Resistant Gram-Negative BacilliESBLs and Other Bad Bugs

David P. Dooley, FACPUTHSC-San Antonio

Audie Murphy VA HospitalSan Antonio, TX

Resistant GNBThe 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 proportionof selected gram-negative organisms reported for pneumonia from theNational Nosocomial Infections Surveillance system, 1986–2003.

Gaynes R CID 2005 (CDC)

Resistant GNRs

Prevalence of isolates of multidrug-resistant gram-negative bacilli recoveredwithin 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 GNBThe 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 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?

Resistant GNB

• Organisms of concern:– Pseudomonas aeruginosa– Acinetobacter baumannii– Enterobacteriaceae:

• Klebsiella pneumoniae• Enterobacter spp. (esp cloacae)• E. coli• Serratia marcescens

Hyle EP Arch Int Med 2005 (HUP)

Sites of infection with extended-spectrum β-lactamase–producing Escherichia coli and Klebsiella species: 187 patients at HUP, over 5 y

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

Delay in initial antimicrobial therapy and mortality.

Hyle EP Arch Int Med 2005 (HUP)

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: <1% of Klebsiella with ESBLs!)

Resistant GNBEpidemiology

• 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 Med2002;136:834

Resistant GNBEpidemiology

• Risk of deep infection >> if previously colonized (40 fold)

• 15% of colonized patients go on to invasive infection

• Rare “community-acquired”

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

Resistant GNBEpidemiology: 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 GNBBasis 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 GNBBasis 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 GNBBasis of Resistance: Example

Klebsiella pneumoniae, old TEM 1:Amp RKeflex RCefoxitin SCefotaxime/ceftriaxone SCeftazidime SCefipime SZosyn SCipro SAminoglycoside SBactrim S

Resistant GNBBasis of Resistance: Example

Klebsiella pneumoniae, old TEM 1; new ESBL:Amp R RKeflex R RCefoxitin S SCefotaxime/ceftriaxone S RCeftazidime S RCefipime S (S)Zosyn S SCipro S (S)Aminoglycoside S (S)Bactrim S (S)

Resistant GNBBasis 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 GNBBasis of Resistance: Example

Klebsiella pneumoniae, old TEM 1; new ESBL; Amp-CAmp R R RKeflex R R RCefoxitin S S RCefotaxime/ceftriaxone S R RCeftazidime S R RCefipime S (S) (S)Zosyn S S RCipro S (S) (S)Aminoglycoside S (S) (S)Bactrim S (S) (S)

Resistant GNBBasis 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 GNBDeceptive Susceptibility Testing: ESBLs

May Look Sensitive

Klebsiella pneumoniae Amp RKeflex RCefoxitin SCefotaxime/ceftriaxone SCeftazidime (S)Cefipime SZosyn SCipro SAminoglycoside SBactrim S

Resistant GNBDeceptive Susceptibility Testing: Amp-C’s

May Look Sensitive Early OnEnterobacter spp. Amp-C early Amp C 3-10 d laterAmp R RKeflex R RCefoxitin S RCefotaxime/ceftriaxone S RCeftazidime S RCefipime S (S)Zosyn S RCipro (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 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

Rahal et alClin 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 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 2003;24:362

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/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 GNBInfection 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 GNBInfection Control Issues

– Hand hygiene*– Cohorting patients*, cohorting staff*– Good staffing ratios*

* Good evidence intervention works

Resistant GNBInfection Control Issues

• Cautions:

– Contact precaution data is not usually in isolation

– Active surveillance costs:• Money• Time• Effort