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