Download Remove catheter - ANNA Jersey North Chapter 126

American Nephrology Nurses Association
Management of Common Types of
Infections in Patients Receiving
Chronic Renal Replacement Therapy
Sarah Tomasello, PharmD, BCPS
Clinical Associate Professor
Rutgers, The State University of New Jersey
Clinical Specialist – Nephrology
Robert Wood Johnson University Hospital
New Brunswick, NJ
[email protected]
Outline of Presentation
• Infections in patients on hemodialysis
– Risk factors
– Common “Bugs and Drugs”
– Pharmacokinetic parameters and alterations
– Administration and dosing
– Monitoring therapy and altering regimen
• Catheter related infections
• Peritonitis
Risk factors for Infection
• Weakened immune function
– Immunosuppressive agents, uremia
• Indwelling catheters
– Vascular Access
• Catheter > AVG (arteriovenous graft) > AVG (arteriovenous fistula)
– Presence as well as manipulation
• Dialysis unit exposure
– Care givers, patients
• Comorbidities
– Diabetes (~50%)
Issues Related to Hemodialysis
• Intermittent clearance
– Generally three times a week
• Vascular access
• Type of filters
– “High-Flux”
• Filter re-use
• Dialysis adequacy
– Time on HD
– Blood flow rate
Common Drugs Used and Why?
• Cephalosprins
– Cefazolin, ceftazadime, ceftriaxone,
• Quinolones
– Levofloxacin, ciprofloxacin
• Vancomycin
• Aminoglycosides?
– Gentamicin, tobramycin, amikacin
• Long half-life (t ½)in ESRD patients
• Can be dosed with/right after hemodialysis
What about “The
Vancomycin
• Glycopeptide
• Empiric therapy for gram+ (MRSA)
• Concerns
– Resistance
• 1 gram every week
• 1 gram followed by 500mg Q HD
Vanco
• “Mississippi mud”
• Crystalline Degradation Product 1 (CDP1)
• Higher trough for resistant organisms or hard
to penetrate areaaas
• Assays
– high performance liquid chromatography (HPLC)
– Fluorescence polarization immunoassays (FPIA)
Hu et al. Ther Drug Monitor 12 562-569, 1990
Vancomycin Toxicities
•
•
•
•
“Red Man’s” Syndrome
Ototoxicity
Nephrotoxicity
Increased risk of toxicity with aminoglycoside
antibiotics
• Thrombocytopenia
Rybak et al. Antimicrob Agents Chemother 1999;43:1549-1555
Types of Bacteria
Common to
dialysis patients
bioweb.uwlax.edu/.../whatisbacteria.htm
Properties of Dialyzable Drug*
• Molecular weight
–High-flux may eliminate drugs up to 5000
daltons
• Vd
– > 1 L/kg not readily dialyzed
–Must be water soluble
• Protein Binding
–Highly protein bound (>96%) not as dialyzable
– Watch “narrow therapeutic window” agents
– Or saturated plasma proteins (toxicologic emergencies)
* May be removed during dialysis
Pharmacokinetic Parameters
A = Absorption
D = Distribution
M = Metabolism
E = Elimination/Excretion
Alterations in Kidney
Dysfunction
Absorption and Bioavailability
• DECREASED
– Altered GI emptying (diabetes)
– Altered pH (H2 antagonists, proton pump
– Edema of GI tract (fluid overload) inhibitors, antacids)
– Drug Interactions (antacids, iron, etc…)
• INCREASED
– Decreased first pass effect
– Decreased metabolism by uremic toxins
– Decreased enzymatic activity in kidney, liver, GI tract
Volume of Distribution (Vd)
• Plasma Protein Binding
– Albumin is major plasma protein
– Acidic drugs bind to albumin
• Phenytoin, valproic acid, salicylates
– Changes in albumin effect Vd
•
Alterations in binding sites
Increased free concentrations (more effect?)
vs
Increased rate of clearance? (excreted more rapidly?)
Volume of Distribution
Plasma Protein Binding (cont.)
• Alpha-1-acid glycoprotein (AAG)
– Binds basic drugs
– AAG up-regulated in kidney disease
– “Expect” a decreased free-fraction
• This has not been observed in vitro studies
Causes of Hypoalbuminemia
•
•
•
•
Malnutrition
Nephrotic syndrome
Liver disease
Accumulation of competitive inhibitors
– Uremic toxins
– Metabolites
(Normal serum albumin concentration ~4g/dL)
Clinical Significance of Changes
in Volume of Distribution:
WATER
• Increased fluid volume
– Interdialytic weight gain
– Effects drug “peak”concentration
• Rapid fluid removal,
– Redistribution (re-equilibrium)
– Affects therapeutic drug monitoring (TDM) in
serum
Hemodialyzer
• Selectively permeable membrane
• Solute (drug) molecules pass through
“selectively” based on MW and size
• Composed of many types of fibers
• Blood flows through 5000-20,000 hollow
fibers
• Dialysate flows on outside of fibers
Hemodialysis System
Hollow Fiber Dialyzer
Definitions
• Diffusion- passive movement of particles
from high concentration to low
concentration. Limited by filter.
• Ultrafiltration- Removal of plasma water by a
procedure
• Convection- movement of particles with
movement of water in which they are
dissolved. Due to ultrafiltration, also limited
by filter
MW of Common Drugs
•
•
•
•
•
Digoxin: 781 Daltons
Vancomycin: 1,486 Daltons
Gentamicin: 149 Daltons
Cefazolin: 477 Daltons
Erythropoietin: 30,400 Daltons
Molecular Weight
High Flux Dialyzer
Blood
Dialysate
MW cutoff < 5,000 daltons (up to 20,000?)
Protein Binding
albumin
albumin
albumin
Blood
= Drug
Dialysate
Protein Binding
Normal
Uremia
albumin
albumin
albumin
albumin
albumin
albumin
albumin
albumin
albumin
albumin
albumin
=Drug
albumin
Competitive inhibitors
“uremic
slime”
Volume of Distribution
Tissue Compartment
Plasma Compartment
Renal Elimination
Or Dialysis
Optimizing Therapy
• Altering dose and dosing interval depends
on efficacy and toxicity parameters
– Peak effect for efficacy
• aminoglycosides
– Trough effect for efficacy/toxicity
• digoxin, antiepileptics, aminoglycosides
– Steady state for efficacy
• antihypertensive agents
• beta-lactam antibiotics
GFR
nl GFR
Drug Concentration
Continuous Infusion
hours
Steady State
24
48
72
96
120
144
kidney dysfunction
Drug Concentration
Accumulation at same dose and
dosing interval
Normal function
Trough
hours
24
48
72
96
120
144
Lower dose, same dosing
interval
Normal kidney function
Decreased kidney function
Drug
Concentration
Max effective dose
Trough
hours
24
48
72
96
120
144
Same dose, normal kidney function
Extended interval in altered renal function
Drug Concentration
Max effective dose
Trough
Time (hrs)
TIME Dependent Killing
Example: Vancomycin
HD TIW, MWF
80
M a x i m u m
T h e r a p e u t i c
C o n c e n t r a t i o n
( M T C )
70
mcg/mL
60
50
40
30
20
10
Minimum
0
1st Dose
MON
tu
WED
Inhibitory
th
FRI
sa
Concentration
su
MON
tu
(MIC)
WED
th
X
factor
FRI
sa
su
Concentration Dependent Killing
This is the dosing regimen we
were trying to emulate.
Matsuo et al. "Administration of
Aminoglycosides to
Hemodialysis Patients
Immediately before Dialysis: a
New Dosing Modality."
Antimicrobial Agents and
Chemotherapy 41.12 (1997):
2597-601. Print.
Dosing Tobramycin “Pre-HD”
14
12
280mg ppst HD
Drug Concentration
10
8
240 mg Pre HD
310mg post HD
6
4
310mg Pre HD
2
0
1-Sep
2-Sep
3-Sep
4-Sep
5-Sep
6-Sep
7-Sep
8-Sep
9-Sep
10-Sep 11-Sep
Tobramycin Course
Date
Time
Dose
Comment
9/2
12:00 am
90 mg IVPB
1 mg/kg (4:30pm)
9/3
12:00 pm
240 mg IVPB
Pre HD
9/5
5:00 am
310 mg IVPB
Pre HD
9/8
12:00 pm
310 mg IVPB
Post HD
*9/12
11:00 am
280 mg IVPB
Post HD
*Dose was held on 9/10
Drug Dosing for Hemodialysis
• Use recommendations from literature*
– Dose for CrCl < 10-15 ml/min on HD
– IV IDEALLY given TIW during/after HD
– Supplemental dose post-HD if needed
• Daily Dialysis
– Very little literature (use professional judgment)
• MONITOR
– Subjective and objective efficacy and toxicity
– Therapeutic drug monitoring if available (and PK
calculations)
*See previous slides 30-32
Drug Levels in HD (Dialyzable)
Cpeak
Cpre-HD
K off HD
Conc
Next Dose
ctrough
Pre HD HD End HD
Time
Redistribution Phenomenon
Koff HD
Conc
Pre HD HD
Time
End HD
POINTS TO REMEMBER
• MONITOR!!!
– Therapeutic drug levels (if appropriate)
• MUST be taken at the proper times
– Subjective and objective signs of efficacy and
toxicity
– Watch for idiosyncratic or “expected” adverse
drug events
Risk factors for Infection in
Peritoneal Dialysis
•
•
•
•
Patient technique
Provider technique
Immunocompetence
Cormorbid disease states
Peritonitis
• Incidence
– 1 episode for every 12-24 patient months
• Signs and Symptoms
–
–
–
–
–
Cloudy drainage
Abdominal pain
Fever
Nausea/vomiting
Fever > 37ºC
• Diagnostic criteria
– Dialysate WBC count > 100/mm3 (> 50% PMNs)
– Organism on culture?
Drug Regimens to Treat Peritonitis
• Several review articles on drug delivery using
intraperitoneal route (IP)
– Watch for compatibility issues*
• Use International Society of PD Guidelines for the
treatment of PD related peritonitis**
• Use primary literature
*Intraperitoneal administration of drugs in peritoneal dialysis patients: A review of compatibility and
guidance for clinical use peritoneal dialysis international 2009;29:5–15
.**International ad hoc committee on peritoneal dialysis related infections. International society for
peritoneal dialysis - guidelines for the treatment of peritonitis in adults. Peritoneal dial int 2005;25:107131.
Treatment of Peritonitis
•
•
•
•
Give intraperitoneally (IP) if possible
Empiric therapy
Cover both gram positive and negative
Combination first and third generation
cephalosporin
– Cefazolin and ceftazidime
• Narrow coverage based on culture report
– not always cultured
• Complications
– Fibrosis and scarring
Peritoneal Dialysis Catheter Infections
• Incidence
– Once per 1-2 patient years
• Organisms
– staph aureus, staph epi, pseudomonas
• Prophylaxis for nasal carriers of Staphylococcus
aureus?
– rifampin 300 mg BID x 5 days every three months
– intranasal mupiricin BID x 5 days every month
– exit-site mupiricin topically every day
PD Dialyzability Factors
Inflamed peritoneum during infection
Blood flow - may affect drug transfer
Dwell time
Residual renal function
Dialysate dextrose concentration- increase
causes more ultrafiltration
• Generally, high drug absorption but low drug
clearance for PD
•
•
•
•
•
Dosing Drugs for Patients on PD
• Molecular size- not as important as HD,
increased permeability
• PB- highly PB not removed
• Vd- Increased Vd means less removed, more
absorbed into the body
• Water solubility- required for removal
• Ionization- highly ionized neither absorbed or
removed
Common Agents to Treat
Peritonitis
• Tables from ISPD guidelines 2005 update
Issues Related to IP Administration
• Patient education
• Compatibility
• Clearance
– Increased peritoneal membrane permeability
during acute infection
– Decreased permeability with fibrosis and sclerosis
secondary to infection and inflammation
Catheter-Related Bacteremia (CRB)
• “Biofilm infection”
• Catheter removal creates a requirement for the
use of temporary catheters and risk of their
associated complications
– Multiple procedures, hospitalization period,
increased costs
– Loss of central venous entry site
• Dialysis patients must continue to receive dialysis
treatments, therefore, catheter removal is not a
feasible option
Beathard GA et. al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21(6):528-538
50
Incidence of CRB
• Rate is less than uncuffed catheters
– Tunneled catheters: 1.6-5.5 episodes/1000
days
– Uncuffed cathers: 3.8-6.6 episodes/1000 days
• Morbidity and mortality due to metastatic
infections: 3.2%-50%
Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538
51
Pathogenesis
• >99.9% bacteria grow as aggregated “sessile
communities” attached to surfaces
• Hallmark of biofilm-related infections:
resistance to anti-microbials and host defenses
• Develop in steps:
1. Microbial attachment to the catheter surface
2. Adhesion, growth and aggregation of cells into
microcolonies
3. Maturation and dissemination of progeny cells for
new colony formation
Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem
Dial. 2008; 21 (6):528-538
52
Risk factors
• Skin and nasal colonization with
staphylococcus
• Catheter hub colonization
• Prolonged duration of usage
• Thrombosis
• History of previous CRB
• Frequency of catheter manipulation
• Diabetes mellitus
• Iron over-load
• immunocompromised
Beathard , et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538.
53
Prophylaxis of CRB
 Local antiseptic application
 Catheter placement
 Systemic prophylactic antibiotics
 Aspirin
 Exit-site infection
 Daily catheter site care
 Cleansing site
 Bandage covering site
 “Lock” solutions
Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538.
54
Diagnosis
•
•
•
•
+ blood culture
No other apparent source of infection
Symptomatic patient
Isolation of the same organism from a
semiquantitative culture of the catheter tip
(>15 colony-forming units)
National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice
Recommendations for Vascular Access. Am J Kidney Dis 2006; 48: S176-322.
55
Clinical pearls
 s. aureus, pseudomonas or candida species
 Remove catheter
 Other gram- or coagulase- staph. organisms
 adjunctive antibiotic lock therapy for 3 weeks
AND/OR
 guidewire catheter exchange
 Catheter locks to be used WITH systemic antimicrobial therapy
 instill post HD, dwell until next HD, aspirate, instill
fresh lock post HD repeat TIW with HD
 Treat for 7-14 days
Mermel, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related
infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.
56
Exit Site Infections
• Redness, crusting, and/or exudate
• NO systemic symptoms
• Negative blood cultures
1. Apply topical antibiotics
2. If tunnel drainage - intravenous antibiotics
3. No response - remove the catheter.
National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations
for Vascular Access. Am J Kidney Dis 2006; 48: S176-322.
57
Treatment CRB
•
Intravenous antibiotics
•
Remove the catheter
–
–
•
Stable, asymptomatic
–
–
•
Symptomatic >36 hours
Patient is unstable.
Change catheter over a guidewire
Minimum of 3 weeks of systemic antibiotic therapy
New permanent access
–
–
Placed AFTER course of antibiotics AND
Blood cultures, have been negative for at least 48 hours
National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for
Vascular Access. Am J Kidney Dis 2006; 48: S176-322.
58
Empiric Treatment
• Cefazollin OR vancomycin plus gram-negative rod coverage
(Vancomycin plus gentamicin)
• Vancomycin: 20 mg/kg loading dose, then 500 mg each
subsequent dialysis session
• Gentamicin (or tobramycin): 1mg/kg, not to exceed 100mg
after each dialysis session
• Ceftazidime: 1g IV after each dialysis session
“Cath lock”
• Concentrated antibiotic solution with/without
anticoagulant agent. Dwelled in lumen of the
dialysis catheter at the end of each dialysis
session until the beginning of next session
• Goal: sterilize the catheter biofilm while
salvaging the catheter
• Antibiotic concentrations must be 100-1000
times greater to kill sessile bacteria within a
biofilm
Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related
infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.
60
Antibiotic lock solutions
• Success rate
– 87%–100% gram-negative pathogens
– 75%– 84% Staphylococcus epidermidis
– 40%–55% for hemodialysis-associated CRBSI
due to S. aureus
• Clinical success of salvaging the catheter
and eradicating CRB depends upon the
bacterial pathogen involved
Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related
infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.
61
Examples of Cath-Lock Formulas
1. Gentamicin 5mg/ml and heparin 5000 U/mL
2. Cefazolin 10 mg/ml + gentamicin 5 mg/ml+
heparin 1000 U/ml kim
3. Vancomycin 25mg/mL+gentamicin sulphate
40mg/mL +heparin 5000 U/mL (al)
4. Cefotaxime (10mg/ml) and heparin 5000
U/mL
1. McIntyre CW, et al. Kidney International. 2004; 66:801-805.
2.Kim SH, et al. Kidney International 2006; 69:161-164.
3. Al-Hwiesh AK. Saudi J Kidney Dis Transplant. 2008; 19(4):593-602.
4. Saxena AK, Panhotra BR, Sundaram DS, et al. Nephrology. 2006; 11:299-305.
Administration of an antibiotic lock
Image derived from: Allon M. Current management of vascular access. Clin J Am Soc Nephrol. 2007; 2:786-800.
63
QUESTIONS?