Transcript Resistant Gram-Negative Bacilli

Resistant Gram-Negative Bacilli
ESBLs and Other Bad Bugs
David P. Dooley, FACP
UTHSC-San Antonio
Audie Murphy VA Hospital
San Antonio, TX
Resistant GNB
The Problem
• Still common in their nichés; level
prevalance of GNBs, but
resistance rising
Results of intensive care unit surveillance revealing percentages of gram-positive
(Gram Pos) and gram-negative (Gram Neg) pathogens associated with pneumonia,
urinary tract infection (UTI), surgical site infection (SSI), and bloodstream infection
(BSI)—National Nosocomial Infections Surveillance system, 1986–2003.
Results of intensive care unit surveillance for the proportion
of selected gram-negative organisms reported for pneumonia from the
National Nosocomial Infections Surveillance system, 1986–2003.
Gaynes R CID 2005 (CDC)
Resistant GNRs
Prevalence of isolates of multidrug-resistant gram-negative bacilli recovered
within the first 48 h after admission to the hospital, by species. Only 1 isolate
per patient per year was included in the study.
Pop-Vicas, Clin Inf Dis 40:1794 2005 (MGH)
Results of intensive care unit surveillance revealing rates of antimicrobial resistance to
third-generation cephalosporins among Klebsiella pneumoniae isolates (which includes
isolates that were either intermediately susceptible or resistant) and Escherichia coli
isolates—National Nosocomial Infections Surveillance system, 1986–2003.
Gaynes R CID 2005 (CDC)
INCIDENCE RATES OF MULTIDRUG-RESISTANT BACTERIA PER 100 ADMISSIONS:
STAPHYLOCOCCUS AUREUS (LINE WITH BLACK DIAMONDS), PSEUDOMONAS
AERUGINOSA (LINE WITH WHITE DIAMONDS), ENTEROBACTERIACEAE (LINE WITH
BLACK BOXES), AND ACINETOBACTER BAUMANNII (LINE WITH WHITE BOXES).
Lepelletier D ICHE 2004--Nantes
Resistant GNB
The Problem
• High mortality
• Narrowing therapeutic options
–Down to carbapenems,
polymixin B
New antibacterial agents approved in the United States,
1983–2002, per 5-year period.
Spellberg B et al. Clin Inf Dis 2004
Resistant GNB
The Problem
• Hard to detect: may be in your
building for months/years before
you get worried
• Not sexy; no media exposure
–How to compete with alarms
about MRSA?
Resistant GNB
• Organisms of concern:
– Pseudomonas aeruginosa
– Acinetobacter baumannii
– Enterobacteriaceae:
•
•
•
•
Klebsiella pneumoniae
Enterobacter spp. (esp cloacae)
E. coli
Serratia marcescens
Sites of infection with extended-spectrum β-lactamase–producing
Escherichia coli and Klebsiella species: 187 patients at HUP, over 5 y
Hyle EP Arch Int Med 2005 (HUP)
Resistant GNB
Clinical Significance
• High mortality, especially with pneumonia
or BSIs
• Clear effect of delay in appropriate therapy
on survival
– 40-100% mortality when treating apparently
susceptible deep infections with Klebsiella
with cephalosporins
Delay in initial antimicrobial therapy and mortality.
Hyle EP Arch Int Med 2005 (HUP)
Resistant GNB
Clinical Significance
• NNIS data
– 20% of ICU Klebsiella isolates are resistant to
30 cephalosporins
– 30% of ICU Enterobacter isolates similar
– 6% of E. coli isolates similar
– (Netherlands: <1% of Klebsiella with ESBLs!)
Resistant GNB
Epidemiology
• Risks for acquisition: No surprises
– Current and previous abx Tx
– Older patient (>60 y)
– ICU stay; prolonged ICU stay
– IV catheters; tubes of every kind
– NH/LTCF denizen (1/2 colonized with ESBLs!)
– H2 receptor blockers (Zantac et al)
– Chronic liver/renal disease
Safdar N,
Maki DG,
Ann Int Med
2002;136:834
Resistant GNB
Epidemiology
• Risk of deep infection >> if previously
colonized (40 fold)
• 15% of colonized patients go on to
invasive infection
• Rare “community-acquired”
Resistant GNB
Epidemiology: when/how acquired?
• Horizontal transfer vs endogenous source
– Unlike MRSA, VRE---overwhelmingly
horizontal transfer
– Endogenous:
• Enterobacteriaceae seldom spontaneously
resistant; Pseudomonas not cultured from normal
individuals (Acinetobacter +/-)
• But resistance in same clone emerges commonly
under antibiotic pressure
Resistant GNB
Epidemiology: when/how acquired?
• Clearly some horizontal transfer though
• How?
– 5% (<< MRSA) of area around bedside of
colonized patients are colonized with resistant
GNBs---but they’re there– environmental
reservoir
• (Clearly documented point source outbreaks)
– Large (undetermined) percentage of
colonization occurs through HCWs hands
(esp Klebsiella and Acinetobacter)
PERCENTAGE OF HAND IMPRINT CULTURES YIELDING PATHOGENS AFTER CONTACT WITH
ENVIRONMENTAL SURFACES NEAR PATIENTS IN OCCUPIED PATIENT ROOMS OR IN ROOMS THAT
HAD BEEN CLEANED AFTER PATIENT DISCHARGE.
Bhalla A ICHE 2004 (Cleveland)
Larson EL et al Ped Crit Care Med 2005
Distribution of infant and nurse clones identified as unique strains, strains
shared between nurses and infants, and strains shared between nurses or
among infants.
Waters V, Clin Inf Dis 2004 (Columbia)
Resistant GNB
Basis of Resistance
• Pseudomonas aeruginosa, Acinetobacter
spp. Intrinsically resistant through multiple
mechanisms:
– β-lactamases—many possible
– Aminoglycoside modifying enzymes
– Porin mutations, with abx exclusion
– Efflux pumps up and running
– Topoisomerases for FQs
Resistant GNB
Basis of Resistance
• Enterobacteriaceae: β-lactamases rising
– 1960’s—routine enzymes (TEM 1, SHV 1):
ampicillin, Keflex resistant
– 1980’s—mutations; “extended spectrum”—
DNA encoded on plasmids, jump to other
GNBs easily
• Active against 30 cephalosporins, aztreonam
• Not active (stay susceptible) against cefoxitin,
cefotetan, and β-lactamase inhibitors (Zosyn,
Augmentin, Unasyn)
– Currently >100 ESBLs recognized
Resistant GNB
Basis of Resistance: Example
Klebsiella pneumoniae, old TEM 1:
Amp
R
Keflex
R
Cefoxitin
S
Cefotaxime/ceftriaxone
S
Ceftazidime
S
Cefipime
S
Zosyn
S
Cipro
S
Aminoglycoside
S
Bactrim
S
Resistant GNB
Basis of Resistance: Example
Klebsiella pneumoniae, old TEM 1; new ESBL:
Amp
R
R
Keflex
R
R
Cefoxitin
S
S
Cefotaxime/ceftriaxone
S
R
Ceftazidime
S
R
Cefipime
S
(S)
Zosyn
S
S
Cipro
S
(S)
Aminoglycoside
S
(S)
Bactrim
S
(S)
Resistant GNB
Basis of Resistance
• Amp C β–lactamases: newer, broader R
– Chromosomal: don’t jump so much
– Mostly on Enterobacters; rare Kleb
– Do cause R to cefoxitin, and β–lactamase
inhibitor combinations
Resistant GNB
Basis of Resistance: Example
Klebsiella pneumoniae, old TEM 1; new ESBL; Amp-C
Amp
R
R
R
Keflex
R
R
R
Cefoxitin
S
S
R
Cefotaxime/ceftriaxone
S
R
R
Ceftazidime
S
R
R
Cefipime
S
(S)
(S)
Zosyn
S
S
R
Cipro
S
(S)
(S)
Aminoglycoside
S
(S)
(S)
Bactrim
S
(S)
(S)
Resistant GNB
Basis of Resistance
• ESBLs and Amp-C β–lactamases are inoculum
dependent
– Usual tests are at low inoculum; may look S
– In vivo, high loads of bugs common; clinical failures of
the “S” abx is common
• Requires special testing techniques
– If not performed, ESBL/Amp-C bugs may look S but
your patients are dying
– CLSI recommends specific testing; if ESBL or Amp C
are found, trust NO and treat with NO β-lactam except
carbapenem (imipenem, meropenem, ertapenem)
Resistant GNB
Deceptive Susceptibility Testing: ESBLs May
Look Sensitive
Klebsiella pneumoniae
Amp
Keflex
Cefoxitin
Cefotaxime/ceftriaxone
Ceftazidime
Cefipime
Zosyn
Cipro
Aminoglycoside
Bactrim
R
R
S
S
(S)
S
S
S
S
S
Resistant GNB
Deceptive Susceptibility Testing: Amp-C’s
May Look Sensitive Early On
Enterobacter spp. Amp-C early Amp C 3-10 d later
Amp
R
R
Keflex
R
R
Cefoxitin
S
R
Cefotaxime/ceftriaxone
S
R
Ceftazidime
S
R
Cefipime
S
(S)
Zosyn
S
R
Cipro
(S)
(S)
Aminoglycoside
(S)
(S)
Bactrim
(S)
(S)
Double-disk
susceptibility test
for ESBLs, this time
in Enterobacter
cloacae.
AMC (center) =
clavulanic acid;
FEP = cefepime;
CAZ = ceftazidime;
CXT = cefotaxime;
CRO = ceftriaxone
Resistant GNB
Treatment
• Must pick adequate coverage immediately
(reviewed already).
– Greater survival differences in under-treated
resistant GNBs than even under-treated
MRSA
– Patients at risk should receive broader
coverage
– Carbapenems; +/- double GNB coverage
Rahal et al
Clin Inf Dis
2002;34:501
“Squeezing the balloon”. Evolution and control of antibiotic resistance
among gram-negative bacilli at New York Hospital Queens. ICU, intensive
care unit.
Resistant GNB
Infection Control Issues
• Prevention of transmission of resistant
Staphylococcus aureus and Enterococcus
specifically addressed in 2003 SHEA
guideline*
– Call for active surveillance cultures, based on
• Recognition that colonization precedes infection
• Response with barrier precautions works to reduce
clinical infections
• Response if wait till clinical cultures return positive
is less impressive (vs no help)
* Muto CA ICHE 2003;24:362
Resistant GNB
Infection Control Issues
• HICPAC guidelines address all MDROs*
Call for measured response:
Active surveillance (rectal cultures in case of ESBLs)
if institution “has a problem”
• Otherwise, adjust level of
surveillance/recognition to overall need, or focus
on geographic areas in house (e.g., ICUs)
• Decisions made on basis of your institution’s
amount of problem, resources, administration’s
interest†
* Siegel et al www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf
† Discussion at Jackson M et al AJIC 2004;32:504
Resistant GNB
Infection Control Issues
• Other components of infection control:
– Antibiotic stewardship program*
• Probably as or more important here than for other
MDRO’s
• Carbapenems for empirical therapy; avoid
ceftazidime; avoid 30 cephalosporins in general
(Zosyn maybe helfpul)
– Contact precautions*: interrupt environmental
risk
• Determine clonality if available (also, ? Point
source?)
* Good evidence intervention works
Resistant GNB
Infection Control Issues
– Hand hygiene*
– Cohorting patients*, cohorting staff*
– Good staffing ratios*
* Good evidence intervention works
Resistant GNB
Infection Control Issues
• Cautions:
– Contact precaution data is not usually in
isolation
– Active surveillance costs:
• Money
• Time
• Effort