID 2004
US, CDC
Pediatric MDR Bacterial Infections: can we treat?
Timeline of Key Antibiotic Resistance Events
CDC
Pediatric MDR Bacterial Infections: can we treat?
An estimated 721,800 HAI in U.S. in 2011.
•
•
•
•
•
22% pneumonia, 22% surgical-site, and 17% GI
Clostridium difficile the most common pathogen (12%)
14% in children < 18 years of age
26% device-associated (CLABSI, Foley-UTI, and VAP)
HAI kill at least 23,000 people each year
CDC and Magill S et al. 2014
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MDR gram positive infections
• MDR S. pneumoniae
– Do not treat viral URIs with antibiotics!
– Antibiotic overuse (amoxicillin largely sufficient)
• Methicillin-resistant S. aureus (MRSA)
– Community-acquired (CA) versus HA
Pediatric MDR Bacterial Infections: can we treat?
State-to-state variation in antibiotic prescriptions per 1000 persons of
all ages: opportunities to prevent unnecessary treatment
Pediatric MDR Bacterial Infections: can we treat?
Judicious Use of Antibiotics for URIs in Children
• Doctors prescribe antibiotics 62% of the time if they perceive
parents expect them but only 7% of the time if they don’t.
Mangione-Smith R et al.1999
• Risks: diarrhea, dermatitis, C difficile colitis, antibiotic resistance
• 1st-line therapy
• AOM: Watchful waiting if > 2 years old, Amoxicillin + clavulanate
• Sinusitis: Amoxicillin + clavulanate
• Confirmed GAS pharyngitis: Amoxicillin (once a day) or penicillin
• Avoid azithromycin and oral 3rd-generation cephalosporins
Hersh AL et al. 2013
*
*
*
* Formerly, increasing incidence of MDR serotype 19A
Prevnar 13 is effective against serotypes 1, 3, 4, 5, 6A, 6B, 7F,
9V, 14, 18C, 19 A, 19F, and 23F
Kyaw et al 2006
Pediatric MDR Bacterial Infections: can we treat?
Effectiveness of Various Antibiotics Against Penicillin
Resistant Pneumococcus
Antibiotic
Amoxicillin
MIC 90 ( g/ml)
S
I
R
0.03 0.1-1
2-4
Peak Concentrations
Serum
MEF
3.5-7
1-6*
Cefuroxime
Ceftriaxone
Cefprozil
0.12
0.06
0.25
1-4
1
4-8
4-16
1-4
32
2-7
171
6-26
1-2
35
2
Loracrabef
Cefixime
2
0.5
64
16
128
64
13-19
3-4
2-4
1-2
*Doubling the dose would increase MEF peak concentrations
to exceed the MIC 90 of resistant strains
Dowell PIDJ 1999
Pediatric MDR Bacterial Infections: can we treat?
Which the optimal empiric antibiotic for hospitalized child
with community-acquired (CAP) lobar pneumonia?
A.
B.
C.
D.
High dose ampicillin
Extended-spectrum cephalosporin
Macrolide
Vancomycin
• Narrow- as effective as broad-spectrum empiric antibiotics
(duration of O2 and fever, and LOS). Queen MA et al. 2014
• If PCN MIC < 2 g/ml, consider high-dose PCN
• If 3rd-gen ceph MIC > 8, consider vancomycin or clindamycin
Pediatric MDR Bacterial Infections: can we treat?
S. pneumoniae ceftriaxone in vitro “resistance”
(up to 40%): What is the clinical relevance?
• Ceftriaxone remains clinically effective against “resistant”
blood/lung infections due to high achievable serum levels
• CNS infections may fail treatment due to lower achievable
levels in CSF:
– Susceptible*
– Resistant*
MIC <0.5 (meningitis)
MIC >2.0 (meningitis)
<1.0 (non-meningitis)^
>4.0 (non-meningitis)^^
– ^Use of interpretive data for non-meningitis requires doses
appropriate for severe pneumococcal infection
– ^^Use empiric vancomycin + 3rd generation cephalosporin to treat
meningitis due to resistant strains
*revised NCCLS MIC break-points (microgms/mI)
Pediatric MDR Bacterial Infections: can we treat?
Guidance on Empiric Treatment of Severe
Pneumococcal Infections (USA)
• Pneumococcal conjugate vaccines have reduced
pneumococcal disease incidence
• There is an increasing likelihood that a case of invasive
pneumococcal infection will be MDR
• Pneumonia
– Avoid macrolides (high resistance rates)
– “High dose” ampicillin effective against intermediate/high PCN
resistance
• Meningitis (beyond the neonatal period)
– Empiric ceftriaxone plus vancomycin
– Add rifampin if high-level ceftriaxone resistant
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MDR gram positive
infections: Methicillin-resistant S. aureus (MRSA)
The most effective oral
antibiotic for empiric treatment
of community-acquired cellulitis
in a 5- year old child in Newark
in 2014 is
A. Clindamycin
B. TMP/SMX
C. Cephalexin
D. Doxycycline
E. TMP-SMX
F. A or C
Pediatric MDR Bacterial Infections: can we treat?
Considerations in Empiric Antibiotic Treatment of
Skin/Soft Tissue Infections
Purulent abscess
•Usually S. aureus
•I&D without antibiotics
may be sufficient
•Perform wound cultures
routinely
Isolated non-purulent
skin/soft tissue cellulitis
•Usually S. aureus or
GA HS
•Consider therapy against
GA HS, MSSA, and MRSA
streptococcus (GA HS is
resistant to TMP/SMX!)
Pediatric MDR Bacterial Infections: can we treat?
Optimal empiric antibiotic therapy of skin/soft tissue
infections in an era of increasing MRSA rates
• MRSA rates among all S. aureus infections generally > 50%
– 50% MRSA among all S. aureus isolates at Jacobi Pediatrics by 2009
– > 10-fold increase (from 0.8% to 9.2) in CA-MRSA colonization in
children in Nashville between 2001-2004
Creech B et al. 2007
• Consider disease severity when selecting therapy
.
Pediatric MDR Bacterial Infections: can we treat?
CA-MRSA differs genotypically and is distinct from
HA-MRSA (not a hospital strain that “escaped”)
• SCCmecIV (contains mecA that makes PBPs inaccessible)
inserted in to virulent MSSA strains
• USA300, a predominant strain implicated in unrelated outbreaks
of CA-MRSA across the US Kazakova SV et al 2005, Moran GJ et al. 2006
– Contain Panton-Valentine leukocidin gene (a secreted tissue toxin)
– Linked to more severe SSTI, pneumonia, and skeletal infections
– Contains the msr(A) erythromycin resistance gene and SCCmec type IV.
• Often retain susceptibility to clindamycin, TMP-SMX,
doxycycline, fluoroquinolones or rifampin
Pediatric MDR Bacterial Infections: can we treat?
The optimal IV antibiotic choice for empiric treatment
of hematogenous osteomyelitis in a previously
healthy 12 year old is
A. Vancomycin
B. Clindamycin
C. Linezolid
D. Daptomycin
E. TMP/SMX
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MRSA infections: optimal
empiric antibiotic therapy for skeletal infections
• Consider clindamycin, vancomycin OR linezolid
• S. aureus is isolated in half of all culture positive casesadditional bacterial pathogens include GA HS, GB HS, E.
coli, S. pneumoniae, K. kingae*
*Often resistant to vancomycin and clindamycin
yet susceptible to PCN, cephalothin,
cefotaxime, gent, chloramphenicol, tetracycline,
TMP/SMX, and CIPRO
Pediatric MDR Bacterial Infections: can we treat?
Is CA-MRSA associated with worse clinical outcomes?
• Skeletal infections: increased rate of bone abscess
(Saavedra-Lozano J, et al. 2008) and prolonged fever
(Carrillo-Marquez MA et al. 2009) relative to MSSA.
• USA300 MRSA infection independently predicts early
complications for hospitalized adults with
pneumonia (OR, 2.6; P = .02) but not CLABSI. (Lessa
FC et al. 2012)
Pediatric MDR Bacterial Infections: can we treat?
A two-year old male with a small BSA (2%) third-degree burn
develops high fever, tachycardia, hypotension, anemia and a
rash (Figure). Appropriate initial management should include
A. Empiric Linezolid
B. Debridement plus empiric Clindamycin
C. Debridement plus empiric Vancomycin
D. Debridement plus empiric Vancomycin
plus Nafcillin + Clindamycin
Pediatric MDR Bacterial Infections: can we treat?
Clindamycin Disk (“D”) Induction Test for inducible
macrolide-lincosamide-streptogramin B resistance
• Perform on all MRSA isolates that
are clindamycin susceptible yet
erythromycin resistant
• Predicts clinical failure of
clindamycin therapy
Erythromycin
Clindamycin
Pediatric MDR Bacterial Infections: can we treat?
Increasing Clindamycin Resistance Among MRSA in 57
Northeast US Military Treatment Facilities. (Braun L et al. 2005)
Pediatric MDR Bacterial Infections: can we treat?
Caveats: empiric use of clindamycin against skin, soft
tissue and skeletal infections
• Group B Streptococcus (GBS) infections in early infancy
period (birth-3 months), clindamycin resistance in 38.4% of
perinatal GBS rectovaginal cultures obtained in 2010-2011
Back EE et al. 2012
• Strains that are phenotypically clindamycin-susceptible yet
harbor inducible MLSB gene may become resistant
• Kingella kingae skeletal infections-high rates of resistance
to clindamycin and inherent resistance to vancomycin
Yagupsky P et al. 2012
Pediatric MDR Bacterial Infections: can we treat?
Standard dosing of vancomycin for children with
invasive MRSA may not be adequate
• Active surveillance of MRSA MIC trends is important
• If MRSA/MSSA with MIC of > 1.0 g/mL is common
– Standard empiric vancomycin dose (40 mg/kg/d) may not
achieve the optimal pharmacodynamic target of AUC24/MIC 400
– Use 60 mg/kg/d
– If MIC > 2.0 g/mL, consider alternatives to vancomycin
• Further pharmacokinetic and pharmacodynamic studies
are needed in children to optimize vancomycin dosing
Fymoyer A et al. 2009
Pediatric MDR Bacterial Infections: can we treat?
Vancomycin-resistant Staphylococcus aureus
• MRSA strains with vancomycin MIC>1-1.5 g/mL
are becoming increasingly common
• Vancomycin susceptible: ≤1 g/mL
– Maintain trough concentration ≥ 10 mg/L to avoid
resistance (≥ 15 mg/L if the MIC is 1 g/mL)
• Vancomycin intermediate (VISA): 4 to 8 g/mL
• Vancomycin resistant (VRSA): ≥16 g/mL /mL
Pediatric MDR Bacterial Infections: can we treat?
Alternatives to vancomycin to treat MRSA in
children: Limited armamentarium?
• Linezolid is a suitable alternative to vancomycin for
infections caused by MRSA, especially those also
resistant to clindamycin
• Only two new classes of antibiotics approved since the
1970s
– oxazolidinones (linezolid 2000) and
– cyclic lipopeptides (daptomycin - 2003)
• All other antibiotics are derivatives of existing classes
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MRSA (CDC)
Drug
(year
approved)
Key Targeted
Pathogens
Comments
Linezolid (2000)
Staphylococcus
Enterococcus
(IV/PO) Resistance in targeted pathogens
still uncommon
Daptomycin
(2003)
Staphylococcus
Streptococcus
Enterococcus
(IV) may be superior to either Linezolid or
Vancomycin against CNS infections,
bacteremia and R-sided endocarditis;
not active in pneumonia
Children 3 to 24 months of age require
higher mg/kg doses (Bradley JS et al 2014)
Emerging resistance in all of the targeted
pathogens (albeit at low rates).
Quinupristin/Dal
foprisitin (1999)
Staphylococcus
Streptococcus
Side effects common (not 1st-line) %
resistance remains low in the US.
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MRSA (CDC)
Drug
(year
approved)
Key Targeted
Pathogens
Comments
Ceftaroline
(2010)
Staphylococcus A cephalosporin drug, effective against MRSA
Streptococcus
(resistance is rare).
Telavancin
(2008)
Staphylococcus (IV) Approved for treatment of gram-positive
Streptococcus
SSTI. Should not be used in a woman of
Enterococcus
childbearing age without a pregnancy test.
Marginal versus MRSA
Gram-positive
Phase III studies in ABSSSI and cSSTI show
bacteria
that tedizolid 200 mg/day X 6 days was noninferior to linezolid 600 mg twice daily X 10 days
Tedizolid
phosphate
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MRSA (CDC)
Drug
Key Targeted
Comments
(year
Pathogens
approved)
Dalbavancin Gram-positive Active against VISA, once weekly IV
bacteria
slowly cidal, not dialyzable if toxicity
Oritavancin
marginal versus VRSA
Gram-positive active against both VISA and VRSA
bacteria
cidal
Telavancin
ods regimens
Gram-positive Active against VISA, marginal versus VRSA Cidal
bacteria
ods regimens,
Tigecycline
Broadspectrum
useful for mixed infections possibly including
MRSA
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MDR gram negative
infections
• Community-acquired urinary tract infection
• Hospital-acquired gram negative infections
• Limited treatment options
Antibiotic resistance is natural, ancient, and hard wired
(Bhullar K et al. 2012)
• Somewhere in nature there
likely is present resistance to
every potential natural
antibiotic as will as the ability to
evolve resistance to any
synthetic agent
• Use of any antibiotic exerts
selective pressure to develop
intrinsic, acquire from other
bacteria, or mutate resistance
• Certain organisms evolve
resistance while on therapy,
e.g. pseudomonas, MRSA
(esp. in severe chronic illness)
• Increasingly, spontaneous
primary MDR infections
• Carbapenems no longer a
cure-all for GNR
Pediatric MDR Bacterial Infections: can we treat?
“Multi-drug resistant” Enterobacteriaceae:
Definitions
• “Resistance to antimicrobials usually kept in reserve”
• Highly variable definitions in recent survey: 22 unique “MDR”
definitions for Enterobacteriaceae Drees M et al. 2014
• Standard definitions* Magiorakos AP et al. 2012
• MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories
• XDR: non-susceptible to ≥1 agent in all but ≤2 categories.
• PDR: non-susceptible to all available antimicrobial agent
*For standard definitions see Clinical Microbiology and
Infection, openly accessible at:
http://onlinelibrary.wiley.com/doi/10.1111/j.14690691.2011.03570.x/pdf
Pediatric MDR Bacterial Infections: can we treat?
Multi-drug resistance among gram-negative
bacilli
• Most common in Enterobacteriaceae, Pseudomonas
aeruginosa, Acinetobacter
• Mobile genetic elements contain multiple resistance genes
plus broad spectrum beta-lactamases.
• Empiric broad-spectrum cephalosporin use associated with
ESBL-bacteria in a NICU Le J. et al 2008
• Types of broad spectrum beta-lactamases
– ESBL, AmpC (third generation cephalosporin resistance)
– Carbapenemase (NDM, KPC, VIM, IMP, OXA-48)
• May be difficult to impossible to treat!
Pediatric MDR Bacterial Infections: can we treat?
Clinical and Cost Impact of MDR GNB
• Associated with longer LOS compared with antibioticsusceptible infection Folgori L et al. 2014
• ESBL-producing Enterobacteriaceae, MDR P. aeruginosa
and carbapenem-resistant Acinetobacter HAI are
associated with increased mortality rates (all others have
no clear increased mortality risk) Giske CG et al. 2008
Pediatric MDR Bacterial Infections: can we treat?
Increasing prevalence of antimicrobial resistant
GNB in children developing countries
• Bacteremia causes an estimated 6% of neonatal and
14% of under 5-year-old deaths worldwide
• The lack of cheap antibiotics is critical constraints in lowand low-middle-income countries
• Data from studies of 4710 neonates with gram-negative
bacteremia in developing countries in Asia
– median E. coli ampicillin resistance rate was 97%
– median E. coli, Klebsiella and Enterobacter ceftriaxone
resistance rates ranged from 74 to 80%
Black RE et al. 2008
Pediatric MDR Bacterial Infections: can we treat?
Common childhood uropathogens*
Gram positive
Gram negative
•
•
•
•
•
•
E. coli*
54 - 67%
Klebsiella 6 - 7%
Proteus
5 - 12%
Serratia
Enterobacter
Pseudomonas 2 - 6%
•
•
•
•
Enterococcus 3 - 9%
Group B strep (neonates)
Staph aureus
Staph saprophyticus
– adolescent girls
*Based upon multiple surveys in USA and Europe (2005-2008)
** E. coli resistance patterns: Ampicillin 38 – 65%, Amox/clav 7 – 43%,
Bactrim 8 – 53%. Similar rates of resistance for Klebsiella and Proteus sp.
Pediatric MDR Bacterial Infections: can we treat?
Risk factors for UTI with drug resistant bacteria
• Child care attendance
• Family members colonized with resistant
organisms
• Age
• Hospital exposure
• Urinary tract malformations
• Current or past antimicrobial exposure
– Recent Rx for OM, pharyngitis, pneumonia, SSTI
– Antimicrobial prophylaxis
Pediatric MDR Bacterial Infections: can we treat?
MDR CA-E. coli (UTI) at Jacobi Hospital: Few remaining
options for oral therapy?
• 17 of 335 E. coli urine isolates had in vitro resistance to amoxicillin/clav.,
cephalexin and TMP/SMX
• All of 15 of these empirically treated with amoxicillin/clav. had clinical
resolution and negative urine cultures 2-3 days later and no complications
• Conclusions:
– Clinical cure in cases of in vitro resistant CA amoxicillin/clav.-E. coli
– Achievable urine levels of amoxicillin/clav. likely exceed standard in vitro
MIC resistance cut off.
Pediatric MDR Bacterial Infections: can we treat?
Increasing Antibiotic-Resistant Pediatric UTIs
• Contributing factors: Poor empiric prescribing, no urine
testing, and nonselective use of prophylaxis
3rd-generation cephalosporin use for children with UTIs doubled in
the US between 1998 to 2007 Copp H et al. 2011
• Practice changes to curb growing resistance rates:
– Routine urinalysis and urine culture testing: treat only when
indicated and tailor broad-spectrum therapy
– Use antibiotic prophylaxis only in patients with high-grade
VUR and high-grade hydronephrosis
– Use local antibiograms, ideally pediatric-specific with inpatient
versus outpatient data, to guide therapy
Edlin RS et al. 2014
Pediatric MDR Bacterial Infections: can we treat?
What’s on the Horizon…..
• Increasing MDR gram-negative UTIs rates in children
• Emerging severe MDR gram-negative threats:
– Extended-spectrum β-lactamase–producing organisms (ESBL),
– AmpC β-lactamase–producing organisms
– Carbapenem-resistant Enterobacteriaceae (CRE), P.
aeruginosa, and A. baumannii are associated with a 21%
mortality rate in children < 15 years old Maltezou, HC et al. 2013
… and challenges:
–
–
–
–
How to treat based on in vitro resistance breakpoints?
How to define organ-specific or tissue-specific “breakpoints”
How to predict and suppress emergence of resistance?
How to treat nearly pan-drug resistant species?
Pediatric MDR Bacterial Infections: can we treat?
Effective therapy against MDR gram-negative
infections in critically ill children
requires…
is hampered by…
• Proper culture techniques
• Limited antibiotic options
• Timely initiation of therapy
• Lack pharmacokinetic/
• Selection of active agents that
pharmacodynamic and clinical
penetrate to the site
outcome data in children
• Adequate dose and interval to
• Dependence upon extrapolation
optimize effectiveness
from adult studies that lack
• Prompt removal/drainage of
effective comparators
infected sources
Must use in vitro data, observational data, and clinical experience to
guide therapy
Hsu AJ. 2014
Pediatric MDR Bacterial Infections: can we treat?
Clinicians’ Knowledge, Attitudes, and Practices
regarding Infections with MDR-GNB in ICUs
True or False?
Carbapenem agents are ineffective for
GNB expressing extended-spectrum βlactamases
Tigecycline is an option for hospitalassociated pneumonia caused by MDR
Pseudomonas aeruginosa
Carbapenem-resistant Klebsiella
species are usually susceptible to
quinolone agents
Quinolone agents exhibit concentrationdependent killing
After Zhou JJ et al. 2014
Maximizing pharmacodynamics-based dosing
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Azithromycin
Clindamycin
Oxazolidinones
Vancomycin
Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Pharmacokinetic and pharmacodynamics parameters of antibiotics on a
concentration vs time curve. Roberts JA, et al. 2009
Proposed treatment algorithm for carbapenem-resistant Gram-negative organisms.
*
Courter JD et al 2009
*Nonprotein bound meropenem serum concentrations
that exceed the MIC for 40% of the time (T>MIC) for
organisms with MICs up to 8 μg/mL are achieved with
prolonged or continuous infusions in children
Daikos GL 2012
Pediatric MDR Bacterial Infections: can we treat?
Combination therapy with > 2 agents with differing kinetics
and tissue penetration against MDR GNR
1. May achieve additive or synergistic killing (may antagonize!)
– Bioreactor chamber testing models synergy in vivo (more reliable
than checkerboard testing): synergy observed with the following
combinations against AmpC, ESBL and CRE gram-negative bacilli
• Doripenem plus colistin (against Klebsiella)
• Meropenem plus levofoloxacin (against pseudomonas)
• Colistin plus rifampin (against Pseudomonas or Acinetobacter)
2. May prevent the emergence of resistance! (as in TB therapy)
– Tobramycin to prevent resistant to cefepime Drusano GL et al. 2003
– Avibactam plus ceftaroline prevents ESBL resistance
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MDR GN
Drug
Key Targeted
Pathogens
Comments
Moxifloxacin
Enterobacteriaceae The only quinolones approved for pediatric use
Staphylococcus
are levofloxacin (for the post exposure
Streptococcus
treatment of inhalation anthrax) and
ciprofloxacin (for anthrax and complicated UTI).
Cross-resistance among quinolones.
Resistance is increasing.
Tigecycline
Enterobacteriaceae
Staphylococcus
Streptococcus
Enterococcus
New class (glycylcyclines) active against most
carbapenemase+, ESBL+, and quinolone
resistant Enterobacteriaceae.
Limited effectiveness against certain A.
baumannii with MIC > 2 mg/L; poor clinical
outcomes in and in CLABSI (despite
demonstrating in vitro susceptibility). Resistance
is emerging. Data in children > 8-years old
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MDR GN
Drug
Key Targeted
Pathogens
Comments
Gemifloxacin
Enterobacteriaceae
Streptococcus
Treatment of mild to moderate communityassociated respiratory disease. Crossresistance with other fluoroquinolone drugs
Doripenem
Enterobacteriaceae
P. aeruginosa
Acinetobacter spp.
Streptococcus spp.
Data down to neonate
May overcome low-level resistance of A.
baumannii and P. aeruginosa strains.
Inferior to imipenem for VAP. High-level
resistance has emerged reducing its overall
effectiveness
Ertapenem
Enterobacteriaceae
Staphylococcus
Streptococcus
Approved for use in children > 3 months of
age. Carbapenem-resistant Enterobacteriaceae (CRE) are spreading rapidly.
Pediatric MDR Bacterial Infections: can we treat?
Recently Approved Drugs against MDR GN
Drug
Key Targeted
Pathogens
Comments
Ceftaroline
Enterobacteriaceae Effective against MRSA (rare resistance). Non
Staphylococcus
inferior to other cephalosporins for
Streptococcus
Enterobacteriaceae. Active against AmpCproducing Pseudomona and E. coli. Ineffective
against ESBLs (may be overcome by
avibactam).
Ceftazidimavibactam
(QIDP
2013)
ESBL-, AmpC-, or
Klebsiella
pneumoniae
carbapenemaseproducing
Enterobacteriaceae
MDR P. aeruginosa
Pediatric studies ongoing. The addition of
avibactam to ceftazidime improves its in vitro
activity against Enterobacteriaceae and P.
aeruginosa. Inactive against Acinetobacter,
Burkholderia, and most anaerobic gramnegatives. Treatment of complicated UTIs
intra-abdominal infections (with metronidazole)
Pediatric MDR Bacterial Infections: can we treat?
Suggested Antimicrobials for the Treatment of
MDR Gram-Negative Infections in Children
ESBL–producing
organisms
First-Line Agents
Meropenem
Imipenem-cilastatin
Second-Line Agents
Ciprofloxacin
Trimethoprim-sulfamethoxazole
UTIs
Ertapenem
UTIs
Piperacillin-tazobactam
Nitrofurantoin (cystitis)*
Oral fosfomycin (cystitis)
Aminoglycosides (cystitis)
AmpC β-lactamase– Meropenem
producing organisms Imipenem-cilastatin
Cefepime
Trimethoprim-sulfamethoxazole
Ciprofloxacin
*The use of nitrofurantoin should be limited to cystitis as treatment
failures have been observed when prescribed for pyelonephritis.
Pediatric MDR Bacterial Infections: can we treat?
Suggested Antimicrobials for Treatment of
Severe MDR Gram-Negative Infections in
Children
First-Line Agents
Carbapenem-resistant Prolonged infusion meropenem
Enterobacteriaceae
PLUS aminoglycoside OR
fluoroquinolone OR
colistin* 5 mg/kg/dose
Carbapenem-resistant Prolonged infusion meropenem
Pseudomonas
PLUS aminoglycoside OR
aeruginosa
fluoroquinolone OR colistin
Carbapenem-resistant Prolonged infusion meropenem
Acinetobacter
PLUS aminoglycoside OR
baumannii
fluoroquinolone OR colistin
Second-Line Agents
Tigecycline
IV fosfomycin (limited
availability)
Oral fosfomycin
(cystitis)
Fosfomycin
Ampicillin-sulbactam
Tigecycline
* Colistin (polymixin) is active against most gram-negative bacilli except for Pseudomonas mallei,
Burkholderia cepacia, Proteus, Providencia , Serratia , Edwardsiella and Brucella , (12-17% of S.
maltophilia are resistant)
Pediatric MDR Bacterial Infections: can we treat?
Polymixin (colistin) use and its toxicities in children are
poorly understood
• Cell-wall acting bactericidal and anti-endotoxin activity
• Can be administered IV, IM or by nebulization
• Susceptibility testing
– Colistin disk: susceptible if the zone of inhibition is >11 mm
– Broth micro dilution:
susceptible MIC < 4 mg/L
resistant MICs >8 mg/L
• Nephro- and neurotoxicity are the most common toxicities
– Dose-dependent, usually reversible if early discontinuation
– Avoid use with other nephrotoxic agents.
– Modify dose for renal failure
M. Falagas M et al 2005
Pediatric MDR Bacterial Infections: can we treat?
Polymixin synergy
Landman et al. 2008.
Pediatric MDR Bacterial Infections: can we treat?
Use of IV Colistin Among Children in the US: Query of
Pediatric ID specialists (2005-2011)
Number of children prescribed IV colistin
.
Tamma PD et al. 2012
Pediatric MDR Bacterial Infections: can we treat?
Use of IV Colistin Among Children in the US (2005-2011 )
• Prescribed by only 22% of 239 Pediatric ID specialists
• Use to treat MDR Pseudomonas or Acinetobacter baumanii; CPE
and ESBL-producing Enterobacteriaceae
• Additional antimicrobials administered to 84% of cases
• Resistance to colistin developed in 20.5% of isolates
• Toxicities
– Nephrotoxicity in 22% (more common in children ≥13 yrs)
– Neurotoxicity (reversible) observed in 4.3%
Tamma PD et al. 2012
Pediatric MDR Bacterial Infections: can we treat?
Antibiotic Options for Multidrug-Resistant
Gram-Negative Bacilli
Nicasio AM et al. 2008
Pediatric MDR Bacterial Infections: can we treat?
Novel strategies to treat MDR GN infections
• Monte Carlo stimulation modeling to predict success based on (variable)
population pK and MIC distributions of only 20 to 30 subjects
• Use ANY FDA-approved ACTIVE drug even if not pediatric approved
• Direct delivery to attempt to maximize concentration at infection site
• Non-traditional susceptibility testing in tissue culture: macrolides inhibit
pseudomonas influx pumps making it susceptible (in vivo correlate?)
Buyck JM et al. 2012
• “High dose-Short course” to reduce bacterial load/avert resistance
• Pipeline antibiotics
– Ceftazidime + avibactam phase I pediatric study (7/14 completion)
– All others only in adult pipeline, or not yet advanced to human trials
Pediatric MDR Bacterial Infections: can we treat?
C. difficile hospitalization and mortality rate trends
among adults, USA (CDC)
Hospitalizations increasing*
Mortality rates plateauing
*Is the apparent increase in infection rate reflect better detection or over diagnosis?
Pediatric MDR Bacterial Infections: can we treat?
Clostridium difficile (CDI)
• Responsible for 12% of all HAI Magill S et al. 2014
• Toxin causes pseudomembranous colitis, toxic mega
colon, colonic perforation, sepsis
• Antibiotic exposure increases risk
• Increasing rates and severity of CDI since 2003 due to
– Increasing fluoroquinolone use in adults
– Inadequate hand hygiene
– Emergence of new C. difficile strain: Greater virulence, 20-fold
higher toxin production, often fluoroquinolone resistant
Pediatric MDR Bacterial Infections: can we treat?
Age-specific incidence Clostridium difficile infection per
10,000 pediatric hospitalizations in US, 1997–2006
Health Care Utilization Project Kids' and Inpatient Database (CDC)
Pediatric MDR Bacterial Infections: can we treat?
Which is an appropriate testing strategy to confirm
the diagnosis of Clostridium difficile infection?
A. Stool culture
B. C difficile toxin enzyme immunoassay on 3 consecutive
stool specimens
C. C difficile nucleic acid-based assay on a single stool
specimen
D. Stool ova/parasite trichrome stain
Clostridium difficile Diarrhea in Children: Diagnosis,
Management, and Prevention. Medscape. Jan 24, 2014.
Pediatric MDR Bacterial Infections: can we treat?
What is the recommended therapy for a child with
moderate initial Clostridium difficile infection?
A. Vancomycin given intravenously
B. Metronidazole given IV and vancomycin given PO
C. Metronidazole given orally
D. Metronidazole given PO with an ant peristaltic medication
Clostridium difficile Diarrhea in Children: Diagnosis,
Management, and Prevention. Medscape. Jan 24, 2014.
Pediatric MDR Bacterial Infections: can we treat?
Guidelines for C. difficile treatment
Bauer MP et al. 2009; Cohen SH et al. 2010
Pediatric MDR Bacterial Infections: can we treat?
Guidelines for C. difficile treatment
Bauer MP et al. 2009; Cohen SH et al. 2010
Pediatric MDR Bacterial Infections: can we treat?
Guidelines for C. difficile treatment
• Vancomycin use to treat the 1st episode of CDI in
children admitted to children's hospitals in the US
Increased significantly (P = 0.005) between 2006-2011.
• There is no empirical evidence to suggest superiority of
oral vancomycin over oral metronidazole.
Schwenk HT et al. 2013
Pediatric MDR Bacterial Infections: can we treat?
Prevention of Antibiotic-Associated Diarrhea
• Appropriate antibiotic use: Reduced fluoroquinolone and
cephalosporin use led to a 60% drop in CDI use in England
• Probiotics? Controlled trials ongoing
• C difficile spores persist: Use gowns and gloves!
• Alcohol does not kill C difficile spores effectively: Hand
washing with soap and water is optimal
• Most disinfectants are not sporicidal: Use sodium
hypochlorite to clean rooms
• Hospitals following infection control recommendations
lowered rates by 20% in less than 2 years
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MRSA infections:
Summary
• MRSA accounts for > 50% of CA S. aureus infections
• Most CA isolates carry the PVL gene, associated with increased
virulence and morbidity (USA 300)
• Include anti- GA HS coverage in empiric Rx of SSTI
• I&D alone may be sufficient for uncomplicated abscesses
• Clindamycin-resistance frequency is increasing
• Include vancomycin for severe suspected MRSA infections
• Linezolid is a safe and effective alternative against VISA
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MDR GNB infections:
Summary
• Adversely affect cost and health outcomes
• Carbapenems are no longer a cure-all for GNR
• Broad-spectrum cephalosporin use contributes to
emergence of ESBL-bacteria
• Practice changes to curb growing UTI resistance rates:
– Routine urinalysis and urine culture testing:
– Selectively use antibiotic prophylaxis:
– Use local antibiograms
• Consider the possibility of MDR CRE, ESBL and/or
quinolone resistant bacteria in choosing empiric Rx
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in MDR GNB infections:
Summary
• Lack of pediatric pK/pD and clinical outcome data
• Maximize pharmacodynamics-based dosing (e.g. continuous
infusion for meropenem)
• Use combination therapy for additive or synergistic effect, or
to prevent emergence of resistance.
• Newer compounds (e.g. avibactam plus ceftaroline) may
improve options
• Polymyxins: use as a last resort (limited pediatric pK/pD data,
reversible nephro- and neurotoxicity)
Pediatric MDR Bacterial Infections: can we treat?
Emerging challenges in C. difficile infections:
Summary
•
•
•
•
•
The most common HAI pathogen
Overuse of flouroquinolones contributes to CDI
Nucleic acid-based assay should be used to diagnose
Overuse of oral vancomycin to treat in children
Metronidazole PO is 1st-line agent for mild-moderate
disease
• Strict hand-hygiene and environmental decontamination
are critical to control
Pediatric MDR Bacterial Infections: can we treat?
Opportunities and novel approaches to prevent
HAI in children
• Surveillance of MDR GNR in High-risk Neonates?
Colonized infants are at risk for MDRGN infection
important reservoir for nosocomial transmission
Simon A et al. 2013
• Infection Prevention
– Hand washing, etc
– Fomites (stethoscopes, white coats, etc)
• Diagnose and treat infections effectively
• Vaccination- S. aureus, C. difficile, Pseudomonas?
Always wash your hands!
Pediatric MDR Bacterial Infections: can we treat?
Fomites: White coats and Accessories
• White coats are frequently contaminated with potentially
harmful bacteria, such as Staphylococcus aureus, gramnegative bacteria, and others, including MDR pathogens.
Banu A et al. 2012.
• Bare Below the Elbows (BBE) bans the wearing of long
sleeves watches, wristbands, bracelets, or rings to
enable better hand and wrist hygiene. (No proven
benefit). National Health Service UK 2007
.
Pediatric MDR Bacterial Infections: can we treat?
Fomites: Neckties, Identification Badges and
Personal Items
• Hand and stethoscope contamination correlate
directly
• Secure neckties and other personal apparel
items by a white coat or other means to prevent
contact with the patient
• Any item that comes into direct contact with the
patient or environment should be disinfected
regularly, replaced, or eliminated
Longtin Y, et al. 2014.
Pediatric MDR Bacterial Infections: can we treat?
Every time antibiotics are prescribed:
1. Order cultures before antibiotics are given and start
drugs promptly.
2. Specify indication, dose, and expected duration in the
patient record.
3. Reassess within 48 hours and adjust Rx if necessary or
stop Rx if indicated.
After CDC Vital Signs, 2014
Pediatric MDR Bacterial Infections: can we treat?
Considerations for common prescribing situations
• UTIs: Do culture results represent true infection and
not colonization?
– Assess for signs and symptoms of UTI.
– Obtain urinalysis with every urine culture.
• Pneumonia: Do symptoms truly represent pneumonia?
• MRSA: Is MRSA growing in clinically relevant
cultures?
– Do not use vancomycin to treat infections caused by MSSA!
• Always treat for recommended length of time
After CDC Vital Signs, 2014
Pediatric MDR Bacterial Infections: can we treat?
Common Clinical Syndromes: Durations of
Antimicrobial Treatment
• Community-Acquired Pneumonia: 10 days
• Ventilator-Associated Pneumonia: 7 days, (15 days
for nonfermenting Gram-negative organisms)
• Urinary Tract Infections due to E. coli
– Acute uncomplicated cystitis (treat for 3-10d):
– Pyelonephritis: 7 days may be adequate
• Uncomplicated SSTI: 5-10 days (5 generally adequate)
• Complicated Intra-abdominal Infections: 4-7 days
After Septimus EJ et al. 2012
Pediatric MDR Bacterial Infections: can we treat?
Opportunities and novel approaches to prevent
HAI in children: Vaccines
• Nosocomial viruses
– Rotavirus
– Norovirus (pipeline)
– Influenza
• MDR pathogens
–
–
–
–
Pneumococcus: conjugate (PCV13) and 23-valent polysaccharide (PPV23)
S. aureus (pipeline)
Pseudomonas (vaccine or mAb Rx) (pipeline)
Klebsiella pneumoniae
• C. difficile toxoid (pipeline)
Use antibiotics wisely
Do not!
• treat viral infections with
antibiotics
• treat contamination or
colonization
• treat with mild doses of
antibiotics over long periods
• continue empiric treatment if
no pathogen isolated
• use vancomycin, quinolones
or cephalosporins needlessly
• use antimicrobial prophylaxis
indiscriminately
Do
• use shortened antibiotic
courses with proven
efficacy (OM, pharyngitis)
• use a combination of drugs
to treat a bacterial infection
• use local antibiogram data
• promote adherence –
(improve palatabity)
• reduce use of antibiotics in
domestic livestock
• stop therapy when infection
is cured or unlikely
Pediatric MDR Bacterial Infections: can we treat?
Opportunities and novel approaches to prevent
HAI in children: parting thoughts
• Changes in antibacterial regimens may reduce one
problem yet opportunistic bacteria may fill the vacant niche.
• Aim for a better balance between the accumulation of
resistance and new antibacterial development.
Livermore DM et al. 2003
Clinicians Hold the Solution (CDC)