The Other Pandemic

What’s new with drug resistant gram negatives?

Well, its not good!

Matthew P. Muller, MD, PhDInfection Prevention and Control

St. Michael’s Hospital

Case #1Elemam et al, CID 2009;49

• A 70 year old woman was admitted from a LTCF in New York City with dysuria, suprapubic pain and tenderness and a foley catheter

• She had recently been hospitalized for pneumonia secondary to a KPC-producing K.pneumoniae treated with tigecycline and polymyxin B

Case #1

• A urine culture was positive for klebsiellapneumonia that was highly resistant

• MIC to tigecycline was 4 ug/ml• MIC to polymycin B was 96 ug/ml• Therapy was initiated with tigecycline and

rifampin

Case #1

• After 10 days of treatment her symptoms persisted

• Antibiotic therapy was stopped and she was sent back to the long term care facility

• Her symptoms resolved gradually but her urine cultures remained positive for pan-drug resistant klebsiella

Case #2• A 67 man developed a hepatic abscess post

whipples procedure• A drain was inserted and cultures grew

Klebsiella pneumoniae and Enterobactercloacae

• Both isolates were carbapenem resistant but susceptible to tigecycline and polymyxin B

• He was treated with tigecycline but had a prolonged course with multi-organ dysfunction

Case #2

• The patient was then transferred to a different hospital

• On admission he was febrile, ventilated and had an abdominal drain in situ

• Blood cultures were negative• CT scan demonstrated a large hepatic

abscess; the drain was not in the correct position

Case #2

• Polymyxin B was added to tigecycline and the drain was replaced

• He then developed septic shock• Cultures of the abscess were positive for

E.cloacae, K.pneumoniae, Enterococcusfaecium

• The E.cloacae and K.pneumoniae were both KPC producers

Case #2

• The K. pneumoniae was Tigecyclineresistant and MIC to polymyxin B was >16

• Patient taken to OR for surgical drainage• Post-op blood cultures were positive for K.

pneumoniae• The patient died several days later of

septic shock

Welcome to the post-antibiotic era

• How did this happen?

Antimicrobial mechanisms effective against gram negative bacteria

• Inhibitors of cell wall synthesis (beta-lactams)• Interference with nucleic acid synthesis

(fluoroquinolones)• Inhibition of protein synthesis (aminoglycosides,

glycylcyclines)• Inhibition of a metabolic pathway

(cotrimoxazole)• Disruption of the bacterial membrane (colistin,

polymyxin B)

Evolution of β-lactamases

• Penicillin isolated (1929)• Penicillinase isolated from E.coli (1940)• Penicillin enters clinical practice as

treatment for gram positive organisms (1940’s)

• Pencillinase producing S.aureus identified (1942) and begins causing hospital outbreaks

Evolution of β-lactamases

• Ampicillin enters clinical practice as a ‘broad spectrum’ penicillin with gram negative activity (1961)

• E.coli with plasmid encoded β-lactamase(TEM-1) identified (1963)

• Plasmid encoded TEM-1 spreads rapidly to other species (e.g. haemophilus, neisseria)

Evolution of β-lactamases• Third generation cephalosporins developed to

resist currently existing beta-lactamases (e.g. TEM-1, SHV-1)

• Third generation cephalosporins enter clinical practice in the 1980’s

• Mutation in SHV-1 to SHV-2 leads to ESBL phenotype (1984) in E.coli and K.pneumoniae

• ESBL resistant to penicillins and first, second and third generation cephalosporins

Antimicrobial mechanisms effective against gram negative bacteria

• Inhibitors of cell wall synthesis (beta-lactams) (carbapenems are an exception)

• Interference with nucleic acid synthesis (fluoroquinolones)

• Inhibition of protein synthesis (aminoglycosides, macrolides, tetracyclines,glycylcyclines)

• Inhibition of a metabolic pathway (cotrimoxazole)

• Disruption of the bacterial membrane (polymyxins)

How do we get from beta-lactamasesto multi-drug resistance?

• While beta-lactamases were evolving, so were plasmid mediated mechanisms of resistance to other antibiotics

• ESBL producing Enterobacteriaceae (ESBL-E) first emerged in settings with high antibiotic selective pressure (ICU)

• Plasmids carrying >1 antibiotic resistant determinant are more successful than plasmids carrying only an ESBL in this type of environment

Antimicrobial mechanisms effective against gram negative bacteria

• Inhibitors of cell wall synthesis (beta-lactams) (carbapenems are an exception)

• Interference with nucleic acid synthesis (fluoroquinolones)

• Inhibition of protein synthesis (aminoglycosides) (tigecycline is an exception)

• Inhibition of a metabolic pathway (cotrimoxazole)

• Disruption of the bacterial membrane (polymyxins)

But we still have the fluoroquinolones, right?

• In a prospective study of klebsiellabacteremia, 16% of FQ susceptible Klebsiella were ESBL producers and 60% of FQ resistant Klebsiella were ESBL producers

– Paterson, CID 2000• 50% of ESBL-E are fluoroquinolone

resistant– Lautenbach, CID 2001

Antimicrobial mechanisms effective against gram negative bacteria

• Inhibitors of cell wall synthesis (beta-lactams) (carbapenems are an exception)

• Interference with nucleic acid synthesis (fluoroquinolones)

• Inhibition of protein synthesis (aminoglycosides) (tigecycline is an exception)

• Inhibition of a metabolic pathway (cotrimoxazole)

• Disruption of the bacterial membrane (polymyxins)

How do we get from MDR to KPC?

• Treatment of serious ESBL-E with third generation cephalosporins is associated with clinical failure

• Infection with ESBL-E are associated with increased length of stay and cost

• Bacteremia with ESBL-E is associated with a 2-fold increased risk of death

• Other agents commonly used for the treatment of GNB can not be used for EMPIRIC treatment due to risk of resistance

How do we get from MDR to KPC?

• Experts recommend carbapenems for severe ESBL-E infections

• What happens? Clinicians use carbapenems for the treatment of all ESBL-E infections (mild and severe) as well as for ESBL-E colonization (e.g. asymptomatic bacteriuria) that doesn’t need treatment

• The results? Increasing resistance to carbapenems!

Antimicrobial mechanisms effective against gram negative bacteria

• Inhibitors of cell wall synthesis (beta-lactamsincluding carbapenems)

• Interference with nucleic acid synthesis (fluoroquinolones)

• Inhibition of protein synthesis (aminoglycosides) (tigecycline is an exception)

• Inhibition of a metabolic pathway (cotrimoxazole)

• Disruption of the bacterial membrane (polymyxins)

Mechanisms of Carbapenem resistance

• Combined mechanisms– modification of outer membrane permeability,

up regulation of efflux pumps, and hyper-production of AmpC or ESBL beta-lactamases

• Carbapenemases– Metallo-Beta-Lactamases (VIM, IMP)– Extended Spectrum oxacillinases (OXA-48)– Clavulanic acid inhibited beta-lactamase

(KPC)

Ambler Classification

• CLASS MECH EXAMPLES• A Serine KPC

• B Zinc IMP,VIM

• C Serine AmpC

• D Serine OXA-48

Klebsiella producing carbapenemase (KPC)

• First identified in US (1996)• Hydrolyzes all beta-lactam molecules including

penicillins, cephalosporins, monobactams and carbapenems

• Can be mistaken for ESBL• KPC alone reduce susceptibility to

carbapenemes but additional mechanisms may be required to achieve resistance (e.g. impaired outer membrane permeability

KPC• KPC are plasmid mediated and move

easily between species ‘there is more to Canadian tire than just tires’

• How confusing is this “klebsiella producing carbapenemase producing E.coli”

• KPC carrying plasmids usually carry aminoglycoside resistance determinants and may carry FQ resistance determinants and multiple ESBLs

KPC

• KPC are common in NYC but have spread globally with specific hot spots (Israel, Greece)

• NYC data suggests clonal spread between facilities (78/95 isolates from 10 hospitals were same clonal type)

– Bratu S, CID 2007;44

• Israeli strains likely originated in US

Risk Factors for KPC

• Prolonged hospitalization• ICU stay• Invasive devices• Treatment with antibiotics (but not

necessarily carbapenems)• (Travel to endemic area)

The Real Risk Factors

• Selective Pressure due to antibiotics• Patient to Patient Transmission

Treatment Options for KPC• Non-beta-lactam choices are often limited

to polymyxins (colistin, polymyxin B) and tigecycline

• Some US ICU’s are using colistin as first line empiric therapy for VAP in select patients

• None of these are good choices and resistance to these agents has been described

Pan-drug resistant Klebsiella• Inhibitors of cell wall synthesis (beta-lactams

including carbapenems) • Interference with nucleic acid synthesis

(fluoroquinolones)• Inhibition of protein synthesis (including

tigecycline• Inhibition of a metabolic pathway

(cotrimoxazole)• Disruption of the bacterial membrane

(polymyxins)

The post-antibiotic era

• What can we do? What are we doing?

Infection Control for ESBL-E

• The are no guidelines for the control of ESBL-E

• Experts agree only on the obvious– Wash your hands– Investigate outbreaks

• The is no consensus on the approach that should be taken in the ‘non-outbreak’setting

Practice Variation• Survey of large hospitals in Ontario and

Quebec, 2002 [Muller et al, CCDR, 2002]– ¼ recommend routine practices, ¾ recommend

contact precautions– Of those recommending contact precautions, 70%

recommend isolation• Survey of Toronto area hospitals, 2008 [K.Katz,

NYGH]– 40% do admission screening for ESBL– 10% don’t use isolation/contact precautions– 90% do (70% all ESBL, 20% all AmpC, 20% only if

risk factors for transmission)

What Infection Control Interventions Should be Undertaken to Control MDR GNB?

[Harris AD, et al. CID 2006:43S2]

• Should active surveillance be performed for MDR GNB? Should contact isolation be used for patients colonized or infected with MDR GNB?

• Key Parameters = Attributable fraction of resistance due to antibiotic use vs. patient-to-patient transmission

• No accurate estimation of these parameters exist for MDR GNB in the non-outbreak setting

13% of ESBL-EC colonization was due to transmission

Upper estimate was 39%

Conclusion -- transmission is not an important cause of ESBL E.coli colonization in the ICU setting

52% of ESBL-KP colonization in an ICU was due to transmission

Conclusion – pt-to-pt transmission is an important cause of the acquisition of ESBL-KP colonization

Infection control for ESBL-E• Implication of this debate is that there is not

enough evidence to justify surveillance and contact precautions/isolation

• But 10% transmission over time could lead to a big problem! Why not deal with both risk factors (transmission and antibiotic selective pressure)

• Maybe if we had controlled ESBLs, we wouldn’t have had to use so many carbapenems……

Systematic Review of IPAC strategies for ESBL

• We looked for experimental or quasi-experimental studies looking at enhanced routine practices, surveillance, isolation or contact precautions as strategies to reduce ESBL incidence

• We found 4 low quality studies that were impossible to interpret

Conclusions of Review• All studies were uncontrolled,

retrospective, and poorly designed• There is currently no empiric evidence to

suggest which, if any, infection control interventions reduce ESBL-E incidence in the non-outbreak setting

• No studies were REB approved – Thus, a critical knowledge gap exists but no research is being done to address it

CDC recommendations for KPC

• Contact precautions for colonized or infected patients with carbapenem resistant Enterobacteriacae

• Point prevalence studies on high risk units if KPC have been identified at your facility

• If clinical cultures are positive or colonization is detected then conduct active surveillance until transmission is terminated– MMWR, March 20, 2009

Conclusions• The situation is ‘complicated’ with multiple

mechanisms of resistance, mobile genetic elements, diffusion of resistance from acute care to chronic care to the community, limited antibiotic options

• The solution (if there is one) will require leadership and cooperation between geographic regions, infection control, public health, physicians, etc.

What can we do now?• Enhanced infection control

– Hand hygiene, disinfection of equipment, single rooms for all patients

– Surveillance and enhanced precautions for MDR GNB

• Antimicrobial stewardship• Good clinical care

– Aggressive diagnosis and less emphasis on empiric therapy

– Source control• Prioritize research to demonstrate the efficacy of

the above