Resistant Gram-Negative Bacilli ESBLs and Other Bad Bugs

1
Resistant Gram-Negative BacilliESBLs and Other
Bad Bugs

• David P. Dooley, FACP
• UTHSC-San Antonio
• Audie Murphy VA Hospital
• San Antonio, TX

2
Resistant GNBThe Problem

• Still common in their nichés level prevalance of
  GNBs, but resistance rising

3
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, 19862003.
4
Results of intensive care unit surveillance for
the proportion of selected gram-negative
organisms reported for pneumonia from
the National Nosocomial Infections Surveillance
system, 19862003. Gaynes R CID 2005 (CDC)
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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 401794 2005 (MGH)
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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 isolatesNational
Nosocomial Infections Surveillance system,
19862003. Gaynes R CID 2005 (CDC)
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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
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Resistant GNBThe Problem

• High mortality
• Narrowing therapeutic options
• Down to carbapenems, polymixin B

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New antibacterial agents approved in the United
States, 19832002, per 5-year period.
Spellberg B et al. Clin Inf Dis 2004
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Resistant GNBThe 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?

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Resistant GNB

• Organisms of concern
• Pseudomonas aeruginosa
• Acinetobacter baumannii
• Enterobacteriaceae
• Klebsiella pneumoniae
• Enterobacter spp. (esp cloacae)
• E. coli
• Serratia marcescens

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Sites of infection with extended-spectrum
ß-lactamaseproducing Escherichia coli and
Klebsiella species 187 patients at HUP, over 5 y
Hyle EP Arch Int Med 2005 (HUP)
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Resistant GNBClinical 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

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Delay in initial antimicrobial therapy and
mortality.
Hyle EP Arch Int Med 2005 (HUP)
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Resistant GNBClinical 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 lt1 of Klebsiella with ESBLs!)

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Resistant GNBEpidemiology

• Risks for acquisition No surprises
• Current and previous abx Tx
• Older patient (gt60 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

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Safdar N, Maki DG, Ann Int Med 2002136834
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Resistant GNBEpidemiology

• Risk of deep infection gtgt if previously colonized
  (40 fold)
• 15 of colonized patients go on to invasive
  infection
• Rare community-acquired

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Resistant GNBEpidemiology 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

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Resistant GNBEpidemiology when/how acquired?

• Clearly some horizontal transfer though
• How?
• 5 (ltlt MRSA) of area around bedside of colonized
  patients are colonized with resistant GNBs---but
  theyre there environmental reservoir
• (Clearly documented point source outbreaks)
• Large (undetermined) percentage of colonization
  occurs through HCWs hands (esp Klebsiella and
  Acinetobacter)

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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)
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Larson EL et al Ped Crit Care Med 2005
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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)
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Resistant GNBBasis of Resistance

• Pseudomonas aeruginosa, Acinetobacter spp.
  Intrinsically resistant through multiple
  mechanisms
• ß-lactamasesmany possible
• Aminoglycoside modifying enzymes
• Porin mutations, with abx exclusion
• Efflux pumps up and running
• Topoisomerases for FQs

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Resistant GNBBasis of Resistance

• Enterobacteriaceae ß-lactamases rising
• 1960sroutine enzymes (TEM 1, SHV 1)
  ampicillin, Keflex resistant
• 1980smutations extended spectrumDNA encoded
  on plasmids, jump to other GNBs easily
• Active against 30 cephalosporins, aztreonam
• Not active (stay susceptible) against cefoxitin,
  cefotetan, and ß-lactamase inhibitors (Zosyn,
  Augmentin, Unasyn)
• Currently gt100 ESBLs recognized

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Resistant GNBBasis 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

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Resistant GNBBasis 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)

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Resistant GNBBasis of Resistance

• Amp C ßlactamases newer, broader R
• Chromosomal dont jump so much
• Mostly on Enterobacters rare Kleb
• Do cause R to cefoxitin, and ßlactamase
  inhibitor combinations

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Resistant GNBBasis 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)

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Resistant GNBBasis of Resistance

• ESBLs and Amp-C ßlactamases 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 ß-lactam
  except carbapenem (imipenem, meropenem, ertapenem)

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Resistant GNBDeceptive Susceptibility Testing
ESBLs May Look Sensitive

• Klebsiella pneumoniae
• Amp R
• Keflex R
• Cefoxitin S
• Cefotaxime/ceftriaxone S
• Ceftazidime (S)
• Cefipime S
• Zosyn S
• Cipro S
• Aminoglycoside S
• Bactrim S

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Resistant GNBDeceptive Susceptibility Testing
Amp-Cs 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)

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Double-disk susceptibility test for ESBLs, this
time in Enterobacter cloacae. AMC (center)
clavulanic acid FEP cefepime CAZ
ceftazidime CXT cefotaxime CRO ceftriaxone
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Resistant GNBTreatment

• 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

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Rahal et al Clin Inf Dis 200234501
Squeezing the balloon. Evolution and control
of antibiotic resistance among gram-negative
bacilli at New York Hospital Queens. ICU,
intensive care unit.
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Resistant GNBInfection 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 200324362
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Resistant GNBInfection 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/recognitio
  n to overall need, or focus on geographic areas
  in house (e.g., ICUs)
• Decisions made on basis of your institutions
  amount of problem, resources, administrations
  interest

Siegel et al www.cdc.gov/ncidod/dhqp/pdf/ar/mdr
oGuideline2006.pdf
Discussion at Jackson M et al AJIC 200432504
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Resistant GNBInfection Control Issues

• Other components of infection control
• Antibiotic stewardship program
• Probably as or more important here than for other
  MDROs
• 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
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Resistant GNBInfection Control Issues

• Hand hygiene
• Cohorting patients, cohorting staff
• Good staffing ratios

Good evidence intervention works
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Resistant GNBInfection Control Issues

• Cautions
• Contact precaution data is not usually in
  isolation
• Active surveillance costs
• Money
• Time
• Effort