ABCs for MDROs and ESBLs

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ABCs for MDROs and ESBLs

• Mohamad G Fakih, MD, MPH
• St John Hospital and Medical Center

5/15/08
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A Reminder from History

• 1940s the birth of antimicrobials
• 1950s Staphylococcus aureus resistant to PCN
• 1960s resistance to Sulfa in gram negatives
• 1970-1980s strong ?-lactam agents for S.aureus,
  emergence of MRSA
• 1980s cephalosporins with broad spectrum
  coverage, emergence of ESBL
• 1990-2000s VRE, VISA
• 2002 VRSA

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Resistance in ICU NNIS 2004(AJIC 200432470-85)
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Resistance in ICU NNIS 2004(AJIC 200432470-85)

• MRSA increased from 50 to 60
• Klebsiella pneumoniae resistant to 3rd gen
  cephalosporins increased by 50 to reach 21

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Gve and G-ve Organisms
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Gram ve cell wall
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Gram Positives

• Staphylococcus aureus
• Enterococcus species

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Staphylococcus aureus
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Staphylococcus aureus

• ?-lactamase production almost all
• Methicillin resistance PBP-2a production with
  low affinity to all ?-lactams (mecA gene)
• Heterogenous expression of gene
• Inducible and constitutive
• Health associated and community acquired

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MRSA is Reported Resistant to all Cephalosporins
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MRSA Susceptible to Clindamycin
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Clindamycin Resistance and S.aureus(Infect Dis
Clin N Am 18 (2004) 401434)
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MLS phenotype In MRSA that was previously
reported as clinda suceptible. D test
Siberry, CID 2003 37 1257-60
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MRSA with no Inducible Clindamycin Resistance
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MRSA Clindamycin Inducible Resistance
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MSSA Clindamycin Susceptible
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MSSA Clindamycin Inducible Resistance
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Methicillin (oxacillin)-resistant Staphylococcus
aureus (MRSA) Among ICU Patients, 1995-2004
Source National Nosocomial Infections
Surveillance (NNIS) System
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VISA (GISA)

• VISA resistance related to excess production of
  cell wall material, penicillin-binding protein 2
  (PBP2), with formation of multicellular
  aggregates that clump and prevent access of
  vancomycin to its target sites
• No Van A, B, or C genes
• Contains 3-5 times more PBP2 compared to
  susceptible strains
• Vancomycin MICs are 4-8 µg/mL

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VRSA (GRSA)

• 1st reported case June 2002, in Michigan patient
  with DM, on dialysis with infected foot ulcer.
  The ulcer culture grew VRSA, VRE, and Klebsiella
  sp. VRSA isolated from catheter, ulcer, and exist
  site (MIC gt128 ?g/ml). Isolate had the Van A gene
  from enterococci, and the Mec A gene. Patient was
  treated with TMP/Sulfa.

MMWR 2002 51 (26) 565-6
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VRSA

• vancomycin MICs are 16 µg/mL

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Vancomycin resistance-Enterococcus (Murray EID
1998 437-47)
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Vancomycin resistance

• Van A high level resistance to Vanco (gt64).
  Transposon (Tn 1546). Inducible, D-Ala-D-Lac
• Van B high level resistance to Vanco, not
  teicoplanin, inducible, D-Ala-D-Lac
• Van C low level resistance to vanco, susc.
  Teicoplanin, nontransferable species specific
  genes ( E. gallinarum- Van C1 E. casseliflavus-
  Van C2), D-Ala-D-Ser
• Van D acquired, D-Ala-D-Lac, mostly faecium
• Van E acquired, D-Ala-D-Ser, faecalis

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Enterococcus

• Intrinsically resistant to carboxypenicillins,
  cephalosporins, TMP/Sulfa, clindamycin
• Susceptible to PCN G, Ampicillin, Piperacillin,
  Vancomycin
• Rare instances of ß-lactamase production for E.
  faecalis
• Other agents linezolid, Daptomycin

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Enterococcus

• E. faecalis (gt90 of isolates)
• E. faecium (almost 50 VRE)

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Vancomycin-resistant Enterococi Among ICU
Patients, 1995-2004
Source National Nosocomial Infections
Surveillance (NNIS) System
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VRE Increase over Time(Am J Med 2006119(6A),
S11S19)
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GNB ?-lactamases

• Molecular classes classified based on primary
  structure (A through D)
• Functional groups classified based on substrate
  spectrum and responses to inhibitors

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Bush-Jacoby-Medeiros grouping
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NEJM 2005 352380-91
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Plasmid encoded ?-lactamases(G-ves)

• Broad spectrum TEM-1 (Enterobacteriaceae, P.
  aeruginosa, H. influenzae, N. gonorrhea), TEM-2
  (Enterobacteriaceae), SHV-1 (Enterobacteriaceae)
• Oxacillinases OXA-1 and OXA-2 (Enterobacteriaceae
  , P. aeruginosa)
• Carbenicillinases BRO-1, BRO-2, BRO-3
  (Branhamella), PSE-1 (Enterobacteriaceae, P.
  aeruginosa)

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Plasmid encoded ?-lactamases(G-ves)

• Extended spectrum (class A oxymino-
  ?-lactamases) related to TEM, SHV, OXA
• resistance to cefotaxime, ceftazidime, aztreonam
• TEM derived (K. pneumoniae), SHV derived (K.
  pneumoniae), inhibitor resistant ( E. coli), OXA
  derived (P. aeruginosa)

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Plasmid encoded ?-lactamases(G-ves)

• Class C cephamycinases resistance to cefoxitin,
  cefotetan (K. pneumoniae, C. freundii, E.
  aerogenes)
• Carbapenemases resistance to Imipenem, Meropenem
• Metalloenzymes (P. aeruginosa, S. marcescens, K.
  pneumoniae)
• Nonmetalloenzymes (Acinetobacter baumanii)

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Inhibitor Resistant ?-Lactamases

• At least 19 inhibitor resistant TEM -lactamases
• E. coli, K. pneumoniae, K. oxytoca, P. mirabilis,
  and C. freundii
• Resistant to sulbactam and clavulanate,
  susceptible to tazobactam

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(Clin Microbiol Rev 2001 14 (4) 933-51)
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ESBL K. pneumoniae(Infect Dis Clin N Am 18
(2004) 401434)
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Blood Cx Enterobacter cloacae
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3rd generation cephalosporin-resistant Klebsiella
pneumoniae Among ICU Patients,1995-2004
Source National Nosocomial Infections
Surveillance (NNIS) System
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Acinetobacter sp

• Gram-negative coccobacillus
• Community alcoholism, cigarette smoking, chronic
  lung disease, diabetes mellitus
• Hospital LOS, surgery, broad-spectrum
  antibiotics, TPN, central catheters, urinary
  catheters, ICU, mechanical ventilation

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Acinetobacter Infections

• Community alcoholism, cigarette smoking, chronic
  lung disease, diabetes mellitus
• Hospital LOS, surgery, broad-spectrum
  antibiotics, TPN, central catheters, urinary
  catheters, ICU, mechanical ventilation
• Pneumonia, catheter related BSI, UTI, soft
  tissue, meningitis (neurosurgery)

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Characteristics of Acinetobacter Outbreaks
1977-2000 (ICHE 2003 24284-295)

• Reported mainly ICU, but also outbreaks on
  general wards, burn units, cardiac cath, urology,
  oncology, hemodialysis, nursery
• Sources of outbreaks ventilator spirometers,
  mouthpiece of resuscitator bag, valve reservoir
  of ventilator, reusable ventilator tubing,
  temperature probe of ventilator humidifier,
  multiple dose acetyl cysteine nebulizer

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Characteristics of Acinetobacter Outbreaks
1977-2000 (ICHE 2003 24284-295)

• Up to 25 of HCW hands were colonized with
  Acinetobacter in outbreaks
• Hand hygiene, use of disposable tubing, and
  single use products led to control

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Carbapenem Resistance NY City (Clin Infect Dis
2003 37 214-20)

• A. baumanii isolates from 15 major hospitals
  Brooklyn 12/00 to 2/01.
• Resistant MIC of 8 mg/mL to meropenem or
  imipenem
• Susceptible to polymixin 2 mg/mL

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Carbapenem Resistance NY City (Clin Infect Dis
2003 37 214-20)
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Screening and Management of MDROs
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Definition of MDRO(Am J Infect Control
200735S165-193)

• Microorganisms resistant to one or more classes
  of antimicrobial agents
• Examples MRSA, VRE, some GNB
• GNB extended spectrum beta-lactamases (ESBLs),
  eg, Escherichia coli and Klebsiella pneumoniae,
  Acinetobacter baumannii

CDC MDRO Guidelines
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Significance of MDRO Infections (Am J Infect
Control 200735S165-193)

• Increased lengths of stay, costs, and mortality
• ICUs have a higher prevalence than non-ICU
  settings
• Resistance rates associated with hospital size,
  tertiary-level care, and facility type (NH)

CDC MDRO Guidelines
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Transmission (Am J Infect Control
200735S165-193)
Cannot control

• Vulnerable patients (severe disease, postop,
  immunocompromised, indwelling medical devices)
• Antimicrobial use
• Transmission from larger numbers of colonized or
  infected patients (colonization pressure)
• Transmission through contaminated hands of care
  givers
• Patients may be exposed to MDROs through
  different facilities that they visit
• Colonized HCWs are a rare source of MDRO
  transmission

CDC MDRO Guidelines
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Factors for Acquisition of MDROs(CID2006
43S5761)
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How to Prevent Antimicrobial Resistance(Am J
Infect Control 200735S165-193)

• Optimal management of vascular and urinary
  catheters
• Prevention of lower respiratory tract infection
  in intubated patients
• Accurate diagnosis of infectious etiologies
• Judicious antimicrobial selection and
  utilization.

CDC MDRO Guidelines
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(Am J Infect Control 200735S165-193)
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Multiple Interventions are Necessary to Lead to
Control

• Education, hand hygiene, contact precautions,
  surveillance cultures of patients, culturing
  staff, environmental cultures, extra cleaning,
  reduce sharing equipment.
• So it is not only isolation that leads to
  reducing transmission
• It is compliance, compliance, and compliance with
  hand hygiene!!!

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Infection control precautions toprevent
transmission (Am J Infect Control
200735S165-193)

• Follow standard precautions in all health care
  settings (IB).
• Implement CP for all patients known to be
  colonized/infected with target MDROs (IB).
• When single-patient rooms are available, assign
  priority for these rooms to patients with known
  or suspected MDRO colonization or infection. Give
  highest priority to those patients who have
  conditions that may facilitate transmission, eg,
  uncontained secretions or excretions. When
  single-patient rooms are not available, cohort
  patients with the same MDRO in the same room or
  patient care area (IB).
• Implement patient-dedicated use of noncritical
  equipment (IB).

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How do we know that transmission is minimized?

• ICU at SJHMC hand hygiene compliance increased
  to 90 when observer known, 50-60 with
  unidentified observer, and 20 at night shift
  with unidentified observer!
• How do we reduce fomite transmission sharing
  equipment between patients with MDRs and others?
• How do we make sure that environmental cleaning
  is done correctly?

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Support Needed when Using ASC (Am J Infect
Control 200735S165-193)

• Personnel to obtain the appropriate cultures
• Microbiology laboratory personnel to process the
  cultures
• Mechanism for communicating results to caregivers
• Concurrent decisions about use of additional
  isolation measures triggered by a positive
  culture (eg, contact precautions)
• Mechanism for assuring adherence to the
  additional isolation measures.

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Universal Screening for MRSA and Nosocomial
Infection (JAMA 2008299(10)1149-1157)

• Prospective cohort study July 04 -May 06
• Swiss teaching Hosp 21,754 surgical patients
  comparing 2 MRSA control strategies (rapid
  screening on admission plus standard infection
  control measures vs standard infection control
  alone).
• 12 surgical wards assigned to either the control
  or intervention group for a 9-month period, then
  switched over to the other group for a further 9
  months (cross-over).

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Universal Screening for MRSA and Nosocomial
Infection (JAMA 2008299(10)1149-1157)

• Intervention group rapid screening MRSA, if
  positive, contact isolation, use of dedicated
  material (gown, gloves, and, if indicated, mask),
  adjustment of perioperative antibiotic
  prophylaxis of MRSA carriers, computerized MRSA
  alert system, and topical decolonization (nasal
  mupirocin ointment and chlorhexidine body
  washing) of known MRSA carriers for 5 days
• Specimens sampling of the anterior nares and
  perineal region and other sites (catheter
  insertion sites, skin lesions, or urine) when
  clinically indicated

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Universal Screening for MRSA and Nosocomial
Infection (JAMA 2008299(10)1149-1157)
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Universal Screening for MRSA and Nosocomial
Infection (JAMA 2008299(10)1149-1157)
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Universal Screening for MRSA and Nosocomial
Infection (JAMA 2008299(10)1149-1157)

• Intervention periods 93 patients (1.11 per 1000
  patient-days) developed nosocomial MRSA infection
  compared with 76 in the control periods (0.91 per
  1000 patient-days P.29).
• Fifty-three of 93 infected patients (57) in the
  intervention wards were MRSA-free on admission
  and developed MRSA infection during
  hospitalization.
• Conclusion A universal, rapid MRSA admission
  screening strategy did not reduce nosocomial MRSA
  infection

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Availability of Equipment with Isolation
Precautions(Journal of Hospital Infection (2007)
65, 81-90)
Isolation till ASC out
Isolation with those with ve Cx
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CA-MRSA Replacing Hospital Associated Strains
So does it make sense to just focus on the
organism instead of concentrating on factors that
facilitate transmission?
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The 1 million Question

• Ok, you find that patients are colonized with
  MRSA. Is contact precautions enough to reduce
  transmission? Is hand hygiene enough if it were
  implemented with excellent compliance? Or is it
  multiple factors including patients
  susceptibility to acquire MRSA?