Transcript Beyond ESBL’s and KPC’s: The Silent Pandemic in Gram Negative Organisms Trish M.
Beyond ESBL’s and KPC’s: The Silent Pandemic in Gram Negative Organisms
Trish M. Perl, MD, MSc Professor of Medicine, Pathology and Epidemiology Johns Hopkins University Senior Epidemiologist Johns Hopkins Health System [email protected]
Thanks and Disclosures
• Disclosures: Pfizer (advisory board), Merck (grant), Medimmune (grant) • I will be talking about off label uses of some antibiotics in these highly resistant organisms
Objectives
• • • Describe emerging patterns of resistance in GNRs Review risk factors associated with resistant GNRs Discuss some therapeutic considerations while treating resistant GNRs
How Big is the Problem?
Luna et al. Crit Care Res Pract 2014: 480463
What about the specifics
Luna et al. Crit Care Res Pract 2014: 480463 Luna et al. Crit Care Res Pract 2014: 480463
Why Do I Care
Mechanisms of Gram (-) Resistance
• Production of a β-lactamase – Acquired on a plasmid or transposon ESBL KPC – Encoded within a chromosome Amp C
• • •
Extended-spectrum β-lactamases (ESBL)
Production of a β-lactamase acquired on a plasmid or transposon – Non-inducible (produced all of the time) – Transferable First described: TEM-1, TEM-2, and SHV-1 – Mutations increase the size of the active site pocket or alter its binding characteristics to allow larger cephalosporins to enter – – Resistance to PCN, 1 st and 2 nd generation cephalosporins Easily inhibited by β-lactamase inhibitors Over 200 types documented
• • • •
Extended-spectrum β-lactamases (ESBL)
Most common in
Klebsiella spp.
and
E. coli
Modifications of TEM and SHV enzymes – Cause decreased susceptibility to 3 rd generation cephalosporins and aztreonam Rarely found in other organisms (Proteus, Serratia, Salmonella, Citrobacter, PSA, etc
)
Over 200 types documented
Global distribution of ESBL
’
s
Gales et al Clinical Infectious Diseases 2001;32:S146-S155
Global Distribution of ESBL
’
s
Gales et al Clinical Infectious Diseases 2001;32:S146-S155
Management of Infections with ESBLs
• • • • Cephamycins (cefotetan, cefoxitin), β lactam/ βLIs, fluoroquinolones, and carbapenems have in vitro activity Drug of choice: carbapenem (s) – – Resistant to ESBL-mediated hydrolysis Includes: ertapenem (1 gm IV/IM daily) Alternatives – FQ: cross-resistance common – – β-lactam/βLIs: inoculum issues Tigecycline No evidence to support “ double coverage ”
What Happens to Patients Treated with Cephalosporins?
• • • 60-70% failure when 3rd generation cephalosporins are used to treat bacteremia Inoculum effect – Liberated enzyme from dead bacterial cells reduces the concentration of the antibiotic – MIC of cephalosporins increases when the inoculum of organisms is increased 10-100-fold (10 6 -10 7 cfu/mL) UTI may be exception because of high urinary β lactam concentration in urine.
Paterson et al. J Clin Micro. 2001;39:2206.
How About Cephamycins?
• • Role of cefamycins: more stable than other cephalosporins to ESBL-mediated hydrolysis, but limited clinical info Role of cefepime: – – Also inoculum effect problem If must use: high doses (2 g q 8) +/- AG
Fluoroquinolones and ESBLs
• • Conflicting data – 85 ESBL-producing
K pneumoniae
bacteremias (many centers, 1996-97) had lower mortality with carbapenems (3.7%) than FQ (36.4%) – 133 ESBL-producing
K. pneumo and E. coli
bacteremias (one center, 1998-2002) had no mortality difference between carbapenems (13%) and FQ (10%) Rx Evidence for inoculum effect with cipro in one study
Paterson DL, et al. Clin Infect Dis. 2004;39:31-37.
Kang et al. Antimicrob Agent Chemo. 2004;48:4574.
Endimiani A et al. Clin Infect Dis. 2004;38:243.
De-repressed Amp C β-lactamases β-lactamases that hydrolyses penicillins, 1 st and 3 rd – 2 G cephalosporins and monobactams nd Enzyme is NOT inhibited by clavulanic acid Most of the time, chromosomely mediated INDUCIBLE resistance in
Enterobacter
spp
., Serratia
spp
., Morganella
spp
.
and
Citrobacter
spp
.
and in other
Enterobacteriaceae
Derepressed Amp C β-lactamases
• • • Currently no micro testing for Amp C 20-30% risk of clinical failure when 3 rd generation cephalosporin is used to treat
Enterobacter
spp.
• Once de-repressed mutants are selected, they are stable (and can spread to other patients) FQ and carbapenems can be used, cefepime more controversial
What About Cefepime?
• • • • 96 patients with confirmed infections with Amp C β lactamase –producing organisms. Propensity score matching of patients infected with Amp C β-lactamase–positive organisms treated with cefepime or meropenem yielded 32 well-balanced patient pairs.
No difference in 30-day mortality (odds ratio, 0.63; 95% confidence interval [CI](,0.23
–2.11; P = .36) or length of hospital stay after infection (relative risk, 0.96; 95% CI, .79
–1.26; P = .56) between the 2 groups.
Caution is the small numbers of patients studied.
Tamma et al. CID 2013:57;781
Unexpected Epidemiology
• • • • • Outbreak of ESBL
K. pneumoniae
(clonal) in 2008 156 patients colonized – 22% infected 35% of the hospital kitchen – screened surfaces or foodstuff were colonized 6 (14%) of 44 food handlers found to be fecal carriers HCWs negative
Calbo et al. (2011) Clin Infect Dis 52:743-749
ESBL-producing Enterobacteriaceae in Retail Meat
• 262 fresh meat samples (Netherlands) • 30% of all food samples positive for ESBL producing Enterobacteriaceae – 80% of chicken samples • Similarity between strains and ESBL enzymes in food and human samples
Overdevest et al. (2011) Emerg Infect Dis 17(7):1216-22
MLST Patterns of
E. coli
from Chicken / Other Meat and Human Rectal Swabs and Blood Cultures
Overdevest et al. (2011) Emerg Infect Dis 17(7):1216-22
Patients, Retail Meat and Poultry Share same ESBL Genes, Plasmids & Strains
• Of 98 retail meat samples: – – 94% contained ESBL-producing isolates 39% of these belonged to
E. coli
genotypes also present in human samples “These findings are suggestive for transmission of ESBL genes, plasmids and
E. coli
isolates from poultry to humans, most likely through the food chain.”
Leverstein-van Hall et al. (2011) Clin Microbiol Infect (Epub 6 April)
Carbapenemases
• • The emergence of ESBL-producing
Enterobacteriaceae
has lead to an increase in carbapenem use. Carbapenemases confer resistance to all b -lactams (penicillins / cephalosporins and carbapenems) and the
bla
gene is commonly associated with resistance genes • • The carbapenemases are classified into 3 categories New York City--carbapenem-resistant
K pneumoniae
rose from 9% in 2002 to 18% in 2004, to 38% in 2008. • KPC, the most important carbapenemase in
Enterobacteriaceae
, is endemic in USA [8% of
Klebsiella
in 2007 – 37 States] •
30 day mortality 41.7% Southern Medical Journal 2011(104), Tumbarello et al. CID 2012;55(7);943-50.
The resistance in Enterobacteriaceae:
b
-lactamases
Nordmann P., Cuzon G., Naas T., Lancet Infect Dis 2009; 9:228-236
Southern Medical Journal • Volume 104, Number 1, January 2011
Spread of KPC-containing
Klebsiella pneumoniae
from Greece - Travelling
Slide
1 4 1 1 2 1 1 1 1
Wernli D et al. PLoS Medicine 2011
•
NDM-1
NDM-1 (New Dehli metallo b -lactamase) first described in Dec 2009 in Swedish patient returning from India with MDR-
K. pneumoniae
infection • According to most recent data, first strains appeared in India as early as 2006 • Epidemiology first associated with India, Pakistan and the UK and then cases reported in many countries
Yong et al. Antimicrob Ag Chemother 2009;53:5046-5054
NDM-1 Microbiology
Kumarasamy K. et al Lancet Infect Dis 2010; 10 August 11
Kumarasamy K. et al Lancet Infect Dis 2010; 10 August 11
NDM-1 Around the World
Rolain, J.M., et al. Soc Clin Microbiol Infect Dis 2010;16: 1699-701.
Sources: More Unexpected Epidemiology
• • • • • • • Measure the prevalence of NDM-1 gene in drinking water and in pooled water from streets and small streams (“seepage”) in New Delhi Sep 26-Oct 10, 2010 Swabs of seepage water (n=171) and public tap water (n=50) collected from sites within 12 km radius of New Delhi Samples sent to UK and assessed for
bla
NDM-1 by PCR and DNA probing Compared to sewage effluent samples (n=70) from Cardiff, Wales (UK) as controls Performed susceptibility testing and typing Assessed plasmid transfer vs temperature
TR Walsh et al. Lancet Infect Dis 2011;11: 355 –62
Results
NDM-1 positive samples, New Delhi Water 2/50 (4%) Seepage 51/171 (30%) ALL seepage and water samples grew bacteria on cefotaxime containing media 94% seepage and 28% water samples grew bacteria on meropenem containing media Main commercial and financial center
Mean Temperatures in New Delhi (Bar) vs Ideal Plasmid Transfer Temperatures (Line)
Bacterial Strains Carrying NDM-1*
• • • • • • • Previously described
Citrobacter fruendii Escherichia coli Klebsiella pneumoniae Shigea boydii Vibrio cholera Aeromonas caviae Salmonella spp.
*All NDM-1 Enterobacteriaceae had multiresistant phenotypes • • • • • • • • Not previously described
P. aeruginosa P. putida P. pseudoalcaligines P. oryzihabitans Sutonella indologenes Stenotrophomonas maltophilia Achromobacter
spp.
Kingella denitrificans
The Newest Twist
• • • • 60 yo male transferred to a US hospital TA grew NDM-1 producing
K. pneumoniae
Surveillance cultures grew NDM-1 producing Salmonella Argues for prompt identification of patients at risk
Savard et al AAC 2011
Can Carbapenems Be Used?
• • Not recommended if resistant If MIC in susceptible range, consider extended infusion meropenem – – Meropenem 2 g IV Q 8H Dose infused over 3 hours as opposed to 30 minutes
Colistin (Polymixin E)
• • • • • • Colistin has no activity against Proteus, Serratia, Providentia, Burkholderia, GN or GP cocci Broth dilution titers ≤ 2 µg/mL accepted as susceptible Antibacterial action: cell membrane disrupted by binding of drug to phospholipids Concentration dependent Dose: 5 mg/kg/day divided into 2 doses Major toxicities – Renal impairment – – Neuromuscular blockade Neurotoxicity (many different manifestations
)
Tigecycline for Resistant GNR
• • • 18 pts who got ≥ 7 days of tigecycline Acinetobacter —10 cases – – 4 negative outcomes/5 positive outcomes 5/9 cases had intermediate resistance at start 4/5 died due to infection 1 case of emergence of resistance on therapy (MIC went from 2 to 12 mcg/mL) 1 case of persistent bacteremia Enterobacteriaceae —8 cases – 2 KPCs, 5 ESBLs, 2 AMP-Cs – – 3 negative outcomes/2 positive/3 unknown 1 case of persistent bacteremia
Should We Consider Several Agents?
• 3 Italian Centers, 125 patients with bloodstream infections with KPC;
Tumbarello et al. CID 2012;55(7);943-50
Rahal JJ. Clin Infect Dis. 2006;43:S95
.
Desperation
New Agents
• • Ceftibiprole and ceftaroline – MRSA activity! (high affinity for PBP-2a) – But Gram (-) spectrum not different from ceftriaxone Doripenem –
In vitro
, some activity against carbapenem resistant PAE
Study
Does Contamination of a Prior Room Increase the Risk of Acquisition?
Pathogen Likelihood of acquiring HCAI if prior room occupancy Martinez 2003 Huang 2006 Drees 2008 3 2 1 VRE – cultured w/in room VRE – prior room occupant MRSA – prior room occupant VRE – cultured w/in room VRE – prior room occupant VRE – prior room occupant w/in 2.6x
1.6x
1.3x
1.9x
2.2x
2.0x
Shaughnessy 2011 4 Rosa 2014 5 previous 2 weeks
C. difficile
– prior room occupant
A. baumannii
resistant to 2.4x
2.8X
carbapenems
A. baumannii
– prior room 3.8x
Nseir 2010 6 occupant
P. aeruginosa
– prior room 2.1x
occupant
Martinez et al. Arch Intern Med 2003; 163: 1905-12.; Huang et al. Arch Intern Med 2006; 166: 1945-51; Drees et al. CID 2008; 46: 678-85; Shaughnessy. ICHE2011;32:201-206; Rosa et al. ICHE 2014:35;430-3; Nseir et al. Clin Microbiol Infect 2010 (in press).
Do KPC’s Contaminate Rooms?
• 31% of interactions with patients with Klebsiella resulted in HCW or gown/glove contamination • Activities associated with contamination included manipulation of catheter or drain, more than 2 contacts with the patient or the environment, being a PT, RT> RN> MD
Rock et al. ICHE 2014; 35:426-8
•
NDM-1 Infection Prevention Approaches
Themes – Pro-active planning – Preemptive screening/isolation of high risk patients – – Contact precautions Screening of patients in surrounding area – – – Peri-rectal/rectal swab + Enhanced IC/AM Monitoring in laboratory with appropriate protocols —eg modified Hodge test
Summary
• • • • Resistant Gram-Negative organisms are emerging as significant pathogens that disseminate quickly and widely. ESBLs and CREs are of increasing importance and require a thoughtful approach to antibiotic choice Transmission and sources may be novel and associated with food and water You still need to wash your hands and isolate patients