Catheterrelated Bloodstream Infections

1
Catheter-related Bloodstream Infections
Antibiotic Lock Solutions

• Brandon Bookstaver, PharmD, BCPS
• Infectious Diseases Specialty Resident
• June 12, 2006

2
DisclosuresSection of Infectious Diseases

• Kevin High
• Grant/Research Support Cubist Pharmaceuticals,
  Astellas Pharma US, Inc.
• Consultant Merck Co., Inc.
• Speakers Bureau Pfizer Pharmaceuticals
• James Peacock, M.D.
• Ownership in Common Stock Pfizer
  Pharmaceuticals
• Sam Pegram, M.D.
• Grant/Research Support Roche, Bristol-Myers
  Squibb, Gilead, Schering-Plough, Tibotec
  Pharmaceuticals
• Consultant Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Gilead,
  Roche
• Speakers Bureau Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Merck,
  Pfizer Pharmaceuticals

3
Disclosure (continued)Section of Infectious
Diseases

• Aimee Wilkin, M.D.
• Grant/Research Support Abbott Laboratories,
  GlaxoSmithKline, Tibotec Pharmaceuticals,
  Bristol-Myers Squibb Company, Gilead
• Christopher Ohl, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Gene-Ohm Sciences, Merck Pharmaceuticals
• Speakers Bureau/Consultant Ortho-McNeil
  Pharmaceuticals, Cubist Pharmaceuticals,
  Sanofi-Aventis Pharmaceuticals, Pfizer
  Pharmaceuticals, Bayer Pharmaceuticals

4
Disclosure (continued)Section of Infectious
Diseases

• Tobi Karchmer, M.D.
• Grant/Research Support Gene-Ohm Sciences
• Speakers Bureau Pfizer Pharmaceuticals, Cubist
  Pharmaceuticals, Cepheid,
• Gene-Ohm Sciences
• Consultant C.R. Bard
• Robin Trotman, D.O.
• Speakers Bureau Pfizer Pharmaceuticals

5
Biofilm
Donlan RM, et al. Clin Microbiol Rev. 2002
Apr15(2)167-93.
6
Objectives

• Describe the formation of a bacterial biofilm and
  its clinical impact
• Review the definition, diagnosis, and impact of
  catheter-related bloodstream infections (CRBSIs)
• Review the role of antibiotic lock (ABL)
  solutions in the management of CRBSIs
• Highlight new data regarding ABL solutions

7
Visit to Webster's

• a microbially derived sessile community
  characterized by cells that are irreversibly
  attached to a substratum or interface or to each
  other, are embedded in a matrix of extracellular
  polymeric substances that they have produced, and
  exhibit an altered phenotype with respect to
  growth rate and gene transcription.

Costerton JW, et al. Sci Am. 197823886-95.


Donlan RM, et al. Clin
Microbiol Rev. 200215167-93.

8
Biofilm formation
Schneegurt, MA. Wichita St. University,
Microbiology 103.
9
Why form a bioflim?
Jefferson KK. FEMS. 2004236163-73.
10
Biofilm resistance to antimicrobials

• Delayed penetration of antimicrobial through the
  matrix
• Ciprofloxacin in P. aeruginosa¹
• Tobramycin and gentamicin in P. aeruginosa²
• Altered growth rate of organisms within biofilm
• gt 10 fold decrease in growth rate in K.
  pneumoniae³
• S. epidermidis ciprofloxacin inactivation
  higher, the slower the rate of cell growth4
• Other physiological changes resultant of gene
  repression or induction
• rpoS gene in E. coli in response to environmental
  stress5

¹Suci PA, et al. Antimicrob Agents Chemother.
1994382125-33. 4DuGuid IG, et al. J.
Antimicrob Chemother. 199030791-802.

²Hatch RA, et al.
Antimicrob Agents Chemother. 199842974-77.
5Adams JL, et al. Appl Environ Microbiol.
1999654285-87.

³Anderl JN, et al. Antimicrob Agents
Chemother. 2003471251-56.

11
Susceptibility of biofilm organisms
ª Minimal biofilm eradication
Adapted from Donlan RM, et al. Clin Microbiol
Rev. 200215167-93.
12
Catheter-related bloodstream infections (CRBSI)

• Majority of cases associated with CVCs
• Avg. rate of 5.3 CRBSI per 1,000 catheter days¹
• Estimated 250,000 cases annually²
• ICU 80,000 cases
• Costs 25,000/case
• Annual cost 6.25 billion
• Mortality ranges from 12 - 35¹,²

¹CDC. Am. J. Infect. Control. 199826522-33.
³Schaberg DR, et al. Am. J. Med.
199191(3B)S72-75.

²Kluger Dm, et al. 39th ICAAC.
Abstract 1913. 1999514.
4CDC. Am. J. Infect.
Control. 199927520-32.
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Definition Diagnosis of CRBSI

• Clinical signs symptoms of infection
• Culture data
• Blood cultures drawn through CVC peripheral
  (i.e. PIV)
• Catheter tip/segment
• Time to positivity versus quantitative data

Mermel LA, et al. Clin Infect Dis. 200132249-72.
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Management of CRBSIs

• Treatment of choice
• Remove the catheter
• Systemic antibiotics
• Antibiotic lock therapy
• Further diagnostics

Patient organism specific
Mermel LA, et al. Clin Infect Dis.
200132249-72.

Rosen AB, et
al. Ann Intern Med. 1999130810-20.
Fowler VG, et al. J
Am Col. Cardiol. 1997301072-78.
15
Tunneled CVC / Implantable Device Related BSI
Uncomplicated
Complicated
Tunnel Infection / Port Abscess
S. aureus
CoNS
GNR
Candida spp.
Retain Systemic ABX 7d ABX lock 10 - 14d Remove
if clinical deterioration or persisting
or relapsing bacteremia
Remove Systemic ABX 14 d if TEE (-) Salvage
Therapy TEE (-) Systemic ABX ABX lock 14
days Remove if clinical deterioration
or persisting or relapsing bacteremia
Remove Systemic ABX 10 - 14 days Salvage
Therapy Systemic ABX ABX lock 14 days If no
response then remove Systemic ABX 10 - 14 days
Remove CVC Antifungal therapy Continue for 14
days from last () blood culture
Remove CVC Treat 10 -14 days
Adapted from Mermel LA, et al. Clin Infect Dis
200132249-72. (permission from Christine
Hansen, PharmD)
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Role of Antibiotic Lock (ABL) Therapy

• Prevention Guidelines¹
• Use prophylactic antibiotic lock solution ina
  patient with a long-term cuffed or tunneled
  catheterwho has a history of multiple CRBSIs.
  Category II
• Treatment Guidelines²
• Antibiotic lock therapy is recommended for
  treatment when the catheter is retained. B-III
• Highlights studies showing success with
  combination of parenteral antibiotics lock
  therapy

¹Mermel LA, et al. Clin Infect Dis
2002351281-307.

²Mermel, LA, et al. Clin Infect Dis
2001321249-72.


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ABL Therapy in CRBSI

• High antibiotic concentrations required
• Antibiotic-anticoagulant combinations

Bestul MB, et al. Pharmacother 200525211-27.
Donlan RM, et al. Clin Microbiol
Rev. 200215167-93. Pascual A, et al. J Hosp
Infect. 199324211-18.
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ABL Technique

• Heparin requirements
• Dialysis catheters
• 2,500 5,000 units/mL in lock solution
• Other CVCs
• 10 100 units/mL in lock solution
• Typical port requires approximately 3 mL of fill
  volume
• WFUBMC send 5 mL syringes (with 3 mL of lock
  solution) per port

19
ABL Literature
Published Data gt 20 antimicrobials
ABL commonly used in practice

• Vancomycin
• Cephalosporins
• AGs
• TCNs
• Linezolid
• Quinupristin/Dalfopristin
• Clindamycin
• Amphotericin B

• Vancomycin-Heparin
• Gentamicin-Heparin
• Minocycline-EDTA
• Cefazolin-Heparin

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Vancomycin lock solutions
¹Poole CV, et al. Nephol Dial Transplant.
2004191237-44. ²De Sio L,
et al. Pediatr Infect Dis J. 200423963-5.
³Rjinder BJ, et al. J Antimicrob Chemother.
20055590-94.
21
Gentamicin lock solutions
¹Krishnasami Z, et al. Kidney Int.
2002611136-42.
²McIntyre CW, et al. Kidney Int.
200466801-5. ³Dogra GK, et al. J Am Soc
Nephrol. 2002132133-39.
22
Minocycline-EDTA (M-EDTA) lock solutions
¹Chatzinikolaou I, et al. Clin Infect Dis.
200336116-19.

²Bleyer A, et al. Infect Control Hosp
Epidemiol. 200526520-24.


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Issues with current therapy

• Vancomycin
• Selecting out for vancomycin-resistant
  enterococci
• Poor penetration in biofilm layer
• Gentamicin
• Concerns of toxicity with systemic absorption
• Compatibility issues
• Minocycline
• Intravenous formulation no longer available
• Cefazolin
• In vitro data demonstrates poor results vs.
  biofilm
• Heparin based solutions
• Heparin intolerant/allergic patients
• Concern for accidental IV push
• Compatibility issues
• Promotes bacterial growth

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Efficacy of daptomycin, tigecycline, cefazolin,
and gentamicin lock solutions using an in vitro
model of intravenous catheter infection

• Brandon Bookstaver, PharmD, BCPS
• John Williamson, PharmD, BCPS
• Robert Sherertz, MD
• B. Keith Tucker, BS

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Objective

• Purpose
• Evaluate the efficacy of the candidate lock
  solutions of daptomycin, tigecycline, cefazolin,
  and gentamicin in a model of intravenous catheter
  infection
• Outcome
• Time-kill analysis at time points 0, 2, 4, 24
  hours

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Antibiotic /- Anticoagulant Lock
Solutions
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Methods

• Prepared inoculum of test organism
• ?
• 1-cm Hickman-catheter segments placed in 4mL of
  inoculated Tryptic Soy Broth (TSB) and incubated
  for 24 hours
• ?
• Catheter segments removed and placed in the lock
  solutions for the specified time periods (0, 2,
  4, and 24 hours)
• ?
• Catheter segments were removed at specified time
  points sonicated vortexed then diluted and
  plated on blood agar
• ?
• Colony forming units (CFU) were counted after 24
  hours of incubation and converted to log10
• ?
• Each test was performed in quadruplicate

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Daptomycin Saline vs. Daptomycin LR-
Time-kill Analysis vs. Staphylococcal spp. -
Daptomycin Saline

Log10 (CFU)

Daptomycin LR
Time (hours)
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Methicillin-resistant S. aureus- Time-kill
Analysis -
Log10 (CFU/mL)
Log10 (CFU/mL)
Log10 (CFU)
Time (hours)
Time (hours)
Time (hours)
30
Methicillin-sensitive S. aureus- Time-kill
Analysis -
Log10 (CFU)
Time (hours)
31
P. aeruginosa- Time-kill Analysis -
Log10 (CFU)
Log10 (CFU/mL)
Time (hours)
Time (hours)
32
Limitations

• Laboratory reproducibility
• Contamination
• Variability in colony counts
• Heparin not included as lock solution

33
Conclusions

• Daptomycin results improved with reconstitution
  in lactated ringers
• Gentamicin EDTA and Tigecycline EDTA showed
  the greatest efficacy for all Staphylococcal
  species
• Candidate lock solutions deserve further in vivo
  investigation

34
On the horizon

• Expanding use of ABL more research
• Doxycycline (or tigecycline) replacement for
  minocycline
• Newer generation of antibiotics
• Antifungal locks (Amphotericin-B)
• Ethanol based lock solutions¹
• Questionable anticoagulant effect adverse
  effect potential²
• FDA concerns
• Ethical concerns in RCT evaluating efficacy and
  cost-effectiveness of ABL
• European based trials

¹Metcalf SCL, et al. J Infect.
20044920-2. ²Laird J, et al. J
Infect. 200551338-41.
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Summary

• Biofilm formation on intravascular catheters
  creates an antibiotic resistant environment
• 100 -1000 times MIC required
• ABL therapy has a role in prevention and should
  be considered as adjuvant therapy in treatment
• Catheter removal not feasible
• Continued research needed to identify potential
  ABL solutions as their use continues to expand
• EtOH lock solutions
• EDTA based solutions

36
Catheter-related Bloodstream Infections
Antibiotic Lock Solutions

• Brandon Bookstaver, PharmD, BCPS
• Infectious Diseases Specialty Resident
• June 12, 2006